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Volume 5 Issue 2

PEER REVIEWED

Brexit and the Animal Health Sector 2 Years on from the UK EU Referendum For Dogs, Time Alone May Mean Depression Daycare is a Healing Option Rabies – Still a Disease to be Feared But Vaccination is Winning the Battle in Many Areas of the Globe Effect of Amino Acid and Peptide Complex AB070597 on Renal Function in Dogs with Chronic Kidney Disease Official Supporting Associations -

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CONTENTS 06 FOREWORD WATCH PAGES

MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker Project Director Clive Baigent, PhD clive@iahjmedia.com EDITORIAL MANAGER Virginia Toteva virginia@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com BUSINESS DEVELOPMENT Michael Andre michael@iahjmedia.com ADMINISTRATOR Barbara Lasco FRONT COVER © istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.animalhealthmedia.com International Animal Health Journal – ISSN 1758-5678 is published quarterly by PHARMAPUBS. The opinions and views expressed by the authors in this

Journal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 5 Issue 2 June 2018 PHARMA PUBLICATIONS www.animalhealthmedia.com

08 A New World – A New Approach? In the farming industry, as we gear up for change and very likely a different world to the one we are in today, many potential incentives, developments and long overdue initiatives are in train, many of which would previously have met with fierce resistance and a thousand reasons why they cannot or would not work in today’s world. Gwyn Jones of RUMA explains how, collectively, we can improve our performance by ridding ourselves of endemic diseases where possible, and control and minimise others, leading to healthier stock, more valuable stock and more productive stock, with less antibiotic use. 10 How Collaboration Drives Innovation and Quality in Animal Health Product Development The binary relationship between client and contract organisations is crucial in the development of cuttingedge animal health products and technologies. True collaboration, from inception to completion, guarantees a better end product. We call this process ‘Molecule-toMarket’ and it’s paying off for clients around the world searching for new solutions to diseases and conditions impacting animal health. Doug Cleverly at Argenta discusses how effective and innovative partnerships in animal health development can be the collaboration. REGULATORY & MARKETPLACE 14 Brexit and the Animal Health Sector – Two Years on from the UK EU Referendum The UK’s decision to exit from the EU, now two years ago, was not anticipated by the UK animal medicines industry, which for many years has been well integrated in European supply chains. However, since June 2016 NOAH has been working to understand the implications of Brexit for the industry and to ensure continuity of supply of medicines for UK vets and animal keepers. The UK regulator, the Veterinary Medicines Directorate (VMD), is working with NOAH in an effort to ensure that a full complement of medicines will still be available in the UK on day one of Brexit, to minimise the potential for disease spread and animal suffering. Dawn Howard at NOAH says that this work continues, as concern is mounting that time is running out to allow businesses to be able to execute a smooth Brexit process without interruption to the availability of veterinary medicines. 16 Improving the Regulatory and Trade Environment for US Animal Feed Manufacturers is Crucial for Supporting Affordable, Abundant Food Options Globally Just as humans need a balanced diet to stay healthy, animals need the right nutrition throughout all stages of their lives to continue producing healthy, wholesome meat, milk, fish and eggs for our food supply. Joel G. Newman at the American Feed Industry Association says that for one in nine people around the world, undernourishment is a real and daily struggle and that agriculture must continue to innovate and produce 70 per cent more food over the next 30 years to accommodate a growing world population, but this must be done in a sustainable way, given the earth’s natural resources are finite and precious. 20 M2 + C = The Essential Elements for Startup Success The life sciences encompass a broad range of activities that include human and animal health but there are large International Animal Health Journal 1


CONTENTS differences between investments in human health and those in animal health. There are also differences within animal health itself. For example, companion vs. production animal markets are usually lumped together but are very different in focus and drivers. Dr Sam AlMurrani at Babylon BioConsulting LLC discusses why money and technology do not alone lead to commercial success in the absence of a good market, good management and focus on the consumer. 34 For Dogs, Time Alone May Mean Depression. Daycare is a Healing Option Dogs can suffer from a dog version of depression when they have been left alone at home. As not everybody can afford to stay at home or to move their office to home, and that’s where “doggy daycare” comes in. In this article, Carissa D. Lamkahouan, a freelance newspaper and magazine journalist, describes when the owners can take advantage of dog daycare services.

RESEARCH & DEVELOPMENT

26 Comparative Medicine: Similarities Between Domestic Animals and Humans – Do These Help in Translational Medicine? Although appearances can be deceptive, there are considerable biological similarities between humans and animals. At the physiological and anatomical level, the similarities are remarkable. Animals ranging from mice to monkeys have the same organ systems, which function in a very similar manner to that of people. This means

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that many human and animal diseases are also highly similar. Tas Gohir at Royal Veterinary College (RVC) reckons that for the purpose of human therapeutic development, it is a question of identifying which animals have physiological and biochemical systems of interest, that are sufficiently similar to human. 30 Organic Trace Minerals: Optimised Stability Enhances Bioavailability Organic trace minerals (OTMs) are recognised globally as being a more bioavailable source of mineral than their inorganic counterparts. Whilst there are many forms of mineral products available in the marketplace for use in animal nutrition, these have unfortunately been generically entitled “organic trace minerals” by virtue of the fact that the trace elements in question are complexed or otherwise associated with organic molecules. Dr Richard Murphy at Alltech’s European Bioscience Centre explains that despite the confusing and often contradictory information that exists, mineral chelation is a relatively straightforward process governed by some fundamental chemistry basics. 34 Rabies – Still a Disease to be Feared but Vaccination is Winning the Battle in Many Areas of the Globe Rabies is a deadly disease, normally spread to humans from infected animals through a bite, scratch, or even a lick on broken skin. Without prompt treatment, the disease is invariably fatal. This is why many countries have made great efforts to eliminate the disease within

Volume 5 Issue 2


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CONTENTS their borders but, despite this, rabies is still widespread across large areas of the globe. In this article, Dr Med. Vet. Verena Ziethlow at IDT Biologika will explain in detail about the new generation oral rabies virus vaccines. 38 Effect of amino acid and peptide complex AB070597 on renal function in dogs with chronic kidney disease The management of chronic kidney disease (CKD) in dogs remains a challenge to veterinary professionals and exerts financial burdens on their owners. Expanded knowledge and improvement in treatment would benefit all. Dr Randy Aronson at Bio Health Solution describes a study that was to examine whether AB070597, a dietary-supplement compound of six amino acids and one peptide, can slow, halt, or reverse the decline of renal function in dogs with CKD. 34 The Importance of Cobalamin (Vitamin B12) in Dogs and Cats and Evidence for Oral Supplementation Cobalamin is a water-soluble, cobalt-containing B vitamin which plays an essential role in many physiological processes, including cellular metabolism, DNA synthesis, amino acid metabolism, fatty acid metabolism, nerve myelination and haematopoeisis. Cats and dogs, like humans, are unable to synthesise cobalamin, hence they rely on dietary intake to maintain adequate tissue levels. Some bacteria found in the gastrointestinal tract can produce cobalamin; however, since they are present only in the large intestines of dogs and cats, the cobalamin production occurs too distal to be of any benefit to the animal itself. Gemma Ellse at Protexin Veterinary discusses why cobalamin is so important. TECHNOLOGY 40 Why Good Tablet Design is Important in Animal Medicine and How to Achieve it Just as good tablet design is extremely important in the manufacture of pharmaceuticals for humans, the same applies for animal dosage forms. Tablets are used to deliver drugs in an effective and safe manner, and although less dominant in veterinary medicine, tablets or boluses are still a significant method to administer

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medication. In this article, Alex Bunting at I Holland will consider the most important elements when designing tablets for animals. 40 A Comparison of DIY and Custom EDC Solutions: Which is the Best for Your Study? Reducing costs while maximising efficiency is often a driving force in determining electronic data capture solutions (EDC) for clinical research. A self-customised EDC product becomes a more attractive option over a custom-built solution when it comes to minimising cost and working within a strict budget. A DIY solution empowers each clinical team with the ability to build their own electronic study and control the build process according to their unique specifications and timelines. However, with any DIY solution, there can be tradeoffs in cost and time, as each client’s team is responsible for building their study and quality-testing their CRFs. Corina Bereanu and Karina Loyo at Prelude Dynamics discuss what the advantages and tradeoffs are with each solution. SPECIAL FEATURE 44 Bayer’s Care4Cattle Initiative An Interview with Almut Hoffmann, Head of Global Marketing Farm Animal Products. 50 Moredun: A Blueprint for Private-public Partnership Bringing Economic Benefit Through Innovative Science Moredun Research Institute is a world-renowned research facility actively involved in research to detect, prevent and control diseases of livestock and to promote higher standards of animal health and welfare through research and education. Elisabeth Innes from Moredun Research Institute explains that the application of scientific research to bring both economic and societal benefits and the research outputs from the Institute have made a major impact both in the UK and globally, due in large part to the unique relationship with the farming community and the emphasis the organisation puts on effective knowledge exchange with livestock producers.

Volume 5 Issue 2


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FOREWORD Rabies is an avertable viral disease caused by the rabid animal to the warm blooded animals (zoonotic) especially human. Rabies occurs in more than 150 countries and territories. According to an estimation by WHO, almost 55,000 people die because of rabies every year. The Dogs are the major reason behind this, approximately 99% human deaths caused by dog's bites. Developing and under developing countries, both are the victims of rabies. With the post-exposure preventive regimes, 327,000 people can prevent this disease annually. The common mode of transmission of rabies in man is by bite of a rabid animal or the contamination of scratch wounds by virus infected saliva. Rabies is an acute infection of the central nerves system (CNS) which is almost invariably fatal. Following inoculation, the virus replicates in the striated or connective tissue at the site of inoculation and enters the peripheral nerves through the neuromuscular junction. It then spreads to the CNS in the endoneurium of the Schwann cells. Terminally, there is widespread CNS involvement but few neurons infected with the virus show structural abnormalities. The nature of the profound disorder is still not understood. There is no certain cure for rabies except supportive care. Rabies can be prevented before the latent symptoms can develop, consists of giving a person an injection of rabies immune globulin and another injection of rabies vaccine as soon as possible after the bite or exposure to saliva from an infected animal. Human rabies immune globulin is used or injected at the bite area immediately because it attacks the virus and slow down or stop viral progression through the nerves. Timing and the ability of the patient to respond by making a good immune response is a key to patient survival. Untreated or inappropriately treated rabies is almost always fatal because treatment is supportive only to limit the patient's pain. An effective new rabies treatment regime that gives the protection from the disease is developed by the scientists. The treatment regimes are; Post-exposure prophylaxis and Pre-exposure prophylaxis. Rabies is a viral disease that can be spread by domestic and wild animals. Many countries having the status of high-risk areas but most of the countries around the globe gained the status of rabies free territories. This shows that rabies can be successfully ruled out from the high-risk areas by taking preventing measures. The advent of scientific medicine also makes rabies control possible. Public awareness in this regard can play major role. There is needed to take little care and change of lifestyle to avoid these kinds of viral diseases.

In the Regulatory & Market Section Dawn Howard at NOAH explains the position within the Animal Health Sector over Brexit, two years on from the UK EU Referendum and Joel G. Newman at the American Feed Industry Association says that for one in nine people around the world, undernourishment is a real and daily struggle and that agriculture must continue to innovate and produce 70 per cent more food over the next 30 years to accommodate a growing world population, but this must be done in a sustainable way, given the earth’s natural resources are finite and precious. In the Research & Development Section, Tas Gohir at Royal Veterinary College (RVC) discusses Comparative Medicine: Similarities between Domestic Animals and Humans – Do These Help in Translational Medicine? Although appearances can be deceptive, there are considerable biological similarities between humans and animals. At the physiological and anatomical level, the similarities are remarkable. Tas Gohir reckons that for the purpose of human therapeutic development, it is a question of identifying which animals have physiological and biochemical systems of interest, that are sufficiently similar to human. I hope you enjoy this issue of IAHJ, and my team and I look forward to bringing you more exiting features in the Autumn Issue.

Virginia Toteva Editorial Manager

In this issue of IAHJ Dr Med. Vet. Verena Ziethlow at IDT Biologika explains in detail about the new generation oral rabies virus vaccines.

EDITORIAL ADVISORY BOARD Germán W. Graff Research Reference Laboratory Specialist, IDEXX BioResearch Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association Carel du Marchie Sarvaas Executive Director Health For Animals Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC Sven Buckingham - Buckingham QA Consultancy Ltd. Dan Peizer - Director Animal Health at Catalent Pharma Solutions Dawn Howard - Chief Executive of the National Office of Animal Health (NOAH) Jean Szkotnicki - President of the Canadian Animal Health Institute (CAHI) Dr Kevin Woodward - Managing Director KNW Animal Health Consulting Norbert Mencke - VP Global Communications & Public Affairs Bayer Animal Health GmbH 6 International Animal Health Journal

Volume 5 Issue 2


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A New World – A New Approach?

I am struck by shifting attitudes in the farming industry as we gear up for change and very likely a different world to the one we are in today. Many potential incentives, developments and long overdue initiatives are in train, many of which would previously have met with fierce resistance and a thousand reasons why they cannot or would not work in today’s world. The fact that we are leaving the EU (in some form) is now accepted; as is the fact that any support for agriculture will be different; and the likelihood of greater competition from imports as a result of international deals struck around the globe is accepted as well. In a previous world, any one of those would have been seen as an impossible challenge to be fought tooth and nail. To add in the demand for higher environmental and animal welfare standards, coupled with lower antibiotic use at a time when farmers are likely to be under more pressure than ever before, would be seen as the straw that could break the camel’s back. And that is before we mention veganism and supermarket consolidation, the terrible spring weather and other issues. Yet, there is no revolution, no mass protests on the streets of London; not yet, anyway! The reason for this is that farming leaders know that such momentous proposals need properly crafted and carefully considered responses. Shouting from the rooftops and organised opposition is not going to work this time. There is the small matter that 60% of our farmers voted to leave the EU to consider! There will have been a host of different reasons why farmers voted to leave, but a desire to disrupt the status quo and change our current course of action will have been one. So vote to leave they did, and industry leaders need to cope with that and offer solutions, protecting their farmers as much as possible whilst accepting facts that may be hard to swallow. There is always a silver lining to any cloud and this one is no different. I am delighted to see Defra, led by Michael Gove, committing to the Livestock Improvement Programme (LIP), which will enable this country to benefit from a national database, the likes of which Ireland, Holland, Denmark, Israel, New Zealand and many others have benefitted from for many years. This database will not only replace the creaking, fragmented systems we currently have, but will allow a huge single bank of information to be acquired; a bank of data which will enable us to properly benchmark our industry, improving competitiveness. Realising a step-change in productivity is going to be essential in order to compete in the new world, and each sector has its own challenges and they all start from different positions. Some sectors depend on export; others undersupply the home market. Some are already fairly competitive internationally, others not so. However, it does seem that the 8 International Animal Health Journal

top 25% in each sector can hold their own on an international stage and are relatively safe, so the task in hand is to bring the next 50% up as near that standard as possible. The bottom 25% need to consider their position and either make extraordinary progress or find a different path. Huge efforts have been made over the years to assist those who are struggling, and progress has been held back to try and assist those who find it difficult or are not that interested in keeping up. I detect a very different mood in the industry now, a much harder attitude towards those who are not up to standard. There is a real drive to tackle health and welfare in the livestock sectors and a full-on attack on endemic disease. Many talk of compulsory programmes – even legislation – in order to eradicate some endemic diseases and gain full control of others. There is an appetite to raise farm assurance standards, or introduce schemes which reward good practice and high standards only. I see industry pressure on antibiotic use yielding very good results as each sector delivers year-on-year reductions, showing the world that UK agriculture has got its act together and will show what can be done as a large producer of food. This will of course depend on progress being maintained and keeping our foot on the gas, which I am confident we will do. Human medicine is working hard to achieve similar results under the ‘One Health’ banner, and we need to avoid being deterred by the cry that other countries in the world are falling behind. We lead by example and all will benefit as international markets seek out meat and dairy produced to the highest standards. Food safety is of course a given and whilst we do have the challenge of food fashion, food fads and anti-livestock farming groups, we can ride out most of that criticism by raising standards and doing the job well. I see this industry raising its game further over the coming years. Yes, there will be some pain; yes, there will be difficulties and, in some cases, great turmoil. However, there will also be opportunities for entrepreneurs and young entrants. The size and scope of these opportunities will depend largely on the challenge, once we know where we are in the scheme of things. If the challenge is great, then land prices and rents will fall; painful for some but presenting opportunities for others. No government sets out to damage their agricultural sector, for that would be foolhardy and carries great risk. However, leaving the EU forces the government to look at serious agricultural reform due to the financial pressures that such a move presents. Couple that with the fact that most MPs (of all parties) share a real dislike of the Common Agricultural Policy (CAP) with many farmers. So if all believe a reform is overdue, then it is guaranteed. The last real agricultural reform was in 1947 and it transformed the industry, introducing a period of stupendous growth and productivity, and successive prime ministers used to hold up the agricultural ‘revolution’ to other industries as an Volume 5 Issue 2


WATCH PAGES incentive to do much better. Farmers basked in that glory for decades, but slowly the shine has dulled and as the CAP has lost its way, so farmers have found themselves under pressure today. In the new world, there is an opportunity to put that right and once again stand on our own two feet, be proud of what we do, pitch our ingenuity, inventiveness and resilience against others, and competing with our EU neighbours and others in the world. Collectively we can improve our performance by ridding ourselves of endemic diseases where possible, controlling and minimising others, leading to healthier stock, more valuable stock, more productive stock with less antibiotic use.

Gwyn Jones Gwyn Jones was born into a hill farming family in Snowdonia, North Wales. Gwyn trained as an engineer with Rolls Royce in Shropshire, and worked in London for a specialist engineering company before deciding to go back to agriculture, working on a large estate in North Wales whilst attending college (Llysfasi and Aberystwyth). Gwyn is now immersed in off farm activity as well as farming with his daughter Gwenan (past three years) at Boughton Dairy, Tillington, near Petworth, West Sussex. Email: wealdclay@btinternet.com

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International Animal Health Journal 9


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How Collaboration Drives Innovation and Quality in Animal Health Product Development The binary relationship between client and contract organisations is crucial in the development of cutting-edge animal health products and technologies. True collaboration, from inception to completion, guarantees a better end product. We call this process ‘Molecule-to-Market’ and it’s paying off for clients around the world searching for new solutions to diseases and conditions impacting animal health. In January of this year, Animal Pharm awarded Best Companion Animal Product 2017 to Galliprant® (grapiprant tablets), a new chemical entity that Argenta Limited helped developed and manufacture. This collaboration shows just how effective and innovative partnerships in animal health development can be. Argenta’s ‘Molecule-to-Market’ approach is, essentially, a completely comprehensive service. It involves taking an idea from concept right through to manufacturing; we are hands-on in every step of the pharmaceutical research & development, clinical development and manufacturing processes, as the client’s ideas are taken up the value curve. The result is an innovative solution to help companies address animal health diseases and conditions and is an approach taken care of by the various Argenta departments all over the world. It’s probably why, these days, 80 per cent of our R&D projects are ‘Molecule-to-Market’ projects. But it wasn’t always so. When Aratana’s founders approached us in 2009, the process wasn’t something Argenta had ever gone through with a United States-based client. Aratana’s founder and CEO, Dr Steven St Peter, wanted to translate a range of chemistries, originally created for human health, into first-of-their-kind therapeutics that would aid the health of animals. In those days, Aratana was in the very early stages of formation. Aratana originally liaised with Argenta via our US subsidiary AlcheraBio. Subsequently, the Aratana business relationship included utilising our experience to seek further specific development and manufacturing advice. As our relationship with Aratana continued, we started work on Galliprant. Our R&D team was engaged to investigate the product for the control of pain and inflammation in dogs with osteoarthritis. It was brand new chemistry; working with a new chemical compound and its application in animal health had been relatively unexplored. Aratana had only a few grams of the compound and was the only company in the world to possess it. Argenta began R&D with a miniscule amount to create a product that worked. Argenta became the research engine for the product. To get the very best result, we mapped out which areas of the business were best to work on the product: invention work and chemistry R&D were carried out in New Zealand 10 International Animal Health Journal

and methodologies to control quality were worked through the US R&D facility based at Kansas University. In parallel, AlcheraBio supported Aratana in conducting the clinical R&D via its network of veterinarians in the US. Argenta knew success with regulatory agencies relied on being hyper-conscious of quality and on the integrity of the data that the company supplied, so focus became more critical than ever. Our tracking, protocols, project management skills and technical prowess had to meet the needs of rigorous review processes. Once the formulation was right and the data for the pain product was proven through initial lab studies, Aratana moved forward with a development programme in the clinic. When it came to the regulatory review process of Galliprant with the Food and Drug Administration’s Center for Veterinary Medicine (CVM), Aratana told us that they wanted a hard-to-achieve single review cycle of the manufacturing regulatory section. It meant that we had to do our due diligence 10 times over and develop strategies to cover every situation. Fortunately, commitment to promise is one of our company values and something we take very seriously. CVM did approve the Chemistry and Manufacturing Controls (CMC) section within one 180day review cycle. The product was then manufactured at Argenta’s facility in Auckland, New Zealand and packaged at AML Riverside, our Fort Dodge, Iowa facility, before successfully launching in the US market in February 2017. Our technical ability, capacity to deliver, plus our combination of pharmaceutical contract research and contract manufacturing is what makes Argenta unique in the animal health industry. In ‘Molecule-to-Market’ projects, the relationship between the client and us dictates the success or failure of a drug candidate. It’s also the key to sustainability; clients come back because our solutions are highly beneficial to their business but also because they like us. That combination has seen us provide services to a vast range of clients globally – from small and medium-sized enterprises (SMEs) to some of the largest industry players. Our current client base is truly global but with key emphasis on Europe, the United States, Australasia and beyond. Argenta still works with Aratana on projects and they have additionally purchased and licensed one of our original innovation technologies. When I talked recently to Dr St Peter about our relationship, he said: “The Aratana and Argenta collaboration on Galliprant was practical and balanced in approach, but there was always flexibility, and a willingness to accept inherent uncertainty and adapt accordingly. Most importantly, we’ve learned through the collaboration that Argenta has transparency and integrity.” Blue-sky Thinking Besides good relationships, creativity is key to success in our business. The science of animal health might not initially seem like a hugely creative field but, given the limitations when trying to communicate medicinal benefits with Volume 5 Issue 2


WATCH PAGES animals, the levels of innovation and creativity required are vast. Innovation is key, and you can’t have innovation without creative thinking. Creativity drops when compliance increases. And compliance is a crucial part of what we do. So, to boost creativity, we established an Innovation department in 2013. It helps us to cast off the shackles and flex our creative muscles. The value chain has always been research and then manufacturing, but creativity takes it a step further. The Innovation team has to come up with something that doesn’t exist; to work in paradigm shifts and disruption. They’re linking five or 10 disparate facts to come up with something that’s never been seen before. You need to give latitude for that to happen, within the confines of a job. That’s something we focus on at Argenta because the future of the company relies on it. So, our Innovation department invents products supported by patent, patentable technologies that are meaningful in animal health. They’re inventions that are based on a gap we see on the market. Dr Steven St Peter has also noted, “Aratana and Argenta both have a passion for innovation. It’s important for Aratana to build our reputation as pioneers and surround ourselves with collaborators who are equally passionate and innovative.” Creativity in this business is about finding new ways to do things, but that’s not limited to brilliant science. People in our plants in Auckland, Iowa and Scotland think of things that save time and people’s workload; that’s creative thinking too. What Lies Ahead When we look to the future of Argenta, the purview is

wider than innovation, and it’s wider than just products. The new trends in animal health also affect our business and inform the work we are doing. In companion animals, where pets are very much a part of the family, money doesn’t necessarily dictate decisions about care. There’s an emotional investment and owners make emotional decisions about treatments. That’s why we’re seeing a growth in the solutions people want for their animals. Even though pets are just 40% of the animal health market and a fraction of the animals in the world, there’s a lot of potential for growth. And with the increasing need to produce animal protein for the human population, technologies to meet this need in production animals will be developed and evolve to meet this growing need. R&D will power that evolution and push our business forward.

