Compendium Equine | January 2009

VOLUME 4 NUMBER 1 JANUARY/FEBRUARY 2009

3 CE Contact Hours | CompendiumEquine.com | Peer Reviewed

Vol 4(1) January/February 2009

COMPENDIUM EQUINE CONTINUING EDUCATION FOR VETERINARIANS®

Managing

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Pathophysiology of

Osteoarthritis O Osteoarthriti Clinical Snapshot

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PAGES 1–48

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Refereed Peer Review

Nutramax_Cosequin_use.qxp:1

12/18/08

12:18 PM

Page 1

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Photograph by Anthony Trollope

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January/ February 2009 Vol 4(1) CompendiumEquine.com | Peer Reviewed | Free CE

EDITORIAL BOARD Michelle Henry Barton, DVM, PhD, DACVIM The University of Georgia Internal Medicine

EDITOR IN CHIEF James N. Moore, DVM, PhD Department of Large Animal Medicine College of Veterinary Medicine The University of Georgia Athens, GA 30602 706-542-3325 Fax 706-542-8833 jmoore@uga.edu

Gary M. Baxter, VMD, MS, DACVS Colorado State University Acupuncture, Surgery Jim Belknap, DVM, PhD, DACVS The Ohio State University Soft Tissue Surgery Bo Brock, DVM, DABVP (Equine) Brock Veterinary Clinic, Lamesa, Texas Surgery Noah D. Cohen, VMD, MPH, PhD, DACVIM (Internal Medicine) Texas A&M University Internal Medicine Norm G. Ducharme, DVM, MSc, DACVS Cornell University Large Animal

Compendium Equine is a refereed journal. Articles published herein have been reviewed by at least two academic experts on the respective topic and by the editor in chief.

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Raymond J. Geor, BVSc, MVSc, PhD, DACVIM Michigan State University Metabolism, Nutrition, Endocrine-Related Laminitis Katharina Lohmann, MedVet, PhD, DACVIM (Large Animal) University of Saskatchewan Large Animal Robert J. MacKay, BVSc, PhD, DACVIM (Large Animal) University of Florida Large Animal Rustin M. Moore, DVM, PhD, DACVS The Ohio State University Surgery Debra Deem Morris, DVM, MS, DACVIM East Hanover, New Jersey Internal Medicine P. O. Eric Mueller, DVM, PhD, DACVS The University of Georgia Soft Tissue and Orthopedic Surgery

Susan C. Eades, DVM, PhD, DACVIM (Large Animal) Louisiana State University Large Animal

Elizabeth M. Santschi, DVM, DACVS The Ohio State University Surgery

Earl M. Gaughan, DVM, DACVS Littleton Large Animal Clinic Littleton, Colorado Surgery

Nathaniel A. White II, DVM, MS, DACVS Virginia Polytechnic Institute and State University Surgery

Any statements, claims, or product endorsements made in Compendium Equine are solely the opinions of our authors and advertisers and do not necessarily reflect the views of the Publisher or Editorial Board.

Change Is Good Introducing exciting changes to Compendium Equine!

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Features 16

❯❯ Laurie Beard Most foals experience one episode of diarrhea before they are 6 months of age. Learn how to manage the most common causes of diarrhea in foals (from neonates to weanlings). Because diagnosis plays an important role in choosing the correct treatment and preventing outbreaks, diagnostic testing for common pathogens that result in foal diarrhea is discussed.

CompendiumEquine.com | Peer Reviewed | Free CE

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CE Feature Pathophysiology of Osteoarthritis

Sebastian Knight

January/February 2009 Vol 4(1)

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❯❯ Jorge U. Carmona and Marta Prades Osteoarthritis (OA) is the most common joint disease in humans, horses, and dogs. Learn about the relevant molecular aspects of the etiopathogenesis of OA and the potential therapeutic molecular targets for controlling this disease.

48

The Final Diagnosis Just Another Unusual Day ❯❯ Ronald E. Gill Depending on the circumstances, horses can seem either surprisingly fragile or unbelievably tough. Without question, the mare in this case belongs in the latter category.

Departments 8

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Reading Room Technical Large Animal Emergency Rescue Clinical Snapshot Colic in a Quarter Horse ❯❯ Gal Kelmer

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Tachycardia and Tachypnea in a 2-Day-Old Thoroughbred ❯❯ Nora Nogradi and Michele Frazer

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Severe Forelimb Lameness in a Quarter Horse ❯❯ Shirley Weisler and Gal Kelmer

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This is my horse

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There is no one in the world I'd rather share the Olympic podium with. In 1984, as a young girl, I got to see Eventing for the first time at the Olympics. From that point, I knew what I wanted to do. The sport was so physically demanding. The horses were the ultimate cross trainers. It required stamina, style and bravery.

So after finishing school, I went to work for a local stable. They had just purchased McKinlaigh, considered by many too big for eventing.

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The Editor’s Desk ❯❯ James N. Moore, DVM, PhD, Editor in Chief (jmoore@uga.edu)

The New World Disorder and the New Year

T

ired of hearing about the “Down” Jones average and the nearly $1 trillion bailout?

I sure am. From everything I’ve seen and read, it appears that those of us in the working middle class are the culprits behind this fiasco.

Collectively, we wanted to live too high on the hog, borrowed too much, spent too much, and now owe too much to too many banks. Of course, the fact that three banks sent credit card applications to our cat, and that every car maker in the world still advertises 0% financing and “no payments until the end of time,” has nothing to do with the pickle we’re in.

the banks and companies that we either bought too many things from or are now ignoring. Given the stack of 1 trillion greenbacks and the fact that there are about 100 million workers in this country, why not send each of us a check for $10,000?

I don’t know about you, but I’d promise to spend just the right amount.

On a much brighter note, 2009 is going to be a great year for Compendium Equine. In response to feedback from you, this year we’ll be starting new topical series on equine dentistry, nutrition, and surgery. From the Horse’s Mouth will ruminate on topics such as wolf teeth, Food Stuff will serve hot topics such as nutraceuticals, and Cutting to Cure will take an in-depth look at topSo not only did we mess things up by ics such as urolithiasis. We’re hopeful that you’ll buying too much, we’re now making find these new series as informative as the others we’ve been providing these past few years. The things worse by spending too little. journal will also contain some great articles on other topics of interest, including ultrasonograThe other critical aspect of this financial crisis phy of the stifle, pleuropneumonia, hemostasis, is that it is fueled by poor consumer spending. head shaking, colitis, and cantharidin toxicosis.

So not only did we mess things up by buying too As you know, Compendium Equine is your jourmuch, we’re now making things worse by spend- nal, so please let us know what you’d like to see, ing too little. The fi x for this crisis? Parcel out $1 and we’ll do our best to provide it. trillion (that’s a 1 with 12 zeros trailing along) to Happy New Year, and enjoy the bailout!

8

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

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Reading Room ❯❯ Reviewed by Amy I. Bentz, VMD, DACVIM, Veterinary Learning Systems, Yardley, Pennsylvania

A

T SOME POINT IN OUR CAREERS, large animal veterinarians face a challenge unique to our profession—rescuing large animals from an acute, physical crisis. It may be an older horse that has slipped on ice and needs assistance to stand, a horse that has fallen into a swimming pool, an overturned livestock trailer on a highway, or a national disaster such as Hurricane Katrina, involving thousands of displaced people and animals.

Readers of this textbook will gain tremendous understanding of how to handle many common and unusual large animal rescue scenarios.

Title: Technical Large Animal Emergency Rescue Authors: Rebecca Gimenez, PhD, Tomas Gimenez, MVZ, DMV, and Kimberly A. May, DVM, MS, DACVS Publisher: Wiley-Blackwell Year: 2008 Pages: 409 ISBN: 978-0-8138-1998-3/2008

TO LEARN MORE For further information about this book or to order a copy, visit

www.blackwellpublishing.com

10

Our large animal patients present a unique challenge due to their size and the nature of their fightor-flight response. In addition to emergencies in rural settings, there are many large animals in suburban and urban settings, necessitating knowledgeable first responders who can provide aid quickly in less-thanideal environments.

The textbook titled Technical Large Animal Emergency Rescue provides answers to pertinent questions large animal veterinarians would ask when faced with this challenge.

Through 22 chapters and many excellent pictures, this book offers a framework on which to base logistics regarding rescuing one animal or many animals. The large animal rescue scenarios described in this text involve equine, bovine, caprine, swine, and camelid animals. Each chapter describes a technical large animal emergency rescue (TLAER) method in depth, including “Incident Prevention and Evacuation Planning,” “Understanding Large Animal Behavior in T L A ER Incidents,” “Technical Large Animal Emergency Rescue Scene Management,” “Loose Large Animals,” and “Learning from Actual Incident Scenarios.” There is also an excellent chapter titled “Barn and Wildfires,” which includes sections on barn construction considerations and sprinkler systems to prevent

fires from destroying barns. “Large Animal Field Emergency Medicine” is an important chapter that I hope will be expanded in future editions. The four appendices focus on communication options, TLAER equipment, equipment vendors, and TLAER training recommendations for student competency goals. The references section is comprehensive and includes many timely sources for additional reading.

To quote the Boy Scout motto, “Be prepared!” Readers of Technical Large Animal Emergency Rescue will gain tremendous understanding of how to handle many common and unusual large animal rescue scenarios. This text is a must-have for large animal veterinarians, whether they practice ambulatory medicine, work in public service, or are interested in animal rescue and disaster medicine. This book is also a useful training tool for veterinary technicians and veterinary students. The tragedy of Hurricane Katrina on both human and animal levels underscores the immediate need for us to plan for future disasters in our communities and nation, and this text will be an invaluable tool for many people. On a personal note, I wish this textbook had been available when I graduated from veterinary school in 1997. It would have been well-worn in my time as an ambulatory veterinarian!

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

Merial_EQUIOXX_Use.qxp:Sound Technologies_USE

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EQUIOXX® (firocoxib).

Care for the pain. Care for the horse.

EQUIOXX is proven p to relieve the pain p and inflammation of equine q g selective COX-2 inhibitor, EQUIOXX blocks osteoarthritis. A highly prostaglandins t l di that th t may be b responsible ibl for f inflammation i fl ti while hil sparing potentially beneficial prostaglandins.†,1 For safe, 24-hour prescription pain relief ask your Merial Sales Representative about EQUIOXX or visit www.equioxx.com. †

Clinical relevance has not been determined.

EQUIOXX is the only NSAID approved for use up to 14 consecutive days at AQHA2 and USEF3 events. Merial is an official animal health care partner of the AQHA.

Official product of

Percent of horses that improved after 14 days of treatment.*, 4 Data collected at nine locations, from 240 horses 2 to 37 years of age. a

La

a

a

a

a

a

*Not a claim of superiority.

NSAIDs should be used with caution at the recommended dose — and EQUIOXX is no exception. However be confident that EQUIOXX has undergone rigorous safety studies, including: A study evaluating clinically relevant side effects showed no significant adverse events when EQUIOXX was used up to 5X the recommended dose for 30 days.5 A study showed no significant effects on hematology, chemistry, urinalysis or bleeding time when EQUIOXX was used above the recommended dose for 92 days.5

As with any prescription medication, prior to use, a veterinarian should perform a physical examination and review the horse’s medical history. A veterinarian should advise horse owners to observe for signs of potential drug toxicity. As a class, nonsteroidal anti-inflammatory drugs may be associated with gastrointestinal and renal toxicity. Use with other NSAIDs, corticosteroids or nephrotoxic medication should be avoided. EQUIOXX has not been tested in horses less than 1 year of age or in breeding horses, or pregnant or lactating mares. For additional information please refer to the prescribing information or visit www.equioxx.com.

Data on file at Merial, “Clinical Experience Report, PHN 471, Target Animal Safety Evaluation, Firocoxib (ML-1,785,713) Oral Paste for Horses.”

American Quarter Horse Association. Show rules & regulations. Official Handbook of Rules and Regulations. 2008:128.

Available at: http://www.aqha.com/association/registration/pdf/showrules_08.pdf. Accessed February 1, 2008.

3 United States Equine Federation. Drugs and Medications Guidelines. 2007:2-3.

Available at: http://www.usef.org/documents/competitions/2007/2007DrugsMedsGuidelines.pdf. Accessed February 13, 2008.

4 Doucet MY, et al. Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. Journal of the American Veterinary Association 2008;232(1):91-97.

5 Data on file at Merial, Safety Studies, PR&D 0016801 and PR&D 0030701.

1 2

See Page 12 for Product Information Summary 1-888-MERIAL-1

Circle 139 on Reader Service Card

®EQUIOXX is a registered trademark of Merial. ©2008 Merial Limited. Duluth, GA. All rights reserved. LAGEEQX810 (3/08)

EQUIOXX® (firocoxib) Oral Paste for Horses Non-steroidal anti-inflammatory drug for oral use in horses only.

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Indications: EQUIOXX® Oral Paste is administered for up to 14 days for the control of pain and inflammation associated with osteoarthritis in horses.

Contraindications: Horses with hypersensitivity to firocoxib or other NSAIDs should not receive EQUIOXX® Oral Paste.

Warnings: For oral use in horses only. Do not use in horses intended for human consumption.

Human Warnings: Not for use in humans. Keep this and all medications out of the reach of children. Consult a physician in case of accidental ingestion by humans.

Animal Safety: Client should be advised to observe for signs of potential drug toxicity and be given a Client Information Sheet with each prescription.

For technical assistance or to report suspected adverse events, call 1-877-217-3543.

Precautions: Horses should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests should be conducted to establish hematological and serum biochemical baseline data before and periodically during administration of any NSAID. Clients should be advised to observe for signs of potential drug toxicity and be given a Client Information Sheet with each prescription.

See Information for Owner or Person Treating Horse section of this package insert.

Treatment with EQUIOXX® should be terminated if signs such as inappetence, colic, abnormal feces, or lethargy are observed.