Dr. Doug Cleverly Dr. Doug Cleverly co-founded Argenta in 2006 and serves as the company’s Chief Executive Officer. A formulations chemist with extensive experience in animal health, he has led Argenta from start-up phase through periods of rapid growth to where it is today. Dr. Cleverly’s experience in local and global product development and management expertise have fueled Argenta’s growth into a company that is not only a leader in animal health research but also manufactures products for several key players in the global animal health industry. Email: doug.cleverly@argentaglobal.com

Regulatory support for CMC and Quality Assurance The team at Cyton has significant experience with CMC requirements for registration of standard dosage forms and also those specific to veterinary medicine; such as intramammaries, intraruminal devices and spot-on products. Our CMC expertise can be used flexibly, through complete project management or support with specific tasks.

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International Animal Health Journal 11


REGULATORY & MARKETPLACE Brexit and the Animal Health Sector – Two Years on from the UK EU Referendum

The UK’s decision to exit from the EU, now two years ago, was not anticipated by the UK animal medicines industry, which for many years has been well integrated in European supply chains. However, since June 2016, NOAH has been working to understand the implications of Brexit for the industry and to ensure continuity of supply of medicines for UK vets and animal keepers. The UK regulator, the Veterinary Medicines Directorate (VMD), is working with NOAH in an effort to ensure that a full complement of medicines will still be available in the UK on day one of Brexit, to minimise the potential for disease spread and animal suffering. But as this work continues, concern is mounting that time is running out to allow businesses to be able to execute a smooth Brexit process without interruption to the availability of veterinary medicines. It has also become clear that the impact will not just be on UK medicines supply. The risk to supply will impact many other member states – in particular Ireland and smaller or more vulnerable markets. We are working hard to raise the profile of the particular issues we face, and to ensure we do not get lost among the needs of much larger sectors. For example, in May 2018, European association AnimalhealthEurope, NOAH and the Irish association APHA, jointly organised an event at the European Parliament highlighting the sector’s concerns. Co-hosted by two UK MEPs, Julie Girling (EPP) and James Nicholson (ECR), Vice-President of the European Parliament, Irish MEP Mairead McGuinness also joined the event, where Brexit’s wider implications to the medicines supply of the EU27 as well as the UK were discussed. Continuity of supply has been identified as a critical concern. The production of veterinary medicines and supply to the UK – and indeed EU-27 – market is totally dependent on complex supply chains that must continue to function effectively after the UK leaves. These supply chains will span the new UK-EU border post-Brexit. Raw materials will need to arrive at manufacturing sites and veterinary medicines will need to be transported across this border to meet market requirements. Any border delays, complex processes or increased costs will risk medicines availability. NOAH members have been working hard to adjust their businesses to Brexit – both in relation to the UK and the EU-27 – but currently over 70% report that they are only ‘somewhat prepared’ for a hard Brexit and less than 10% consider their business to be ‘prepared’ for a hard Brexit. This is neither through lack of effort, nor through unawareness of the need to act, but due to the magnitude of the tasks involved in such a specialist sector. A transition period – generally called the implementation period – is vital to give time for preparations to take place both in the UK and EU-27, and while this will help, the potential long-term implications to medicines availability also cannot be underestimated. 12 International Animal Health Journal

NOAH has welcomed the UK government’s efforts to secure an implementation period, but to make informed business decisions, clarity is urgently needed about the detail of how this will operate. Even then, the proposed transition period until December 2020 might not be enough. What was clear from the May European Parliament event was that until there is clarity in relation to the big political picture, more detailed discussions cannot take place, say, in the European Parliament to try to agree solutions to our sector’s concerns. Moreover, there is currently no binding agreement, yet industry must make choices and potentially irreversible decisions now, based on the possibility of working without an implementation period or facing a hard Brexit on 30 March 2019. NOAH conducted a survey (May 2018) with its members to assess their current ‘Brexit preparedness’. Seventy per cent of NOAH members either have UK manufacturing or use UK contract manufacturers. In some cases these are largescale manufacturing operations supplying not just the EU but a global market, and companies report that it will be very difficult to relocate to the EU-27 by 30 March 2019. Over 60% of those companies supply medicines to the EU market and the future supply of anything from 40 to 80% of their products will be affected. In addition, over 80% have EU-registered products that are batch-released in the UK. In some cases, up to 100% of their EU products are batch-released in the UK. Batch-release testing, vital to ensure the animal medicines are good quality, is a specialist process requiring licensed facilities and skilled staff which cannot be moved overnight. Many businesses are already planning to invest heavily in new EU facilities for their European market but this is unlikely to be completed by 30 March 2019, and in many cases they will struggle to complete the move by the proposed implementation period end of December 2020. In addition to where medicines and vaccines themselves are manufactured, there is a very real concern about product packaging. This is an important part of the overall product which carries legally compliant information and is vitally important for veterinary surgeons and animal keepers to ensure medicines are used correctly. The majority of UK companies supplying medicines to the EU market report that they are highly unlikely to be able to make the legally required changes to packaging by 30 March 2019. This means that, unless a solution is found and the implementation period confirmed, perfectly safe medicines will go to waste, supply will be interrupted and animals cannot be treated. There are implications for which medicines will be available in which market immediately post-Brexit and equally to the innovation and development of new medicines. Decisions to develop a new veterinary medicine are often made on a geographical basis, i.e. a treatment for a disease occurring in a number of countries where the animal population is sufficient to obtain a return on investment, and the EU is often viewed as a single region. Post-Brexit, to ensure that access to new medicines is not delayed or lost for UK animals and to encourage companies to remain in the UK, some form of UK/EU ‘mutual recognition’ which permits a UK-registered Volume 5 Issue 2


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product access to the ‘EU region’ animal population and vice versa is needed. Significantly, a large proportion of veterinary medicines are dual-labelled for the UK and other member states such as Ireland, without some form of agreement to continue these products will no longer be economically viable for either the UK or EU markets. For example, of the veterinary medicines available in Ireland, up to 70% share labelling with the UK, accounting for 60% of turnover. This will obviously have a huge potential impact if labelling between UK (post-Brexit) and Ireland can no longer be shared. Every manufacturer would from that moment onwards have to produce dedicated packs for the Irish market, with all the associated costs of smaller-volume runs, separate labelling, and most importantly, separate stockholding. Some packs would justify the additional complexity and costs to allow supply to continue in the Irish market, but many potentially would not, and lesser-volume products will become permanently unavailable in Ireland. Vaccines are a particular example: many have short shelf-life (some as low as 14 days) and will be some of the most vulnerable products if a pragmatic solution cannot be found to the labelling question. Overall, Brexit will have a ‘moderate’ to ‘severe’ impact on the financial viability of their EU businesses in the short term. The longer-term impact on finance availability for research, innovation and new product development is unknown but will undoubtedly take some time to recover, something which is not good for UK or EU businesses – not the outcome we want for the health and welfare of all our animals. The UK exit from the EU represents an unprecedented challenge in terms of scale and scope for NOAH member businesses. The continued health of UK businesses depends on clarity from government, clarity on the implementation period and future trading conditions and the development of a UK regulatory system firmly based on internationally recognised science and technical expertise. It should be www.animalhealthmedia.com

aligned, where necessary, with the new EU legislation for veterinary medicines, as this is more supportive of innovation than the current regulatory environment. It will be important to ensure vets and animal keepers continue to have access to the medicines they need to maintain the animal health and welfare expected by the British public. The UK government must deliver a regulatory environment to encourage innovation, investment, productivity and the development of new veterinary medicines. Animal diseases do not recognise borders. The ultimate goal is to ensure continuity of animal medicines availability for all veterinary surgeons, farmers and pet owners throughout Europe to safeguard animal health and welfare. For that, workable solutions need to be put in place to ensure minimum disruption to product development and approval and to maintain authorisations. It is especially important that veterinary products that are legally released onto the market before 30 March 2019 remain available both in the UK and the EU-27 after the UK departure.

Dawn Howard Dawn Howard is Chief Executive of NOAH. Prior to joining NOAH in 2014, Dawn was based in Brussels and spent a number of years representing UK agriculture in the office of the UK National Farmers Union, where her responsibilities included animal health and welfare. She later headed up the European body for farm animal breeders, EFFAB. Dawn previously worked in Defra’s animal health and welfare policy unit in Westminster and prior to that, both plant health and pesticides policy in York, originally joining as a field-based inspector. Whilst originally qualified as a botanist, Dawn has a passion for raising animal health and welfare standards.

International Animal Health Journal 13


REGULATORY & MARKETPLACE Improving the Regulatory and Trade Environment for US Animal Feed Manufacturers is Crucial for Supporting Affordable, Abundant Food Options Globally

Experts often say that breakfast is the most important meal of the day. Whether it be a hearty helping of bacon, eggs and pancakes or a quick yogurt and coffee, it kickstarts your body into gear, providing the fuel you need to start your day off right. We know that a healthy diet, like exercise, is critical to one’s ongoing growth and development, but for one in nine people around the world, undernourishment is a real and daily struggle. In the United States alone, roughly 41 million people suffer from hunger – a staggering figure for an industrialised country. I, like many leaders in agriculture, wake up every morning wrestling with the great burden and responsibility of knowing that more must be done to address global hunger. I also recognise that agriculture must continue to innovate and produce 70 per cent more food over the next 30 years to accommodate a growing world population, but must do so in a sustainable way, given the earth’s natural resources are finite and precious. The feed industry, which I’m proud to be part of, plays a small, yet critical role in addressing this global challenge. Just as humans need a balanced diet to stay healthy, animals need the right nutrition throughout all stages of their lives to continue producing healthy, wholesome meat, milk, fish and eggs for our food supply. In the United States, more than 5700 animal food manufacturing facilities are responsible for producing highquality and safe animal feed to help farmers and ranchers keep their livestock and poultry happy and healthy. In 2016, the feed industry provided over 214.4 million metric tons of animal food to feed the country’s roughly 11.73 billion livestock, poultry, aquaculture and horses. This process is highly regulated and manufacturers must comply with all applicable state, national and international regulations and standards.

international levels. Based in the Washington, D.C. area, it is our job at AFIA to represent the business, legislative and regulatory interests of the US animal food industry and its suppliers before members of Congress, the White House, regulators, and state feed control officials. AFIA’s members include more than 680 domestic and international companies, such as livestock feed and pet food manufacturers, integrators, pharmaceutical companies, ingredient suppliers, equipment manufacturers and supply companies that provide other products or services to animal food manufacturers. The association is also recognised as the leader on international industry developments, representing the industry at global forums, including within the International Feed Industry Federation (IFIF). Over the past year, AFIA has worked on several initiatives to encourage policy-makers to reform regulations that do nothing to improve animal health and welfare, yet have the potential to block innovation from reaching the marketplace and drive up the cost of food for consumers. AFIA has also been working with Congress and the Trump administration to encourage a “do no harm” approach to existing and new trade agreements that support the export of US animal feed and pet food products, and our high standards in safe manufacturing, globally. The association, through its public charity, the Institute for Feed Education and Research (IFEEDER), has also been leading efforts to improve the industry’s environmental footprint and educate consumers about where their food comes from. AFIA Calls for Responsible US Regulations that Address True Animal Health Risks The animal food industry is regulated by the US Food and Drug Administration. In recent years, the FDA has modified or put in place regulations that address real concerns to the benefit of public and animal health. However, the industry continues to face regulatory challenges from the agency that are burdensome, outdated and do nothing to improve animal or public health. The most pressing example of this is the Food Safety Modernization Act (FSMA). Signed into law in 2011 by then President Barack Obama, this expansive regulation provides the FDA with sweeping new authorities and requirements in which to regulate the animal food industry. Of note, FSMA’s animal food rule, which mirrors a rule for human food, even though the two industries are vastly different, authorised the agency to mandate current good manufacturing practices (CGMPs) and ensure firms not only conduct analyses of the hazards within their facilities, but document and control for these threats before they become issues. It is estimated that if fully implemented, this law will cost the US feed and pet food industries more than $1 billion annually with little improvement to animal health, animal food safety or other real benefit.

The American Feed Industry Association (AFIA) helps the industry navigate this regulatory framework and policy discussions happening at the state, national and 14 International Animal Health Journal

Given the industry has known the major feed hazards for decades and has been mitigating those risks, this rule seems to be an answer in search of a problem and has the ability to drive up the cost of feed for producers, which consequently trickles down to the prices consumers pay Volume 5 Issue 2


REGULATORY & MARKETPLACE for meat, milk and egg products. In looking at the number and volume of reportable feed incidents where a serious adverse consequence or death in either humans or animals were reported to the FDA, AFIA found very little evidence that the industry is full of risks in need of such expansive prevention efforts. A miniscule number of these incidents, in terms of the nearly 1 billion tons of feed manufactured in the last five years, come from unknown hazards, but more so from human errors that would not have been prevented by any current FSMA rule.

trade agreements, which allows for the flow of goods. Over the past year, the industry has actively been engaged in discussions to renegotiate and negotiate trade agreements with several countries.

The Trump administration has vowed to repeal two federal regulations for each one put in place, and AFIA has been using the opportunity to urge the FDA to consider streamlining or removing regulations and record-keeping requirements that are unclear, duplicative, antiquated or do nothing to enhance the safety of America’s animal food supply. AFIA has also been calling upon the agency to establish speedier and more consistent ingredient review processes that allow innovative products to come to market to benefit animal nutrition, animal food safety and human food safety.

Even on the campaign trail, then-presidential candidate Donald Trump made it clear that his “America first” agenda would mean renegotiating or ending trade agreements that he did not feel were supportive of US-manufactured goods. Upon taking office, he immediately withdrew from the Trans-Pacific Partnership (TPP), with 11 Asia-Pacific countries, leaving a large gap for how the US feed industry could compete in the Oceanic region. Now, the remaining TPP signatories are moving forward with the Comprehensive and Progressive Agreement for Trans-Pacific Partnership with plans to begin implementing it in the coming months.

In recent years, the FDA’s process for approving new ingredients has been stagnant at best, costing the industry an average $1.75 million annually in lost revenue. What is worse, the agency’s ongoing delays have effectively stalled new ingredients from reaching the marketplace, meaning safe ingredients that could improve the health and welfare of the nation’s livestock, poultry and pets are left sitting on the shelves for upwards of three years. US ranchers and farmers are losing out, and the industry’s competitiveness in the global marketplace will continue to diminish if this does not change.

Given Mexico’s and Canada’s reliance on US animal food exports, as the country’s first and second most important trading partners, AFIA has made it a priority to work with the others in the US agricultural community over the past year on the renegotiation of the North American Free Trade Agreement (NAFTA). The 1994 tripartite agreement is the world’s largest free trade area and grants most-favourednation status to each of the parties, eliminates most tariffs and trade barriers between the parties, and establishes a number of other procedures for resolving trade disputes, protecting intellectual property and company products, and easing access into the markets.

AFIA has continued to press the FDA to recognise the American Association of Feed Control Officials’ Official Publication as the legal framework for state feed control officials to follow when approving new ingredients. This publication is already recognised by many state feed control laws and international agencies as the legal framework, and AFIA believes that should the FDA make this change, it would greatly improve the opportunities for the sale of new ingredients in the marketplace. Feed Industry Urges Trump Administration to Protect International Trade Benefits Besides encouraging a responsible regulatory framework, given the global nature of the food supply, the US feed industry also depends on reliable trading partners and free

Source: US Department of Agriculture's Foreign Agricultural Service www.animalhealthmedia.com

In 2017, the US animal food industry exported roughly $11.4 billion in feed, feed ingredients and pet food products. The top countries that import US animal food products include: Mexico, Canada, Japan, China, South Korea, Indonesia, the Philippines, Colombia, Turkey and Thailand.

The Trump administration has threatened to withdraw from NAFTA, but AFIA, with other organisations, have been calling on the administration and the US Congress to “do no harm” to the agreement. Since NAFTA’s implementation in 1994, animal food exports to Canada and Mexico have almost tripled, growing from $764 million to roughly $3 billion in 2016. Abandoning the agreement would be detrimental to the animal food industry, resulting in a rise in tariffs on US exports to the two countries and greatly diminishing the industry’s competitiveness in the global marketplace. Another agreement the industry has been closely engaged in is with South Korea. Last June, President Trump announced his desire to renegotiate the US-Korea Free Trade Agreement (KORUS), in large part due to the trade deficit the country has with South Korea. KORUS entered into force in March 2012, and since then, has facilitated growth in US animal food and pet food exports by offering zero tariffs on these products. For example, US animal food and pet food exports to South Korea have gone from $554 million in 2012 to $580 million in 2016, a 4.7 per cent increase. With the immediate elimination of the 5 per cent tariff on dog and cat food under KORUS, there has been a 67 per cent increase in exports of those products alone to South Korea. Although many market access constraints still remain, AFIA is hopeful that renegotiating KORUS will provide an opportunity for the US industries to address, or at a minimum to highlight, some of these issues. Industry Leads Way in Developing Internationally Recognised Sustainability Model Along with the agriculture industry as a whole, the US animal food industry is also committed to improving its International Animal Health Journal 15


REGULATORY & MARKETPLACE have a responsibility to continue producing high-quality, safe animal feed in a safe and sustainable way so that consumers around the world can continue having access to a safe, abundant and affordable food supply.

US greenhouse gas emissions by industry segment based on data from the US Environmental Protection Agency.

sustainability efforts. The industry has been an integral partner in the Livestock Environmental Assessment and Performance (LEAP) Partnership, which released in 2016 a gold-standard model for organisations around the world to accurately measure the environmental impact of their livestock feed production processes. This model, the result of more than three years of hard work between AFIA, the European feed industry, the International Feed Industry Federation, and the Food and Agriculture Organization (FAO) of the United Nations, is now the standard by which all livestock and poultry organisations, universities and other organisations can use to assess the emissions generated by species over their total lifecycles. Already, the model has concluded that the US livestock and poultry sectors contribute less than 4.2 per cent of total US greenhouse gas emissions. As a next step, AFIA is also participating in the North American Global Feed LCA Institute (GFLI) project. This initiative is creating regional databases and a modelling tool to benchmark the environmental impact of feeding livestock and poultry production based on the scientifically robust life-cycle analysis (LCA) methodology for feed developed under LEAP. GFLI is providing the tools and data and is urging the feed industry to use a harmonised set of standard methods to monitor feed ingredient LCA, which will encourage and demonstrate continuous improvement throughout the feed industry. Inspired by the North American and European Union projects, China and Brazil, as well as the global aquaculture industry, have also pledged to develop their own regional databases. Moving forward, the industry continues to find that one of its greatest challenges lies in the fact that many consumers within the United States and around the world are removed from the immediate throes of agriculture. They do not understand how their food is made, where it comes from or how the agriculture industry is continuously improving to be more sustainable, and often pit fearmongering tactics against science and level-headed decision-making. We have already seen how these loud voices can bend the ears of food retailers and policy-makers, searching for a larger market share and/or re-election. We continue to urge decision-makers not to make regulatory and policy changes that do not improve animal health and welfare, yet have the potential to block innovation, restrict choices in the marketplace, raise food prices, and prevent the world’s hungriest from eating their next meals. In the US feed industry, we feel the weight of the world’s hungry on our shoulders and know that we 16 International Animal Health Journal

Joel Newman Joel Newman is the American Feed Industry Association’s president, CEO and corporate treasurer. Newman has more than three decades of diverse executive experience in agribusiness, with United Cooperative Farmers, Maple Leaf Foods and Agway. Newman represents AFIA on international issues and serves as a director and on the executive committee of the International Feed Industry Federation.

Volume 5 Issue 2


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International Animal Health Journal 17

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REGULATORY & MARKETPLACE M2 + C = The Essential Elements for Startup Success

There’s a significant failure rate for startups in the life sciences. It ranges from 80%-90%. The startling thing is that even companies backed by venture capital still fail at a rate of three out of four. However, taking money from a corporate venture capital (CVC) firm (an investment arm of a large company or strategic player in the same sector), increases success twofold. This was illustrated in data from Thomson Reuters in the PwC/NVCA MoneyTree™ Report in 2015, that showed that between 2001 and 2015, CVC firms participated in 23% of biotech financing but they were equity holders in 48% of the sector’s IPOs and M&As. So, technology by itself is not enough and neither is money, but money with experience can make a difference. I’ll come back to this point a little later. The life sciences encompass a broad range of activities that include human and animal health, but there are large differences between investments in human health and those in animal health. There are also differences within animal health itself. For example, companion vs. production animal markets are usually lumped together but they are very different in focus and drivers. Nonetheless, my attention here, given the venue for the article, is going to be animal health in general. I am often asked by clients, interested investors and entrepreneurs, what makes a successful startup in the life sciences? To me, the answer is uniform although nuanced. First, what is success? In my view, success is evident when a technology is commercialised. Some people may define success as closing a capital raise round or licensing a technology to a strategic partner. I agree to some extent because those are steps in the right direction, but success in getting a driver’s licence can’t be assumed to have been achieved by simply getting a ride to the test location or even driving the test course. I am a little old-fashioned in that I still like to see something at the end that people or their pets can actually use. Over the years and through the experience of working with investors, strategics and entrepreneurs, I have distilled the elements of success, that is getting something commercialised, into three main drivers. This is not to insinuate that these are the only elements, but they appear to be time and time again what make a particular startup opportunity an eventual success. The elements that are focused on here are not given their due and usually rank behind the seemingly unending fun that is “raising capital” which is closely followed by “having a great technology” at least in the eyes of the startup entrepreneur(s). It’s important to emphasise here that raising capital and having a good technology are indeed both important. But I’ve seen plenty of startups with solid but not necessarily earth-shattering technologies using smaller injections of cash over time that have paid dividends in spades to the founders. 18 International Animal Health Journal

The first element and the most important is the Market. The foremost question in investors’ minds is “how big is the market?”. This question is usually (or should be) either number one or number two in the sequence of questions that are asked for any given investment opportunity. Of course, the market must be demonstrably big and pass subsequent due diligence. Larger markets command attention from investors and business development specialists in large companies much more than any other aspect in an investment. If one is lucky enough to have a reasonable technology (doesn’t have to be “great”) in a large market, where there’s a dearth of options and especially where there’s a market leader that other companies want to compete with, this usually opens many doors. This seems to be true even if the technology is at an early stage, when the majority of potential strategic partners would normally shy away. Investors often talk about the “addressable market” and in most cases the calculation is made on the back of an envelope by multiplying the number of, say for the sake of argument, total dogs in the US by the fraction of dogs with the condition of interest, by the estimated fraction of dogs whose owners will pay for the treatment by the price of the treatment. That is the simplistic, and often incorrect, way of estimating the market. There are many variables that must be considered. For example, we see many companies that are developing technologies that could be used to treat cancer in dogs. Invariably, we see the calculation as outlined above. This does not consider important factors such as the willingness of a pet owner to put their sick dog through any kind of therapy, knowing that the animal will still have a somewhat diminished quality of life and only live for a few additional months. Not to mention the burden that a sick pet places on the owner. Furthermore, unless the treatment is “vastly” superior to mainstay chemotherapy, the chances are your average generalist veterinarian will not even consider it as an alternative. These hurdles, combined with the potential added cost, will severely impact the true market size. This issue is not unique to cancer treatments but applies across the board to varying degrees. In addition to the points made above, other considerations would have to include that only about 60% of all companion animals ever go to see a vet, and a significant portion of these pets will only go once a year or for emergencies only. This then has to be squared with the owner’s “ability/ willingness to pay”. Even though we hear that people will pay “anything” for their pets that are regarded as family members, real calculations of cost start creeping in, for both the vet as a business owner and the pet owner, somewhere around the $3000 mark. This is true even for people who may consider themselves fanatics when it comes to their pets. Market estimates from the production animal side are no less complicated. The short version of all of this is that market is an extremely important consideration and entrepreneurs must pay more than a passing glance to it, or they will disappoint their investors. The second element that is extremely important for success is the Management. In many cases, especially for Volume 5 Issue 2


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startups, the management is the inventor of the technology or people around the inventor of a technology. This is where trouble starts. Being a good or even great scientist does not mean that one can manage a company, or people, or negotiate a licensing deal effectively, in fact, in the majority of cases, the opposite is true.

now do offer a business class or two to their students before graduation, but the reality on the ground is that the majority of vets learn how to run a business as they are doing it and many of them flounder. This is no different than hiring a sales team that can’t sell but you can always replace a sales team.