As a class, cyclooxygenase inhibitory NSAIDs may be associated with renal and gastrointestinal toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Patients at greatest risk for adverse events are those that are dehydrated, on diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Concurrent administration of potentially nephrotoxic drugs should be carefully approached or avoided. NSAIDs may inhibit the prostaglandins that maintain normal homeostatic function. Such anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease that has not been previously diagnosed. Since many NSAIDs possess the potential to produce gastrointestinal ulcerations, concomitant use with other antiinflammatory drugs, such as NSAIDs or corticosteroids, should be avoided or closely monitored. The concomitant use of protein bound drugs with EQUIOXX® Oral Paste has not been studied in horses. The influence of concomitant drugs that may inhibit the metabolism of EQUIOXX® Oral Paste has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy.

Clinical Snapshot Particularly intriguing or difficult cases

Case Presentation #1 ❯❯ Gal Kelmer, DVM, MS, DACVS, The University of Tennessee An 8-year-old Quarter horse mare presented to the Koret Veterinary Medicine Teaching Hospital in Israel for evaluation of colic. The mare had been exhibiting signs of abdominal pain since early that morning, and the referring veterinarian had treated her with flunixin meglumine and replacement fluids administered via a nasogastric tube. Because the mare had not responded to initial therapy, she was referred for further evaluation and treatment. On presentation at the hospital, the mare had a distended abdomen and was consistently pain-

ful; a gas-distended colon was noted during rectal palpation. Exploratory celiotomy was performed. In addition to left dorsal displacement of the large colon with a nonstrangulating (180˚) volvulus, a lesion (A) was noted.

1. What diagnosis should be made?

2. What clinical signs are typically associated with this lesion?

3. What secondary problems may be caused by this lesion?

4. What treatment options are available for this problem?

SEE PAGE 14 FOR ANSWERS AND EXPLANATIONS.

A

The safe use of EQUIOXX® Oral Paste in horses less than one year in age, horses used for breeding, or in pregnant or lactating mares has not been evaluated.

Consider appropriate washout times when switching from one NSAID to another NSAID or corticosteroid.

Adverse Reactions: In controlled field studies, 127 horses (ages 3 to 37 years) were evaluated for safety when given EQUIOXX® Oral Paste at a dose of 0.045 mg/lb (0.1 mg/kg) orally once daily for up to 14 days. The following adverse reactions were observed. Horses may have experienced more than one of the observed adverse reactions during the study.

Adverse Reactions Seen In U.S. Field Studies

Adverse Reactions

EQUIOXX n=127

Active Control n=125

Abdominal pain

0

1

Diarrhea

2

0

Excitation

1

0

Lethargy

0

1

Loose stool

1

0

Polydipsia

0

1

Urticaria

0

1

EQUIOXX® (firocoxib) Oral Paste was safely used concomitantly with other therapies, including vaccines, anthelmintics, and antibiotics, during the field studies.

Information for Owner or Person Treating Horse: You should give the Client Information Sheet to the person treating the horse and advise them of the potential for adverse reactions and the clinical signs associated with NSAID intolerance.

Adverse reactions may include erosions and ulcers of the gums, tongue, lips and face, weight loss, colic, diarrhea, or icterus. Serious adverse reactions associated with this drug class can occur without warning and, in rare situations, result in death.

Clients should be advised to discontinue NSAID therapy and contact their veterinarian immediately if any of these signs of intolerance are observed. The majority of patients with drug-related adverse reactions recover when the signs are recognized, drug administration is stopped, and veterinary care is initiated.

Storage Information: Store below 86°F (30°C). Brief excursions up to 104°F (40°C) are permitted.

How Supplied: EQUIOXX is available in packs of 20, 72 and 216 individually-boxed syringes. Each syringe contains 6.93 grams of EQUIOXX® paste, sufficient to treat a 1250 lb. horse.

For technical assistance or to report suspected adverse reactions, call 1-877-217-3543.

NADA 141-253, Approved by FDA EQUIOXX is a registered trademark of Merial Limited, Duluth, Georgia, USA. ® 1050-2012-01 Rev. 02-06 Copyright© 2006 Merial Limited. All Rights Reserved.

U.S. Pat. No.: 5981576, 6020343

SHARE YOUR PICTUREPERFECT CASES IN CLINICAL SNAPSHOT

Challenge your colleagues with a particularly intriguing or difficult case in Clinical Snapshot. Submit your photo(s) along with a brief case description, at least one test question, and detailed answers to each question posed. Each published submission entitles you to an honorarium of $100.

For more details, call 800-426-9119, extension 52434, or email editor@CompendiumEquine.com.

12

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They say having the right tool is keyy for any job. job Consider Cons sider irap thera therapy py your power tool t for lamene lameness. ss.

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ound the world for a variety of iinflammatory nflammatory conditions, inc irapTM ther therapy rapy is used in horses ar around including luding joint muscle approach patient’s own lameness,, tendon, ligament and musc le injuries. This innovative ap pprroach o uses the patient patient’ s ow wn blood as therapeutic syringe produces conditioned (ACS),, whic which a therapeu utic tool. The patented syrin ge pr ro oduces autologous con nditioned serum (ACS) ch contains your beneficial anti-inflammatory and rregenerative ege e enerative cytokines. For more mo ore information contact y our distributor distributor sales orr c call Dechra Customer Service att 1 1-866-933-2472. s ales rrepresentative epresentative o all D echra C ustomer S ervice a -866-933-2472.

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Circle 149 on Reader Service Card

Clinical Snapshot Answers and Explanations Case Presentation #1 SEE PAGE 12 FOR CASE PRESENTATION.

A

1. Mesodiverticular band. The band is

4. Typically, the lesion is benign and

a remnant of the embryonic vitelline artery, which supplies blood from the aorta to the yolk sac. Consequently, it is a congenital anomaly that is typically found at the distal jejunum as a thin band of connective tissue between the mesentery and the antimesenteric portion of the serosal surface.

2. In most cases, a mesodiverticular band is an incidental finding that does not cause any clinical signs, as in this case.

3. Small intestinal volvulus and small intestinal strangulation by the band.1

no treatment is necessary. In this case, when the small intestine was decompressed, the band seemed to impede movement of fluid along the lumen of the jejunum; therefore, the band was removed. When the band causes small intestinal strangulation, resection and anastomosis may be indicated according to the viability of the intestine involved.

Reference 1. Abutarbush SM, Shoemaker RW, Balley JV. Strangulation of the small intestine by a mesodiverticular band in three adult horses. Can Vet J 2003;44:1005-1006.

3 CE Contact Hours | CompendiumEquine.com | Peer-Reviewed

Coming Soon in Compendium Equine

Managing

Foal Diarrhea FREE E

CE E

Pathophysiology of

Osteoarthritis O Osteoarthriti Clinical Snapshot

3

FR

N

FO EE ow R C off EA o CH nta erin CE c g AR t TI Ho CLE u ! rs

` The First Premolar Teeth ` Stifle Ultrasonography ` Shock-Wave Therapy

Vol 4(1) January/February 2009

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Managing Foal Diarrhea ❯❯ Laurie Beard, DVM, MS, DACVIM Kansas State University

At a Glance Initial Management Page 16

Diagnostic Testing for Common Pathogens Page 17

Specific Treatments Page 18

Common Medications for Foal Diarrhea Page 20

Prevention and General Management Page 23

16

D

iarrhea is a common problem in foals, most of which experience one episode of diarrhea before they are 6 months of age. In most of these cases, the diarrhea is mild and medical treatment may not be necessary.

In other cases, the diarrhea is severe with accompanying clinical signs of sepsis and septic shock, requiring aggressive medical treatment. The most common noninfectious causes of diarrhea in foals include foal heat and nutritional or dietary factors. The most common infectious causes of diarrhea in foals include rotavirus, Salmonella spp, Clostridium perfringens (types A and C are the most common), or Clostridium difficile. Less common causes of infectious diarrhea include coronavirus, Cryptosporidium parvum, other anaerobic bacteria, or Strongyloides westeri. Escherichia coli infection is a common cause of neonatal septicemia and is often listed as a cause of diarrhea in foals. However, the identification of enterotoxigenic E.

coli is rare in foals, and E. coli is considered normal flora. The exact role of E. coli in equine neonatal diarrhea has not been determined. In addition to the pathogens already listed, infection with Lawsonia intracellularis (resulting in proliferative enteropathy) or parasites commonly causes diarrhea in older foals and weanlings. Rhodococcus equi infection can result in diarrhea in older foals but is uncommon. This article focuses on managing the most common causes of diarrhea in foals (from neonates to weanlings). Diagnostic testing for common pathogens that result in diarrhea in foals is discussed because diagnosis plays an important role in choosing the correct treatment and preventing outbreaks.

Initial Management The initial management of foal diarrhea should be based on the patient’s signalment, history, and physical examination.

The foal’s signalment provides impor-

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

©2009 Sebastian Knight/Shutterstock com

Therapeutics in Practice

©2009 Sebastian Knight/Shutterstock.com

Managing Foal Diarrhea tant information for determining the etiology.

For example, foal heat is the most common cause of diarrhea in foals 5 to 10 days of age.

However, foals younger than 1 week have an increased risk for sepsis resulting from Salmonella, rotavirus, or clostridial infections. A history of diarrhea in other foals on the premises is highly suggestive of an infectious and contagious pathogen. The onset of diarrhea coincident with or following antimicrobial administration is suggestive of C. difficile infection. C. difficile is associated with antimicrobial use but can also be a primary pathogen in foals.1 A history of an inadequate deworming regimen in an older foal or weanling might suggest parasitism as a likely cause of diarrhea.

A thorough physical examination is important for assessing the foal’s condition and determining the appropriate treatment. For example, a bright, alert, afebrile 7-day-old foal that is nursing readily and has soft feces likely has foal heat diarrhea and requires minimal intervention. In contrast, a weak, depressed, recumbent foal with pipe-stream diarrhea requires significant intervention. A foal with diarrhea and clinical signs such as fever, depression, anorexia, and colic requires medical attention. To create a minimum database, blood should be collected to obtain a complete blood count, serum chemistry profile, and fibrinogen concentration. Additional diagnostic testing should include collection of feces for specific pathogen testing, assessment of passive transfer (the IgG concentration) in neonates, blood culture (aerobic and anaerobic), and arterial blood gas sampling.

Characterization of the foal’s diarrhea is imperative to diagnosis. Neonatal foals nursing from their dams have dog-like feces and usually have one or two bowel movements per day. Hemorrhagic diarrhea is strongly suggestive of clostridial enterocolitis. In contrast to diarrhea caused by other pathogens, clostridial diarrhea is usually not associated with failure of passive transfer.1,2 There is an increased risk of bacteremia in neonatal foals with Salmonella infections. Therefore, Salmonella spp should be high on the differential list for a neonate with diarrhea and septic arthritis.

In many cases, the diarrhea associated with Salmonella, rotavirus, or clostridial infection is clinically indistinguishable, and all three

possibilities should be considered. L. intracellularis infection should be high on the differential list for a 4- to 7-month-old foal with weight loss, edema, hypoproteinemia, and hypoalbuminemia. Abdominal ultrasonography (especially of foals with abdominal pain) can help assess bowel motility, detect distention of the small intestine, and measure bowel wall thickness. Abdominal ultrasonography of foals with clostridial enterocolitis may reveal gas and fluid-filled loops of large and small intestine. Segmental, marked thickening (6 to 12 mm; normal jejunum: 3 mm) of small intestine is often detected in foals infected with L. intracellularis. While not seen commonly, “dummy” foals with neonatal encephalopathy may develop necrotizing enterocolitis and segmental intestinal lesions with diarrhea.

Diarrhea is a common problem in foals. Medical management of diarrhea in foals with accompanying clinical signs of sepsis and septic shock requires aggressive treatment.

Diagnostic Testing for Common Pathogens Diagnostic testing is useful in managing foal diarrhea because some pathogens require specific treatment (TABLE 1). Diagnostic tests for Salmonella spp include fecal cultures (five serial fecal samples) and/or polymerase chain reaction (PCR) analysis of feces. Five serial fecal samples that test negative are considered the gold standard to rule out Salmonella infection. PCR is more sensitive for detecting Salmonella spp, requires less time than culture, and requires only one fecal sample; however, PCR techniques have limitations, including false-positive results and the inability to differentiate between live and inactivated organisms. Bacterial culture and sensitivity testing of Salmonella spp enables clinicians to choose the most appropriate antimicrobial treatment.

Diagnostic tests for clostridial enterocolitis include fecal culture and toxin analysis. Toxin analysis is probably more important because there are nontoxigenic strains of C. difficile and C. perfringens, and it is often difficult to grow

CriticalPo nt A thorough physical examination is important for assessing the foal’s condition and determining the appropriate treatment. For example, a bright, alert, afebrile 7-dayold foal that is nursing readily and has soft feces likely has foal heat diarrhea and requires minimal intervention.

CompendiumEquine.com | January/February 2009 | Compendium Equine: Continuing Education for Veterinarians ®

17

Therapeutics in Practice TABLE 1

Foal Diarrhea: Associated Pathogens, Specific Diagnostic Tests, and Treatment

PATHOGEN

SPECIFIC DIAGNOSTIC TEST(S)

TREATMENT

Clostridium difficile

Anaerobic fecal culture (toxigenic and nontoxigenic strains; can be difficult to culture; requires an anaerobic culture tube)

Metronidazole

Toxin analysis (PCR or ELISA) Clostridium perfringens

Anaerobic fecal culture (types A and C are most common; type A is also normal flora; type C is not commonly detected in normal foals and horses; requires an anaerobic culture tube)

Metronidazole and C. perfringens types C and D antitoxin

Toxin analysis (ELISA to detect enterotoxin): unknown significance at this time Lawsonia intracellularis

PCR testing of feces (false-negative results have been reported)

Tetracycline (oxytetracycline or doxycycline) Macrolides and chloramphenicol have also been used

Serology (false-negative results have been reported) Rotavirus

Electron microscopy

Supportive

ELISA or latex agglutination Salmonella spp

Five serial fecal cultures (results of sensitivity testing can help in choosing an antimicrobial)

Blood culture (neonate)

Broad-spectrum antimicrobials, but, if possible, select specific antimicrobials for Salmonella spp (aminoglycosides [gentamicin and amikacin], thirdgeneration cephalosporin [ceftiofur]) cultured in a fecal or blood sample

Fecal egg count or presence of larvae in feces

Fenbendazole

PCR testing

Small strongyles

CriticalPo nt In neonatal foals or foals younger than 6 months with diarrhea accompanied by signs of sepsis (e.g., depression, lack of nursing, fever, hypothermia), broad-spectrum antimicrobials are indicated because of the risk of bacterial translocation across the compromised gastrointestinal (GI) barrier and possible bacteremia.