Whomever is at the helm is especially important for venture capital groups, because they have to deal with the individual(s) on an ongoing basis and if they don’t feel that they can do that effectively, well there’s plenty of fish in the sea; they will pass on the investment. For a strategic partner company where a technology will be eventually in-licensed, who is the management is less of a problem (although it could be painful to negotiate with them). But it’s more of an issue for the startup company with the technology because, not knowing when they are out of their depth in, for example, how to approach a licensing deal and where to push back and what to accept could be detrimental.

If you do some market research and ask vets about who influences their decisions, their answer invariably is going to be “the client”. This is particularly true for products designed for companion animals. But the same principle also carries through to the feed lot manager or the farmer. In general, consumers of animal health products are looking for value demonstrated by having clearly effective products, that fill their need at a reasonable price. It is no surprise that tick and flea medications are veterinary blockbusters because the consumer need is enormous, and the products are evidently effective, very easy to use and available at prices that consumers can justify. From a production animal point of view, a technology that fits seamlessly within the daily workflow will score big points with farmers and feed lot managers.

The most successful outcomes are achieved when the clients have come to the realisation that they need help and that they may be experts in their field of invention, but running a viable company is a completely different beast that requires an entirely different skill set and temperament. Having the right people in the right positions within any company (all the way up to the very big ones), is absolutely essential to how that company will fare in the market. Who manages a company has implications all round and although the risk can be mitigated by, for example, a strong board, it’s still, in my view, number two in the elements that define success of a startup. To emphasise this point, I go back to the initial paragraph in this article – taking money from a venture capital firm is a big step forward, but is not enough to ensure that a startup is successful, and 75% of venture-backed companies still fail. But taking money from the investment arm or a larger company as a stand-alone equity investment or an equity investment/licensing deal combination can move the needle significantly because it brings to the table additional experience in regulatory, manufacturing and consumer-facing aspects (sales and marketing) that are, in my view, essential for success. This brings me nicely to the third element of success, which in my view has to be focus on the Consumer. Most biotech, pharmaceutical, biologic and diagnostic developing companies forget this important element. This is mainly because they feel that they will be selling their wares through a distributor, a veterinary office or out-license altogether to a larger company and simply forget about it. Losing sight of the consumer is not just a problem with startup companies but also the majority of larger companies who seem to think that, for example, the vet is the consumer because they sell to the vet. On the face of it, this is correct. But dig slightly deeper and you’ll find that you do this at your own peril. Vets are not trained in business. Some vet schools www.animalhealthmedia.com

So how do you take the consumer into account if you are not directly selling to them? The answer is first, create needed products that people will want and can afford to buy. Second, enable vets and distributors to sell more effectively by understanding their limitations and providing the necessary support and training; and third, continually communicate with and educate the consumer (directly or indirectly) on what the product(s) can do. Having an effective management team will have a great influence here because they have to be able to recognise what the market need is and how to differentiate their technology from competitors in the eyes of the consumer. All in all, money and technology do not alone lead to commercial success in the absence of a good market, good management and focus on the consumer. Focusing on these elements will not guarantee success but will create the best conditions for achieving it.

Dr. Sam Al-Murrani Dr. Sam Al-Murrani, CEO, Babylon BioConsulting LLC, a human and animal health-based consultancy firm specializing in valuations, investor outreach, due diligence, business development and intangible asset management. He is also Managing Director for Bimini LLC, a privately owned manufacturer of Pet dose-form health supplements and health treats. Email: murrani@babylonbioconsulting.com

International Animal Health Journal 19


REGULATORY & MARKETPLACE For Dogs, Time Alone May Mean Depression. Daycare is a Healing Option

For years, pups Lucy and Graci spent their days alone indoors, logging long hours away from their owners, Robert and Janelle Meyer. Despite being part of a loving home and well looked after by their dedicated caregivers, Lucy and Graci’s time apart from the Meyers took its toll. “While we worked our dogs were, unfortunately, home by themselves about eight to nine hours a day,” said Robert Meyer, who lives with his wife in Texas. “We’d come home, and they were lethargic, or they’d have accidents in the house, which is not something they’d normally do.” The Meyers, who have owned and fostered dogs for more than 30 years, could easily spot irregularities in Lucy and Graci’s behaviour. “We love dogs and we know dogs. We noticed Graci never used to be afraid of thunder and lightning, but then she became terrified of it and then she taught the other dog to be afraid too. It was horrible,” Robert said. “I also think the stress of being alone and trying to hold in (bowel movements) left lasting negative effects on Graci’s digestive tract.” Worried how their dogs were responding to their lengthy daytime absences, the Meyers decided to move Robert’s business to their home. Home alone no more, the dogs are much happier, and it shows. “Wherever we go, they go, and they are so happy they even smile,” Robert said. “They’re in heaven because we’re home with them.” Dr Lore Haug, a veterinarian and one of only two boardcertified veterinary behaviourist specialists practicing in Texas, is not at all surprised by this. “Do I think a dog can suffer from a dog version of depression? Absolutely,” she said. “With most dogs, it’s not really their function to be locked in a house for hours a day with nothing to do. They lack stimulation and can suffer from anxiety and stress because most of them like to be hanging out with their owner or with someone else.” It sounds simple: To stave off depression, ensure dogs have someone to hang out with. Of course, not every dog owner can simply move their office home. That’s where “doggy daycare” comes in. Dog Daycare Takes Off Over the last three decades, the dog daycare industry has emerged and grown to provide millions of dog owners worldwide with options for work-time and daytime care. Businessman and inventor Joseph Sporn is credited with creating dog daycare in the United States when he opened 20 International Animal Health Journal

Yuppie Puppy in 1986 in New York City. His original idea was an instant hit, garnering international attention from CNN, The Australia Times, The Daily News, The New York Times, and others. “Being home alone is definitely not the best thing for dogs, so daycare is a good antidote for that,” said Sporn, who still operates Yuppie Puppy today. “It’s all about letting dogs be dogs. That’s our number one goal in providing this service. That’s how I started it, and that’s how I keep it.” Dr Haug says dog daycare can provide a viable alternative to leaving dogs home alone all day -as long as owners know what to look for. “Look for a facility with a lot of space, forced nap time, a personality assessment of the dog and one staff member on the floor for every 5-8 dogs,” she said. “I suggest using daycare a maximum of three times a week unless you’re using it temporarily to help cover for a problem, like with a storm-phobic dog.” The doctor added that owners should also look for daycares where staffers are trained in behaviour education. Basic Instinct Daycare can help prevent loneliness and anxiety in dogs by offering them opportunities to play, burn energy through indoor and outdoor exercise and socialise with other canine friends. It also facilitates dogs’ natural instincts, especially when it comes to forming packs. “Like humans, dogs have a basic need to be part of a group, to be included and to be around other dogs,” Sporn said. “They’re pack animals, so there is a biological need to find where they fit into the pack. Wherever they fit in is where they’re meant to be.” Sporn said he’s always amazed by how quickly dogs develop their own social structure. “It is a marvel of nature to watch dogs socialise and then watch how quickly they find their place in the pack,” he said. “In fact, it happens so fast that you have to really pay attention to notice it. It happens in a matter of, I’d say, 10-20 seconds of them walking into the room.” Dogs’ desire to connect comes as no surprise to Gina Cox, a dog owner who lives in Texas. Her German Shepherd Max attends Camp Bow Wow daycare once or twice a week. All she has to do is mention daycare to her pup and he’s jumping eagerly at the door, excited and ready to go. “After going only a few times, he was in love with it,” Cox said. “When he comes home he’s exhausted because he’s so active when he’s there. He doesn’t even eat, he just wants to play and be in there with all the other dogs.” Even though Cox doesn’t work outside the home, she said she quickly recognised Max’s need to be around his own kind and to learn how to control and to improve his behaviour when around other dogs. Volume 5 Issue 2


REGULATORY & MARKETPLACE “With separation anxiety, it’s a test of time,” he explained. “What we do is we allow the owner to stay here for a bit longer than usual at drop-off time or let them come back into the main room for a bit.” He said this allows the dog to become comfortable in the new space and demonstrates that his or her owner is coming back. “We want the anxious dog to feel like the daycare is a place where their owner has been and is coming back to, like an extension of their own home,” Sporn said. “We know the dog will be upset when the owner leaves, even detecting their scent for 10-15 after they leave, and often the dog will try to run and pick up the scent once it’s gone, so we encourage owners not to linger too close outside once they leave.”

“Before I took him to daycare I would bring him to a dog park, but often he was growling at the other dogs. So the main reason I started was for his socialisation and to have playdates with other dogs,” she said. “I just think it’s better for his mental and physical health.” Cox can’t speak to her dog Max’s place in the daycare “pack,” but she can confirm the relationship he’s forged with one dog in particular, a female named Heidi whom Cox refers to as Max’s “girlfriend”. Sporn said Max and Heidi’s close relationship is another normal part of canine behaviour. In addition to being part of a pack, he said it’s not unusual for dogs at Yuppie Puppy to seek out a “snuggle buddy”. “They find this partner quickly and will stay with them consistently,” he said. “It’s a very good thing for them.” Warding Off Depression For dogs attending daycare to combat depression and loneliness, it’s not just a matter of dropping off the animal and leaving it to its own devices. At Yuppie Puppy, Sporn said he and his team have procedures to deal with depressed dogs, including a specific dropping-off routine. “We greet each dog that comes in, we have eye contact, we touch the head and have a friendly warm hello for every animal; that’s very important,” he said. “We also make sure every owner says goodbye to their dog properly.” Sporn explained a dog may be depressed for a variety of reasons, including too much time home alone, multiple stays at a shelter, or a sick and/or absent owner. Despite these stressors, daycare can still make a positive impact in a pup’s life.

Despite some challenges with depressed dogs or those dealing with separation anxiety, Sporn insists daycare and the regular routine, exercise and social interaction it provides is always a better option than staying home alone. “No question about it,” he said. Is Your Dog Depressed? According to the American Veterinary Society Behavior and the American College of Behaviorists, depression in dogs can manifest ways. In fact, problems can be easy to spot as mimic depressive signs in humans.

of Animal Veterinary in several they often

If you suspect your dog is suffering, look for these signs: 1. 2. 3. 4. 5.

Change in or loss of appetite; Change in sleeping habits; Having bathroom accidents inside; Withdrawal; Destructive behaviour and/or chewing furniture and household items; 6. Excessive barking and howling; 7. Hiding or pacing. Is Daycare Right for Your Dog? Dog daycare can help alleviate depression and anxiety in many dogs, but it’s important to understand it’s not a cureall. Dr Haug is quick to point out not all dogs thrive in daycare. For example, dogs who don’t like other dogs may become more stressed out in a daycare environment. That’s why it’s important for dog owners to pay close attention to how their dog reacts when they arrive at daycare. “If he doesn’t want to go, that’s a huge red flag that the dog’s not having a good experience,” says Haug.

“A depressed or worried dog will still be worried in daycare, but the difference is they’re not alone (like they might be at home), they’re around their (dog) friends,” he said. “Like with people, support makes all the difference, so it’s good when a depressed or lonely dog shows up for daycare and they bring whatever self they are that day.”

Physical and psychological factors can also play a part in how well a dog adjusts to daycare. Dogs who are older or ill, and dogs that have trouble walking or enduring rough play, may not be happy in daycare. Dogs who are undersocialised and afraid of humans and other dogs may not be good candidates for daycare.

However, it’s not always depression that’s plaguing dogs who spend their days alone; sometimes these animals are dealing with separation anxiety, as well. In these cases, Sporn said he and his employees have to devote a bit more time to making the animal comfortable and integrating them into the dog daycare setting.

Daycare owner Sporn agrees with Dr Haug: Not all dogs are a good fit for daycare. That’s why he says it’s good practice to screen potential daycare dogs, a practice the doctor advocates for as well. Although Sporn’s centre accepts all breeds without discrimination, his staff does look for certain behaviours or risk factors.

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International Animal Health Journal 21


REGULATORY & MARKETPLACE To break up the monotony of an eight-hour wait, Dr Haug suggests hiring a dog walker to visit and exercise the dog during the day. But what if daytime visitors, food puzzles, and afterwork attention aren’t enough to lift your dog out of her funk? In some situations, Dr Haug says medications like Prozac may help depressed dogs bounce back. “There are a variety of similar or identical medications to those we use for people that we can give to dogs,” she said, adding sometimes the animal needs to take medication regularly, or only requires it during a stressful event such as a storm or prolonged absence from its owner. The Bottom Line Dog lovers recognise the joy pups can bring to a family, but it’s important to remember that there’s more to owning a pet than simply feeding and walking them. An avid animal lover and lifetime mother to dogs, cats and rabbits, Lindsay Bourgeois knows the importance of giving animals the attention they need, whether they’re in daycare or not. She bemoans how some dog owners don’t take the job as seriously as they should. “Some people think they can just get a dog and play with it a little bit and that’s enough, but it’s not,” said Bourgeois, who lives in Louisiana. “Dogs are a huge responsibility and they need a lot of attention.” Sporn couldn’t agree more. “It’s not a good idea to take a female who’s in heat or a dominant male who’s not neutered. These dogs will want to impregnate the females and dominate the pack,” Sporn said. “We don’t want tests of will to distract us all day long.”  Human-aggressive or dog-aggressive canines also are not accepted, he said. Daycare Alternatives But what to do if you can’t afford daycare or don’t have access to one in your area? Thankfully there are steps you can take to make sure your dog remains healthy, both mentally and physically. The American Society for the Prevention of Cruelty to Animals emphasises at least a half an hour each day of exercise for your dog, particularly immediately before the animal is left alone, to calm the animal and encourage rest while you’re away. When you return, make sure to take time to greet your animal enthusiastically and affectionately and perhaps play a new game or take him to a new outdoor play spot. A walk is good at this time, as well. Also, make sure to provide food puzzle toys that stimulate dogs’ minds as well as a variety of edible and inedible chew toys. Like exercise, chew toys and puzzles calm dogs and keep them engaged, encouraging stress relief. It’s also important to spend quality time with your dog upon your return home. Sporn suggests lots of touching and talking. “Dogs have a different sense of time than we do in that their time seems longer to them than it is to us,” he says. “For those eight hours you’re at work, the dog is waiting for you to come home. When you return you need to show some excitement to see them.” 22 International Animal Health Journal

“One of the things I love about dogs is the consistency, stability, routine and unconditional love we get from them. That should be paid back at least as much as we get it,” he said. “We should all be paying service to our dogs as they pay service to us.” Depending on your dog’s age, personality and temperament, that “service” might include telecommuting, dog daycare, medication or dog-walking services. The important thing, experts say, is that owners recognise signs of depression and anxiety and feel empowered and informed enough to make the right choice. Dr Haug said this is nothing more than what dogs deserve. “Once you get the animal it’s a ward of your care, and it’s your obligation not to do what you want but to do what the animal needs,” she said. “Hopefully those two things coincide.”

Carissa D. Lamkahouan Carissa D. Lamkahouan is a freelance newspaper and magazine journalist based out of Houston, Texas, USA. For more than 20 years she has covered health and fitness, education, the arts, business, small-city government and religion for publications in the United States, the United Kingdom and Egypt. Email: cdlamkahouan@gmail.com

Volume 5 Issue 2


Teaming up for animal health

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GD Animal Health, P.O. Box 9, 7400 AA Deventer, the Netherlands, T. +31 (0)570-63 33 91, F. +31 (0)570-63 41 04 www.gdanimalhealth.com, gdacademy@gdanimalhealth.com www.animalhealthmedia.com

International Animal Health Journal 23

TESTING RvA L 120


RESEARCH AND DEVELOPMENT Comparative Medicine: Similarities Between Domestic Animals and Humans – Do these Help in Translational Medicine?

Although appearances can be deceptive, there are considerable biological similarities between humans and animals. At the physiological and anatomical level, the similarities are remarkable. Animals ranging from mice to monkeys have the same organ systems, which function in a very similar manner to those of people. This means that many human and animal diseases are also highly similar. For this reason, about 90% of veterinary medicines are the same, or very similar, to those used in human patients. On the whole, while there are obviously differences, the similarities between humans and animals far outstrip the differences in physiological and biochemical function. To a large extent this is not surprising, bearing in mind evolutionary linkages. It is, for example, well known that humans share over 90% of their DNA with other mammals. The study of comparative genomics helps to understand how species have evolved and what genes regulate species specific traits. Where differences between animals (including humans) exist, these can, in fact, also give powerful insights into mammalian physiology and disease resistance and may even suggest novel targets for drug treatments. By way of an example, type 2 diabetes is common in people and cats that are obese, whereas obese dogs rarely suffer from type 2 diabetes. If we understood why obesity in dogs does not predispose them to type 2 diabetes, this might help us to find new ways of preventing this problem from occurring in overweight people and cats. Following a good basic understanding of a human disease process in vitro, it is still necessary to test hypotheses and ideas in a living animal model where all the physiological systems interact. At the present time, a test tube environment cannot provide the dynamics and interactions of a live animal system. While not perfect, animal models allow a much closer approximation than in vitro studies of how a medical intervention is likely to work in people. As discussed above, there are differences between species and between individuals within a species, which must be considered when extrapolating results to humans. Knowledge of comparative physiology is important to determine which species is the most appropriate model to undertake a proof of concept study for a particular treatment. Therefore, for the purpose of human therapeutic development, it is a question of identifying which animals have physiological and biochemical systems of interest, that are sufficiently similar to human. Rodent models of some diseases have not proved successful in predicting the likelihood of success of treatments for some human diseases. For example, cancers are difficult to model in laboratory animals, whereas some naturally occurring cancers in dogs are very similar to those in people, and those dogs with currently untreatable disease might benefit from the use of developmental treatments. Their response to treatment would, in turn, benefit medical science and help in deciding which drugs should go into human clinical trials. In summary, greater cooperation between human clinicians, veterinarians and the biomedical scientists who generate the new knowledge 24 International Animal Health Journal

which underpins both disciplines would be highly beneficial for both professions. An historical perspective on the relationship between human and animal medicine is revealing, especially the work undertaken by the veterinarian and historian, Abigail Woods (2017). Traditionally, historians have propagated the view that human and veterinary medicine have always operated as separate domains. Woods’ research gives a novel commentary on the evolving relationship between human and veterinary medicine following the creation of the Royal Veterinary College (RVC) in 1791. It is generally acknowledged that it was the founding of the RVC that gave birth to the veterinary profession in Britain. Woods coherently argues that when the RVC was set up, the study of veterinary medicine was considered continuous with its human counterpart, not separate from it. However, within the first 40 years of the creation of the RVC, veterinary and human medicine evolved into two separate fields having different institutions, professional bodies and teaching curricula, and their relationship became much more fluid. At its inception in the UK, veterinary education existed as a ‘branch’ of human medicine and was grounded in the study of man. The veterinary arena was also partially populated with human surgeons, with veterinary and medical educations considerably integrated. It is also interesting to note that many medics were strong supporters of the creation of the RVC, including the prominent surgeon, John Hunter, who was its Vice President in the early days of the College. Many others were on the board of the RVC. Those human clinicians connected with the RVC were not necessarily concerned with practising the

Volume 5 Issue 2


RESEARCH AND DEVELOPMENT establish veterinary medicine as an independent discipline, rather than a sub-category of human medicine. In this way One Medicine became Two. The separation of the two professions has not necessarily benefited them and was certainly not based on biological differences between their patients, as development of treatments can be remarkably similar between humans and animals. Today there are many advocates of Comparative Medicine (One Health or One Medicine), particularly from the veterinary profession.

veterinary art themselves, but a key driver for them was using animals for the improvement of human surgery. The medical community at that time were driven by the principle that human and animal medicine shared the same fundamental biological laws. They sought to understand diseases, such as rabies and glanders, which were transmitted between them, to better differentiate species similarities and differences through comparative anatomy as well as to advance physiological understanding via animal experimentation. They very much advanced the One Medicine concept. This situation largely existed until the 1830s, by which time many veterinarian reformers were voicing concerns about what actual contribution the medical community had made to veterinary medicine. These reformers, including many human surgeons amongst their number, concluded that veterinary medicine had benefited little from its association with its human counterparts – the benefits had all seemed to have gone the other way. The ambition of the reformers was to

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The opportunities for translating new treatments between animals and humans are many. Finding more ways of working together to make such translation happen more effectively would be enormously beneficial to both veterinary and human patients. Just by way of some examples, below are outlined some interesting cases currently being undertaken at the RVC that have important implications for translational medicine: •

Dogs with idiopathic epilepsy have been shown to benefit from inclusion of medium-chain triglycerides (MCT) in their diets. This has been shown to improve seizure control, if used as a supplement to drug therapy. This is something that had been also been demonstrated in human patients. The canine work at the RVC has led to the launch of Purina’s Pro Plan Veterinary Diet that includes MCTs for dogs with epilepsy.

A study known as EPIC has found that administration of pimobendan to dogs with myxomatous mitral valve disease, results in prolongation of the preclinical period by about 15 months. This provides a substantial clinical benefit and interest has been expressed by cardiologists for use in human patients. Pimobendan is a drug which was initially developed for human medicine, designed to sensitise the calcium binding protein in cardiac muscle to

International Animal Health Journal 25


RESEARCH AND DEVELOPMENT calcium. This should mean it would increase the force of contraction of heart muscle without a rise in intracellular calcium and increase in energy expenditure required for the heart muscle to relax, both of which are problems of other positive inotropic drugs. This drug was abandoned after very early clinical trials in selected human patients. The remarkable effects the drug has in dogs on cardiac remodelling in the early stages of mitral valve disease have made medical cardiologists think this drug should be re-examined more thoroughly in human medicine. The question remains as to how it is working in dogs – calcium sensitisation is not its only action. •

Treatment for recurrent laryngeal neuropathy in horses using functional electrical stimulation (FES). This has been shown to be highly effective in opening airways in horses with this condition. A collaboration is currently underway with human clinicians as a potential treatment for vocal cord paralysis.

One in four diabetic cats has been found to be suffering from hypersomatropism-induced (HST) diabetic mellitus. It has been found that if HST is diagnosed (screening with IGF-1) and surgically treated, most of these cats have diabetic remission. If the HST remains undiagnosed, the diabetic cat tends to be very difficult to control since growth hormone is an insulin antagonist. Further work suggests not only a genetic link to acromegaly, but also one relating to environmental organohalogenated contaminants. The research further demonstrates that feline HST, phenotypically and genetically resembles that in humans. HST studies in people are currently being progressed, based on this underlying research in cats.

Considerable work has been undertaken on biomarkers for the early detection of chronic kidney disease (CKD). One aspect of this research in cats identifies FGF-23, which is elevated in the pre-azotemic stage of CKD, as the most sensitive and earliest indicator of bone and mineral disturbances in CKD. This is a diagnostic test that is also applicable to humans.

A number of other areas of such translational research could be highlighted, including, for example, the parallels between feline cardiomyopathy and the similar condition in man. Or the use of animal models that may eventually lead to a treatment for an equivalent human disease. The list of possible opportunities for veterinarians and human clinicians to work together towards comparative medicine goals is extensive. Transfer of knowledge between veterinary and human medicine

is important for advances in both disciplines. In particular, this applies to chronic diseases of ageing (arthritis, cancer, chronic kidney disease and neurodegenerative diseases). Most laboratory animal models of these diseases are acute models and poorly mimic the chronic and slowly progressive pathology seen in diseases associated with ageing. Dogs and cats age much faster than humans, yet the pathology of these chronic diseases is very similar. Species differences and comparative genomics provide further insights. By working together, it is likely that new treatments will emerge to the benefit of people and our companion animals. In summary, for the benefit of their patients, it is highly important to find ways that enable animal and human clinicians to work together more effectively, especially if the One Health objectives are to be met.

Acknowledgements to the following for their valuable contribution to this article: Professor Jonathan Elliott, VicePrincipal Research and Innovation, Royal Veterinary College Elizabeth Hawes, who studied Modern History at Keble College, University of Oxford and has a special interest in the history of science and medicine REFERENCES 1.