18

the anaerobic Clostridium spp in culture. Toxin analysis for C. difficile (toxins A and B) can be conducted using commercial immunoassays (ELISA) or PCR. Diagnosis of C. perfringens is more difficult. There is debate over exactly which toxin results in disease, and C. perfringens type A is also considered normal flora in foals and horses.3 C. perfringens type C is rarely found in the feces of normal horses and foals and results in more severe diarrhea than does type A.1–3 A commercial ELISA is available for detecting C. perfringens enterotoxin, but the importance of this toxin is unknown.1–3 Anaerobic culture of C. perfringens is recommended. The isolate should be typed by PCR analysis for toxin gene sequences.

Diagnosis of rotavirus can be made by commercial assays (latex agglutination and ELISA) or electron microscopy. Electron microscopy can also identify less common viral pathogens, such as coronavirus. Further diagnostic tests for L. intracellularis include serology and PCR

analysis of feces, but false-negative results have been reported.4 Parasitic infections that result in diarrhea in foals older than 3 months commonly include cyathostomes (small strongyles).

Diagnosis of diarrhea due to small strongyles can be difficult because fecal egg counts can be low or negative as a result of prepatent or hypobiotic infection.

Specific Treatments In neonatal foals or foals younger than 6 months with diarrhea accompanied by signs of sepsis (e.g., depression, lack of nursing, fever, hypothermia), broad-spectrum antimicrobials are indicated because of the risk of bacterial translocation across the compromised gastrointestinal (GI) barrier and possible bacteremia.1 Intravenous (IV) administration of antimicrobials is usually necessary in neonatal foals because of their small muscle mass and the long duration of antimicrobial administration. Commonly used antimicrobials include

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

Managing Foal Diarrhea aminoglycosides (e.g. amikacin) and penicillin Fluid Therapy (TABLE 2). The aminoglycoside gentamicin is In mild cases of diarrhea, normal hydration not recommended in foals, especially critically of foals may be maintained by nursing or by ill neonatal foals, because of potential nephro- administration of oral fluids. Severely affected toxicity. Third-generation cephalosporins such foals are often unable to maintain hydration as ceftiofur sodium are an alternative. A high without additional support, and neonatal foals dose of ceftiofur sodium in neonatal foals is are more likely than older foals to require IV recommended by some clinicians5 (TABLE 2). fluid therapy. Assessment of hypovolemia is Foals are at greater risk for bacteremia and more difficult in neonatal foals than in adult sepsis due to Salmonella spp; therefore, anti- horses, but clinical signs include dry, tacky oral microbials effective against Salmonella spp mucous membranes, tachycardia, a prolonged (usually aminoglycosides or third-generation capillary refill time (>2 seconds), sunken eyes, cephalosporins) are recommended. a poor pulse rate, and decreased urine proMetronidazole is recduction. Prolonged skin ommended for treating tenting can be difficult clostridial colitis.1,2 There to observe in neonates Nonspecific treatment are reports of metronidabecause of poor skin of diarrhea in foals often zole-resistant C. difficilee turgor. Further assessisolates from foals in cerment of hydration can includes administration tain geographic locations.6 be based on daily body Vancomycin is an antimiweight (weight loss or of intravenous fluid crobial commonly used to failure to gain weight therapy, antimicrobials, treat humans with C. difm ay i nd ic ate hy p o ficile; however, because off volemia) and laboraand intestinal protectants concerns of development tory data (packed cell and absorbents. of resistance to vancomyvolume; total protein, cin, particularly among albumin, and ser um multidrug-resistant bactecreatinine concentraria, vancomycin should be used very carefully tions; and urine specific gravity). Reliance on in veterinary patients.1,6 Other reported thera- serum total protein alone can be misleading pies for clostridial enterocolitis include the off- because of the effects of passive transfer, loss label use of C. perfringens C and D antitoxin of protein from the GI tract, or elevation of (oral and IV administration),2 although its effi- globulin and fibrinogen concentrations due to cacy in foals is unknown. It is recommended inflammation or infection. The serum creatithat the antitoxin be given very slowly (and nine concentration usually increases because diluted in saline or lactated Ringer’s solution). of hypovolemia but can also be increased Pretreatment with diphenhydramine is recom- in renal failure or in newborn foals born to mended by some clinicians.2 mares with placental insufficiency. If renal Antimicrobial choices recommended for function is normal, the urine specific gravtreating L. intracellularis include oxytetracy- ity can be useful. Neonatal foals usually have cline, doxycycline, macrolides (erythromycin, dilute urine (e.g., 1.001 to 1.002) in response azithromycin, and clarithromycin, with or with- to their diet of milk with a high water conout rifampin), and chloramphenicol.7 I prefer tent. A urine specific gravity greater than 1.020 oxytetracycline or doxycycline because of their indicates that fluid losses are not being met. low cost and reduced risk of diarrhea compared Hospitalization (or referral) is recommended with that associated with macrolides (especially for foals with diarrhea severe enough to warerythromycin) and because of human health rant IV fluid therapy. concerns associated with chloramphenicol.7 A A detailed discussion on the use of IV fluids suspected small strongyle infection can be and treatment of electrolyte abnormalities in treated with a larvicide using fenbendazole for foals is beyond the scope of this article, but 5 days. Moxidectin (which may have larvicidal there are several articles on this subject.1,8 The efficacy against small strongyles) is not recom- ideal crystalloid fluids for reestablishing normal hydration include lactated Ringer’s solumended in foals younger than 4 months.

CriticalPo nt The aminoglycoside gentamicin is not recommended in foals, especially critically ill neonatal foals, because of potential nephrotoxicity.

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19

Therapeutics in Practice

TABLE 2

Common Medications for Foal Diarrhea

MEDICATION

DOSAGE

NOTES

REFERENCE

Amikacin

21–25 mg/kg IM or IV q24h (monitor peak and trough levels)

Amikacin is the preferred aminoglycoside in foals, but use it with caution, obtain half-hour peak levels to ensure the proper therapeutic level, and adjust the dose if necessary.

Magdesian5

Monitor renal values (e.g., creatinine, blood urea nitrogen, and 23-hr amikacin trough levels) before administration of a second dose.

Bismuth subsalicylate and kaolin/pectin

0.5–4 mL/kg PO q6–24h

—

Magdesian1

Ceftiofur sodium

4–10 mg/kg IM or IV q12h; 10 mg/kg IV q6h

—

Magdesian,5 Palmer8

Clostridium perfringens types C and D antitoxin

Off-label use: 50 mL in 1 L of fluid at a rate of 250 mL/hr up to 4 hr

—

MacKay2

and/or 50 mL PO once Di-tri-octahedral smectite (Bio-Sponge Powder, Platinum Performance)

3 tbsp (27.6 g) in 30 mL of water PO q6–12h; discontinue 1 day after resolution of clinical signs; discontinue after 7 days if there is no clinical improvement

—

Manufacturer’s recommendation for foals with intestinal disease

Doxycycline

10 mg/kg PO q12h

—

Sampieri et al7

Fenbendazole

10 mg/kg PO q24h for 5 days

—

—

Lactase

6000–9000 U/50-kg foal q3–8h

—

Magdesian1

Metronidazole

10–15 mg/kg PO q8–12h

Because metronidazole can cause depression, especially at higher doses, monitor mentation closely.

Magdesian,1 MacKay,2 Magdesian5

15–25 mg/kg PO q6ha 20–25 mg/kg PO q12h as crushed tablets in aqueous suspensionb Omeprazole

4 mg/kg PO q24h (not labeled for use in foals younger than 4 wk)

—

Magdesian1

Oxytetracycline

6.6 mg/kg IV q12–24h

—

Sampieri et al7

Penicillin (potassium)

20,000–40,000 IU/kg IV q6h

—

Magdesian1

Saccharomyces boulardii

10 × 109 PO q12h in adult horses; there are no published reports for foals; anecdotal use of 5 × 109 colony-forming units PO q12–24h

—

Desrochers et al11

Sucralfate

20 mg/kg PO q6h

—

Magdesian1

a

Sweeney RW, Soma LR, Woodward CB, Charlton CB. Pharmacokinetics of metronidazole given to horses by intravenous and oral routes. JAVMA 1986;47(8):1726-1729.

Baggot JD, Wilson WD, Hietela S. Clinical pharmacokinetics of metronidazole in horses. J Vet Pharmacol Ther 1988;11:417-420.

b

20

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

Managing Foal Diarrhea tion, Plasma-Lyte 148 (Baxter International), or Normosol-R (Abbott Laboratories). To correct hypovolemia in neonatal foals, administration of IV uid boluses (10 to 20 mL/kg [500 to 1000 mL for a 50-kg foal]) slowly (over 20 to 30 minutes) is recommended. Careful reevaluation of hydration status (clinical signs [e.g., mentation, pulse quality, distal limb temperature], laboratory data, and urine production) is recommended after administration of each bolus.

Often, critically ill neonatal foals with severe diarrhea appear comatose and recumbent; however, after a few liters of IV uids, the foals can sit in sternal recumbency or stand and become bright and alert. IV uids are often continued to provide maintenance and replace ongoing losses. Maintenance uid rates for neonates younger than 60 days are approximately 80 to 120 mL/kg/day (approximately 4 to 5 L for a 50-kg foal); these rates decrease to 60 mL/kg/day for foals older than 60 days. The ongoing uid losses are difďŹ cult to determine in foals with diarrhea but can be estimated by the frequency, amount, and consistency of feces. If the ongoing losses are signiďŹ cant, uids are often delivered at two to three times

maintenance to maintain hydration. In many instances, uids are given as a bolus because the foal is in the same stall with the mare. This p y in ambulatory y foals should be attempted only

Diagnosis of the cause of diarrhea in foals is important because certain pathogens require speciďŹ c therapies. The most common infectious causes of diarrhea in foals include rotavirus, Salmonella spp, Clostridium perfringens, Clostridium difďŹ cile, Lawsonia intracellularis, and internal parasites.

CriticalPo nt To correct hypovolemia in neonatal foals, administration of IV uid boluses (10 to 20 mL/kg [500 to 1000 mL for a 50-kg foal]) slowly (over 20 to 30 minutes) is recommended.

Careful reevaluation of hydration status (clinical signs [e.g., mentation, pulse quality, distal limb temperature], laboratory data, and urine production) is recommended after administration of each bolus.

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Therapeutics in Practice

CriticalPo nt Foals with diarrhea should be isolated from healthy mares and foals. It is important to practice good hygiene (e.g., foot baths) and wear protective clothing (e.g., gloves, disposable gowns or coveralls). Salmonella and clostridial organisms are also human pathogens; therefore, hand washing with antimicrobial soap or the use of an alcohol-based hand sanitizer is required for people handling foals with diarrhea.

22

that are not septic. If the foal is severely ill or recumbent, it should be separated from the mare to allow constant-rate infusion of fluids.

Withholding or restriction of milk should be considered in foals with severe clostridial enterocolitis, colic, abdominal distention, and ileus.1 If milk is withheld or restricted, the administration of partial or total parenteral nutrition is necessary.1 Significant electrolyte and acid–base abnormalities are very common in foals with severe diarrhea; therefore, frequent laboratory testing (complete blood count, serum chemistry profile, arterial blood gas analysis) may be necessary to facilitate proper therapy and provide additional treatment, such as sodium bicarbonate therapy, when needed.

Plasma and Colloids Plasma (1 to 2 L in a 50-kg foal) and synthetic colloids (e.g., hetastarch) are useful for increasing oncotic pressure and maintaining circulatory volume in foals with hypoproteinemia (<4 g/dL) and hypoalbuminemia (<2 g/dL).

The foal’s temperature, pulse, and respiration should be monitored closely during a plasma transfusion, and plasma should be delivered slowly to monitor for potential anaphylactic reactions. Plasma has additional benefits, including provision of antibodies (it is indicated in neonates with failure of passive transfer), clotting factors, antithrombin, and other proteins. Oral and IV plasma and hyperimmunized plasma (which is from horses vaccinated against clostridial toxins and Salmonella spp) may also help treat sepsis and endotoxemia.1

Antiinflammatory and Antiendotoxic Medications The careful use of NSAIDs such as flunixin meglumine is indicated to provide analgesia and decrease inflammation, fever, and the effects of endotoxin; however, it is not recommended in foals younger than 1 month because of potential nephrotoxicity. NSAID use is not without risk, as it potentially reduces GI mucosal perfusion and decreases epithelial migration and healing.1 Therefore, it is important to avoid these drugs in volume-depleted foals or to use small doses (0.25 to 0.5 mg/kg q8–12h) as infrequently as possible.1 Polymyxin B, which is commonly given to adult horses to

treat endotoxemia, is not used frequently in neonates because of concerns of nephrotoxicity (many septic foals present with azotemia).