Woods, A. “One Medicine to Two: The Evolving Relationship between Human and Veterinary Medicine in England, 1791 – 1835. Bull Hist Med. 2017. Fall; 91(3): 494 - 523

Tas Gohir Tas Gohir is Head of Knowledge Transfer and Impact at the Royal Veterinary College (RVC). He has previously worked in business development roles within the biomedical industry and has over 12 years’ experience of university IP commercialisation, including human medical technology.

26 International Animal Health Journal

Volume 5 Issue 2


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International Animal Health Journal 27


RESEARCH AND DEVELOPMENT

Organic Trace Minerals: Optimised Stability Enhances Bioavailability Organic trace minerals (OTMs) are recognised globally as being a more bioavailable source of mineral than their inorganic counterparts. Whilst there are many forms of mineral products available in the marketplace for use in animal nutrition, these have unfortunately been generically entitled “organic trace minerals” by virtue of the fact that the trace elements in question are complexed or otherwise associated with organic molecules. Typically speaking, OTMs can be produced through numerous mechanisms, depending on the trace mineral product being manufactured. The process of complexing or chelating elements such as copper, iron or zinc, for instance, typically involves reacting inorganic mineral salts with a suitable bonding group such as a peptide or amino acid, after which the mineral becomes part of a biologically stable structure. Numerous production processes have been developed, ranging from highly specific and controlled reaction processes to more involved chemical synthesis routes. Given the vastly different products that exist in the marketplace, the importance of understanding the physical differences between them cannot be understated. A greater understanding of the basics behind these products will allow end users to differentiate between them, not only in terms of their physical makeup, but also in terms of likely behaviour in vivo. Complexes or Chelates? Generally speaking, the term “complex” can be used to describe the product formed when a metal ion reacts with a bonding group or ligand that contains an atom that has a lone pair of electrons. In the complex, the ligand is bonded to the metal ion through donor atoms such as oxygen, nitrogen or sulphur. Ligands that contain only one donor atom are termed “monodentate”, whilst those that contain two or more donor atoms capable of bonding to a metal ion are termed “bi-”, “tri-” or “tetradentate”. These multi-donor species can also be referred to as “polydentate”. When such ligands bond to a metal ion via two or more donor atoms on the same ligand, the compIex formed contains one or more heterocyclic rings that contain the metal atom. Such complexes are termed as “cheIates” (from the Greek chele, referring to a crab’s claw). Amino acids such as glycine are examples of bidentate Iigands that bond to metal ions via an oxygen of the carboxylic acid group and the nitrogen of the amino group. In contrast, ethylenediaminetetraacetic acid (EDTA) is an example of a hexadentate Iigand containing six donor atoms. It forms highly stable complexes with most metal ions and, in fact, is not particularly useful for the formation of mineral chelates, as the bioavailability of such complexes is negligible. 28 International Animal Health Journal

It must also be remembered that while all chelates are complexes, not all complexes are chelates. Indeed, whilst the overall theory behind chelation is simple, there are a number of criteria that must absolutely be met in order to ensure the generation of a stable mineral chelate: •

A chelating ligand must contain at least two atoms capable of forming bonds with the metal ion.

The ligand must form a heterocyclic ring, with the metal as the closing member of the ring.

It must be physically (sterically) possible to chelate the metal.

The ratio of the ligand to the mineral must meet minimum requirements for stability.

True chelates have the “ring structure” formed by bonding between the amino and carboxyl ends of the amino acid and the metal ion. Amino Acids and Peptides as Ligands The chemistry behind OTMs has created a great deal of confusion in the animal feed industry. Terms such as “metal amino acid complexes”, “metal amino acid chelates”, “metal polysaccharide complexes” and “metal proteinates” abound, yet official definitions remain vague and unhelpful. As an example, definitions of the most common organic trace minerals used in agricultural practice as laid down by the Association of American Feed Control Officials (AAFCO, 1998) are illustrated in Table 1. In deference to the AAFCO definitions, Table 2 gives an overview of the European Union classification of organic zinc products, from which one can appreciate the stark differences between the official terminologies used for regulatory control and the obvious confusion that can occur when comparing products.

Metal amino acid complex: The product resulting from complexing of a soluble metal salt with an amino acid(s). Metal amino acid chelate: The product resulting from the reaction of a metal ion from a soluble metal salt with amino acids with a mole ratio of 1 mole of metal to 1 to 3 (preferably 2) moles of amino acids to form coordinate covalent bonds. The average weight of the hydrolysed amino acids must be approximately 150 and the resulting molecular weight of the chelate must not exceed 800. Metal polysaccharide complex: The product resulting from complexing of a soluble salt with a polysaccharide solution. Metal proteinate: The product resulting from the chelation of a soluble salt with amino acids and/or partially hydrolysed protein. Table 1. AAFCO definitions for organic mineral complexes Volume 5 Issue 2


RESEARCH AND DEVELOPMENT Zinc chelate of amino acids hydrate: Zinc amino acid complex where the zinc and the amino acids derived from soya protein are chelated via coordinate covalent bonds, as a powder with a minimum content of 10% zinc. Characterisation of the active substance: Chemical formula: Zn(x)1–3nH2O, x = anion of any amino acid from soya protein hydrolysate. Maximum of 10% of the molecules exceeding 1,500 Da. Zinc chelate of protein hydrolysates: Zinc chelate of protein hydrolysates as a powder with a minimum content of 10% zinc. Minimum of 85% zinc chelated. Characterisation of the active substance: Chemical formula: Zn(x)1–3 · nH2O, x = anion of protein hydrolysates containing any amino acid from soya protein hydrolysate. Zinc chelate of glycine hydrate (solid): Zinc chelate of glycine, hydrate, as a powder with a minimum content of 15% zinc. Moisture: maximum 10%. Characterisation of the active substance: Chemical formula: Zn(x)1-3 · nH2O, x = anion of glycine. Zinc chelate of glycine hydrate (liquid): Liquid zinc chelate of glycine, hydrate, with a minimum content of 7% zinc. Characterisation of the active substance: Chemical formula: Zn(x)1-3 · nH2O, x = anion of glycine. Table 2. European Union classification of organic zinc products

An important feature of organic chelates is their enhanced stability due to the conformation in which the metal is held by the bonding group(s). In general terms, the stability of a chelate is the defining characteristic of its bioavailability and chelates with low stabilities will see the effectiveness of the product reduced to that of the corresponding inorganic salt. Individual bonding groups such as amino acids or peptides have the potential to form complexes or chelates with varying degrees of stability. It is reasonable to expect that bonding groups, such as peptides, which have a greater number of donor atoms, would have higher stabilities than simple amino acids such as glycine. Following this logic, one would anticipate that peptidebased chelates would have the necessary physico-chemical properties to ensure wide-ranging stability under conditions of changing pH. Stabilising a Chelate: The Effect of Ligand When trying to compare chelates or complexes on the basis of “which is best under this set of conditions”, one really needs to consider many different factors. However, it is useful to compare products in terms of what’s known as their “stability constant”. A stability constant (also known as a “formation constant” or a “binding constant”) is an equilibrium value for the formation of a complex or chelate in solution. The overall stability constant is the product of all stepwise stability constants. For example, if K1 and K2 are the stability constants for the addition of the first and second ligand, respectively, then the overall stability constant (β2) is K1 x K2. This value is a relative measure of the strength of the interaction between a metal and the ligand in a chelate or complex. We can derive this value by measuring the relative proportions of metal ([M]), ligand ([L]) and chelate ([ML]): [L] + [M] ↔ [ML] www.animalhealthmedia.com

Note that there are a number of influencing factors that play a role in this equilibrium: • •

pH significantly influences the equilibrium between ML and L+M. Additional factors also influence this, such as the type and makeup of ligand, relative proportions of [L] to [M], etc.

Ultimately, the stability constant, β, can be defined as a measure of the ratio of the chelate concentration to the concentrations of the free metal and ligand under a given set of conditions. For simplicity, it can be represented as follows: β = [ML] / [L][M] Essentially, what this tells us is that the greater the value of the stability constant β, the greater the proportion of the chelate or complex that is present relative to free ligand ([L]) or free metal ([M]) at a given pH. Typically, the stability constant is presented in log values and can serve as a useful guide when comparing different bonding groups. The stability constants for a range of ligands, including single amino acids, di-peptides, tri-peptides, etc., can be readily obtained from the NIST stability constants database, which calculates the value considering relative pH, ionic strength, temperature, ligand type, ligand and metal concentrations. Consider the data in Table 3, which compares a range of ligands when complexed with copper under the same physiological conditions. For simplicity, the stability values (log data) have been transformed and compared on a relative basis to that of glycine. The molecular weight of each ligand is also indicated. As the type of bonding group changes, so too does the strength of the bond between it and the copper group; some bond copper tightly and some bond copper very weakly. The same holds true for all other minerals such as zinc, manganese and iron.

Bonding group

Relative stability

Propionic acid (74 Da) Methionine hydroxy analogue (150 Da) Met (m.wt. 149 Da) Gly (m.wt. 75 Da) His-Ser (m.wt. 260 Da) His-Met (m.wt. 304 Da) Gly-Cys (m.wt. 196 Da) Gly-Lys (m.wt. 221 Da) Tyr-Trp (m.wt. 385 Da) Ala-Lys (m.wt. 238 Da) Tyr-Lys (m.wt. 327 Da) EDTA

1 x 10-6 2.63 x 10-6 0.5 1 2.5 2.5 21 2,818 3,235 9,549 186,208 5.6 x 1010

Adapted from: Critically selected stability constants of metal complexes, NIST Database 46. Table 3. Relative stabilities of organically bound copper complexes

What this indicates is that the size of the bonding group is not the most critical factor influencing bond strength and, ultimately, stability of a chelate. Claims of superiority based on size clearly have little merit. However, simply increasing the number of amino acids in a ligand may not increase the stability of the metal complex and thus may not necessarily increase the relative proportion of bound mineral. International Animal Health Journal 29


RESEARCH AND DEVELOPMENT Ultimately, not only does the type of amino acid influence the stability of a given chelate, but the position of amino acids in a peptide can also significantly influence how the ligand and mineral interact. This is illustrated in Table 4, where it can be appreciated that the most critical factors are the sequence and position of amino acids, rather than the overall size.

Bonding group

Relative stability

Gly-Gly-Gly (m.wt 225 Da)

1

Gly-Gly-His (m.wt. 305 Da)

270

Gly-His-Gly (m.wt. 305 Da)

8,511

Table 4. Role of amino acid sequence on chelate bond strength and stability

The substitution of a histidine into the tripeptide Gly-Gly-Gly to yield Gly-Gly-His, for instance, enhances the stability value and thus the relative proportion of bound mineral (copper, in this instance). Furthermore, changing the position of this histidine within the tripeptide sequence (to form Gly-HisGly, for example) can result in a further increase in the bond strength and, as such, an increase in the proportion of bound mineral. In practical terms, simple changes in the configuration of amino acids in this tripeptide result in a greater proportion of bound mineral relative to free mineral and ligand. Essentially, mineral chelate stability can be significantly influenced not only by the type of amino acid, but also the configuration of amino acids in a peptide sequence. From a production standpoint, it is important to note that the extent and type of hydrolysis of a protein source to form short chain peptides can significantly influence the sequence of amino acids present in these peptides. The production of an “optimal” protein hydrolysate for mineral chelation can be effected through careful selection of the hydrolysis conditions. This ensures that the peptide hydrolysate will have the necessary properties to ensure constancy and mineral binding stability under conditions of changing pH. A recent study using potentiometric-based techniques analysed a range of commercial OTMs using a copper ionselective electrode to determine their in vitro stabilities over a pH range reflective of physiological conditions (Figure 1). In this work, samples were reconstituted and suspended prior to titration of the supernatants, with subsequent measurement of the percentage of bound copper over a pH range of 3 to 8. This confirmed that notable differences exist in the pH-

dependent stability of commercial OTMs, with the amount of bound copper varying considerably between samples. Furthermore, the data indicates that some OTMs have low or no capacity for stable mineral bonding at acidic pH, with obvious impacts on the bioefficacy of the products. These differences can be attributed to not only the type of bonding group used, but also to the production process used to generate the same. Ultimately, the stability of an OTM is of paramount importance to its bioavailability. During transit through the gastrointestinal (GI) tract and as the pH decreases or acidifies, all OTMs are subjected to physiological forces that can result in the bound mineral complex dissociating and releasing free mineral ions. There are a number of negative consequences to this pH-induced dissociation of OTMs. For instance, the charged free mineral ion can react with negatively charged plant components such as phytic acid, which may be present in the GI tract or, worse still, can form so-called “hydroxides” upon reaching the more alkaline environment in the intestine. This can lead to the phenomenon of pH-induced hydroxypolymerisation and result in precipitation of the mineral, and thus lead to a very significant reduction in bioavailability. Essentially, complexes or chelates with low stabilities will not deliver the mineral to the sites of absorption in the intestine and reduce the effectiveness of the product to that of the corresponding inorganic salt. We need to maximise the pHdependent stability of OTMs to increase mineral uptake in the intestine. In essence, the higher the stability of an OTM, the greater its bioavailability is likely to be. Premix and Feed Antagonisms Increasingly, the agonistic and antagonistic effects of feed components have come under scrutiny, with choice of components gaining increasing importance in diet formulation. The possibility for negative interactions occurring between individual components within premixes and feeds is high and often overlooked, as are the underlying effects at a cellular level following digestion and absorption of the mineral source. Recent studies have focused on assessing these potential antagonisms. The differential effects noted indicate that not all chelates are created equal; moreover, they all differ in terms of their stabilities, releasing mineral in a pH-dependent fashion based on the pH in the local micro-environment. This instability results in some chelates having a negative impact on premix and feed components. Data detailing the potential in vitro interaction between inorganic and organic chelated sources of iron, zinc and copper with three commercially available phytase preparations illustrates the potential for component-based antagonism. The study also investigated whether the degree of enzyme inhibition was dependent on the type of OTM used as a mineral source. The authors demonstrated that a highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration existed. Peptide-based chelates were consistently and significantly less inhibitory than the majority of the other sources (Figure 2).

Figure 1. Potentiometric titrations of commercial copper (II) chelates over a pH range of 3–8 30 International Animal Health Journal

The consequences that this mineral-induced inhibition of enzyme activity has for premix and feed formulation are tremendous, and go some way toward explaining the variation noted in supplementation response. It may well be that the trend toward superdosing of phytase activities in diets is an unintentional consequence of the negative interactions of premix components. Volume 5 Issue 2


RESEARCH AND DEVELOPMENT

Figure 4. Relative stability of vitamin E following exposure to organic (OTM) and inorganic (ITM) sources of Fe2+

Figure 2. Sigmoidal dose-response curves representing the effect of Fe2+ sources on P. lycii phytase activity

Additional research assessing the effect of chelate source and concentration on the efficacy of antioxidants such as BHT has established that commonly used antioxidants can be compromised by the use of inorganic minerals (Figure 3). The data further indicates that in some cases, chelates can also have a significant negative effect on antioxidant activity. Essentially, the use of weakly chelated minerals may result in a reduction in the efficacy of feed antioxidants such as BHT. The use of chelated minerals with high stability may result in a sparing effect on antioxidant activity.

Overall, it is clear that organic mineral chelates have far less potential for reactivity compared to inorganic mineral sources. However, organic trace mineral products with suboptimal stabilities can result in inhibition of enzyme activity, induce vitamin instability and result in reduced antioxidant function. These effects can have negative consequences on not only feed quality, but also on animal health and performance. Ultimately, diet formulators may well need to pay greater attention to their choice of mineral product to not only minimise the financial costs associated with any potential negative interactions, but also to maximise animal wellbeing. Conclusions Despite the confusing and often contradictory information that exists, mineral chelation is a relatively straightforward process governed by some fundamental chemistry basics. By carefully considering factors important in mineral chelation, one can begin to distinguish between the products on the basis of their biological stabilities and thus biological bioavailability. Ultimately, the stability of an OTM is of paramount importance to its bioavailability. During transit through the GI tract and as the pH decreases or acidifies, all OTMs are subjected to physiological forces that can result in the bound mineral complex dissociating and releasing free mineral ions. Organic trace minerals with optimised stability and bond strength will have far less potential for reactivity compared to inorganic sources. However, different forms of organic trace mineral will react differently and cause greater or less inhibition of enzyme activity, vitamin stability and antioxidant function, depending on source.

Figure 3. Relative activity of antioxidant (BHT) following exposure to organic (OTM) and inorganic (ITM) sources of Fe2+

In trace mineral premixes, oxidation-reduction reactions are the predominant cause of vitamin instability. The type of trace mineral will influence its reactivity, and, more critically, the form that the trace mineral is presented in has an even more significant role to play in influencing vitamin stability. Welldocumented studies examining vitamin stability in mineral premixes containing inorganic sulphates demonstrate that inorganic minerals are detrimental to the stability of vitamins. Depending on the individual product, however, the use of chelated minerals may not cause such a dramatic decrease. A recent study illustrates these effects nicely (Figure 4). The study, which examined vitamin E function following shortterm inclusion in mineral premixes containing either inorganic or organic trace minerals demonstrates the importance of carefully choosing premix components. A clear difference can be noted in terms of the pro-oxidant potential of some of the mineral sources, further indicating the contrasting stabilities, and thus reactivities, of individual products. www.animalhealthmedia.com

Ultimately, diet formulators may well need to pay greater attention to their choice of individual component to minimise the financial costs associated with negative interactions, which could be significant. REFERENCES 1. 2.

3.

4.

Byrne, L.A. (2010) Analytical assessment of peptide-metal interactions and subsequent stability. Ph.D. Thesis. Dept. of Biology, National University of Ireland, Maynooth, Ireland. Byrne, L.A., Hynes, M.J., Connolly, C.D. and Murphy, R.A. (2011) Analytical determination of apparent stability constants using a copper ion selective electrode. Journal of Inorganic Biochemistry, 105(12):1656-1661. Byrne, L.A., Jacques, K.A. and Murphy, R.A. (2018) Assessment of organic mineral chelate stability using computational and experimental approaches. Intl. Poult. Sci. Forum, Atlanta, GA, USA, 29-30 January, pg 90-91, 2018. Concarr, M.J., Lagoda, M., Byrne, L.A. and Murphy, R.A. (2016) The effect of mineral source and level on the activity of antioxidants. EAAP, 67th Annual Meeting, Belfast, UK 29 Aug - 2 Sep, 2016. International Animal Health Journal 31


RESEARCH AND DEVELOPMENT

5.

Connolly, C. and Murphy, R. (2016). The use of spectroscopy in the field of mineral analysis. Feed 2016, Geel, Belgium, October 19-20. 6. Dos Santos, T. (2010) Optimisation of phytase production by Aspergillus niger using solid state fermentation. M.Sc. Thesis. Dept. of Biology, National University of Ireland, Maynooth, Ireland. 7. Gaffney, M. (2017) Organic Trace Minerals: Getting the most out of phytase. WATT Pig International, May 2017. 8. Murphy R.A. (2015) OTM bond strength, relative stability. Feedstuffs, July 2015. 9. Murphy, R.A. (2016) The influence of minerals on the stability of premix and feed components. Feed Navigator. http://www.feednavigator.com/Product-innovations/ The-influence-of-minerals-on-the-stability-of-premixand-feed-components 10. Murphy, R.A. (2016) Mineral form's influence on enzyme supplementation response, http://www.wattagnet.com/ articles/25983-mineral-forms-influence-on-enzymesupplementation-response 11. Murphy, R.A. (2017) Organic trace minerals: enhanced stability ensures efficacy. Pig International, Sept., 14-18. 12. O’Rourke, R., Gaffney, M., Byrne, L. and Murphy, R. (2016) The effect of mineral source and level on the activity of exogenous phytase. 67th Annual Meeting of the European Federation of Animal Science (EAAP), Belfast, NI. 13. O’Rourke, R., Gaffney, M., Byrne, L., Jacques, K. and Murphy, 32 International Animal Health Journal

R. (2016) The impact of mineral source on the activity of exogenous phytase. Poultry Science Association, New Orleans, LA, USA. 14. Santos, T., Connolly, C. and Murphy, R. (2015) Trace element inhibition of phytase activity. Biological Trace Element Research. 163(1-2): 255-65.

Dr Richard Murphy Dr Richard Murphy is the research director at Alltech’s European Bioscience Centre in Dunboyne, Ireland. He received a bachelor’s degree in biochemistry in 1994 and a doctorate from the Department of Biochemistry at the National University of Ireland, Galway in 1999. Murphy maintains strong links with numerous academic institutions and is an adjunct professor on the faculty of science and health studies at Dublin City University. He also sits on the board of management of the National Institute for Cellular Biology at Dublin City University, where he is the external chairman. Email: rmurphy@alltech.com

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Rabies – Still A Disease to be Feared – but Vaccination is Winning the Battle in Many Areas of the Globe Rabies is a deadly disease, normally spread to humans from infected animals through a bite, scratch, or even a lick on broken skin. Without prompt treatment the disease is invariably fatal. This is why many countries have made great efforts to eliminate the disease within their borders but, despite this, rabies is still widespread across large areas of the globe. The only continent in the world totally free from rabies is Antarctica – and that’s because no mammals live there! The first written evidence appearing in about 2000BC suggests it to be the oldest known infectious zoonotic disease in the world. While ancient people did not know that it was caused by a virus, they were aware that it could be transmitted from dogs to humans. However, four millennia later it is still causing deaths. It is estimated that, globally, 60,000 people die from rabies every year. In India alone, considered to be the country with the most human cases – although it is not an officially notifiable disease there – it is thought there are 20,000 to 30,000 cases annually. In China and other Asian countries where autopsies are not carried out due to cultural considerations, diagnosis is often based on clinical symptoms. The number of cases, therefore, is based on ‘best guesses’ following dog-bite incidences in humans. Rabies is an acute infection of the central nervous system, caused by lyssaviruses. In humans, the incubation period can vary from under a week to over a year. Early symptoms can include malaise, headaches, fever and sensitive skin, followed by anxiety, confusion and the classic fear of water followed by paralysis, coma, and finally death. Not surprisingly, it is classed as one of the most horrendous diseases humans can contract. Both domestic and wild animals can carry the rabies virus and they may be able to transmit the disease before it is apparent that they are ill. It is estimated that, each year, 15 to 20 million people are vaccinated against rabies after being bitten by a potentially-rabid animal. Without post exposure prophylaxis (PEP), with life-saving vaccines hundreds of thousands more people would be dying from rabies every year. So it can be seen it is still a large-scale problem even 4000 years later. There are islands, both large and small, such as Australia, Great Britain and New Zealand, that are free from the rabies virus, but where countries are part of a larger land mass, problems remain as wildlife do not respect political borders! This has been the case in Europe, for instance. After the Second World War, fox rabies spread through Europe quite rapidly. Detected initially around the Kalingrad region of Russia, between Poland and Lithuania, it quickly spread across the breadth of Europe from western France and down to Greece. Given the seriousness of the disease, this ‘invasion’ of fox rabies stimulated research into the best way of vaccinating such a widespread wildlife population. Catching foxes by trapping them for individual vaccination would be difficult, time-consuming and costly. Immunising enough animals by this method would also be unlikely to be very successful in establishing a sufficient level of ‘herd immunity’. 34 International Animal Health Journal

As a result, research into oral vaccines for animals against rabies was instigated and in 1978 the first field trial took place in Switzerland. Oral vaccines had the big advantage that wildlife did not have to be handled and baits containing the vaccine could be distributed by a variety of methods – by hand, from vehicles and even by air – giving a large area of coverage in a relatively short period of time. IDT Biologika, based at Dessau-Rosslau, Germany, has been in the forefront of this research. In fact, the company helped develop a system of bait distribution known as SURVIS in the mid-1990s: a satellite and computer-aided automatic bait airdrop system allowing targeted deployment of baits from aircraft. SURVIS or SURVIS-derived systems have now become the gold standard in nearly every European call for tenders for combating rabies. The company has just celebrated the production of its 1000th batch of Fuchsoral vaccine, equivalent to 260 million doses in 19 countries around the world – a nearly unparalleled success story, not just for IDT but for rabies control as a whole. The product has made a crucial contribution to the elimination of fox-mediated rabies in Germany and other European countries. Therefore the company, which has been making biological products for nearly 100 years, can claim great expertise in this field. More than 95 per cent of people who die of rabies have been bitten by a rabid dog. In Europe today, very few people die of rabies due to developments in vaccine production and strict controls. Central to this was the vaccination of dogs and stringent control of free-roaming dogs. There have been cases where tourists have become infected while abroad, some deaths from bat-transmitted rabies and organ transplants, but these are rare. Apart from Turkey, since the end of the Second World War dog rabies has not been endemic in any European country. However, once control was achieved over rabies in dogs, attention needed to be focused on wildlife – in Europe particularly, foxes and later raccoon dogs were found to be the principal carriers. One of the problems was that in many countries enormous numbers of wild animals were found to be living in urban areas, posing a direct risk to humans and domestic animals, including dogs, cats and farm animals.

Foxes are one of the main reservoir species for rabies in Europe. Volume 5 Issue 2


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There is a tripartite agreement between the WHO (World Health Organization), OIE (World Organisation for Animal Health) and FAO (Food and Agriculture Organization of the United Nations) to eliminate dogmediated human rabies deaths by 2030. While this is focusing only on dog-related rabies that would mean reducing the number of human cases by more than 95 per cent – a tremendous goal! I feel that the EU has done a great job with the so-called first-generation oral rabies vaccines. They are still the most widely used in Europe because they are highly efficacious. But, of course, there are certain safety considerations. IDT Biologika, aware of this risk, therefore set about developing a new, third- generation oral rabies virus vaccine with a greatly enhanced safety profile. Although they have been very effective in the control of wildlife rabies, it is time to replace first-generation oral rabies virus vaccines with a safer but equally efficient strain which is now available. The third-generation strain does not pose residual oral pathogenicity for wild rodents as observed with firstgeneration vaccine strains. Advances in genetic engineering techniques have enabled the development of the third-generation oral rabies virus vaccines. IDT has just introduced a new live oral rabies vaccine – Rabitec – after ten years' development work and this is seen as a breakthrough because the high degree of attenuation by genetic modifications at multiple sites has greatly increased the levels of safety offered. The use of genetic engineering has decreased the virulence of the parental vaccine strain while maintaining its potency so it still produces a strong immune response. The vaccine strain has the highest level of attenuation currently available on the market for such types of vaccines. In contrast to vaccines that are injected directly into the animal’s body, this oral vaccine is released into the oral cavity when the animal picks up a blister pack. After chewing the bait and perforating the blister pack, the vaccine is released into the target animal’s mouth, where it enters the body through the mucous membranes and tonsils. Any virus that is swallowed is killed while passing through the stomach, so there is no danger of live virus excretion or contamination of the environment by shedding in the faeces, for instance. In the case of Europe, now largely free from foxmediated rabies, obtaining a vaccination belt with the aerial distribution of the vaccine is seen as an important way of safeguarding its borders. To prevent reinfection, the use of vaccines that cannot revert to virulence should be preferred.

Rabitec, a new safe, oral rabies vaccine is presented in a blister pack to immunise foxes and racoon dogs. 36 International Animal Health Journal

The baits can be distributed quickly and easily by air using the SURVIS system and a specially designed dispenser tube.

In addition, worldwide, there are important opportunities to protect endangered species of wildlife, such as the Ethiopian wolf. This is the most endangered canid species in the world, with only a couple of hundred animals in isolated populations in Ethiopia. These could become infected, resulting in entire pockets of populations being wiped out. Another example is the African wild dog – also endangered in certain regions. Oral vaccination makes great sense as capturing animals for direct injection would be highly problematic and probably dangerous. Different species of wildlife present problems in various parts of the world. In Europe it has been raccoon dogs and foxes; in the United States, coyotes, grey fox, raccoons and striped skunks are involved; while in the Caribbean islands, Africa and Asia, it can be different mongoose species. Depending upon the target animals for certain wildlife species, or for dogs, official approval has to be obtained in certain countries. Licensing procedures in Europe are strict and linked to certain species but approval in Europe counts heavily in other parts of the world, many of which have serious problems with rabies. IDT Biologika works with many governmental and nongovernmental organisations and international bodies offering help and advice gathered from more than 25 years of expertise in this very specialised sphere.

Verena Ziethlow Dr. med vet Verena Ziethlow qualified as a vet at the Free University Berlin, Germany and wrote her doctoral thesis in Bern, Switzerland, where her studies involved specific vaccine strains. She then spent time as a scientific assistant at that university before taking up a post in a general veterinary practice in Germany. Following a number of commercial appointments involving training, education and communication, she joined IDT Biologika, where she is now International Product Manager Specialities. Over the past two years, she has worked closely with the team that developed IDT’s new rabies vaccine. Email: verena.ziethlow@idt-biologika.de

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International Animal Health Journal 37


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Effect of amino acid and peptide complex AB070597 on renal function in dogs with chronic kidney disease The management of chronic kidney disease (CKD) in dogs remains a challenge to veterinary professionals and exerts financial burdens on their owners. Expanded knowledge and improvement in treatment would benefit all. The objective of the present study was to examine whether AB070597, a dietary-supplement compound of six amino acids and one peptide, can slow, halt, or reverse the decline of renal function in dogs with CKD. Five dogs with CKD were enrolled in a longitudinal study over 29 weeks. Animals received bi-daily oral doses of AB070597 from the point of enrolment to the end of the study, and blood samples were taken approximately every four weeks (for a total of 10 time intervals) to measure CKD-relevant biochemical parameters. Results The typical decline of renal function reported in dogs with CKD receiving standard palliative care, as measured by significant increases in blood-serum creatinine concentration (SCr), blood urea nitrogen (BUN), blood-serum phosphate concentration (PHOS), and lowered urine specific gravity (USG), was not observed. Median SCr, BUN, PHOS, and USG were stabilised and there was no significant change during any time interval. Conclusions These findings suggest that AB070597 may be a useful tool in stabilising or preventing the progression of CKD in some canines. The formulation warrants further study. Keywords: Chronic kidney disease, renal insufficiency, AB070597, dogs, dietary Introduction CKD is the most common kidney disease in dogs65. Prevalence, however, varies widely from 0.0566, 0.9, 0.5-1.5 to 3.74%68, depending on the source population and inclusion criteria. CKD is less prevalent in dogs than in cats and the age at onset varies due to a number of breed- related diseases which affect the canine kidney. The mean age of dogs diagnosed with CKD is seven years69. Irrespective of disease cause, it is widely accepted that most dogs diagnosed with CKD will progress inevitably to end stage disease and that BUN, SCr, PHOS will increase and USG will decrease significantly3,4,5. Many pathways lead to renal disease in humans, dogs, and other mammals. Mammalian renal architectures are similar, and even though there are some metabolic differences, it is possible to draw from the body of scientific information concerning mammalian renal disease, and with appropriate caution, apply those findings in an attempt to improve available treatment options for dogs with renal dysfunction. The most interesting findings in this context are related to disease progression monitoring via SCr, and data that suggests the role of reactive oxygen species (ROS) in renal cell damage. Certain lipoproteins induce the formation of reactive oxygen species (ROS) in glomeruli and in arteries. Antioxidants 38 International Animal Health Journal

may prevent the damaging effects of these lipoproteins24, 32, 34, 36, 39, 40-43, 47, 55 . Progressive injury results directly and indirectly from angiotensin II receptors via mediators of angiotensin-II-induced renal injury through transforming growth factor-beta, fibroblast growth factor-beta, tumor necrosis factor-alpha and plateletderived growth factor5, 6, 7, 11, 25, 31, 54. In addition, angiotensin increases oxidative stress, which causes a vasoconstrictor effect by increasing the catabolism of nitric oxide (NO)20, 26, 35, 36. Aldosterone is also a major contributor to the progression of CKD26. All of these compounds promote the progression of CKD by enhancing cell growth, fibrosis and inflammation, which destroy tubulointerstitial tissues and glomeruli14. Multiple approaches have been used to prevent the progression of renal disease, such as protein-restricted diets, the control of hypertension with angiotensin converting enzyme inhibitors, diet substitution of saturated fats with polyunsaturated fats, immunosuppressants such as mycophenolate mofetil, corticosteroids such as prednisone1, 36, 52, 57, 58 and morphogenic agents such a bone morphogenic protein-7 (BMP-7)64. None of these treatments hold promise for halting or reversing disease progression, with the exception of BMP-7. Previous studies have shown that BMP-7 can reverse epithelial to mesenchymal transition in murine models of acute renal failure and can promote renal tissue repair64. AB070597 is a cytoprotective agent that reduces damage to renal tubules and increases the glomerular filtration rate (GFR), stimulates gluconeogenesis and suppresses proteolysis in skeletal muscle, has strong antiinflammatory properties, is a precursor for NO production and increases BMP-7 (Archer J, unpublished observations). Methods and Subjects An open-enrolment, open-ended study format was selected so that dogs with confirmed CKD could be added periodically. Dogs were confirmed with CKD if 1) their SCr >/= 2.3 mg/dL, 2) their USG was less than 1.050, 3) their BUN was elevated near or above the high end of the normal range, 4) their PHOS was elevated near or above the high end of the normal range and 5) their clinical history included signs attributable to CKD (i.e. persistent azotemia, chronic polyuria and polydipsia, or small kidneys on abdominal palpitation). If one or more of these signs were present with increased SCr, dogs were considered for inclusion in the study. Dogs with suspected or verified conditions, such as pyelonephritis, uncontrolled hypothyroidism, acute renal failure, cancer, or other CKD-unrelated diseases were excluded. The criteria used to establish the cessation of progressive renal injury were 1) a halt in the rise of SCr, BUN and PHOS and a halt to the decline of USG, all for an extended period of time. No statistically significant deterioration in these values would signify no statistically significant disease progression. Dog owners were given informed consent forms for review and acceptance. The amino acids and peptide in AB070597 were purchased from Spectrum Chemical Company (Gardena, California). Over a 29-week period, five subjects ranging in weight from 3.2 to 18.5 Kg (mean = 7.8, median = 4.7, range = 3.2-18.5 Kg), all on non-protein-restricted commercial diets, received two 1000 mg / 4.5 Kg body weight oral daily doses of AB070597 as a dietary supplement. Doses were mixed with approximately 3 Volume 5 Issue 2


RESEARCH AND DEVELOPMENT millilitres of water and administered directly into each subject’s mouth, or the dose was sprinkled directly on a small amount of food and fed to the subject. AB070597 was readily accepted without rejection. SCr, BUN, PHOS and USG measurements were made for each subject at four-week intervals during the 29week study (mean = 22, median = 16, range = 16-38 weeks). Statistical Analysis Statistical comparisons were made by comparing measured parameters upon entering the study with measured parameters at the end of the study. Values were calculated with the Wilcoxon signed-rank test (VassarStats: Website for Statistical Computation, www.vasarstats.net). Differences were considered statistically significant at P ≤ 0.05 (two tailed). Results Each patient was monitored over the course of the study. Assessments were made for general body condition, weight change and ease of administration of AB070597. There were no owner complaints or concerns regarding administration of the supplement. General body condition, including coat, appearance and grooming habits, improved in each patient, and 60% gained weight, while body weight of the other 40% remained stable without further loss. There were no reports of gastrointestinal upset or diarrhoea. The medians of SCr, BUN, PHOS and urine USG showed no statistically significant change from start to finish Table 1. Discussion

exogenous and endogenous. It exerts a cytoprotective effect against anoxia, ischemia, heat, antibiotics, metals, and indomethacin-induced kidney damage. It also increases the GFR and thereby improves kidney function16, 17, 48. L-glutamine is the precursor of nucleotides and proteins and is the substrate for and stimulates gluconeogenesis in all organs and tissues. This amino acid regulates carbohydrate metabolism and suppresses proteolysis in skeletal muscles and stimulates protein synthesis, thereby counteracting the muscle-wasting effects caused by CKD8,21,23,37,38,46,56,61,62. L- glutamine is also an efficient ROS scavenger63. L-histidine concentrates in the brain at a level five times higher than in blood serum. It is readily available from food, but food intake is reduced in animals with CKD, thereby reducing the normal total cerebral amount. It also has anti-inflammatory properties and counteracts the damaging effects of ROS formed by those processes 15, 44. L-aspartic acid and L-glutamic acid, as sodium salts, are present in all tissues. The highest concentrations are located in the central nervous system. L-aspartic acid sodium is distributed throughout the central nervous system and spinal cord22. L-glutamic acid sodium is distributed in the caudate nucleus and cerebral cortex30. They act as efficient ROS scavengers and thereby protect the kidneys from ongoing damage caused by these ROS radicals63. L-carnosine increases the production of BMP-728. BMP7 induces mesenchymal-to-epithelial transition in renal fibroblasts and facilitates regeneration of injured kidney64.

Table 1. Changes in the measured parameters of the sample population over the study duration.

CKD is a progressive disease that results in significantly increased SCr, BUN, PHOS and lowered USG over time. Oral administration of AB070597 attenuated progression, such that there were no significant (ns) changes in those values. A possible hypothesis is that these results are due to biochemical effects of the individual components of AB070597.

Conclusion Dogs with CKD treated with AB070597, as a dietary supplement, did not experience increased SCr, BUN, PHOS, or a decrease in USG typically seen in dogs with CKD receiving standard palliative care. Treated animals had stable or reduced values for these parameters for up to 29 weeks. Results suggest that the oral supplement AB070597 may promote the maintenance of renal function and potentially attenuate or prevent progression CKD in dogs. Additional studies with more subjects and longer follow-ups are warranted, and future studies of AB070597 and its effect on renal function in dogs employing a much larger population are planned.

L-arginine protects renal tissue from the negative effects of renal ischemia 12, 50, 53, 59 and facilitates the disposal of protein and metabolic waste, and acts globally on muscle metabolism, vascular tone regulation and immune system function, and promotes the release of numerous hormones (glucocorticoids, growth hormone, prolactin, insulin, somatostatins, glucagons, catecholamines) through various pathways, whose disturbance can cause detrimental effects on renal function2, 3, 4, 18. L-arginine admini-stration also relieves a variety of pathological states, including kidney hypertrophy and glomerular thrombosis2, 10, 50, 53 . Glycine is produced in the mammalian body in amounts up to fifty times greater than those taken in daily by diet. Any decrease in its natural production is therefore of concern. The body uses this amino acid to form RNA, DNA porphyrin, bone collagen, glutathione, heme, bile, and salts and for the detoxification and conjugation of toxic products, both www.animalhealthmedia.com

International Animal Health Journal 39


RESEARCH AND DEVELOPMENT REFERENCES 1.

Barsotti G, Cupisti A, Gervasi GB et al. Effects of oral administration of heparan sulfate in the rat remnant kidney model. Nephron 1999; 81: 310–318. 2. Bode-Bager SM, Boger RH, Kienk S et al. Chronic dietary supplementation with L-arginine inhibits platelet aggregation and thromboxane-A synthesis in hypercholesterolemic rabbits in vivo. Cardiovasc Res 1998; 17: 756–764. 3. Boger RH, Bode-Boger SM, Kienke et al. Dietary L-arginine decrease myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis 1998; 136: 67–77. 4. Boger RH, Bode-Boger SM, Mugge A et al. Supplementation of hypercholesterolemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 1995; 117: 273– 284. 5. Cambese VM. Neurogenic factors and hypertension in renal disease. Kidney Int 2000; 57(Suppl 75): S-2–S-6. 6. Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal disease ablation model of chronic renal failure in the rat. Am J Kidney Dis 1995; 26: 861–865. 7. Campese VM, Romo MS, Levitan D, Massry SG. Mechanisms of autonomic nervous system dysfunction in uremia. Kidney Int 1981; 20: 246–253. 8. Cercosimo E, Williams P, Hoxworth B et al. Glutamine blocks lipolysis and ketogenesis of fasting. Am J Physiol 1989; 250: E248–E252. 9. Chunsen D, Junwei Y, Youhua L. Single injection of naked plasmid encoding hepatocyte growth factor prevents cell death and ameliorates acute renal failure in mice. J Am Soc Nephrol. 13: 411-422, 2002. 10. Clarkson P, Adams MR, Powe AJ et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adult. J Clin Invest 1996; 97: 1989– 1994. 11. Converce Rl, Jacobsen TN, Toto RD et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992; 327: 1912–1918. 12. Cooke JP, Singer AH, Tsao PS et al. Antitherogentic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992; 90: 1168–1172. 13. Covic A, Caruntu ID, Marian D, Volovat C, Ghiciuc C, Costin C, Florea L, Cotutiu C, Covic M. Prognosis and treatment of membranous glomerulonephritis-A 5 year prospective study. Rev Med Chir Soc Med Nat Lasi. 2002 Apr-Jun; 104(2): 63-74. 14. D’Amico G. Tubulointerstitium as predictor of progression of glomerular disease. Nephron 1999; 83: 289–295. 15. Decker EA, Ivanov V, Zhu BJ, Frei B. Inhibition of low-density lipoprotein oxidation by carnosine. J Agric Food Chem 2001; 49: 511–516. 16. Doolan PD, Harper HA, Hutchin ME, Alpen EL. The renal tubular response to amino acid loading. J Clin Invest 1956; 35: 888–896. 17. Doolan PD, Harper HA, Hutchin ME, Shreeve WW. Renal clearance of eighteen individual amino acids in human subjects. J Clin Invest 1955; 34: 1247–1255. 18. Drexler H, Zeiher AM, Meinzer K, Just H. Connection of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet 1991; 338: 1546–1550. 19. Eddy AA, Liu E, McCulloch L. Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades. Kidney Int 1998; 53: 1182–1189. 20. Fogo A. Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases. Kidney Int 2000; 57(Suppl 75): S-15–S-21. 40 International Animal Health Journal

21. Garrison R. Lysine, Tryprophan and other amino acids. Copyright 1982 by Keats Publishing, Inc. Printed in United States of America, 27 Pine Street. 22. Graham LT, Shank RP, Werman R, Aprison MH. Distribution of some synaptic transmitter suspects in cat spinal cord glutamic acid, aspartic acid, c-amiobutyric acid, glycine, and glutamine. J Neurochem 1967; 14: 465– 472. 23. Hankard RG, Darmaun D, Sager BK et al. Response of glutamine metabolism to exogenous glutamine in humans: Am J Physiol 1995: 269: E663–E670. 24. Hebert LA, Kusek JW, Greene T et al. Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group. Hypertension 1997; 30: 428–435. 25. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 1998; 339: 799–805. 26. Ibrahim HN, Rosenberg ME, Greene EL et al. Aldosterone is a major factor in the progression of renal disease. Kidney Int 1997; 52(Suppl 63): S-115–S-l19. 27. Ito K, Chen J, Vaughan ED Jr. et al. Dietary L-arginine supplementation improves the glomerular filtration rate and renal blood flow after 24 hours of unilateral ureteral obstruction in rats. J Urol, 2004; Feb; 171(2 Pt 1): 926-30. 28. Ito-Kato E, Suzuki N, Maeno M, Takada T, Tanabe N, Takayama T, Ito K, Otsuka K. 2004. Effect of carnosine on runt-related transcription factor-2/core binding factor alpha-1 and Sox9 expressions of human periodontal ligament cells. J Peridontal Res. 39(3):199-204. 29. Izzo ZI, Izzo MS, Sterns RH, Freeman RB. Sympathetic nervoussystem hyperactivity in maintenance hemodialysis patients. Trans Am Soc Artif Organs 1982; 28: 604–606. 30. Johnson JI, Aprison MH. The distribution of glutamate and free amino acids in thirteen specific regions of the rat central nervous system. Brain Res 1971; 26: 141–148. 31. Katholi RE, Whitlow Pl, Hageman GR, Woods T. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves. J Hypertension 1984; 2: 349–359. 32. Keane WF: The role of lipid in renal disease: future challenges. Kidney Int 2000; 57(Suppl 75): S-27–S-31. 33. Kehrer G, Blech M, Kallerhoff M, Langheinrich M et al. Contribution of amino acids in protective solutions to postischemic functional recovery of canine kidneys. Res Exp Med (Berl); 1989; 189(6): 381-96. 34. Klahr S, Levey AS, Berk GJ et al. The modification of diet in renal disease (MDRD) Study Group. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 1994; 330: 877–884. 35. Klahr S, Morrissey JJ. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int 2000; 57(Suppl 75): S-7–S-14. 36. Klahr S. Prevention of progression of nephropathy. Nephrol Dial Transplant 1997; 12(Suppl 2): 63–66. 37. Kreider M, Stumvoll M, Mever C et al. Steady state and non steady measurement of plasma glutamine turnover in humans. Am J Physiol 1997; 272: E621–E627. 38. Lavoinne A, Baquet A, Hue L. Stimulation of glucogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes. Biochem J 1987; 248: 429–437. 39. Lazarus JM, Bourcoignie JJ, Buckalew VM et al. For the Modification of Diet in Renal Disease Study Group. Achievement of safety of a low blood pressure goal in chronic renal disease in the Modification of Diet in Renal Disease Study. Hypertension 1997; 29: 641–650.595. 40. Levey A, Adler S, Caggiula A et al. For The MDRD Study Group. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 1996; 27: 652–663. 41. Levey AS, Greene T, Schluchter MD et al. The modification Volume 5 Issue 2


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RESEARCH AND DEVELOPMENT of diet in renal disease (MDRD) study and the diabetes control and complications trial (DCCT) research group: glomerular filtration rate measurement in clinical trials. J Am Soc Nephrol 1993; 3: 1159–1171. 42. Beck GJ, Beck RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluter MD, Williams GW. Modification of Diet in Renal Disease (MDRD) study group. Design and statistical issues of the Modification of Diet in Renal Disease Trial. Controlled Clin Trials 1991; 12: 566–586. 43. Greene T, Bourgoignie JJ, Habwe VQ, Kusec JW, Snetsellaar L, Soucie JM, Yamamoto M. Modification of Diet in Renal Disease (MDRD) study group. Baseline characteristics in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1993; 3: 1819– 1834 (original version); 1993; 4: 1221– 1236 (corrected version). 44. Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109–142. 45. Niaudel P, Habib R. Methylprednisolone pulse therapy in the treatment of severe forms of Schonlein-Henoch purpura nephritis. Pediatr Nephrol. 1998 Apr; 12(3): 238-43. 46. Perriello G, Nurjhan N, Stumvoll M et al. Regulation of gluconeogenesis by glutamine in normal postabsorptive humans. Am J Physiol 1997; 272: E437–E445. 47. Peterson J, Adler S, Burkart J et al. For The Modification of Diet in Renal Disease (MDRD) study group. Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Annal Intern Med 1995; 123: 754–762. 48. Pitts R. The effect of infusing glycine and of varying the dietary protein on renal hemodynamics in dog. Am J Physiol 1944; 142: 355–365. 49. Pozzi C, Del Vecchio L, Locatelli F. Immunosuppressive therapy in IgA glomerulonephritis with chronic renal failure; case study presentation and literature review. G Ital Nefrol. 2002 Sep-Oct, 19 (5): 528-8. 50. Reyes AA, Karl IE, Klahr S. Role of arginine in health and in renal diseases. Am J Physiol 1994; 267: F331-F346. 51. Romero F, Rodriguez-Iturbe B, Parra G et al. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999; 55: 945-955. 52. Romero F, Rodriguez-Iturbe B, Parra G et al. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999; 55: 945–955. 53. Rossitch E, Alexander E, Black PM, Cooke JP. L-arginine normalizes endothelium function in cerebral vessels from hypercholesterolemic rabbits. J Clin Invest 1991; 87: 1295–1299. 54. Rump LC, Amann K, Orth S, Ritz E. Sympathetic over-activity in renal disease: a window to understand progression and cardiovascular complications of uremia? Nephrol Dial Transplant 2000; 15: 1735–1738. 55. Schena FP. Management of patients with chronic kidney disease. Intern Emerg Med. 2011; Oct;6 Suppl 1:77-83. 56. Stumvoll M, Meyer C, Kreider M et al. Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans. Metabolism 1998; 47: 1227–1232. 57. Tarif N, Bakris Gl. Preservation of renal function: the spectrum of effects by calcium-channel blockers. Nephrol Dial Transplant 1997; 12: 2244–2250. 58. ter Wee PM, Donker AJ. Clinical strategies for arresting progression of renal disease. Kidney Int 1992; 42(Suppl 38): S-114–S-120. 59. Tsao PS, McEvoy LM, Drexler H et al. Enhanced endothelial adhesiveness is attenuated by L-arginine. Circulation 1994; 89: 23176–2182. 60. Tuttle K, Puhlman M, Cooney S, Short R. Effects of amino acids and glucagons on renal hemodynamics in type 1 diabetes. Am J Physiol Renal Physiol 2002; 282: F103-F112. 61. Varnier M, Leese GP, Thompson J, Rennie MJ. Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle. Am J Physiol 1995; 269: E309–E315. 42 International Animal Health Journal

62. Vu G, Thompson JR. The effect of glutamine on protein turnover in chick skeletal muscle in vitro. Biochem J 1990; 265: 593–598. 63. Yatzidis H. A new, superior, single and stable, amino acid and bicarbonate-based, glucose-free solution for peritoneal dialysis. Dialysis and Transplantation 2002; 31: 143– 150. 64. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9 (7): 964-8. 65. Polzin DJ, Osborne CA, Ross S. Chronic kidney disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, 6th ed. Stephen J. Ettinger, Edward C. Feldman, eds. St Louis, MO; Oxford: Elsevier Saunders; 2005:1756-1785. 66. Macdougall DF, Cook T, Steward AP et al. Canine chronic renal disease: prevalence and types of glomerulonephritis in the dog. Kidney Int 1986;29:1144-1151. 67. Brown SA. Management of chronic kidney disease. In: Elliott J, Grauer GF, eds. BSAVA Manual of Canine and Feline Nephrology and Urology, 2nd ed. Quedgeley: British Small Animal Veterinary Association; 2007:223-230. 68. Sosnar M. Retrospective study of renal failure in dogs and cats admitted to University of Veterinary and Pharmaceutical Sciences Brno during 1999-2001. Acta Veterinariqa Brno 2003;72:593-598. 69. Shaw HS, Ihle, SL. Small Animal Internal Medicine, Darrin Kiessling, ed., Lippincott Williams and Wilkins, Baltimore, Maryland, USA, 1997.