Intestinal Protectants and Absorbents Commonly used GI protectants include bismuth subsalicylate and kaolin/pectin products.1 Bismuth is used to coat the mucosa, and subsalicylate has some antiprostaglandin activity. Kaolin/pectin acts primarily as a mucosal binding agent. It is best to stagger administration of these medications with other oral drugs to avoid nonspecific binding and a reduction in bioavailability.1 Di-tri-octahedral (DTO) smectite, a commercially available natural hydrated clay silicate consisting of sheets of aluminum and magnesium, is effective for managing infectious colitis in humans and other animals. Two recent publications document that DTO smectite binds the exotoxins of C. difficile (toxins A and B) and C. perfringens (α-, β-, and β2-toxin and enterotoxin) to endotoxin in foals.9,10 The administration of DTO smectite should be withheld until at least 6 hours after ingestion of good-quality colostrum in foals younger than 24 hours because it may interfere with colostral absorption.10 Foals with rotavirus and clostridial enterocolitis can develop lactase deficiency secondary to the loss of the small intestinal brush border1; therefore, the use of lactase enzyme may be beneficial in these patients.

The routine use of prophylactic gastric antiulcer medications is controversial in foals.

However, in foals with diarrhea severe enough to necessitate treatment, the use of antiulcer medications may be indicated. Omeprazole, a very effective antiulcer drug, is widely used in foals; however, it is not labeled for use in foals younger than 4 weeks.1 The use of sucralfate could also be considered for treating gastric and other GI ulcers because it binds ulcers, increases local prostaglandin production, and increases local blood flow. Anecdotally, sucralfate also improves fecal consistency and may lead to constipation if given to a foal after diarrhea has resolved.

Probiotics Probiotic administration is popular for treating colitis in horses. Until recently, the use of commercial probiotics in equine medicine was not

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

Managing Foal Diarrhea

supported by clinical studies. Saccharomyces boulardii, a nonpathogenic yeast, has been beneficial for preventing and treating colitis in humans. In a recent prospective, blinded, randomized study in adult horses with colitis, treatment with S. boulardii decreased the severity and duration of diarrhea.11 Cautious use of probiotics in foals (particularly those younger than 24 hours) has been suggested because of concerns of potential bacterial and fungal translocation.1 The use of S. boulardii has not been critically evaluated in foals, but some clinicians, including me, have used it in foals older than 1 week with diarrhea at a dose of 5 × 109 colony-forming units PO q12h.2

Prevention and General Management Foals with diarrhea should be isolated from healthy mares and foals. It is important to practice good hygiene (e.g., foot baths) and wear pro-

tective clothing (e.g., gloves, disposable gowns or coveralls). Salmonella and clostridial organisms are also human pathogens; therefore, hand washing with antimicrobial soap or the use of an alcohol-based hand sanitizer is required for people handling foals with diarrhea.

CONTINUED ON PAGE 26

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Therapeutics in Practice CONTINUED FROM PAGE 23

There are several commonly used disinfectants, each with different properties and antimicrobial spectrums.

However, bleach or hypochlorite (recommended dilution of household bleach: 1:10) has a wide range of germicidal activity. Bleach is inactivated by organic matter and is not effective against rotavirus. Bleach is the most available sporicidal disinfectant, and its use should be considered (after cleaning to remove organic matter) in outbreaks of clostridial colitis. Phenolic disinfectants have broad germicidal activity against bacteria, viruses (including rotavirus), and fungi.

Phenolic compounds are active in the presence of organic matter but are not sporicidal. Peroxygen compounds are newer disinfectants that are effective against a wide range of organisms and are not inactivated by organic matter. According to the manufacturer of Virkon S (DuPont), this peroxygen compound is also effective against bovine rotavirus and clostridial spores.

Prevention of rotavirus outbreaks includes the use of a rotavirus vaccine during gestation (months 8, 9, and 10). Recommendations for preventing clostridial enterocolitis include the use of metronidazole (on newborn foals for 2 weeks), S. boulardii, and DTO smectite2; however, the prophylactic and widespread use of metronidazole in horses is not without con-

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Conclusion Medical management of foals with diarrhea depends on the severity of the diarrhea and clinical signs. Foals with mild diarrhea and an otherwise normal physical examination can be managed with appropriate hygiene measures and careful monitoring of clinical signs. The use of bismuth subsalicylate, kaolin/pectin, sucralfate, DTO smectite, and S. boulardii may be beneficial in these cases. For foals with mild diarrhea that does not require extensive medical treatment, diagnostic testing for infectious (and contagious) pathogens may be helpful in preventing outbreaks of infectious diarrhea (such as on a large broodmare farm). For foals with diarrhea, clinical signs of sepsis, and hypovolemia, hospitalization, with frequent monitoring and aggressive fluid therapy, is often necessary.

References

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cern.6 Treatment with metronidazole predisposes horses to colonization of metronidazole-resistant strains of C. difficile.6 Administration of C. perfringens types C and D antitoxin to foals younger than 6 hours on farms with a history of C. perfringenss diarrhea has been recommended.2 Additional recommendations include vaccination of pregnant mares with C. perfringens C and D toxoid, but the safety and efficacy are unknown.2

12/12/08 1:42:26 PM

1. Magdesian KG. Neonatal foal diarrhea. Vet Clin North Am 2005;21:295-312.

2. MacKay RJ. Equine neonatal clostridiosis: treatment and prevention. Compend Contin Educ Pract Vet 2001;23:280-284.

3. Tillotson K, Traub-Dargatz JL, Dickinson CE, et al.

Population-based study of fecal shedding of Clostridium perfringenss in broodmares and foals. JAVMA 2002;220:342-348.

4. McGurrin MK, Vengust M, Arroyo LG, Baird JD. An outbreak of Lawsonia intracellulariss infection in a standardbred herd in Ontario. Can Vet J 2007;48:927-930.

5. Magdesian KG. Neonatal pharmacology and therapeutics. In: Current Therapy in Equine Medicine. 5th ed. St. Louis: Saunders; 2003:1-5.

6. Magdesian KG, Dujowich M, Madigan JE, et al.

Molecular characterization of Clostridium difficilee isolates from horses in an intensive care unit and asso-

26

ciation of disease severity with strain type. JAVMA 2006;228:751-755.

7. Sampieri S, Hinchcliff KW, Toribio RE. Tetracycline therapy of Lawsonia intracellulariss enteropathy in foals. Equine Vet J 2006;38:89-92.

8. Palmer JE. Fluid therapy in the neonate: not your mother’s fluid space. Vet Clin Equinee 2004;20:63-75.

9. Weese JS, Cote NM, deGannes RV. Evaluation of in vitro properties of di-tri-octahedral smectite on clostridial toxins. Equine Vet J 2003;35:638-641.

10. Lawler JB, Hassel DM, Magnuson RJ, et al. Adsorptive effects of di-tri-octahedral smectite on Clostridium perfringenss alpha, beta, and beta-2 exotoxins and equine colostral antibodies. Am J Vet Res 2008;69:233-239.

11. Desrochers AM, Dolente BA, Roy MF, et al. Efficacy of Saccharomyces boulardiii for treatment of horses with acute enterocolitis. JAVMA 2005;227:954-959.

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• A searchable online archive of features, columns, and departments • FREE online CE • Past CE results right at your fingertips • Web-exclusive videos and News Bits

3 CE CREDITS

CE Article 1

Pathophysiology of Osteoarthritis ❯❯ Jorge U. Carmona, MVZ, MSc, PhD Universidad de Caldas, Colombia Universitat Autònoma de Barcelona, Spain

❯❯ Marta Prades, DVM, PhD, DACVS, DECVS Universitat Autònoma de Barcelona, Spain

Abstract: Osteoarthritis (OA) in horses is a chronic, degenerative process. Affected horses typically have clinical evidence of synovitis, varying degrees of lameness, and progressive loss of joint function. The inciting cause of OA remains unclear; however, factors such as repeated episodes of trauma, joint instability, synovitis–capsulitis, hypoxia and neovascularization, genetic predisposition, and obesity have been related to its development. The biochemical mediators that are synthesized in affected joints are of an inflammatory nature and include catabolic cytokines and enzymes that degrade cartilage and subchondral bone matrix. Although horses with OA can be recognized clinically and treated symptomatically, it is also important for clinicians to understand the cellular and molecular mechanisms involved in the pathologic process.

A thorough understanding of the pathophysiology of the disease can aid clinicians in managing osteoarthritic patients.

O

At a Glance Pathogenic mechanisms Page 28

Biochemical events and pathobiologic consequences Page 30

Catabolic molecules Page 31

Anabolic molecules Page 36

28

steoarthritis (OA), also known as degenerative joint disease, is the most common joint disease that affects humans,1 horses,2,3 and dogs.4 OA is a chronic, degenerative process characterized by progressive cartilage deterioration, subchondral bone remodeling, loss of joint space, marginal osteophytosis, and loss of joint function.1–5 Although the etiology of OA may differ across species or among individuals within a species, some components of the pathophysiology of the disease are consistent.1,3,4 Several theories have been proposed to explain the origin of this disease.

Independent of the initiating cause, however, the development of OA is consistently associated with a cascade of biochemical events mediated by cytokines, proteolytic enzymes, and other proinflammatory substances (e.g., prostaglandins, leukotrienes, nitric oxide). These mediators are responsible for the pathologic features of the disease, which include osteolysis, subchondral bone sclerosis, osteophytosis, articular cartilage erosion, and synovial membrane thickening.5–7 Irrespective of the initiating cause or initial point of injury, eventually all components of the joint become involved in the process. This article summarizes the relevant molecular

aspects of the etiopathogenesis of OA and potential therapeutic molecular targets for controlling this disease.

Pathogenic Mechanisms Several pathogenic mechanisms have been proposed to be involved in the development of OA. They include subchondral bone overload, joint instability (loss of mechanical integrity), synovitis–capsulitis, hypoxia, body mass index as it relates to obesity, and heredity.

Subchondral Bone Overload (Mechanical Stress) A typical finding in horses that exercise at speed is subchondral sclerosis of bone in joints subjected to high weight-bearing impact and shear forces (e.g., carpus and fetlock).3,5 It has been postulated that articular overload, especially of subchondral bone, produces microtrauma, remodeling, hardening, and displacement of the osteochondral line.5 These changes reduce the elasticity and energy-dissipation capacity of the articular cartilage during locomotion.3 Furthermore, the injured tissue fails to heal because of the combined effects of high-impact exercise protocols, a lack of adequate warm-ups and post-exercise stretching, inadequate development of

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

FREE

Pathophysiology of Osteoarthritis CE FIGURE 1

Oblique 60˚, caudolateral–craniomedial radiographic projection of the left femorotibial joint of a 9-year-old intact Andalusian stallion with chronic joint instability due to ligamentous injury.

Note the pronounced marginal osteophytosis on the proximal and caudal aspects (arrows) of the tibia.

proprioception, working musculoskeletal tissue while it is fatigued, poor neuromuscular training, and inadequate rest intervals.8 The results of these forces are mechanical lesions that affect the joint tissue and its extracellular matrix (ECM),3 which may account for the common finding of OA in fetlock joints of performance horses or in knee joints of human athletes.5 However, OA also affects non–weight-bearing joints, such as those in the hands, spine, shoulders, and temporomandibular joints in humans and other mammals.

Consequently, this theory does not completely explain the origin of these lesions, although either misalignment of articular surfaces or abnormalities of deep ligamentous components in the spinal and temporomandibular joints9 may result in abnormal load distribution.

Joint Instability (Loss of Mechanical Integrity) Joint instability can be due to increased ligament laxity, a tear or strain in a ligament (FIGURE 1), or poor conditioning of the muscles that affect the joints. An example of the latter is the increased incidence of OA in the

knees of humans with poor development of their quadriceps muscles.1 Training or racing can create episodes of increased joint laxity, especially when work is performed while an athlete is fatigued. It has been proposed that mechanoreceptors associated with joints lose their efficacy during fatigue, thereby impairing proprioceptive function and increasing the likelihood of injury.10 Joint instability can also occur as the result of intense synovitis that generates excessive amounts of synovial fluid.1,3,5 It has been postulated that the increase in pressure within the joint may produce direct mechanical cartilage damage and anomalous overload forces of subchondral bone regions, thereby perpetuating synovitis.3 In humans, subtle mechanical instability produced by partial traumatic transection of the cranial anterior ligament of the knee can produce OA changes 1 year after the traumatic event.11 This may also occur in horses with posttraumatic arthritis with subtle mechanical impairment of soft tissue periarticular structures. Joint instability is an important cause of OA and should always be considered in affected patients, especially sport horses.

CriticalPo nt Osteoarthritis, also known as degenerative joint disease, is the most common joint disease that affects humans, horses, and dogs.

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29

FREE CE Pathophysiology of Osteoarthritis

Osteoarthritis, a joint disease that affects a variety of species, is characterized by progressive loss of joint function, pain, cartilage destruction, subchondral bone remodeling, thickening of joint capsules, and increased synovial effusion.

Synovitis–Capsulitis The synovitis (i.e., histologic evidence of synovial membrane inflammation) that occurs in horses with OA 2,3,7 can be a primary phenomenon, a consequence of joint trauma or articular overload, or an aftereffect of intraarticular drug injection or infection.3,5,6 The cells that make up the synovial membrane are a rich source of several proinflammatory molecules that can incite and perpetuate articular deterioration if the underlying cause of the inflammation cannot be controlled.1 Because the synovial membrane provides no mechanical protection to the joint, trauma or inflammation of adjacent structures (e.g., joint capsule, ligaments, muscles, tendons) could initiate synovitis and the subsequent development of OA.3,5,6

Hypoxia

CriticalPo nt At the molecular level, OA is the result of an imbalance between the peptides that promote the synthesis of components of the ECM of articular cartilage and those that induce remodeling of these components.