Dr. James Archer Dr. Jim Archer is Director of Research  for  Applied Research Laboratory  (ARL)  in Harbor City, California. In his capacity at  ARL, Dr. Archer investigated the  biochemical and physiochemical  mechanisms of chronic kidney disease (CKD) in mammals and formulated AB070597, a patented (USPTO 9,669,010) compound of amino acids and a peptide.  Prior to his work at  ARL, Dr. Archer conducted research for the United States Department of Defense and Space Optics General, Inc. Email: photoresearch@sbcglobal.net

Dr. Randy Aronson Dr. Randy Aronson a 1980 graduate of the University of Pennsylvania. He completed a rotating internship in 1981. He has been a practicing veterinarian for 35 years and with his wife started PAWS Veterinary Center in Tucson, AZ in 2008. Dr. Aronson utilizes an integrative approach to his diagnostics and therapies, this combines the best of Western or allopathic medicine with holistic modalities. He completed the International Veterinary Acupuncture Society’s acupuncture course, numerous Chinese herbal courses, and many traditional Chinese medicine and nutrition programs and is certified by the Canine Rehabilitation Institute to perform physical therapy in cats and dogs. Email: randy@pawstucson.com

Volume 5 Issue 2


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International Animal Health Journal 43

BVD HISTORY


RESEARCH AND DEVELOPMENT

The Importance of Cobalamin (Vitamin B12) in Dogs and Cats and Evidence for Oral Supplementation What is Cobalamin? Cobalamin is a water-soluble, cobalt-containing, B vitamin which plays an essential role in many physiological processes, including cellular metabolism, DNA synthesis, amino acid metabolism, fatty acid metabolism, nerve myelination and haematopoeisis.1 Cobalamin acts as a co-factor in many important enzymatic reactions involving single carbon transfer, where methyl groups are transferred onto or between biologically important compounds. Cats and dogs, like humans, are unable to synthesise cobalamin, hence they rely on dietary intake to maintain adequate tissue levels. Dietary sources of cobalamin include meat, milk, fish and eggs; deficiencies can therefore be seen with vegetarian and vegan diets. Some bacteria found in the gastrointestinal tract can produce cobalamin; however, since they are present only in the large intestines of dogs and cats, the cobalamin production occurs too distally to be of any benefit to the animal itself. Why is Cobalamin so Important? Given that cobalamin is an essential cofactor for enzyme reactions which occur in cells throughout the body, deficiency can affect the normal functioning of many cells and organs leading to vague and generalised clinical signs. These include anorexia, weight loss,2 failure to thrive,3,4 neuropathies,5,6 immunodeficiency and intestinal changes including villous atrophy and malabsorption.7 Many dogs and cats with hypocobalaminaemia will show signs of gastrointestinal (GI) disease, though it can be difficult to determine whether the GI disease was the cause of the low cobalamin or the result. Despite treatment of the underlying GI disease (e.g. with diet change, anti-inflammatories or immunosuppressants), gastrointestinal clinical signs may not resolve until cobalamin levels have been restored. It has been shown that up to 61% of cats8 and up to 55% of dogs9 with chronic enteropathies may have concurrent hypocobalaminaemia. Studies assessing prognostic factors in canine chronic enteropathies,10 canine exocrine pancreatic insufficiency (EPI),11 and canine lymphoma12 all identified hypocobalaminaemia as a negative prognostic indicator, associated with an increased risk of euthanasia. Serum Versus Intracellular Levels Hypocobalaminaemia is typically described by low serum cobalamin levels. However, there appears to be a discrepancy between serum cobalamin levels and intracellular levels; this has been demonstrated by assessing functional markers. Cobalamin deficiency leads to reduced activity of cobalamin-dependent enzymes. An example is methymalonyl-CoA mutase, which catalyses isomerisation of methylmalonyl-CoA to succinylCoA. In a cobalamin-deficient state there is a reduced activity of the methylmalonyl-coA mutase, causing an accumulation of methylmalonyl-CoA. This enters an alternative pathway, resulting in increased production of methylmalonic acid (MMA). Serum and urinary MMA can therefore be used as markers 44 International Animal Health Journal

of functional cellular levels of cobalamin, and are frequently elevated before serum cobalamin falls beneath the lower end of the reference range. In a human study, 50% of patients with elevated MMA (i.e functional deficiency of cobalamin) were found to have normal serum cobalamin levels.13 Cobalamin and MMA have found to be negatively correlated in both dogs14 and cats;15 in both studies there were animals with elevated MMA, despite normal serum cobalamin readings. For this reason it is advised to supplement cobalamin when serum levels reach the low end of the reference (<400ng/L).16 In order to understand how cobalamin deficiency may arise, we first need to look at the normal absorption pathway. Dietary cobalamin is absorbed via a complex receptor-mediated pathway as shown in Figure 1. Pepsinogens and gastric acid liberate cobalamin from dietary protein in the stomach (2), where it then binds to salivary and gastric R-proteins (3). The R-protein-cobalamin complex enters the duodenum and is broken down by pancreatic proteases (4). Cobalamin then binds to intrinsic factor (IF)(5). All feline IF17 and 90% of canine IF is pancreatic in origin, with the remaining 10% of canine IF produced by the gastric mucosa.18 IF-cobalamin complexes travel through the small intestine to the ileum where uptake of cobalamin bound to IF occurs via receptor-mediated endocytosis(6).19 Cobalamin is then transported to the tissues bound to transcobalamin II in the bloodstream. Since cobalamin is a water-soluble vitamin, any excess is excreted in the urine. Cobalamin Storage Cobalamin, while found in all tissues, is primarily stored in the liver. Hepatic cobalamin stores in humans are sufficient to prevent deficiency for months to years, with a half-life of approximately one year. The half-life of cobalamin in dogs is two months.20 While this is substantially less than that in humans, in both species, excluding congenital abnormalities, hypocobalaminaemia tends to follow chronic disease. It is worth noting that in cats, hypocobalaminaemia may become established earlier in disease states; one study found the halflife of parenteral cobalamin to be 12.75 days in healthy cats, reducing to five days in cats with inflammatory bowel disease (IBD) due to reduced enterohepatic circulation.8 When to Consider a Cobalamin Deficiency Given the complex absorption pathway, there are many ways in which a cobalamin deficiency may arise. 1) Inadequate dietary intake. Commercial, complete pet foods should provide adequate levels of cobalamin; however, home-prepared diets could be deficient. While vegetarian/vegan diets are not advised in dogs and are contraindicated in cats, some owners may insist upon feeding them; these patients should be closely monitored for hypocobalaminaemia. 2) Exocrine pancreatic insufficiency (EPI) can cause hypocobalaminaemia in three ways. a. There is reduced production of pancreatic proteases, hence cleavage of R-protein from the cobalamin in the duodenum is reduced. Volume 5 Issue 2


RESEARCH AND DEVELOPMENT b. There is reduced production of IF from the pancreas resulting in less IF available to bind to cobalamin and transport it to the ileum; ileal absorption is subsequently reduced as it relies on the cobalamin being bound to IF.21

7) Renal disease. Receptor-mediated cobalamin reabsorption occurs in the proximal tubules, hence damage or reduction in number of the proximal tubules may result in decreased reabsorption of cobalamin which has been filtered in the glomerulus.32

c. Undigested foods, altered pH and abnormal enzyme production, hence abnormal digestion, can result in a secondary dysbiosis or small intestinal bacterial overgrowth (SIBO), where the number of cobalaminutilising bacteria will often increase.

8) Familial cobalamin deficiency has been reported in Chinese shar peis,33 giant schnauzers,34 Border collies35 and beagles.36

3) Intestinal dysbiosis. Intestinal dysbiosis can be defined as an alteration in the composition and/or richness (i.e. the number of unique bacterial species) of the intestinal microbiota.22 Microbial dysbiosis can develop following any disruption to the homeostatic mechanisms which regulate the enteric microbiota; it is most commonly seen following reduced gastric acid production, intestinal dysmotility23 and EPI, as explained above. A murine model of SIBO demonstrated competitive uptake of cobalamin by bacteria, especially gram-negative anaerobes.24 Luminal cobalamin available for host absorption is therefore reduced. 4) Chronic enteropathies will often result in hypocobalaminaemia. Hypocobalaminaemia was identified in up to 61% of cats8 and 7â&#x20AC;&#x201C;55% of dogs25-29 with chronic enteropathies. One study detected cobalamin <400ng/L in 81% of dogs with idiopathic IBD.30 Gastrointestinal disease commonly features damage to the ileum and the receptors required for cobalamin-IF complex uptake. 5) Liver disease can result in leakage of stored vitamin B12 from hepatocytes. While this may cause an initial increase in serum cobalamin, more chronic disease can produce severe tissue deficits causing metabolic dysfunction.31 6) Polyuria-polydipsia (PUPD), seen in many disease processes, may cause increased washout of cobalamin in the urine and hence hypocobalaminaemia.

Evidence for the Novel Approach of Using Oral Supplementation in the Management of Hypocobalaminaemia Historically, cobalamin supplementation was always provided via the parenteral route using the protocol shown in Figure 2. The aim of this method was to bypass the IF-dependent, receptor-mediated uptake in the ileum. Vitamin B12 injections can be painful and require multiple trips to the vets, which can be time-consuming and expensive for the owner, often resulting in poor owner compliance. In a study of 135 dogs with EPI and concurrent hypocobalaminaemia, only 3% were given cobalamin injections.37

Figure 2

As described above, normal cobalamin uptake from the diet is reliant on IF. However, it has also been shown in people by radiolabelling cobalamin, that 1.2% of oral cobalamin can be absorbed by passive diffusion across the entire length of the intestine, independent of IF.38 1% of the cobalamin naturally present in the diet would be insufficient to meet daily requirements; however, this can be overcome by hypersupplementation, as demonstrated in a murine model in 1960.39 Also shown in Figure 1, image (7).

Figure 1. The normal absorption pathway of dietary cobalamin. www.animalhealthmedia.com

International Animal Health Journal 45


RESEARCH AND DEVELOPMENT The use of oral cobalamin supplementation to correct hypocobalaminaemia is well established in people. A Cochrane review in 2018 found evidence to suggest oral and intramuscular vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels.40 Oral cobalamin has been shown to be effective at normalising serum cobalamin, even in humans with pernicious anaemia, where IF production is absent.41 Increasing interest in the use of oral cobalamin in dogs and cats over the past couple of years has led to the formation of an oral dosing protocol by Texas A&M University16 (Figure 3).

Figure 5. Cobalamin levels at day 0, day 28 and day 90 when supplemented orally (PO) and parenterally (PE). (Graph from Toresson et al Comparison of efficacy of oral and parenteral cobalamin supplementation in normalising low cobalamin concentrations in dogs: A randomised controlled study. 2018)44

cobalamin levels in hypocobalaminaemic dogs and cats with chronic enteropathies. REFERENCES 1. 2.

Figure 3

Two retrospective studies looking at dogs42 and cats43 with chronic enteropathies and concurrent hypocobalaminaemia demonstrated the efficacy of oral cobalamin at normalising serum cobalamin levels. All dogs and cats in these studies returned to normocobalaminaemia (Figure 4).

3. 4.

5.

6.

7. Figure 4. Cobalamin levels in 51 dogs and 25 cats with chronic enteropathies pre and post oral cobalamin supplementation. (Graphs from Toresson et al. Oral Cobalamin Supplementation in Dogs with Chronic Enteropathies and Hypocobalaminemia. 201642 and Toresson et al Oral cobalamin supplementation in cats with hypocobalaminaemia: a retrospective study. 2017) 43)

Earlier this year, a prospective, randomised controlled study was published comparing the use of oral and parenteral cobalamin supplementation in 49 dogs with chronic enteropathies and concurrent hypocobalaminaemia. It concluded that both methods were effective at normalising serum cobalamin in these patients within 28 days. Furthermore, it showed that the increase in cobalamin was significantly greater in the oral group than in the parenteral group at 90 days.44 In a study of ten dogs with EPI and hypocobalaminaemia, oral cobalamin supplementation normalised the serum cobalamin levels in all cases.45 While the number of patients in this study is limited, and so the data must be interpreted cautiously, the findings suggest that oral cobalamin appears effective at treating hypocobalaminaemia occurring secondary to EPI. Conclusion Cobalamin is essential for the normal functioning of the body; deficiency can cause a variety of symptoms of varying severity. Its complex absorption pathway means deficiency can become established via several routes. While traditionally cobalamin supplementation was given parenterally, evidence to date suggests that there is an IF-independent pathway for cobalamin absorption in dogs and cats. Hypersupplementation with oral cobalamin appears effective at normalising serum 46 International Animal Health Journal

8.

9.

10. 11.

12.

13. 14. 15.

16.

Langan RC, Zawistoski KJ. Update on Vitamin B12 deficiency. Am Fam Physician 2011; 83(12): 1425-1430. Reed N, Gunn-Moore D, Simpson K. Cobalamin, folate and inorganic phosphate abnormalities in ill cats. J feline med surg 2007; 9: 278-288. Fordyce HH, Callan MB, Giger U. Persistent cobalamin deficiency causing failure to thrive in a juvenile beagle. J Small Anim Pract 2000; 41(9): 407-410. Gold AJ, Scott MA, Fyfe JC. Failure to thrive and lifethreatening complications due to inherited selective cobalamin malabsorption effectively managed in a juvenile Australian shepherd dog. Can Vet J. 2015; 56(10): 1029-1034. Battersby IA, Giger U, Hall EJ. Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie. J Small Anim Pract 2005; 46(7): 339-344. Salvadori C, Cantile C, De Ambrogi G, Arispici M. Degenerative myelopathy associated with cobalamin deficiency in a cat. J Vet Med A Physiol Pathol Clin Med 2003; 50(6): 292-296. Arvanitakis C. Functional and morphological abnormalities of the small intestinal mucosa in pernicious anemia--a prospective study. Acta Hepatogastroenterol (Stuttg). 1978; 25(4): 313-318. Simpson KW, Fyfe J, Cornetta A et al. Subnormal Concentrations of Serum Cobalamin (Vitamin B12) in Cats with Gastrointestinal Disease. J Vet Intern Med 2001; 15:26â&#x20AC;&#x201C; 32. German AJ, Day MJ, Ruaux CG, Steiner JM, Williams DA, Hall EJ. Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs. J Vet Intern Med 2003; 17(1): 33-43. Allenspach K, Wielan B, GrĂśne B, Gaschen F. Chronic Enteropathies in Dogs: Evaluation of Risk Factors for Negative outcomes. J Vet Intern Med 2007; 21: 700-708. Batchelor DJ, Noble PJ, Taylor RH, Cripps PJ, German AJ. Prognostic factors in canine exocrine pancreatic insufficiency: prolonged survival is likely if clinical remission is achieved. J Vet Intern Med 2007; 21(1): 54-60. Cook AK, Wright ZM, Suchodolski JS, Brown R, Steiner JM. Prevalance and prognostic impact of hypocobalaminaemia in dogs with lymphoma. J Am Vet Med Assoc 2009; 235(12): 1437-1441. Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and new. Br J Haematol 1997; 97: 695â&#x20AC;&#x201C;700. Berghoff N, Suchodolski JS, Steiner JM. Association between serum cobalamin and methylmalonic acid concentrations in dogs. Vet J 2012; 191(3): 306-311. Worhunsky P, Toulza O, Rishniw M et al. The relationship of serum cobalamin to methylmalonic acid concentrations and clinical variables in cats. J Vet Intern Med 2013; 27(5): 1056-1063. Steiner JM. Cobalamin: Diagnostic use and therapeutic Volume 5 Issue 2


RESEARCH AND DEVELOPMENT

considerations. http://vetmed.tamu.edu/gilab/research/ cobalamin-information (accessed May 18, 2018). 17. Fyfe JC. Feline intrinsic factor (IF) is pancreatic in origin and mediates ileal cobalamin (CBL) absorption. J Vet Intern Med 1993; 7: 133. 18. Batt RM, Horadagoda NU, McLean L, Morton DB, Simpson KW. Identification and characterization of a pancreatic intrinsic factor in the dog. Am J Physiol 1989; 256(3,1): 517523. 19. Batt RM, Horadagoda NU. Gastric and pancreatic intrinsic factor-mediated absorption of cobalamin in the dog. Am J Physiol 1989; 257(3,1): 344-349. 20. Luhby AL, Cooperman JM, Donnenfeld AM. Placental transfer and biological half-life of radioactive vitamin B12 in the dog. Proc Soc Exp Biol Med 1959; 100(2): 214-217. 21. Simpson K, Morton D, Batt R. Effect of exocrine pancreatic insufficiency on cobalamin absorption in dogs. Am J Vet Res 1989; 50: 1233–1236. 22. Suchodolski JS. Diagnosis and interpretation of intestinal dysbiosis in dogs and cats. Vet J 2016; 215: 30-37. 23. Dukowicz AC, Lacy BE, Levine GM. Small intestinal bacterial overgrowth: A comprehensive review. Gastroenterol Hepatol 2007; 3: 112-122. 24. Welkos SL, Toskes PP, Baer H. Importance of anaerobic bacteria in the cobalamin malabsorption of the experimental rat blind loop syndrome. Gastroenterology 1981; 80(2): 313-320. 25. Allenspach K, Wieland B, Grone A, et al. Chronic enteropathies in dogs: evaluation of risk factors for negative outcome. J Vet Intern Med 2007; 21:700-708. 26. Berghoff N, Suchodolski JS, Steiner JM. Association between serum cobalamin and methylmalonic acid concentrations in dogs. Vet J 2012; 191(3):306-311. 27. Craven M, Simpson JW, Ridyard AE, Chandler ML. Canine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995-2002). J Small Anim Pract 2004; 45(7): 336-342. 28. German AJ, Day MJ, Ruaux CG, Steiner JM, Williams DA, Hall EJ. Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs. J Vet Intern Med 2003; 17(1): 33-43. 29. Kathrani A, Steiner JM, Suchodolski J, et al. Elevated canine pancreatic lipase immunoreactivity concentration in dogs with inflammatory bowel disease is associated with a negative outcome. J Small Anim Pract 2009. 50: 126-132. 30. Heilmann RM, Grellet A, Allenspach K et al. Association between fecal S100A12 concentration and histologic, endoscopic, and clinical disease severity in dogs with idiopathic inflammatory bowel disease. Vet Immunol Immunopathol 2014; 158(3-4): 156-166. 31. Baker H, Leevy CB, DeAngelis B, Frank O, Baker ER. Cobalamin www.animalhealthmedia.com

(vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease. J Am Coll Nutr 1998; 17(3): 235-238. 32. Nielsen R, Sørensen BS, Birn H, Christensen EI, Nexø E. Transcellular transport of vitamin B12 in LLC-PK1 renal proximal tubule cells. J Am Soc Nephrol. 2001; 12(6): 10991106. 33. Bishop MA, Xenoulis PG, Berghoff N, Grützner N, Suchodolski JS, Steiner JM. Partial characterization of cobalamin deficiency in Chinese Shar Peis. Vet J 2012; 191(1): 41-45. 34. Fyfe JC, Giger U, Hall CA, Jezyk PF, Klumpp SA, Levine JS, Patterson DF. Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs. Pediatr Res 1991; 29(1): 24-31. 35. Lutz S, Sewell AC, Reusch CE, Kook PH. Clinical and laboratory findings in border collies with presumed hereditary juvenile cobalamin deficiency. J Am Anim Hosp Assoc 2013; 49(3): 197-203. 36. Fordyce HH, Callan MB, Giger U. Persistent cobalamin deficiency causing failure to thrive in a juvenile beagle. J Small Anim Pract 2000; 41(9):407-410. 37. Batchelor DJ, Noble PJ, Taylor RH, Cripps PJ, German AJ. Prognostic factors in canine exocrine pancreatic insufficiency: prolonged survival is likely if clinical remission is achieved. J Vet Intern Med 2007; 21(1): 54-60. 38. Berlin H, Berline R, Brante G. Oral treatment of pernicious anaemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968; 184: 247-258. 39. Okuda K. Vitamin B12 absorption in rats studied by a loop technique. Am J Physiol 1960; 199: 84-90 40. Wang H, Li L, Qin L, Song Y, Vidal-Alaball J, Liu T. Oral vitamin B12 compared with intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev 2018; 3 41. Chan CQ, Low LL, Lee KH. Oral Vitamin B12 Replacement for the Treatment of Pernicious Anemia. Front Med (Lausanne) 2016; 3:38. 42. Toresson L, Steiner JM, Suchodolski JS, Spillmann T. Oral Cobalamin Supplementation in Dogs with Chronic Enteropathies and Hypocobalaminemia. J Vet Intern Med 2016; 30(1): 101-107. 43. Toresson L, Steiner JM, Olmedal G, Larsen M, Suchodolski JS, Spillmann T. Oral cobalamin supplementation in cats with hypocobalaminaemia: a retrospective study. J Feline Med Surg 2017; 19(12):1302-1306 44. Toresson L, Steiner JM, Razdan P et al. Comparison of efficacy of oral and parenteral cobalamin supplementation in normalising low cobalamin concentrations in dogs: A randomised controlled study. Vet J 2018; 232: 27-32. 45. Toresson L, Steiner JM, Suchodolski JS, Spillmann T. Oral Cobalamin Supplementation in Dogs with Exocrine Pancreatic Insuffficiency. Abstract. ACVIM Forum 2017, Washington USA

Gemma Ellse Gemma Ellse MA VetMB MRCVS qualified from the University of Cambridge in 2013. After several years working in small animal general practice she joined Protexin Veterinary as a Veterinary Technical Advisor. Since joining the company she has lectured veterinary surgeons and nurses on the importance of cobalamin and the evidence behind oral supplementation. She is particularly interested in the role that nutraceuticals can play in the management of many diseases. Email: gemma.ellse@protexin.com

International Animal Health Journal 47


TECHNOLOGY

Why Good Tablet Design is Important in Animal Medicine and How to Achieve it Just as good tablet design is extremely important in the manufacture of pharmaceuticals for humans, the same applies for animal dosage forms. Tablets are used to deliver drugs in an effective and safe manner, and although less dominant in veterinary medicine, tablets or boluses are still a significant method to administer medication. Getting tablet design correct has an impact upon anti-counterfeiting, tooling strength, tablet coating, durability and functionality. It also helps to avoid downstream manufacturing problems such as tablet sticking, picking, lamination, capping and premature tooling failures. It is essential to consider these at the beginning of the design process, ensuring a problem-free, high-quality end product. Several elements need to be considered when designing tablets for animals; here we will look at the most important. Tablet Shape and Profile The first thing to consider is the tablet shape and optimum tablet profile. There are two basic tablet shapes, round and non-round; however, the complexity of non-round shapes can be very varied and require specialised tool manufacturing capability. Boluses, which are commonly used for large animals are cylindrical shaped to prevent choking. Due to their size (typically 3 to 16 g) it is important to get the shape correct. ‘Bolus formulation poses challenges because of the high drug to-excipient ratio. Less room is left for diluent, binders, and other adjuvant needed to overcome objectionable features of the drug or to facilitate bolus manufacture.’ These higher numbers of active ingredients in animal formulations bring challenges related to particle size, flow, compressibility, moisture sensitivity, ingredient interaction, content uniformity and quality control (QC) testing. For example, some active ingredients may be available in granular form, while some may be available only in fine powder form. Because of this, the ingredient blend may have many different particle sizes and ingredients with a variety of characteristics. This variation demands the shape and profile to be correct during manufacture. Once the base shape has been decided, tablet size must be determined. Consideration should be given to the type of press available for tablet manufacture as this can limit the size of the tablet. Next follows selection of the tablet. The type of profile required is influenced by several factors: the granule, embossing requirements, coating process, packaging and the company’s branding. Thought should also be given to the volume of the tablet and if it will be coated. Successful coating is dependent on tablet profile. Coated tablets, whether film- or sugarcoated, present challenges for the tablet designer. The 48 International Animal Health Journal

complexity of the coating process is vast. Many of the variables are within the manufacturer’s control but expert tablet design can help eliminate some potential problems. Coated tablets are a popular choice in animal medicine. Administering tablets to animals is not a guaranteed process due to the uncertainty of the tablet being swallowed. Many animals also chew the tablet, exposing the disagreeable taste of the drug. For this reason, flavours or sweeteners are combined or a coating is used. ‘Tablets can be coated to differentiate the product by colour, to help mitigate offensive tasting compounds, or to prevent dusting in the bottle.’ Typically, the centre of a tablet is lower in hardness, so during the coating process core erosion may take place. This is when the tablet comes into contact with the coating pan and other tablets, causing wear. This vulnerability, caused by mechanical stress during coating, can be reduced by avoiding very deep concaves and ensuring a robust design. For film-coated tablets, double radius profiles are the preferred choice. For shallow tablets with hard, sharp edges, the coating process will damage the exposed edge of the tablet, resulting in chipped edges and sometimes cracks. Therefore, flat and shallow tablet profiles should be avoided. Double radius designs ensure a strong tablet edge and a balanced profile, which will roll in the coating pan. Another benefit of the double radius design is that it can accommodate most marking and branding requirements, because it increases the usable surface area available for this. Poor marking and branding design on the tablet can lead to bridging (where the coating collects in the detail on the face of the tablet because the coating does not fully follow the contours of the marking on the tablet core, but bridges over leaving a void under the coating) and infilling (when too much coating material has filled the detail, making it indistinct) during film-coating. Possible causes for this can include: Inadequate adhesion of the film coating – the coating supplier should be consulted to improve the adhesion characteristics of the coating. Inappropriate marking design where the angle may be too acute or too deep (bridging) – The marking should be redesigned in consultation with the tooling supplier. It can also be due to the stroke or section of the embossing being too wide or too shallow (infilling). Inappropriate coating procedure, e.g. spray rate, drying time, etc. – the coating supplier should be consulted. Another problem is twinning – tablets sticking together during coating. This is normally caused by the flat surfaces of the tablets coming into contact and adhering to each other. To avoid this, a slightly curved surface can be Volume 5 Issue 2


TECHNOLOGY applied, which reduces the contact area and eliminates the potential for twinning. Tablet Breakability Good tablet design will enable the tablet to be broken easily and accurately, ensuring that when t is broken, the required tolerance for dosage is achieved. Uneven breaking of a tablet may result in significant fluctuations in the administered dose. The degree of inaccuracy may be associated with breakline design, tablet hardness, and/ or formulation.

Figure 2 shows a stress and fatigue analysis of a punch tip using finite element analysis, or FEA. FEA is a software-based numerical technique for calculating the strength and behaviour of engineering structures. It is used to calculate deflection, stress and strain to determine fatigue limits of both material and design.

Figure 1 Tablet Breaklines

The following factors should be considered when selecting a breakline: Accuracy of breakage, which is important for equal dosage.

to apply a land as it may not be visually acceptable on the finished tablet. Lands that are applied incorrectly, either unevenly or made too large, can present a range of issues, including: flashing or lamination during compression; chipping of the land during take-off, or build-up of coating on the edge of the tablet which eventually will chip. The answer is to always include a blended land as, when applied correctly, it will optimise tablet and tooling strength and performance.

Holding of the tablet and ease of breakage. This relates to tablet size and hardness. Inclusion of other detail, such as a logo, and its influence on the breakline. Product identification must be maintained to ensure brand integrity when the tablet is divided. Robustness of the tablet during compression, coating and packing. Because the tabletâ&#x20AC;&#x2122;s physical qualities are changed by adding a breakline, it may become weaker. The breakline should penetrate into the tablet whilst maintaining an optimised radius and angle. A larger radius usually makes the breakline less effective. Where a breakline is functional and present on both sides of the tablet, alignment of the breakline on the upper and lower punch tips is critical and requires the turret to have a lower key facility. Also, pay attention to breaklines that stand above the punch tip edge. Upper and lower punches must be set correctly for effective tablet ejection and take-off. If not set correctly, damage can occur to the breakline on the punch tip, resulting in catastrophic failure and damage to the tooling and the tablet press. It can also cause severe chipping of the tablet on ejection. Tooling Performance Tablets are becoming more complex in both shape and profile, increasing the demand for tooling strength, durability and overall performance. This has to be a major consideration when designing tablets for veterinary medicine. One of the most important features of any tablet design is the blended land. Often, tablet manufacturers elect not www.animalhealthmedia.com

Figure 3 â&#x20AC;&#x201C; Blended land

Figure 3 shows the application of a blended land to a punch tip. The correct method of applying the land is to ensure that the flat area on the tip edge is maintained, whilst blending the intersection between the profile and the flat. This is achieved by applying a radius to the finished punch tip. A correctly selected and applied blended land provides benefits to handling, loading, setting, tooling strength, the visual appearance of the tablet and ultimately, your brand. Tablet Branding When considering the visual appearance of the tablet, it is important to think about the type of font and logos used for branding. Typefaces and designs must take into account practicality of tablet manufacture. Caution is required during the design process when applying branding to your tablet. Failure to consult with an expert tablet design team could result in a product that looks good on paper but is not practical to produce. For tablets with a logo, the design and placement are very important. The tablet designer should always seek to maximise the face area to avoid picking and lack of distinction. International Animal Health Journal 49


TECHNOLOGY

Figure 6

Figure 4 shows a good example of the importance of spacing on logos. The top example clearly shows the embossing within the safe zone for this particular tablet shape. The bottom example shows embossing that goes beyond the safe zone and, on the side view, you can see how the embossing protrudes.

Occasionally, when there is a need to exceed the safe zone, the best practice is to ensure the detail is spaced far enough away from the edge of the tip. As a general guide, the embossing should sit below the landed edge of the punch tip. If this guide is not followed then the embossing will be unprotected and prone to damage, causing further downstream problems during the tabletting process. The correct font style is also very important to avoid tabletting problems such as ‘picking’. Picking is compressed granule that has adhered to the detail on the punch face, resulting in ‘picking out’ of parts from the tablet face. To reduce picking, the best practice should be to design font styles that have large open counters and no sharp corners, which could act as a trap for granule. Selection of the right font style can also help to avoid coating problems, tooling failures and lack of distinction. When the font has been chosen, it is important to ensure clarity of definition. The profile of the embossing is equally important to reduce picking, and ensure good tablet coating and tooling strength. The best practice is for the stroke angle to be between 70 and 80 degrees. The stroke depth should be 50% of the width and the stroke break radius blends 30% of the stroke depth (Fig 5).

Anti-counterfeiting Techniques As counterfeiters become more technologically advanced, basic tablet designs are more easily reproduced. There are many anti-counterfeiting technologies available to manufacturers. Within tablet manufacture, this is usually done by applying anti-counterfeiting features directly to the tablet. An expert tablet designer can employ techniques to make this more difficult. These are not always visible to the naked eye but ensure that a branded tablet can be identified as an original. Several anti-counterfeiting techniques can be used on each product, to help reduce the risk. For example, altering the thickness of the embossing in places, changing the angle of the lettering, or simply having the logo on different inclines. Although hard to see with the naked eye, expert tablet designers can see the difference between the original and the counterfeit. Conclusion Good tablet design is imperative, whether it is for human or animal medicine, and it is something that should be strongly considered. It is important to consult with an expert tablet designer as early on in the process as possible, who can ensure that designs of tablet or boluses are not only unique and visually appealing, but are also robust and producible in a rigorous tablet manufacturing environment. By making just a few simple changes to a design it can stop future problems, from picking and sticking to counterfeit issues. The importance of design should not be underestimated. Punches and dies are the most critical interface with your end product, the tablet, and together everything should be measured and taken into account before tablet production. REFERENCES 1. 2. 3. 4. 5.

Figure 5

Another technique used to minimise picking is a reduced counter. The counters, which are sometimes referred to as islands, are very vulnerable to picking and granule can easily get trapped in these areas on the punch tip face. The counter is modified to increase the surface area by reducing stroke depth, which will minimise the tendency for the product to pick. ‘Sticking’ of course is another major issue in the design and manufacture of tablets. Sticking differs from picking in that it is granule adherence to the punch tip face, rather than in and around the embossing. This is not normally associated with design, however when picking occurs on a tablet this in turn can result in sticking on the punch tip face by providing a key to which further granule will adhere. 50 International Animal Health Journal

Veterinary Pharmaceutical Dosage Forms: A Technical Note - Ramteke KH*, Joshi SA, Dighe PA and Kharat AR Pharmaguideline.com J Marriott & R Nation, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Melbourne. Protecting your Brand with Anti-Counterfeiting Solution – John Mack Eurostandard Educational Collection, 2010 – I Holland Ltd

Alex Bunting Alex manages the marketing team at I Holland, is a graduate of English and member of the Institute of Digital Marketing. He joined I Holland in April 2008 having spent the previous years working in Environmental Science. Alex was instrumental in the design of the 2010 edition of the widely adopted Eurostandard, educational animations and hosts I Holland’s extensive webinar program. Email: alex.bunting@iholland.co.uk

Volume 5 Issue 2


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International Animal Health Journal 51


TECHNOLOGY

A Comparison of DIY and Custom EDC Solutions: Which is the Best for Your Study? Reducing costs while maximising efficiency is often a driving force in determining electronic data capture solutions (EDC) for clinical research. A self-customised EDC product becomes a more attractive option over a custom-built solution when it comes to minimising cost and working within a strict budget. A DIY solution empowers each clinical team with the ability to build their own electronic study and control the build process according to their unique specifications and timelines. However, with any DIY solution, there can be tradeoffs in cost and time, as each client’s team is responsible for building their study and quality testing their CRFs. A lack of knowledge or expertise with using EDC software can create unforeseen costs and delays for a new or inexperienced team choosing a DIY solution, and in some instances, can become costlier in resources and staff as opposed to using a full-service solution that is built by an experienced EDC software team. The question becomes, how does one determine if one’s study is better suited for a DIY or custom-built solution before making a selection purely based on price? What are the advantages and tradeoffs with each solution? Required Knowledge The first step is to assess your staff’s experience with EDC. This will provide a better approximation of the expected learning curve when choosing DIY over custom-built. If staff are well versed in EDC, either option might be suitable. If staff are inexperienced in working with EDC, or have little confidence, it’s encouraged to think about the requirements for learning the EDC tool as your team will be tasked with putting together an EDC system necessary of capturing all required study data. Not only will time and resources be required, but also an understanding and organisational plan for certain risks involved, like possible delays in study start times, and ensuring data quality is collected and maintained if the proper edit checks are not initially built in. In order to assess your staff’s skills, it is highly recommended that a sandbox be requested from the DIY vendor, prior to engaging in a contract, in order to ensure your staff are able to build the study forms themselves. One of the advantages of a custom solution is that the provider often coaches clients on appropriate edit checks and logic to be used in the study. Prelude Dynamics LLC works with clients on an iterative study development process, closely consulting with clients through the steps of determining appropriate edit checks, calculations, logic, and how to best leverage enhanced functionality of the system. Through this development consultation, your staff learn to think how best to leverage automation in data cleaning. Additionally, when contracting for a custom-built EDC, Prelude provides professional hands-on coaching and training to assist in implementing appropriate testing procedures to ensure the study was set up correctly 52 International Animal Health Journal

and all the protocol requirements are functioning as expected. Conversely, this level of consultation and development support are services not included when clients choose a DIY study build. Unless client’s staff have previous experience with EDC development or are partnered with a knowledgeable database manager, the client is accountable for the database build, testing and UAT processes. While the monitoring and data analytic functionality of the system are already built into the solution, the client is expected to utilise and test such functionality and edit checks against their study’s requirements. For the aforementioned reasons, Prelude would only recommend going the DIY route if your staff are experienced and knowledgeable in building EDC database, tools and forms. Before deciding on a custom-built or DIY study build solution, be sure to qualify your staff’s experience and skills, and development schedule. Size, Duration and Complexity of Study What is the expected size and duration of the study? After all, the size is generally determined by the statistical power necessary for the results of the study. While the complete duration of any clinical trial study is more difficult to ascertain, as actual site and patient enrolment is often unpredictable, a good rule of thumb to follow is the duration of the study should not exceed double the expected time. Generally, quick turnaround studies are less complex in design than longer, longitudinal studies for enrolling patients/subjects, however, there are exceptions to the norm. As an example, challenge studies are generally shorter in duration, lasting for only a few days, but are not necessarily simpler in initial design. Conducting a challenge study with multiple blood draw visits on different schedules that are reliant on a weight-contingent treatment dosing schedule and application of a challenge and a treatment can be extremely complex to design and properly edit a check test, even if only a small sample size of subjects are enrolled. Likewise, a study with relatively simple data collection needs can become quite complex when multiple sites across the globe are used, each requiring forms to display in their own language and requiring translation fields for text entries. Understanding the size, duration and complexity of the study will provide a solid foundation from which to analyse the needs of the study and compare the benefits and drawbacks of DIY vs. custom-built solutions. Study Phase The study phase can be used to predict the likelihood that a current study design will be beneficial for replication. The earlier the phase, the more likely there will be similar studies in the same phase, as modules like dosing and safety and study masking are finalised. Also, the more likely that the study generates supportive data for the function of the drug or device, the more likely it is that the process Volume 5 Issue 2


TECHNOLOGY will proceed to the next phase. In which case, while most studies will have a few changes, the majority of the study forms and study schedule tend to remain similar.

with a custom-built solution, but it’s best to already be aware of the implications of resources in regard to time and costs.

Understanding the nuances of your studies along with method and timing of data collection will be useful when determining if the DIY solution can be adapted to accommodate future follow-up studies. Determining whether the EDC provider also has the ability to provide a custom solution in addition to DIY, specifically for Phase III and IV clinical trials which may require transition between tools as the phases transition and study demands change can be an overall time and cost eliminator, should there be a need to change tools. A provider offering both solutions from the start can help prevent a cumbersome transition. In a reverse fashion, when using a custom-built solution, there is a greater possibility of reusing the study at a discount with minor modifications, if moving to a DIY framework.

Only you can know which tool is right for your clinical study’s needs. A good EDC partner will provide you with their recommendation as to whether your study is a good candidate for a DIY or a custom build. Overall, the simple earlier-phase studies, when there is adequate staff experience, can be handled efficiently using a DIY solution. More complex studies with multiple sites and advanced functionality are better off as custom-built solutions, due to the fact that the typical DIY solution doesn’t have the same level of functionality and built-in support as custom-built studies. Ideally, the best course of action is to identify a vendor that provides both solutions and is able to support your needs for a do-it-yourself approach, during the earlier phases while the IVP is in its early research phase, as well as support your study’s conversion needs during subsequent trial phases into a custom-built, premium functionally advanced study, with ease and unforeseen costs. Having the tools and knowledge of the advantages and disadvantages of EDC software solutions can greatly empower you and your team to make a thoughtful and cost-effective choice.

Asking these types of questions will allow you to more accurately assess the life cycle of the study build costs across all phases; the answer might just surprise you and result in major savings of both time and money. Picture moving through study phases after rigorous building and testing time only to find out the DIY build used in the Phase I and II studies has to be completely redone by another vendor, in order to accommodate their custom solution due to incompatibilities between both software systems. Suddenly, you find yourself not only needing to wait eight weeks for the study to be built, but now having to restart the testing phase, which can result in a huge waste of resources and effort! Functionality Different studies require different levels of functionality. Assess your protocol to determine whether all that is needed is simple electronic data capture, or whether there is a need for more complex functionality to be incorporated, such as a lab interface, image or document upload capacity, inventory management, automatic reconciliation, automatic reordering, automated invoicing, document management, and multi-language capability, to name a few. This helps to provide insight as to the minimum functionality the DIY or custom-built study needs to have. Conduct a side-by side solution assessment to determine whether your protocol has a simpler design or whether it shall require a more complex set of data capture tools and features. Comparing Solutions Now that the experience, skills and capacity of your staff have been evaluated, the size, duration and complexity of the study has been assessed, the study phase, data collection requirements, and cost and logistics have been evaluated, and the functional requirements for the study have been gathered, you are now prepared to conduct a thorough comparison to determine which approach is most appropriate. Be sure to take into account the overall programme and schedule and consider carefully whether one solution is better long term over the other. Perhaps, look for a vendor that can provide both the DIY solution and the case forms you built for early-phase studies and ensure these forms are easily integrated into a larger later-phase study within the programme, while knowing the conversion ramifications for your budget and implementation team. Certainly, it is quite all right to use a DIY EDC provider that might not be compatible www.animalhealthmedia.com

Karina Loyo Dr Loyo is an eClinical Trials Specialist at Prelude Dynamics. She specialises in developing user-friendly interfaces for clinical electronic data capture (EDC), coaches clients through the EDC development process and how to leverage the trial management system functionality for efficient trial operation, delivers training, and consults on best practices in monitoring with EDC, the development of mid-study reporting tools, and final data export. Dr Loyo has been engaged in healthrelated research, education and marketing for 17 years. Her career highlights include working on the System Dynamics Model for CVD Prevention with the CDC, which won article of the year in Health Promotion Practice, and writing the Strategic Plan for Prevention of Obesity in Texas: 2005–2010. Email: kloyo@preludedynamics.com

Corina Bereanu As a project manager with Prelude Dynamics, Corina Bereanu works with clients to customize EDC to capture their study data and provides on-going management for the study databases. She is trained to implement custom built, template studies and DIY EDC tools. She helps ensure quality control by participating as a second tester during the QA process. Corina uses her experience in writing and editing clinical research articles and her BA in Clinical Psychology to assist the marketing team. She received a Bachelor’s in Clinical Psychology with a Minor in Child/Adolescent Psychiatry from New York University. Email: cbereanu@preludedynamics.com

International Animal Health Journal 53


SPECIAL FEATURE

Bayer’s Care4Cattle Initiative

Interview with Almut Hoffmann, Head of Global Marketing Farm Animal Products

Q: In your opinion, what does animal well-being mean and why it is so important for the cattle industry? A:To me, ensuring the health and well-being of the animals in our care is the right thing to do. It is an obligation anyone who has taken on the responsibility to keep animals has and should not differ by the species or the number of animals one cares for. Animal well-being is a fundamental driver for productivity of the animals and is becoming more and more a topic of concern for the consumer. Therefore the livestock industry has a tremendous opportunity to advance both the active engagement in animal well-being and the communication about it. Q: How important is innovation in progressing cattle well-being at a farm level? A:Innovation means something new and different that benefits or adds value to animals, livestock professionals and farming operations. As to my point above, the value of advanced animal well-being can be demonstrated very clearly. For example, innovation in preventative measures and early diagnostics have played an important role in improving animal well-being along with innovation in animal handling and housing. This will certainly continue and the new digital age offers an even broader set of opportunities. Q: What challenges are facing livestock professionals when it comes to advancing the care and well-being of their animals? A: Probably the largest barrier is the required behavioural change with many practices being conducted as they are the known way of doing things. For example, livestock keeps being a very traditional, often family owned business which builds on past experience and inherited knowledge. Change here will come from a fundamental belief that the new way offers benefits to the animals but also to those keeping them. To some, it may seem logical to minimize production costs in order to maximize profit. However, when it comes to animal husbandry, scientific evidence increasingly demonstrates that any investments towards enhancing animal well-being has positive impact on productivity and quality. And many of these changes aren’t necessarily complicated or costly. In short, what is good for the animals is good for the farm. This is why we actively engage with livestock professionals around the world to share knowledge expertise and demonstrate good well-being approaches through best practice case studies. Our aim is to support livestock professionals to further enhance conditions on farms for the benefit of the animals. Q: How has dairy and beef cattle well-being changed in the past decade, and what do you think the future holds? A: There has been much advancement made in this area. One example in dairy would be the reduction of tie stalls, and for beef, transportation conditions have significantly changed as well. Also, many additional opportunities are available to prevent diseases in the first place, starting from hygiene and vaccination measures to the reduction 54 International Animal Health Journal

in densities of animals being kept. However many of these advancements were driven by changes in regulations or market demand. Positive change has also been brought about by innovative thinking livestock professionals and individuals, who continually seek new or better ways and practices in animal husbandry. From my perspective, there is no end point to advancing animal well-being and this will continue to be in emphasis, especially with the introduction of portable technologies which will enable even better disease surveillance and early diagnosis. I also believe that the voice of the consumer will get louder and that many of the changes ahead of us will be driven by their demands. Q: Why did Bayer decide to launch the Care4Cattle initiative and what do you hope to achieve from it? A: Bayer has the fundamental belief that improving lives is never a job finished. It is our responsibility to continuously look for opportunities to further improve the health, and therefore also the well-being, of animals around the globe. We are committed to deliver scientific innovations, as well as new technologies. But also, we want to emphasise the good efforts of livestock professionals who are driving practical well-being advancements on farms because together we can amplify the benefits of good animal wellbeing to millions of individual animals, people and the communities who depend on them. Q: What does the collaboration with WFO mean for the initiative and why is it important? A: Animal well-being is a huge field that is interpreted in many different ways. So it is important for us to have a strong partner that will ensure the perspective of the farmer is kept in mind just as much as the animal’s fundamental needs. Engaging and supporting farmers around the globe, with practical tips and funding through Care4Cattle, is essential and the most impactful way to continuously advance animal well-being. Such a collaboration helps us to build on their knowledge and work hand in hand to get practical solutions. Q: What would Bayer like to see in applications for the grant, are you able to give an example of an innovation a livestock professional has put in place to help with the well-being of their livestock? A: With the Care4Cattle initiative we want to find innovative and practical solutions which advance animal well-being. The grant is aimed to support livestock professionals put their ideas into practice – ideas that make a difference to the well-being of cattle. For us it is important that a project is practically feasible and easy to implement on the farm as we want to follow these projects through implementation. Therefore, applicants need to demonstrate that their project benefits the animals, adds value to the farming operations, is innovative, has an economic viability and is practice-oriented. There are many good examples of how livestock professionals constantly develop new and better ways, especially when it comes to handling of animals. Volume 5 Issue 2


Q: How will the Care4Cattle initiative support the chosen applications? A: The Care4Cattle initiative funds the selected cattle wellbeing projects. With a total of 30.000 Euro we offer targeted support, not only through funding but also by following the projects through to implementation, sharing our knowledge and expertise to help them succeed.