30

A consistent finding during the development of OA is neovascularization, which initially involves the synovial membrane and subsequently the subchondral bone and cartilage.6,7 Although this ingrowth of new vessels increases the delivery of nutrients to the stressed articular cartilage and subchondral bone,1,6 it also contributes to the development of synovitis. In humans, hypoxia is a common component in the pathophysiology of OA and rheumatoid arthritis because the oxygen gradient across articular cartilage may be altered as a result of cartilage thinning and erosion, changes in ECM composition, and the development of cartilage fissures.12 In OA and rheumatoid arthritis, exaggerated expression and limited degradation of two nuclear hypoxia-inducible factors (α1 and α2) occur. The resulting increase in these factors promotes the expression of two angiogenic peptides called vascular endothelial growth

ffactor and platelet-derived cellular endothelial growth factor. Both peptides increase neovascularization and promote vascular permeability in the joint tissue, resulting in edema, protein vascular leakage, inflammation, and cartilage damage.6,12

Body Mass Index/Leptin Leptin, a cytokine produced by white adipocytes, regulates appetite, energy expenditure, and the activity of the physes and the metabolism of bone. Leptin also promotes cellular proliferation and increases the metabolic activity of chondrocytes.9 It has recently been demonstrated that the plasma concentration of leptin is positively correlated with body mass index in humans with OA.13 Furthermore, increased plasma concentration of leptin has been shown to correlate positively with the severity of articular damage in rats.13 To date, there are no reported studies regarding the role of leptin in OA in horses. However, leptin is positively correlated with a high body mass index (obesity) in horses.14

Hereditary Osteoarthritis In humans, OA occurs as a consequence of a genetic defect in collagen type-II (Col-II) assemblage, and there has been speculation regarding genetic mutations in other collagentype codifying genes.15 To date, there is no evidence of a genetic basis for the development of OA in horses.

Biochemical Events and Pathobiologic Consequences At the molecular level, OA is the result of an imbalance between the peptides that promote the synthesis of components of the ECM of articular cartilage and those that induce remodeling of these components. It has been proposed that the overall health of a joint depends on adequate expression of several growth factors.2,4,7 For example, transforming growth factor β (TGF-β)16,17 and insulin-like growth factors (IGFs)18–20 increase synthesis of the ECM. In contrast, cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) promote chemotaxis and degranulation of leukocytes and increased expression of additional proinflammatory mediators, including prostaglandin E2 (PGE2), leukotriene B4 (LTB4), bradykinin, and nitric oxide.1–4

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Pathophysiology of Osteoarthritis CE TABLE 1

Catabolic Cytokines Involved in Equine and Human Osteoarthritis

CYTOKINE

SPECIES

NATURAL SOURCE

STIMULUS

INHIBITION

MECHANISM OF ACTION

IL-1

Equine, human

Chondrocytes, synoviocytes, macrophages, lymphocytes, fibroblasts

Trauma, infection, TNF

IL-1ra, IL-4, IL-10, IL-11, IL-13, TGF-β, PGE2

↑ MMPs, ↑ PGE2, ↑ COX-2, ↑ NO, ↑ TNF, ↑ IL-6 and other catabolic cytokines, ↓ TIMPs, ↓ synthesis of ECM

IL-2

Human

Lymphocytes

IL-1, TNFs

IL-4, IL-10, IL-13, TGF-β, sIL-2R

↑ T and B lymphocyte proliferation, ↑ NK cellular activity, ↑ TNF, ↑ IFN-γ

IL-6

Equine, human

Chondrocytes, synoviocytes, macrophages, lymphocytes, fibroblasts

IL-1 (equine)

IL-4, IL-10, IL-13, sIL-6R

↑ Acute phase proteins, ↑ T and B lymphocyte and fibroblast proliferation, ↑ serine protease inhibitors

IL-8

Human

Macrophages, lymphocytes

IL-1

IL-4, IL-10, IL-13

↑ Neutrophil chemotaxis, ↑ neovascularization, ↑ free radicals

IL-12

Human

Macrophages

IL-1, TNFs

IL-10, IL-11

↑ IL-1, ↑ TNFs, ↑ IFN-γ, ↑ IL-18

IL-17

Human

T lymphocytes

IL-1, TNFs

—

↑ Osteoclast activity, ↑ PGE2, ↑ NO, ↑ chemokines

IL-18

Human

Lymphocytes, synoviocytes

IL-1, TNFs

IL-10

↑ IL-1, ↑ TNF, ↑ IFN-γ, ↑ adhesion molecules

TNF-α

Equine, human

Chondrocytes, synoviocytes, macrophages, lymphocytes, fibroblasts

Trauma, infection, IL-1

IL-4, IL-10, IL-11, IL-13, TGF-β, sTNFRs

↑ PGE2, ↑ COX-2, ↑ NO, ↑ IL-1 and other catabolic cytokines, ↓ TIMPs, ↓ synthesis of ECM

COX-2 = cyclooxygenase 2; ECM = extracellular matrix; IFN-γ = interferon γ; IL = interleukin; IL-1ra = IL-1 receptor antagonist; MMPs = matrix metalloproteinases; NK = natural killer; NO = nitric oxide; PGE2 = prostaglandin E2; sIL-2R = IL-2 soluble receptor; sTNFR = TNF soluble receptor; TGF-β = transforming growth factor β; TIMPs = tissue inhibitors of metalloproteinases; TNF = tumor necrosis factor

IL-1 and TNF-α also increase the activity of several proteolytic enzymes that degrade articular cartilage, most notably the matrix metalloproteinases (MMPs).21–23 Collectively, these substances perpetuate synovitis,2,3,6 initiate articular cartilage damage,1–5 and induce remodeling of subchondral bone.2,8,9 The pathogenesis of OA is orchestrated by a network of overlapping complex molecular mechanisms, resulting in damage to the tissue comprising the joint.1–5 To facilitate the understanding of the most important molecules involved in these processes, we discuss them as either catabolic or anabolic molecules.

Catabolic Molecules Degradation of articular cartilage in the osteoarthritic degenerative process is due to complex interactions and up-regulation of several cata-

bolic molecules, as summarized in TABLE 1.1–5 However, the exact mechanism that triggers the development of OA remains obscure.

Proinflammatory Cytokines Interleukin 1 IL-1 is actually a family of three cytokines composed of two agonist peptides, IL-1α and IL-1β, and the IL-1 receptor antagonist protein (IL-1ra). The biologic effects of the two IL-1 agonist peptides are initiated by binding to a specific receptor.24 Although this same receptor can bind IL-1ra with a similar affinity, it does so without initiating a biologic effect.25 It has been proposed that IL-1β is one of the most important catabolic cytokines involved in OA.1,2,6 The proform of IL-1β is converted inside the cell by IL-1–converting enzyme (also called caspase 1) to produce the active form of

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CriticalPo nt Recent evidence from studies using an in vitro model of equine cartilage degeneration shows that catabolic cytokines (i.e., IL-1 and TNF-α) are solely responsible for initiation of focal cartilage degeneration in OA.

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IL-1β.1 The active form of IL-1β then promotes therapy with the IL-1ra encoding gene has expression of an important transcription factor been evaluated in experimentally induced OA called nuclear factor k-β.4 This factor moves in horses. Although the results of this research into the nucleus, where it interacts with the were encouraging, the effects were transient promoter regions of several genes and par- (28 days), and synovial inflammation occurred ticipates in up-regulation of genes, including as a secondary complication.32 In a differthose that produce secondary proinflamma- ent approach, promising results have been tory peptides (e.g., IL-6, IL-8, IL-12), chemo- obtained using an IL-1–converting enzyme kines, LTB4, PGE2, MMPs, and nitric oxide.1,4,21 inhibitor (pralnacasan) in an experimental IL-1β also inhibits the metabolic pathways p y in model of OA in rats.1 chondrocytes that are used Tumor Necrosis Factor α to repair damaged ECM2; TNF-α is secreted by macreleases proteoglycans from Osteoarthritis is a rophages, chondrocytes, ECM into the synovial fluid3; multifactorial disease inhibits collagen type II synoviocytes, and osteo(Col-II), IX (Col-IX), and XI clasts as a membraneinfluenced by (1) (Col-XI) synthesis; stimulates bound precursor (latent mechanical overload production of abnormal proform) that is activated by a teoglycan molecules; and specific TNF-α–converting during high-impact down-regulates expression enzyme.26–28 There is evidence that this enzyme is of the natural inhibitors off physical activity, joint present in an increased MMPs, called tissue inhibiinstability, and concentration in humans tors of metalloproteinasess with OA 27; the same may (TIMPs).4,21,26–28 repeated trauma While IL-1 has been conbe true in horses. TNF-α and (2) metabolic sidered the main stimulainduces its biologic eftor of the degenerative joint fects by interacting with processes associated disease process, recent intwo families of membrane for mation may refute this receptors—TNF receptor with aging, body hypothesis. In an experimentypes 1 and 2. There is mass index related tal model of OA that used convincing immunologic knockout mice that lacked evidence for the presence to obesity, and the IL-1 gene, lesions and of type 1 TNF receptors hereditary factors. evidence of accelerated cartiin the ECM of cartilage lage catabolism developed in in osteoarthritic humans27 and in synovial memthe lateral tibial plateau off stifle joints that had not undergone surgery.29 brane and noncalcified cartilage in an endoFurthermore, synthesis of MMP-3 initially toxin-induced model of synovitis/arthritis in increased when human chondrocytes were horses.28 Although TNF-α seems to have catabolic cultured with alginate beads and IL-1, and 30 then synthesis decreased. In addition, recent effects similar to those of IL-1 on articular carevidence from studies using an in vitro model tilage,1–3,26 it appears that TNF-α plays a more of equine cartilage degeneration31 shows that important role in the pathophysiology of rheucatabolic cytokines (i.e., IL-1 and TNF-α) are matoid arthritis.1,6,26 In fact, an important way solely responsible for initiation of focal carti- of reducing the effects of TNF-α activity on lage degeneration in OA.31 These findings sug- articular cartilage in humans with rheumatoid gest that IL-1 plays an important regulatory arthritis has been administration of specific role in maintaining normal homeostasis in car- anti–TNF-α antibodies.27 These antibodies have tilage turnover but that its role in OA initiation not been used in treating OA. and progression is perhaps not as critical as Extracellular Matrix–Degrading Enzymes previously thought.

An important part of the research on OA Several enzymes that degrade ECM are uphas been IL-1β blockade. The use of gene regulated by IL-1β and TNF-α. The principal

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Pathophysiology of Osteoarthritis CE TABLE 2

Enzymes Associated with Extracellular Matrix Degradation in Osteoarthritis

ENZYMATIC GROUP

ENZYME

INHIBITORS

CARTILAGE SUBSTRATES SUSCEPTIBLE TO DEGRADATION

Matrix metalloproteinases

Collagenases MMP-1, MMP-8, MMP-13

TIMPs, α2-Mg

Col-II and X, aggrecan, link protein, denaturalized Col-II Col-II, aggrecan, link protein Col-II, V, IX, and X, aggrecan, fibronectin

Gelatinases MMP-2 MMP-9

TIMPs, α2-Mg

Col-X and XI, elastin, denaturalized Col-II Col-X and XI, aggrecan, decorin, elastin, procollagens, link protein

Stromelysins MMP-3 MMP-10 MMP-11

TIMPs, α2-Mg

Col-IV, IX, X, and XI, aggrecan, decorin, elastin, laminin, denaturalized Col-II procollagens, link protein (MMP-3 and 10) Proteoglycans, fibronectin, laminin, denaturalized Col-II

Cathepsin G

α1-PI, α2-Mg

Col-II, aggrecan, elastin, denaturalized TIMPs

Plasmin

α2-Mg, α2-AP

Active pro-MMPs

Aspartic proteases

Cathepsin D

α2-Mg

Aggrecan, denaturalized Col-II

Cysteine proteases

Cathepsin B

Cystatins, α2-Mg

Aggrecan, Col-II, procollagenase activity

Cathepsin K

Cystatins, α2-Mg

Col-II

Serine proteases

α2-AP = α2 antiplasmin; α2-Mg = α2 macroglobulin; α1-PI = α1-plasminogen inhibitor; Col-n = collagen type n; MMPs = matrix metalloproteinases; TIMPs = tissue inhibitors of metalloproteinases

enzymes associated with degradation of ECM in cartilage are the MMPs, aggrecanases, serine proteases, aspartic proteases, and cysteine proteases. Whereas MMPs and serine proteases act at a neutral pH, aspartic proteases and cysteine proteases have greater activity at an acid pH.1,2,6 Relevant details about these enzymes and their capability to degrade ECM substrates in cartilage are summarized in TABLE 2. An imbalance in the production of these enzymes, namely excessive and uncontrolled production, results in irreversible damage to joint tissues and self-perpetuation of the vicious cycle.

Metalloproteinases MMPs belong to a zinc-dependent group of endopeptidases and can be secreted by synoviocytes, chondrocytes, macrophages, and neutrophils. Several members of this family, including collagenases (MMP-1, MMP-8, MMP-13), gelatinases (MMP-2, MMP-9), and stromelysins (MMP-3, MMP-10, MMP-11), are involved in the pathophysiology of OA.21–23,33 These enzymes are secreted as inactive zymogens that are activated by enzymatic cleavage of their catalytic region, which contains the

active zinc-binding site. The effects of the specific MMP depend on the activity levels of the enzymes and the presence of inhibitors such as TIMPs and α2-macroglobulin.2,3 MMP-1 and MMP-13 play prominent roles in the development of OA.7,21,33 MMP-1 is produced primarily by synovial cells that line the joints, and MMP-13 is a product of chondrocytes that reside in the cartilage. MMP-13 degrades the proteoglycan molecule aggrecan, giving it a dual role in matrix destruction.22 Up-regulation of other MMPs, such as MMP-2, MMP-3, and MMP-9, is also increased in OA, and these enzymes degrade noncollagen matrix components in joints. Although there has been considerable effort to design compounds that effectively inhibit either the synthesis or activity of MMPs and thereby minimize connective tissue destruction within joints, these efforts have not been successful.22

Aggrecanases Aggrecanases, which are also called a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), include 19 members that are numbered ADAMTS 1 through 20; there is no ADAMTS-11 because early reports

CriticalPo nt MMPs belong to a zinc-dependent group of endopeptidases and can be secreted by synoviocytes, chondrocytes, macrophages, and neutrophils. Several members of this family, including collagenases (MMP1, MMP-8, MMP-13), gelatinases (MMP2, MMP-9), and stromelysins (MMP3, MMP-10, MMP11), are involved in the pathophysiology of OA.