A Helping Hand for your Key Personnel

Q: How easy is it to apply for the initiative, what does the entry involve? A: The idea that stands behind Care4Cattle is – very much like the projects we want to support – to be practical. If you have a good and innovative idea for a project, the only thing you need is to submit a proposal and to tell us why your project would make a difference. The initiative is open for farmers, veterinarians and researchers – people we see as the key to advancing animal well-being, as they have dedicated their lives to animal health and well-being. In a nutshell, we are looking for livestock professionals around the world who are passionate about advancing cattle well-being and have a concrete idea for new or better ways to further improve on-farm practices. Q: Do you have any advice for livestock professionals looking for ways to advance well-being in their cattle herd and what information is available for them to use on this topic? A: There certainly is no “one size fits all” recommendation. Production systems vary across geographies and so do climate and housing conditions. In order to be sustainable, well-being measures also need to be considered alongside productivity and the environment. Bayer has many examples around the world as to how the different production systems have evolved their way of including animal well-being aspects into their management. We believe that together with the industry, vets and farmers, we can further advance animal wellbeing around the world, tailored to needs of individual farmers and animals. http://go/bayer.com/Care4Cattle

Dr Almut Hoffmann Dr Almut Hoffmann completed her Dr. Vet. Med. at FU Berlin and holds a Diploma in Animal Health Management. After completing her studies she worked as veterinarian in a large animal clinic in Germany. In 2000 she decided to join the Animal health Industry with Fort Dodge and worked in various capacities such as Project Manager and Senior Business Manager, responsible for Germany and Austria and later on European level. Dr Hoffmann joined Bayer Animal Health in 2009 as Global Strategic Marketer, moved on to become Head of Antiinfectives and Biologicals and later Head of Global Launch Team in Global Marketing. Since October 2015, she has taken over as Head of Global Marketing Farm Animal Products in Monheim, Germany. In her free time she enjoys her family, travelling and horse riding. Email: almut.hoffmann@bayer.com

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International Animal Health Journal 55


SPECIAL FEATURE

Moredun: A Blueprint for Private-public Partnership Bringing Economic Benefit Through Innovative Science Moredun Research Institute, situated within Pentlands Science Park on the outskirts of Edinburgh, is a world renowned research facility actively involved in research to detect, prevent and control diseases of livestock and to promote higher standards of animal health and welfare through research and education. The application of scientific research to bring both economic and societal benefits is a real strength of Moredun’s strategy. The research outputs from the Institute have made a major impact both in the UK and globally due in a large part to the unique relationship Moredun has with the farming community and the emphasis the organisation puts on effective knowledge exchange with livestock producers. Moredun was originally established by Scottish farmers in 1920 who were concerned about the serious losses they were experiencing due to disease in their farmed livestock. Within 10 years of the Research Institute opening, Moredun scientists had discovered the causes of several major diseases of livestock and developed effective vaccines and treatment strategies. This success continued and today many of the veterinary medicines and vaccines that are routinely used on the farm have been researched, developed or tested at Moredun. The critical link with the farming community has been a mainstay of Moredun’s success and the Moredun Foundation currently has over 10 000 members from the farming, veterinary and livestock health industries with farmers sitting on Moredun’s governing boards. This ensures that the research outputs, knowledge, skills and expertise generated at Moredun are targeted to improve livestock health and welfare and increase the sustainable efficiency of livestock production, which are vital to help safeguard global food security. The Moredun Foundation is the charitable body under which the other companies and charities of the Moredun group belong. The Moredun Foundation supports animal health and welfare through research and education and governs the work of the Moredun Research Institute. Moredun Scientific is the commercial arm of the Moredun Group offering contract and research, services to the animal health industry. Pentlands Science Park offers incubation units for biotechnology and related companies and provides conferencing and support facilities and the Equine Grass Sickness Fund, administered within the Moredun Foundation is dedicated to supporting and advancing research into grass sickness in horses. Any profits made from the commercial activities of the Moredun Group companies are gift aided back to the Foundation and then used to help support scientific research. Moredun is unique in many ways as it is the only example of a thriving bioscience park centred round a livestock health and welfare research facility. Moredun is also a genuine and well established example of publicprivate partnership and a potential blueprint for cost 56 International Animal Health Journal

and responsibility sharing among governments and stakeholders, including farmers, associated support industries, food processors and food retailers. World Renowned Research Facility Moredun is a unique, state of the art research facility with highly trained staff, purpose built physical resources and the capability of working with a wide range of different pathogens, up to ACDP Category 3. The Institute has multi-occupancy and specialist laboratories and farm units to house ivestock along with specific pathogen free containment rooms and laboratories. Specialist facilities dedicated to understanding the genetics and biological characteristics of a wide variety of different viral, bacterial and parasitic organisms help to identify vaccine candidates, diagnostic antigens and biomarkers of disease. The institute also has a real strength in research into the host-pathogen relationship to understand how pathogens are transmitted to animals, how they cause disease and how the animal can resist the infection. Moredun’s research strategy centres on the multidisciplinary study of specific diseases or conditions and this holistic approach to animal disease research is one of the recognised strengths of Moredun. This knowledge has led to the development of many successful vaccines to prevent and control important diseases of livestock. Although Moredun’s work is largely focussed on safeguarding livestock health, many of the diseases that affect livestock can also cause disease in people and wildlife species. Therefore, the outputs from Moredun’s work are also significant to public, wildlife and environmental health. Moredun’s facilities and resources are accessible to the wider scientific community and Moredun has hosted many visiting scientists from all over the world who come to undertake collaborative work. Disease prevention is better than cure Development of effective vaccines to prevent disease is a major goal of Moredun’s research as this is a sustainable control strategy and reduces reliance on pharmacological drugs and pesticides. A critical component in designing effective vaccines is to understand how the immune system is able to protect the host against a variety of different pathogens. The ability to measure and induce immune responses in livestock using components of pathogens is a requirement for rational vaccine design along with methods to deliver the vaccine to the host to induce the appropriate immune responses. Moredun has a long history in Immunology research in farmed livestock and is recognised as one of the world leading Research Institutes in this area. Scientists have also developed new functional genomic technologies which have accelerated the identification and characterisation of potential vaccine candidates for a range of different pathogens. A variety of disease models have been established both in vivo and in vitro to help test the efficacy of candidate vaccines. Examples of vaccine successes arising from Moredun’s research include those developed against Mannheimia haemolytica, a major cause of acute pneumonia in both Volume 5 Issue 2


SPECIAL FEATURE cattle and sheep; Toxoplasma gondii, a major cause of abortion in sheep; Rotavirus, a serious enteric pathogen and Haemonchus contortus one of the most important nematode parasites of sheep worldwide. Diagnosis and Disease Surveillance The accurate diagnosis of disease is very important to provide a sure basis for treatment and advice on management and control of disease. Moredun’s scientists are involved in developing new and improved diagnostic tests to help detect and identify pathogens and infected and diseased animals. Current emphasis is being placed on the development of rapid and penside diagnostics to allow more effective disease treatment and prevention strategies to be applied. This approach is currently being used to develop a rapid diagnostic to detect sheep infected with sheep scab mite using a lateral flow device and applying microfluidic technologies working in collaboration with engineers. Another approach is to develop a disease syndrome diagnostic platform to enable simultaneous testing for a range of different pathogens involved in causing particular disease syndromes eg: respiratory disease in cattle. Work is also being conducted to develop a new diagnostic test to detect Johne’s disease in cattle at the sub clinical stage using cell-mediated immune markers in infected cattle. This new blood test may be useful for checking breeding stock and replacement animals to reduce the likelihood of introducing sub-clinically infected animals into herds. Moredun conducts disease surveillance within specialist laboratories focussing on the development and application of viral diagnostic tests and in pathology specialising in neurological and reproductive diseases. The surveillance unit also works to alert scientists of new and emerging diseases and pathogens providing a valuable early warning system. Disease management and control Research is also conducted to advise farmers about livestock health management looking at disease prevention and control. A major area of research at Moredun is in the study and management of anthelmintic resistance. Gut roundworm infections are a major impediment to sheep and cattle production worldwide and sustainable control is threatened by the spread of drug resistance. Moredun scientists are working closely with farmers to develop new strategies for targeted anthelmintic use on farms based on live weight gain which has reduced anthelmintic usage, improved animal production performance and maintained the efficacy of the drugs for longer periods. Scientists are also developing sensitive, rapid and high throughput tests which can be used to look at drug resistance of worm populations on farms to allow the farmer and the vet to make informed decisions regarding drug rotation and pasture management. Commercialisation of research outputs The translation of research outputs into practical applications has been a strength of Moredun since it’s founding in 1920 and this philosophy has resulted in the development and application of vaccines, diagnostics and management strategies for the control of infectious diseases. Moredun has developed effective partnerships with commercial companies to help get products to the market place and has also encouraged the development of several spin out companies to commercially develop innovative science. Moredun Scientific is a commercial company that is part of the Moredun Group and the www.animalhealthmedia.com

company’s core business is dedicated to the provision of services to the global animal health, pharmaceutical and biotechnology industries. Profits from the commercialisation of Moredun’s science are donated back into the Moredun Foundation and used to support the scientific research effort to prevent and control livestock disease through research and education. Knowledge Exchange and Education Moredun is committed to ensuring that it’s research outputs bring benefits to the economy and to society at large and therefore knowledge exchange and education are key to Moredun’s philosophy and success. Moredun’s strong relationship with the livestock industry helps to focus the research effort into areas that are of most concern to farmers and vets throughout the UK. The Moredun Foundation has five regional boards representing the views of farmers, vets and animal health advisors in England, Wales and Scotland and Moredun staff work together with the regional advisors to develop and deliver outreach events and roadshows discussing the latest information and technology advances to improve livestock health and welfare. The Moredun Foundation produces regular independent news sheets with facts about specific disease prevalence, transmission, impact, prevention and control to help livestock farmers and vets to keep up to date with recent advances. Moredun had also recently teamed up with animator Selina Wagner to develop some short animated films looking at worm control, and biosecurity, these can be viewed on the Moredun website. https://www.moredun. org.uk/foundation/outreach/animation-series Moredun plays host to numerous undergraduate and postgraduate students and visiting scientists from all over the world who come to the Institute to conduct short or longer term collaborative research projects. School children also take part in short term placements to find out more about working as a research scientist and Moredun scientists work together with school teachers to help develop educational resources to encourage both primary and secondary school pupils to engage with science topics. To find out more about the work of the Moredun Foundation and Moredun Research Institute please visit our website www.moredun.org or contact us at info@ moredun.org.uk

Elisabeth Innes Professor Innes (MBE) leads a research group at the Moredun Research Institute looking at developing solutions to control diseases caused by protozoan parasites. She has published numerous scientific articles and has successfully developed and delivered several externally funded national and international research programmes. She is also Director of Communications at Moredun and holds Honorary Professorships from Heriot Watt University, University of Edinburgh and University of Glasgow. Email: lee.innes@moredun.ac.uk

International Animal Health Journal 57


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International Animal Health Journal 61


NEWS First-of-its-Kind Study Reveals Concern about the Future of the Veterinary Profession Results Presented at 2018 Veterinary Meeting & Expo (VMX) Merck Animal Health (known as MSD Animal Health outside the United States and Canada) today announced the results of a large, well-controlled study with veterinarians designed to definitively quantify the prevalence of mental illness and stress in the veterinary profession and compare the findings to previous studies and the general U.S. population. Conducted in collaboration with the American Veterinary Medical Association (AVMA) and Merck Animal Health, the study found veterinarians age 45 and younger are more likely to experience serious psychological distress and only 27 percent of them would endorse the profession to a friend or family member. “This survey is unique in that, for the first time, a nationally representative sample of veterinarians in the U.S. were asked about their wellbeing, which is a broader measure of happiness and life satisfaction than mental health alone,” said study investigator Linda Lord, Ph.D., D.V.M., academic and allied industry liaison lead, Merck Animal Health. “Based on the survey results, we are particularly concerned about younger veterinarians as they are the future of our profession. We must work together to promote a healthy lifestyle, including work/life balance, access to wellness resources and debt reduction.”

Elizabeth Bradbury from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) said the discovery means that scientists can now precisely control how long a therapy is delivered using a gene ‘switch’. “This means we can hone in on the optimal amount of time needed for recovery,” she said. “Gene therapy provides a way of treating large areas of the spinal cord with only one injection, and with the switch, we can now turn the gene off when it is no longer needed.” Following a traumatic injury to the spine, dense scar tissue forms, preventing new connections being made between nerve cells. The gene therapy causes cells to produce an enzyme called chondroitinase which can break down this scar tissue and allow networks of nerve cells to regenerate. In the study, researchers gave the gene therapy to rats with spinal cord injuries that resembled the type humans develop after traumatic impacts, such as falls or car crashes. New Caudata Rules Set to Come into Force in July Rules to prevent spread of deadly fungus amongst newts and salamanders New rules on the import of Caudata amphibians are to be implemented across the UK following a decision by the European Commission.

Bristol Vets to Benchmark Farm Animal Medicine Use Project will provide beef industry with tools to achieve RUMA targets A new project to quantify and compare farm animal medicine use across UK beef farms has been launched by the University of Bristol. The project, ‘Strategies to benchmark and communicate farm medicine use in cattle operations,’ will begin this summer and run for 18 months. Funded by AHDB Beef & Lamb, it will see farmers given the tools and information needed to accurately assess record and benchmark their medicine use.

The new rules come into force on the 1 July, 2018 and seek to prevent the spread of the fungal pathogen Batrachochytrium salamandrivorans (Bsal) amongst newts and salamanders.

An estimated 700,000 people are killed by drug-resistant infections every year. The responsible use of farm animal medicines is key to combatting the growing problem of antimicrobial resistance (AMR). To maintain animal health and ensure safe and sustainable food production, farmers and veterinary surgeons must demonstrate responsible and evidence-based farm medicine usage. However, beef producers face challenges in achieving recent RUMA targets for medical use, as significant gaps in data exist regarding quantities and types of medicines used.

The Ornamental Aquatic Trade Association (OATA) has urged anyone involved in the import, export or sale of Caudata species to familiarise themselves with the new rules and to ensure any animals they buy and sell conform. Pets, defined as five or fewer animals accompanied by their owner, are excluded from the rules. Acquiring animals from a trade show, shop or hobbyist to become part of a collection is not defined as moving a pet.

In the project, researchers from Bristol Veterinary School will lead the way with farmers and veterinary surgeons to combat AMR by changing antimicrobial use on farms. The study will be funded by the agriculture and horticulture development board AHDB Beef & Lamb and involve a range of industry advisors, including the University of Edinburgh and The Veterinary Medicines Directorate. Gene Therapy Restores Hand Function in Rats with Spinal Cord Injury Rats accurately able to grasp sugar pellets following treatment Researchers from King’s College London have used a new kind of gene therapy to restore hand function in rats with spinal cord injuries. The study tested a kind of gene therapy that could be switched on and off using a common antibiotic. Professor 62 International Animal Health Journal

According to the European Food Safety Authority, Bsal has been detected in different species of salamander across the UK, both kept as pets and in the wild. Cases have been reported in Germany, Belgium, Spain, the Netherlands and the UK. In some salamander species, Bsal has been shown to cause high mortality.

Mammals Becoming more Nocturnal to Avoid Humans Hunting and human infrastructure forcing animals to flee daylight New US research has found that mammals are becoming more nocturnal in response to human activity. A study published in the journal Science shows that, on average, mammals are 1.36 times more nocturnal as a result of human disturbance. This finding was consistent across carnivore and herbivore species of all body sizes greater than 1kg. The study was led by researchers at UC Berkeley, California, and supported by the National Science Foundation. “While we expected to find a trend towards increased wildlife nocturnally around people, we were surprised by the consistency of the results,” explained lead author Kaitlyn Gaynor. “Animals responded strongly to all types of human disturbance, regardless of whether people actually posed a Volume 5 Issue 2


NEWS direct threat, suggesting that our presence alone is enough to disrupt their natural patterns of behaviour.” In the study, researchers monitored 62 species, including deer, tigers and wild boar, across six continents. For each species, the team quantified the difference in animal nocturnally under low and high human disturbance. The researchers found that animals that naturally split their activity evenly between the day and night increased their activity at night by 68 per cent. This pattern held across different types of human disturbance, including mountain biking, hunting and infrastructure such as roads. First Sea Eagle Chick in Orkney for 140 Years RSPB believes first-time parents may have two chicks. A white-tailed eagle chick has hatched in Orkney for the first time in over 140 years, RSPB Scotland has revealed. One chick has been spotted but staff believe there may be two, judging by the behaviour of the parents. Whitetailed eagles, or sea eagles, reappeared in Orkney five years ago, after being wiped out in the UK in the early 20th century. A number of reintroduction programmes, beginning in the 70s, brought the species back to Scotland. Lee Shields, RSPB Scotland’s warden for Hoy, said: “It’s fantastic that the eggs laid in spring have hatched, the first successful breeding season here since the 19th century. This breeding attempt is still at the early stages, with young often in the nest for up to 14 weeks. Everybody was so excited when the first pair arrived and we’ve been keeping our fingers crossed for this ever since. “We were hugely disappointed when a previous pair abandoned the territory last year, so to have at least one chick now is even more special. Zoetis Advises on Treatment to Prevent Acute Fluke in Cattle Fluke in cattle is expected to be a risk earlier this summer following the wet winter. This makes a mid-summer treatment vital to prevent significant losses. Farmers who resorted to grazing cattle earlier this year because of a forage shortage could see an even earlier risk. This is because the mud snail, which is the fluke’s intermediate host, will have thrived in the damp and wet conditions, despite the brief cold snap seen at the start of 2018. There will be a build-up of infective metacercariae on many pastures, which develop into immature fluke when ingested. Additionally, if cattle were not turned out of housing clean of fluke, they will have added to the pasture burden. All of the above means cattle in risk areas may need a mid-summer treatment to prevent costly losses, said Zoetis vet Dr Dave Armstrong. “It is important to remember that both immature and adult fluke cause production loss, therefore, waiting to treat is counterproductive if you have fluke on your farm,” he said. Fluke infected cattle can take 80 days longer to reach slaughter weight, costing between £25-35 extra per head, according to AHDB figures. Studies have also showed fluke to cause reduced reproductive performance in bulls, reduced conception rates in herds, increased age to 1st oestrus of 39-days and, in adults, an increased calving interval of 4.7 days on affected farms. www.animalhealthmedia.com

Dr Armstrong said: “Because a cow’s liver is bigger, they can tolerate a greater fluke burden meaning you won’t see sudden deaths like you would in sheep. However, you will see subclinical disease, which can be costly.” SCOPS Calls for Action after First Reports of Resistance to Group 4 Wormers SCOPS said the recent publication of the first case of resistance to monepantel in the UK is a timely and important reminder to sheep farmers and their advisors. Speaking on behalf of SCOPS, sheep consultant Lesley Stubbings said: “SCOPS welcomes this report because it not only highlights the need for sheep farmer to follow best practice advice, but also reveals the dangers of not integrating the newer wormer groups into on-farm control programmes before the other groups fail. “It is SCOPS’ understanding that the farm concerned had a history of triple resistance to the 1-BZ (white), 2-LV (yellow) and 3-ML (clear) groups of anthelmintics, which meant they were relying almost exclusively on the newer monepantel wormer, the 4-AD (orange) group, for worm control. “Coupled with animals being moved to low challenge pasture following treatment, which is highly selective for resistance, there was the risk of a ‘perfect storm’ in terms of the development of resistance. Other sheep farmers can avoid this situation by following SCOPS guidelines on the use of the 4-AD and 5-SI (purple) wormers.” SCOPS has been advising that the group 4-AD and 5-SI wormers should be carefully incorporated into control programmes on sheep farms for the last eight years (when Zolvix was launched) as a quarantine drench and a mid/ late season treatment for lambs. That advice was given, Ms Stubbings said, in order to avoid this sort of situation where the other three groups are no longer effective and the group 4AD is relied upon. Obese dogs could have similar ‘personality’ traits to overweight humans – new study We’re all told we need to eat healthier and exercise more to combat obesity, but did you know that there’s also an obesity epidemic among pets, at least in the West? Between 39% and 59% of pet dogs in Europe, Australia and the US are estimated to be overweight or obese. In fact, obesity is now considered the biggest threat to the the health and well-being of our pets. Just as in humans, obesity in dogs involves many different factors. Certain breeds of dog seem to be more prone to obesity than others, and scientists have found a genetic mutation that seems to make dogs more likely to seek out food. So genetics certainly seems to be involved, alongside the amount of food and exercise dogs get. But one aspect of obesity in dogs that has received little attention to date is the emotional and cognitive aspect. That is to say, how motivated different dogs are to access food, and how personality traits such as the response to rewards might play a part. In a new study published in Royal Society Open Science, a team of European researchers have looked at just that. They found that overweight dogs were more likely to choose food containing larger amounts of energy, and more likely to hesitate if they didn’t know what kind of reward they were being offered.

International Animal Health Journal 63


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IMV Imaging

Page 37

Kemin Industries Inc.

Page 33

Moredun Scientific

BC

Nutriad

Page 61

Pharma Publications

I hope this journal guides you progressively, through the maze of activities and changes taking place in the animal health industry.

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www.animalhealthmedia.com or email info@pharmapubs.com

64 International Animal Health Journal

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Volume 5 Issue 2


Enhanced Efficiency Sound-Link, BCF’s unique wireless data transmission platform for real time imaging allows image display without any image lag. With Smart-Beam technology we have developed an ultrasound scanner that requires minimal power, with standard Wi-Fi devices used as a primary viewing device.

TM

Be Connected. Be Smart. Let’s Go! Wireless, connected on-farm ultrasound, strengthening the relationship between vets and farmers, ensuring better productivity on the farm and improvement in animal health. Be connected: The Easi-Scan:Go integrates seamlessly with the modern farm. It is a wireless, App based scanner, that can present the ultrasound image on up to 3 devices simultaneously . With the BCF Cloud you have instant access to vital data, enhancing team work and strategic planning.

Be Smart: Smart devices are not only

used to view the image but also to record data. Vets can plan their day with Visits ToDo App and send a notification to the farmer before arrival, reducing waiting time.

Let’s Go: Fast, light and with minimal set up time, the Easi-Scan:Go provides speedy results without sacrificing accuracy. Completely sealed, the scanner is water proof for ease of cleaning and maintaining biosecurity.

USE CALIPERS to measure the embryo size

UP TO 3 iOS OR ANDROID DEVICES can be connected

WATERPROOF Sealed buttons with no connectors.

LOW COST LITHIUM-ION BATTERY up to 5 hours

128 ELEMENTS, receiving on 32 channels, 26 frames per seconds

Discover more at: www.imv-imaging.com/easi-scan-go www.imv-imaging.com

Unrivalled Longevity The Easi-Scan:Go is our most rugged scanner yet. Waterproof and with a strengthened probe cable, the scanner is more durable than ever.

RECORD VIDEOS and save images on your smart devices

850 GRAMS IMPROVED FLEXIBILITY for better cable management

Clever Connectivity Relevant data is uploaded to the BCF Cloud online data storage via Scan-Share. The data can be reviewed, downloaded and shared at any time.

info@imv-imaging.com

+44 (0) 1506 460023

Improved Productivity Used with Visits ToDo App, you can capture cow-side data, making clipboard recording a thing of the past. Engaging both the vet and farmer, ensure diagnostic results are recorded correctly and optimise your farm visits.

facebook.com/imv-imaging

twitter/imv-imaging

Your complete animal imaging solution www.animalhealthmedia.com

International Animal Health Journal 65


We care for animals. And people alike.

NUTRIAD: FEED ADDITIVES WITH AN ADDED HUMAN TOUCH Here at Nutriad, weâ&#x20AC;&#x2122;re just as concerned about the animals we feed, as about our clients â&#x20AC;&#x201C; and their customers. Thus, we only produce the best feed additives and solutions possible, making sure your animals, in their turn, produce their best performance. And making sure your business thrives just as well.

Interested in how we can help your business thrive better? Visit nutriad.com for more information. 66 International Animal Health Journal

Volume 5 Issue 2

IAHJ - Volume 5 Issue 2  
IAHJ - Volume 5 Issue 2  
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