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CriticalPo nt Eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, are metabolites of arachidonic acid that are produced by inflammatory cells, chondrocytes, and synoviocytes. These substances are present in inflamed joints, primarily as the possible result of up-regulation of COX-2 by catabolic cytokines.

of it were later found to describe ADAMTS-5.

Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are the proteolytic enzymes that appear to degrade aggrecans in cartilage in OA.34 Aggrecanases cleave the aggrecan core protein and thus play an important role in the pathophysiology of OA. Synthesis of ADAMTS-4 and ADAMTS-5 in chondrocytes appears to be regulated by IL-1β, and there is convincing evidence that IL-1β down-regulates the synthesis of aggrecanase-1 under certain conditions.1,4 In an experimental model of canine OA, it was observed that a dual inhibitor (licofelone) of the lipoxygenase and cyclooxygenase pathways also inhibited the synthesis of aggrecanases.35 To our knowledge, this inhibitor has not been used in horses.

Serine Proteases Plasminogen activator, bradykinin, plasmin, trypsin, cathepsin G, and elastase are important members of the serine protease family,3 as they can directly cleave ECM molecules. However, the principal catabolic effect of these enzymes is to activate latent proteases, such as the proMMPs.2 There is evidence that IL-1β may promote the action of these enzymes through PGE2-mediated up-regulation of plasminogen activator.3 Bradykinin is an important mediator of synovitis, and a specific bradykinin B2-receptor antagonist has recently yielded encouraging results in treating OA in human knees.1

Eicosanoids Eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, are metabolites of arachidonic acid that are produced by inflammatory cells, chondrocytes, and synoviocytes.

These substances are present in inflamed joints, primarily as the possible result of up-regulation of cyclooxygenase-2 (COX-2) by catabolic cytokines.1–4 PGE2 has important effects in the inflammatory process because it promotes vascular dilation, reduces the threshold for painful stimuli, facilitates up-regulation of plasminogen activator, and promotes degradation of proteoglycans.3,21 However, PGE2 also has antiinflammatory effects by up-regulating expression of antiinflammatory cytokines (TABLE 3) and down-regulating expression of catabolic cytokines and MMPs.3 Therefore, it has been postulated that PGE2 is a necessary component in controlling the inflammatory process.36

34

Leukotrienes, which are produced via the lipoxygenase pathway, cause vasodilation and chemotaxis. There is convincing evidence for the involvement of leukotrienes, specifically LTB4, in the pathogenesis of arthritis. For example, the density of LTB4 type II receptors is increased in synovial membranes of humans with rheumatoid arthritis,37 suggesting that leukotrienes have an important role in the development of synovitis. Furthermore, a positive correlation has been identified between the number of leukocytes and the concentration of LTB4 in synovial fluid in horses with joint disease.38 Collectively, these findings would lend credence to studies comparing LTB4 receptor density in synovial membranes in normal horses and in horses with OA as well as to studies designed to test the efficacy of specific lipoxygenase inhibitors or LTB4 receptor antagonists in horses with OA.4 Inhibition of eicosanoid synthesis is a cornerstone in treating OA in humans and animals. NSAIDs and corticosteroids have been used for this purpose and produce symptomatic relief of pain and synovial effusion.

However, neither form of treatment alters progression of the disease. It is well recognized that corticosteroids are potent antiinflammatories, but they also have effects on not only joints but also metabolism and immunologic responses at a systemic level. Furthermore, corticosteroids produce catabolism of articular cartilage, especially when they are administered repeatedly.

Nitric Oxide Nitric oxide, an inflammatory mediator synthesized by several cell types in joints, diminishes the deposition of sulfate into glycosaminoglycan chains, reduces collagen synthesis, interferes with up-regulation of the IL-1 receptor antagonist,7,39 decreases the activity of growth factors such as TGF-β and IGF-I, and has been postulated to be associated with aberrant apoptosis of chondrocytes in the pathogenesis of OA.40,41 Stimulation of chondrocytes by either endotoxin or IL-1β activates the inducible form of nitric oxide synthase (iNOS) and its associated enzymes.1 Although it does not appear that local iNOS expression plays a key role in the development of synovitis in horses,39 positive correlations (that were not apparent in normal horses) have been demonstrated among artic-

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Pathophysiology of Osteoarthritis CE Growth Factors and Antiinflammatory Cytokines Associated with Equine and Human Osteoarthritis TABLE 3

CYTOKINE

SPECIES

SOURCE IN OA

STIMULUS

MECHANISM OF ACTION

IGFs

Equine, human

Articular cartilage

ECM PG depletion, leptin

↑ ECM synthesis, ↑ catabolic cytokines, ↓ PG degradation

IL-1ra

Equine, human

Monocytes, synoviocytes

IL-4, IL-10, IL-13, TGF-β

Antagonize IL-1 catabolic effects

IL-4

Human

T lymphocytes

PGE2

↓ IL-1, ↓ TNF, ↓ IL-8, ↓ IFN-γ

IL-10

Human

T lymphocytes

PGE2

↑ Lymphocyte proliferation, ↑ immunoglobulin synthesis, ↑ IL-1ra, ↑ serine protease inhibitors, ↓ IL-1, ↓ TNF, ↓ IL-8, ↓ IFN-γ, ↓ PGE2, ↓ NO, ↓ MMPs, ↓ PLA2

IL-11

Human

—

PGE2

↑ Acute phase proteins, ↓ IL-1, ↓ TNF, ↓ IL-12, ↓ IFN-γ

IL-13

Human

T lymphocytes

PGE2

↑ B lymphocyte proliferation, ↑ IL-1ra, ↓ IL-1, ↓ TNF, ↓ IL-8, ↓ IFN-γ, ↓ PGE2

IFN-γ

Human

T lymphocytes

IL-2, IL-12, IL-18

Immunoregulatory cytokine

Leptin

Human

Adipocytes

Obesity, PG depletion?

↑ TGF-β, ↑ IGFs

TGF-β

Equine, human

Articular cartilage

Leptin

↑ ECM synthesis, ↑ catabolic cytokines, ↓ PG degradation, ↑ imbalance in synovial membrane PG synthesis, ↑ osteophytes

ECM = extracellular matrix; IFN-γ = interferon γ; IGF = insulin-like growth factor; IL = interleukin; MMPs = matrix metalloproteinases; NO = nitric oxide; PG = proteoglycan; PGE2 = prostaglandin E2; PLA2 = phospholipase A2; TGF-β = transforming growth factor β; TNF = tumor necrosis factor

ular cartilage damage, chondrocyte apoptosis, and high immunoreactivity to nitrotyrosine (a protein that is closely associated with cellular production of nitric oxide) in osteoarthritic horses.40 In addition to nitric oxide, other free radicals, including superoxide, peroxide, and hydroxyl, are produced as part of the inflammatory response within joints. In turn, these mediators can act on chondrocytes and synovial fibroblasts, modifying their biosynthesis of proteoglycans, collagen, and hyaluronan as well as promoting release of catabolic mediators.3,6 The administration of nitric oxide synthase inhibitors in experimentally induced OA has resulted in reduction of synovial inflammation and destruction of cartilage and bone.1

Clinical Signs Associated with Osteoarthritis Catabolic Molecules It has been postulated that horses with OA have different degrees of pain, synovial effusion, and functional impairment,3 reflecting the effects of the aforementioned catabolic molecules and tissues that comprise joints.3,6 Pain is generally manifested as lameness,

which is the result of joint inflammation, exposure of subchondral bone, neovascularization and neoreinnervation, and increased osseous intramedullary pressure.6 There is no correlation between the apparent degree of pain and the severity of articular lesions.5 The primary network of nociceptors in joints (polymodal mechanoreceptors) is localized in the joint capsule, with receptor types I, II, and III predominating. In contrast, subchondral bone and synovial membrane have a more discrete distribution of type IV (unmyelinated endings) nociceptors, which play an important role in the perception of pain in patients with OA.6,42 Type IV nociceptors are stimulated by lactate, potassium ions, quinines, serotonin, PGE2, and histamine.6,43 These stimuli result in the production of several tachykinins41 (e.g., substance P,43 neurokinin A, neuropeptide Y), calcitonin generelated peptide, vasoactive intestinal peptide, and other substances.42,44,45 These substances stimulate the release of inflammatory mediators that perpetuate the inflammatory response, which is called neurogenic inflammation.1,6,42–44 Substance P is the main neuropeptide related

CriticalPo nt Pain is generally manifested as lameness, which is the result of joint inflammation, exposure of subchondral bone, neovascularization and neoreinnervation, and increased osseous intramedullary pressure. There is no correlation between the apparent degree of pain and the severity of articular lesions.

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CriticalPo nt During the development of OA, an array of growth factors and cytokines are produced to counteract the catabolic effects exerted primarily

by IL-1β and MMPs. Unfortunately, the effects of the catabolic molecules predominate, resulting in the development of severe OA.

36

to inflammation of articular cartilage.1,6,40 Sub- the many growth factors identified in the pathostance P and other neuropeptides have been physiology of OA process, the most important immunolocalized in the synovial subintimae appear to be the families of IGF and TGF-β.6–20 It of healthy and arthropathic horses.43 Substance has been postulated that lesser known anabolic P intensifies articular catabolism and synovial growth factors, such as platelet-derived growth inflammation because it causes up-regulation factor and fibroblastic growth factor, could also of IL-1, MMPs, and PGE2.42–44 Substance P also be important in the disease.2 produces synovial hyperplaInsulin-like Growth Factors sia, local vasodilation, and IGFs are two molecules extravasation of leukocytes The end result of (IGF-I and IGF-II) that beand protein in innervated osteoarthritis is loss long to the insulin family areas.43 The results of a study involving a canine model off and are produced primarily of joint homeostasis OA suggest that antagonism by the liver; these factors are of substance P with an anaalso synthesized by other as the body attempts logue of the anticonvulsant cell types, including those to repair damaged gabapentin reduced synin cartilage.18–20 The primary reserve of IGFs is plasma. thesis of MMPs 1, 3, and 13 tissue. The reparative IGF-I is transported by six and iNOS without causing process becomes binding proteins that modadverse systemic effects.45 These findings suggest that ulate its biologic action.46 ineffective, and a selfAlthough IGF-I is expressed substance P may be a viable in abundance in foal cartherapeutic target in treating perpetuating cycle tilage, its level of expresOA. results in structural sion is diminished in older Joint effusion occurs as horses.19 IGF-I promotes difa consequence of synovimodifications of joint ferentiation of fetal chontis; as blood flow increases, tissue. drocytes and maintenance plasma proteins leak into the of ECM synthesis. In adult interstitium, and synovial cartilage, IGF-I antagonizes fluid production increases.6 Although moderate synovitis may have a posi- IL-1β and reduces catabolism of ECM.2,19,20 With tive effect on the nutrition of articular carti- aging, the concentration of IGF-I required to lage, severe synovial effusion adversely affects maintain adequate synthesis of ECM increases joint function.5,6 Moreover, this degree of effu- dramatically.47 Although the results of in vitro sion can lead to fibrosis of the joint capsule, studies indicate that the supraphysiologic conwhich, in turn, impairs joint function, thereby centration of IGF-I does not affect either choncausing mechanical lameness.3,5 drocyte survival or the quality of the ECM, intraarticular injection of IGF-I promotes tissue Anabolic Molecules repair.2 This approach was tested in horses with During the development of OA, an array of experimentally induced cartilage defects, and growth factors and cytokines are produced to the results indicated that intraarticular injection counteract the catabolic effects exerted pri- of IGF-I produced better evidence of cartilage marily by IL-1β and MMPs.1 Unfortunately, the repair than was seen in joints that were not effects of the catabolic molecules predomi- injected with IGF-I.48 Anabolic and mitogenic nate, resulting in the development of severe effects of IGF-II have been demonstrated in OA. The principal peptide growth factors that IL-1–conditioned equine cartilage, suggesting have anabolic and antiinflammatory effects in that this peptide may have positive effects in horses.20 To date, however, no in vivo studies joints are summarized in TABLE 3. using IGF-II have been conducted in horses.

Growth Factors It is important to note that although the Growth factors are multifunctional peptides IGF-I concentration is increased in horses that have anabolic and proliferative effects on with naturally occurring OA,49 expression of chondrocytes and their surrounding ECM. Of a specific IGF-binding protein that reduces

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Pathophysiology of Osteoarthritis CE the activity of IGF-I is also increased.50 It is possible that antagonism of this binding protein may provide an alternative therapeutic approach to the use of IGF-I alone.

Transforming Growth Factor β Members of the TGF-β superfamily include TGF-β1, TGF-β2, TGF-β3, and a variety of bone morphogenetic proteins.2 It has been postulated that TGF-β has anabolic and proliferative effects on articular cartilage and antagonizes the catabolic effects of IL-1β; however, TGF-β is less potent than IGF-I or IGF-II in this regard.18–20 There is conflicting information about the anabolic effects of TGF-β,4,6 primarily because this peptide has been associated with disorders in ECM synthesis (e.g., imbalances in proteoglycan assemblage) and promotes the synthesis of fibromodulin over that of biglycan and decorin.51 In addition, TGF-β promotes osteophyte formation in joints.6 Although osteophytes can perpetuate the local inflammatory response, it has been postulated that they promote stability of joints.6 Thus, TGF-β may have two roles in the pathophysiology of OA.4,6

Antiinflammatory Cytokines Several antiinflammatory cytokines are produced as part of the inflammatory response and modulate the effects of catabolic cytokines and other inflammatory metabolites. The most important of these include IL-1ra, IL-4, IL-10, and IL-132,26,27 (TABLE 3). IL-1ra blocks IL-1 catabolic effects by coupling its membrane receptor. IL-4, IL-10, and IL-13 up-regulate IL-1ra expression. The use of an equine autologous conditioned serum rich in IL-1ra was evaluated in an equine OA model by Frisbie et al.52 This treatment significantly improved clinical lameness and the histologic appearance of the synovial membrane of the treated horses compared with those of the placebo group.

Therapeutic Use of Growth Factors Anabolic growth factors, specifically IGF-I and TGF-β1, and certain antiinflammatory cytokines, most notably IL-1ra have been evaluated in several animal models of OA for their ability to induce regenerative changes in joints. These growth factors have been tested either by direct intraarticular injection of recombinant peptides or by gene therapy.32 Although the results obtained with purified growth factors

and gene therapy are promising, significant economic restrictions are likely to reduce their use in equine practice. Additional research is needed to determine optimal doses of growth factors, and gene therapy has been used only experimentally.

Platelet concentrates have been used as an autologous source of growth factors, primarily TGF-β1 and IGF-I, in humans undergoing maxillofacial or orthopedic surgery.53,54 This approach has been used in horses, with intraarticular injection of platelet concentrates being used to treat horses with severe joint disease.55 The results of this study were encouraging, with the treated horses having evidence of reduced lameness and joint effusion for 8 months without additional therapies. As with other forms of treatment, larger clinical trials that include appropriate control treatments will need to be conducted to determine whether this treatment will be effective in horses with OA.

Conclusion Appreciation of the molecular mechanisms involved in the pathophysiology of OA makes it easier to understand why many symptomatic approaches to the treatment of this disease have failed. It is important to note, however, that many of the relevant studies to date have been conducted using either in vitro systems or laboratory animal models. Because OA is common in horses, future equine studies may provide the best means of evaluating new treatments7 that could be used in humans.

There is considerably more to learn regarding the pathophysiology and treatment of OA. Biologic manipulation of cells, peptides, and genes directly related to this disease is providing exciting new ways to arrest the progression of OA and restore joint function.

CriticalPo nt Several antiinflammatory cytokines are produced as part of the inflammatory response and modulate the effects of catabolic cytokines and other inflammatory metabolites.

The most important of these include IL-1ra, IL-4, IL-10, and IL-13.

TO LEARN MORE Osteochondrosis: Etiologic Factors (Compendium Equine May/June 2007) Related content on

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References 1. Wieland HA, Michaelis M, Kirshbaun BJ, et al. Osteoarthritis: an untreatable disease? Nat Rev Drug Disc 2005;4:331-344.

2. Platt D. Articular cartilage homeostasis and the role of growth factors and cytokines in regulating matrix composition. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. Philadelphia: WB Saunders; 1996:29-40.

3. McIlwraith CW. General pathobiology of the joint and response to injury. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. Philadelphia: WB Saunders; 1996:40-70.

4. Yves H, Sánchez C, Balligand M. Pharmaceutical and nutraceutical management of canine osteoarthritis: present and future perspectives. Vet J 2005;170:113-123.

5. Pool RR. Pathologic manifestations of joint disease in the athletic horse. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. Philadelphia: WB Saunders; 1996:87-104.

6. Bonnet DS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology 2005;44(1):7-16.

7. McIlwraith WC. Use of synovial fluid and serum biomarkers in equine bone and joint disease: a review. Equine Vet J 2005;37(5):473-482.

8. Kawkak CE, McIIwraith CW, Norrdin RW, et al. The role of subchondral bone in joint disease: a review. Equine Vet J 2001;33(2):120-126.

9. Loeser RF. Systemic and local regulation of articular cartilage metabolism: where does leptin fit in the puzzle? Arthritis Rheum 2003;48(11):3009-3012.

10. Solomonow M, Krogsgaard M. Sensorimotor control of knee stability. A review. Scand J Med Sci Sports 2001;11(2):64-80.

11. Nelson F, Billinghurst RC, Pidoux I, et al. Early post-traumatic osteoarthritis-like changes in human articular. Osteoarthritis Cartilage 2006;14(2):114-119.

12. Giatromanolaki A, Sivridis E, Maltezos E, et al. Upregulated hypoxia inducible factor-1 and 2a pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003;5(4):193-201.

13. Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48(11):3118-3129.

14. Buff PR, Dodss AC, Morrison CD, et al. Leptin in horses: tissue localization and relationship between peripheral concentrations of leptin and body condition. J Anim Sci 2002:2942-2948.

15. Prockop DJ. Heritable osteoarthritis: diagnosis and possible modes of cell and gene therapy. Osteoarthritis Cartilage 1994;7(4):364-366.

16. Fortier LA, Nixon AJ, Mohammed HO, et al. Altered biological activity of equine chondrocytes cultured in a three-dimensional fibrin matrix and supplemented with transforming growth factor beta-1. Am J Vet Res 1997;58(1):66-70.

17. Iqbal J, Dudhia J, Bird JL, et al. Age-related effects of TGF-β on proteoglycan synthesis in equine articular cartilage. Biochem Biophys Res Commun 2000;274(2):467-471.

18. Frisbie DD, Sandler EA, Trotter GW, et al. Metabolic and mitogenic activities of insulin-like growth factor-1 in interleukin-1-conditioned equine cartilage. Am J Vet Res 2000;61(4):436-441.

19. Nixon AJ, Brower-Toland BD, Sandel LJ. Primary nucleotide structure of predominant and alternate splice forms of equine insulin-like growth factor I and their gene expression patterns in tissues. Am J Vet Res 1999;60(10):1234-1241.

20. Davenport-Goodall CL, Boston RC, Richardson DW. Effects of insulin-like growth factor-II on the mitogenic and metabolic activities of equine articular cartilage with and without interleukin 1-β.

Am J Vet Res 2004;65(2):238-244.

21. Tung JT, Arnold CE, Alexander LH, et al. Evaluation of the influence of prostaglandin E2 on recombinant equine interleukin1β-stimulated matrix metalloproteinases 1, 3, and 13 and tissue inhibitor of matrix metalloproteinase 1 expression in equine chondrocyte cultures. Am J Vet Res 2002;63(7):987-993.

22. Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci 2006;11:529-543.

23. Brama PA, van den Boom R, DeGroott J, et al. PR Collagenase-1 (MMP-1) activity in equine synovial fluid: influence of age, joint pathology, exercise and repeated arthrocentesis. Equine Vet J 2004;36(1):34-40.

24. Howard RD, McIlwraith CW, Trotter GW, et al. Cloning of equine interleukin 1α and equine interleukin 1β and determination of their

38

full-length cDNA sequences. Am J Vet Res 1998;59(6):704-711.

25. Howard RD, McIlwraith CW, Trotter GW, et al. Cloning of equine interleukin 1 receptor antagonist and determination of its full-length cDNA sequence. Am J Vet Res 1998;59(6):712-716.

26. Punzi L, Calò L, Plebani M. Clinical significance of cytokine determination in synovial fluid. Crit Rev Clin Lab Sci 2002;39(1):63-88.

27. Fernandes JC, Martell-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002;39(12):237-246.

28. Todhunter PG, Kincaid SA, Todhunter RJ, et al. Immunohistochemical analysis of an equine model of synovitis-induced arthritis. Am J Vet Res 1996;57(7):1080-1093.

29. Clements KM, Price JS, Chambers MG, et al. Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy.

Arthritis Rheum 2003;48(12):3452-3463.

30. Sanchez C, Mateus MM, Defresne MP, et al. Metabolism of human articular chondrocytes cultured in alginate beads. Long-term effects of interleukin 1beta and nonsteroidal antiinflammatory drugs. J Rheumatol 2002;29(4):772-782.

31. Little CB, Flannery CR, Hughes CE, et al. Cytokine induced metalloproteinase expression and activity does not correlate with focal susceptibility of articular cartilage to degeneration. Osteoarthritis Cartilage 2005;13(2):162-170.

32. Frisbie DD, Ghivizzani SC, Robbins PD, et al. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 2002;9(1):12-20.

33. van den Boom R, Brama PA, Kiers GH, et al. The influence of repeated arthrocentesis and exercise on matrix metalloproteinase and tumor necrosis factor α activities in normal equine joints. Equine Vet J 2004;36(2):155-159.

34. Tang BL. ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 2001;(1):33-44.

35. Pelletier JP, Boileau C, Boily M, et al. The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther 2005;7:R1091-R1102.

36. Gilroy DW, Colville-Nash PR, Willis D, et al. Inducible cyclooxygenase may have antiinflammatory properties. Nature 1999;5(6):698-701.

37. Hashimoto A, Endo H, Hayasi I, et al. Differential expression of leukotriene B4 receptor subtypes (BLT1 and BLT2) in human synovial tissues and synovial fluid leukocytes of patients with rheumatoid arthritis. J Rheumatol 2003;30(8):1712-1718.

38. Bertone AL, Palmer JL. Synovial fluid cytokines and eicosanoids as markers of joint disease in horses. Vet Surg 2001;30(6):528-538.

39. Simmons EJ, Bertone AL, Hardy J, et al. Nitric oxide synthase activity in healthy and interleukin 1β-exposed equine synovial membrane. Am J Vet Res 1998;60(6):714-716.

40. Kim DY, Taylor HW, Moore RM, et al. Articular chondrocyte apoptosis in equine osteoarthritis. Vet J 2003;166(1):52-57.

41. Blanco FJ, Guitian R, Vazques-Martul E, et al. Osteoarthritis chondrocytes die by apoptosis. Arthritis Rheum 1998;41(2):284289.

42. Caron JP. Neurogenic factors in joint pain and disease pathogenesis. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. Philadelphia: WB Saunders; 1996:70-80.

43. Kirker-Head CA, Chandna VK, Agarwal RK, et al. Concentrations of substance P and prostaglandin E2 in synovial fluid of normal and abnormal joints of horses. Am J Vet Res 2000;61(6):714-718.

44. O’Connor TM, O’Connell J, O’Brien DI, et al. The role of substance P in inflammatory disease. J Cell Physiol 2004;201(2):167-180.

45. Boileau C, Martel-Pelletier J, Brunet J, et al. Oral treatment with PD-0200347, an α2δ ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes. Arthritis Rheum 2005;52(2):488–500.

46. Harridge SDR. Ageing and local growth factors in muscle.

Scand J Med Sci Sports 2003;13(1):34-39.

47. Platt D, Bayliss MT. Proteoglycan metabolism of equine articu-

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

FREE

Pathophysiology of Osteoarthritis CE lar cartilage and its modulation by insulin-like growth factors. J Vet Pharmacol Ther 1995;18(2):141-149.

48. Fortier LA, Mohammed HO, Lust G, et al. Insulin-like growth enhances cell-based repair of articular cartilage. J Bone Joint Surg (Br) 2004;84(2):276-288.

49. Schramme MC, Clegg PD, Bird J, et al. Insulin-like growth factor I levels in synovial fluid of horses. Proc 14th Annu Sci Meet Eur Coll Vet Surg 2005:120-122.

50. Schramme MC, Clegg PD, Bird J, et al. The effect of joint disease on the levels of insulin-like growth factor I binding proteins in synovial fluid of horses. Proc 14th Annu Sci Meet Eur Coll Vet Surg 2005:128-130.

51. Burton-Wurster N, Liu W, Matthews GL, et al. TGF beta 1 and

3 CE CREDITS

CE TEST 1

This article qualifies for 3 contact hours of continuing education credit from the Auburn University College of Veterinary Medicine. Subscribers may take individual CE tests online and get real-time scores at CompendiumEquine.com. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program.

1. Which molecule is one of the most important catabolic cytokines implicated in the pathophysiology of OA? a. TGF-β b. IL-6 c. IL-1 d. IL-4

biglycan, decorin, and fibromodulin metabolism in canine cartilage.

Osteoarthritis Cartilage 2003;11(3):167-176.

52. Frisbie DD, Kawcak CW, McIlwraith CW. Evaluation of autologous conditioned serum using an experimental model of equine osteoarthritis. Proc Annu Conv AAEP 2005:1205, 2667.

53. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg 2004;62:489-496.

54. Sanchez M, Azofra J, Anitua E, et al. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc 2003;35:1648-1652.

55. Carmona JU, Arguelles D, Climent F, et al. Report of the intraarticular treatment with platelet rich plasma in 7 horses with joint disease. Proc 14th Annu Sci Meet Eur Coll Vet Surg 2005:68-71.

Now that she’s pregnant…

What can you do to improve her chances of producing a live foal?

Careful fetal and placental monitoring from the very beginning of the pregnancy can greatly improve your mare’s ability to carry her foal to term.

2. Which molecules stimulate production of MMPs in equine joint disease? a. PGE2 and nitric oxide b. LTB4 and cathepsin K c. IL-6 and TGF-β d. IL-1 and TNF-α 3. Which metabolite is associated with chondrocyte apoptosis? a. nitric oxide b. PGE2 c. IL-6 d. cathepsin K

Progesterone Levels s Days 1–100. Low progestagens during these days reflect reproductive infection s Days 100 to term. Low progestagens through this time identify mares which may require progestin therapy Equine Chorionic Gonadotropin (ECG) Levels s Days 45–90. Low levels of ECG reflect fetal rejection by the mare Estrogen Levels s Days 100 to term. Certain levels of estrogen reflect viability of fetal-placental Unit Identify or Rule Out Cushings Syndrome

Call BET Labs for a free consultation. bet LABS 1501 Bull Lea Road, Suite 102 Lexington, Kentucky 40511 U 859-273-3036

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CE TEST CONTINUED FROM PAGE 39.

4. Which peptide is associated with the development of osteophytes in OA? a. TNF-α b. IL-4 c. lymphotoxin d. TGF-β 5. Which MMPs have collagenase activity? a. MMPs 1, 8, and 13 b. MMPs 2 and 9 c. MMPs 3, 10, and 11 d. MMPs 2 and 13 6. Which of the following describes the main effect of serine proteases in OA? a. ECM degradation b. up-regulation of IL-1 expression

c. increasing the effects of PGE2 d. pro-MMP activation 7. Which metabolite can down-regulate IL-1 and MMP expression? a. nitric oxide b. LTB4 c. PGE2 d. TNF-α 8. Which organ/tissue is the main producer of IGFs? a. the liver b. the kidneys c. the gut d. bone

9. Which growth factor could be associated with imbalanced proteoglycan synthesis in OA? a. IGF-I b. IGF-II c. TGF-β d. vascular endothelial growth factor 10. Which of the following describes the effects of leptin in OA? a. up-regulation of IL-1 expression b. diminishment of proteoglycan synthesis c. promotion of synovial neovascularization d. up-regulation of IGF-I and TGF-β expression

Clinical Snapshot Particularly intriguing or difficult cases

Case Presentation #2 ❯❯ Nora Nogradi, DVM, and Michele Frazer, DVM, DACVIM, Hagyard Equine Medical Institute A 2-day-old Thoroughbred filly presented with acute generalized weakness, tachycardia, and tachypnea. The filly was ambulatory but appeared slightly depressed and had pale pink mucous membranes. The heart rate was 180 beats/ min, the respiratory rate was 36 breaths/min, and there was marked inspiratory dyspnea. An ultrasonogram of the right thorax was obtained (A). A similar image was obtained on the left side of the thorax.

A

1. What abnormalities are evident in the image?

2. What further diagnostic procedures are indicated?

3. How would you manage this case?

4. What is the most likely cause of this condition in foals of

this age?

5. What is the prognosis?

SEE PAGE 42 FOR ANSWERS AND EXPLANATIONS.

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40

ULTRASONOGRAM of the right side, 11th intercostal space, point of the shoulder using a 2-MHz macroconvex transducer.

Challenge your colleagues with a particularly intriguing or difficult case in Clinical Snapshot. Submit your photo(s) along with a brief case description, at least one test question, and detailed answers to each question posed. Each published submission entitles you to an honorarium of $100.

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News Bits Important news for equine practitioners

The Effect of Genes on the Immune Response to R. equi Infection ❯❯ Stacey Oke, DVM, MSc*

T

wo separate research groups that focused on the genetic factors that affect a horse’s immune response to diseases (e.g., Rhodococcus equi infection) have generated data indicating that interleukin (IL)-1β (or an IL-1β–related pathway) plays an important role. To date, a number of cytokines that are thought to play an important role in inflammation and regulation of the immune system have been identified. These cytokines include Toll-like receptors and galectin-3.

R. equi—an important cause of severe, purulent pneumonia in young horses and immunocompromised humans—is a facultative intracellular pathogen that is able to resist phagocytosis by host macrophages. In the study titled “Lack of galectin-3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection,” Brazilian researchers found that mice lacking galectin-3 (gal3-/-) were more resistant to experimental infection with R. equi than were gal3+/+ mice during the early stages of infection.1 The LD50 for the gal3-deficient mice was seven times higher than that for the wild-type

gal3+/+ mice. Furthermore, higher IL-1β lev- 50 foals as negative or positive for R. equi els were detected in the spleens of gal3-/- based on more than 5000 colonies/mL mice, suggesting that galectin-3 may de- from transtracheal aspirates. In the most crease IL-1β synthesis by macrophages to recent study, they classified these foals ultimately confer resistance to R. equi. as Casp1 174G carriers or Casp1 174G The effect of IL-1β–related genes on negative, and “a significant association the development of R. equi infection (P < .03) with the presence of R. equi in was evaluated by Horin et al.2 Previously, the tracheal lavage was found.” However, this group found significant association there were no statistically significant difbetween horse chromosome 15 (ECA15) ferences between IL-1β and IL-1RN polymicrosatellite markers HMSO1 and morphisms in R. equi shedding status.

HTG06 and infection with R. equi.3 The Further research in horses is warrantgroup stated, “Interleukin-1β subunit and ed, considering the novel findings reportinterleukin-1 receptor–antagonist encod- ed in these studies and the importance of ing genes (IL-1β and IL-1RN) could be R. equi in the equine industry. considered as candidate genes underlying the associations reported.” Therefore, References 1. Ferraz LC, Bernardes ES, Oliveira AF, et al. Lack of in the group’s latest study, it evaluated galectin-3 alters the balance of innate immune cytosingle nucleotide polymorphisms (i.e., kines and confers resistance to Rhodococcus equi invariations in DNA sequences that alter fection. Eur J Immunol 2008;38:1-14.

2. Horin P, Osickova J, Necesankova M, et al. Single a single nucleotide in the genome that nucleotide polymorphisms of interleukin-1beta–related differs between members of the same genes and their associations with infection in the horse.

Dev Biol (Basel) 2008;132:347-351. species or between paired chromosomes 3. Horin P, Smola J, Matiasovic J, et al. Polymorphisms in an individual) in three interleukin-1β in equine immune response genes and their associations functionally related genes: IL-1β, IL-1RN, with infections. Mamm Genome 2004;15:843-850. and Casp1 (interleukin-1β converting enzyme/caspase1 encoding gene). *Dr. Oke discloses that she has received fiUsing polymerase chain reaction test- nancial benefits from Nutramax Laboratoring, these researchers previously classified ies, Inc.

Clinical Snapshot Particularly intriguing or difficult cases

Case Presentation #3 ❯❯ Shirley Weisler, DVM, and Gal Kelmer, DVM, MS, DACVS, University of Jerusalem, Israel A 10-year-old Quarter horse mare presented with severe right forelimb lameness. The mare had been lame for the past 2 years and had been treated with trimming, shoeing, and rest. The lameness gradually worsened and became apparent at a walk 2 months before presentation. The referring veterinarian had performed an abaxial sesamoidean regional nerve block, and marked

improvement in the lameness had been noted. Radiographs of the foot were obtained (A).

1. What is your diagnosis?

2. What are the treatment options?

3. What are potential complications of treatment?

4. What is the prognosis for future athletic activity for this mare?

A

SEE PAGE 43 FOR ANSWERS AND EXPLANATIONS.

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41

Clinical Snapshot Answers and Explanations Case Presentation #2 SEE PAGE 40 FOR CASE PRESENTATION.

A

Body wall

1. Free hypoechoic fluid in the tho-

racic cavity, with the pericardial Lung diaphragmatic ligament floating in it (A).

2. In this case, thoracocentesis yielded bloody fluid with a packed cell volume (PCV) of 34%. Based on this finding and gross appearance of the fluid, hemothorax was diagnosed. Results of a complete blood count (CBC) and serum biochemistry panel were consistent with acute hemorrhage (PCV: 18% [reference range: 33% to 48%]; total protein concentration: 3.5 g/dL [reference range: 6 to 7.9 g/dL]). The results of a clotting profile were within the reference range (activated partial thromboplastin time: 153 seconds [reference range: 131 to 199 seconds]; prothrombin time: 18 seconds [reference range: 15 to 26 seconds]).a 3. Emergency thoracocentesis was performed to allow better expansion of the lungs and avoid reduced cardiac compliance caused by intrapleural bleeding. A blunt teat cannula was used to slowly withdraw fluid to avoid initiating hypotensive shock. Three liters of hemorrhagic fluid was removed from the thorax over an hour. In addition, an IV catheter was inserted, and 5 mg/kg IV of Oxyglobin (Biopure) was administered as a bolus, followed by constant-rate infusion of Normosol-R (Hospira) at a rate of 20 mL/kg/hr. Intranasal oxygen insufflation was initiated at 6 L/min. At the end of the procedure, the foal’s respiratory pattern improved, but tachycardia continued. Based on the foal’s clinical appearance (tachycardia, pale mucous membranes) and CBC results, a blood transfusion was performed. Two liters of whole blood were collected from a suitable donor (both major and minor reactions were negative) and administered to the foal. The filly’s vital parameters improved significantly after the transfusion. A CBC performed the next morning revealed a PCV of 26% and a total protein concentration of 4.3 g/dL. 4. A common cause of hemothorax in neonatal foals is laceration of a thoracic vessel secondary to a fractured rib fragment. In this case, ultrasonography revealed a fracture of the fi fth rib, which was displaced on the left side of the chest. The fractured rib had most likely lacerated a vessel inside the thoracic cavity, resulting in hemothorax.

No rib fractures were found on the right side.

Free pleural fluid Pericardial diaphragmatic ligament Liver

5. Hemothorax is a medical emergency. Once the cardiovas-

cular status of the patient is corrected, evaluation of the rib fracture is recommended to decide whether surgical intervention is necessary. The prognosis depends on the severity of hemorrhage, location of the laceration, and the severity of rib displacement. If surgical correction is necessary, the prognosis is considered to be good for recovery as well as return to athletic function. Medical management is also an option but requires a higher level of monitoring for a few weeks while the fracture heals.

The owners elected not to have surgery performed to stabilize the rib fracture, so the patient was managed medically. While hospitalized, the filly had another hemorrhagic episode that was managed the same way. After 10 days of hospitalization, the patient was discharged to the farm with restricted stall rest for 4 weeks under careful monitoring. The foal is reported to be doing well at 5 months of age.

SHARE YOUR PICTUREPERFECT CASES IN CLINICAL SNAPSHOT

Challenge your colleagues with a particularly intriguing or difficult case in Clinical Snapshot. Submit your photo(s) along with a brief case description, at least one test question, and detailed answers to each question posed. Each published submission entitles you to an honorarium of $100.

For more details, call 800-426-9119, extension 52434, or email

editor@CompendiumEquine.com. a

Reference ranges from Hagyard Equine Medical Institute.

42

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

Clinical Snapshot Answers and Explanations Case Presentation #3 A

B

SEE PAGE 41 FOR CASE PRESENTATION.

1. Type 4 fracture of the distal pha-

lanx. The radiograph (A) shows a medium-sized fracture of the extensor process of the distal phalanx.

No significant degenerative changes are apparent in the distal interphalangeal (coffin) joint. It is essential to localize the lameness to the foot because bony fragments can be incidental findings.

2. Treatment options include conservative management, internal fixation, and fragment removal. Fragment removal is generally the preferred treatment for all fragments1,2 and can be performed by arthroscopy, arthrotomy, or trephination through the hoof wall. In this mare, the fragment was removed using the latter

technique (B). A postoperative radiograph showed complete fragment removal and that the distal phalanx was uniformly smooth (C).

3. For all surgeries that involve the hoof, contamination and infection of the surgical site and the distal interphalangeal joint are of concern.

Incomplete removal of the fragment may lead to secondary osteoarthritis. Postsurgical mineralization of the extensor tendon proximal to its attachment to the distal phalanx may occur.

4. The prognosis for horses from which small fragments have been removed is good; if larger fragments have been removed, the prognosis is fair to good. The prognosis worsens in direct relation to the chronicity of

C

the lesion and the degree of osteoarthritic changes in the distal interphalangeal joint at the time of treatment.3 This mare recovered well from surgery and showed some lameness (localized to the distal interphalangeal joint) that responded well to intraarticular medications; however, 2 months after surgery, the mare suffered an open, complete, displaced tibial fracture and was euthanized.

References 1. Honnas CM, Vacek JR, Schumacher J. Diagnosis and treatment of articular fractures of the equine distal phalanx. Vet Med 1992;87:1208-1214.

2. Braake FT. Arthroscopic removal of large fragments of the extensor process of the distal phalanx in 4 horses.

Equine Vet Educ 2005;17:101-105.

3. Dechant JE, Trotter GW, Stashak TS, Hendrickson DA. Removal of large fragments of the extensor process of the distal phalanx via arthrotomy in horses: 14 cases (1992-1998). JAVMA 2000;217:1351-1355.

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Reader Service # 124 183 162 131 149 122 187 159 137 139 150 192 193 154 147 160

Page # 46 39 14 21 13 46 5 24–25 23 11, 12 45, Back cover 26 Inside front cover 7 9 15 27 Inside back cover

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Product Forum ❯❯ For more information about the products highlighted in this section, fill out and return the Reader Service Card inserted between pages 32 and 33 of this issue.

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Portable Ultrasound Fly Bonnet Absorbine has released the improved UltraShield Draft Size Fly Bonnet for use on horses weighing more than 1100 lb. The bonnets are made with Rip-Shield tear-resistant material and come with flexible netting and safety-release closures. The draft-size bonnet is designed to offer more face protection and a secure fit.

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The SV22 Ultrasound system is SoundVision’s newest portable ultrasound system. The SV22 has one probe and a 10-inch interlaced grayscale screen.

There are veterinary-specific presets and packages and a USB port for easy image export. The SV22 has a 128-frame CINE loop and intelligent zoom for real-time images.

SoundVision | 800-225-7911 | www.soundvisionweb.com Circle Reader Service #106

Storage

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Ancom’s Add-A-Row Filing and Storage System expands the capacity of an office’s record storage without the need for aisles. Steel tracks are secured to flooring in front of existing shelving, with cabinets mounted into mobile carriages, creating a multilayer storage system.

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The Ape Obsleeve Pink has been designed to meet the needs of the growing number of female veterinarians and students. This sleeve is made to fit smaller hands and arms, is 35 inches in length, and is designed with strong seams.

The Obsleeve comes packaged in units of 100 and is made in the United States.

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FCRView is an image management workstation by Fujifilm Medical Systems featuring a complete set of tools for medical image acquisition, processing, viewing, and archiving. FCRView was designed to meet the needs of low- to mid-volume veterinary practices and has customized anatomic menu sets, rapid image preview display, and the ability to flip and rotate from the image preview screen. FCRView’s DICOM image viewer allows full image viewing and manipulation capabilities.

Fujifilm Medical Systems | 800-431-1850 | www.fujimed.com Circle Reader Service #108

Image Management

The product information presented here is provided by the manufacturers and does not reflect endorsement by Compendium Equine.

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CE Calendar January 19–23 31st Lake Tahoe Equine Conference Hyatt Lake Tahoe Incline Village, Nevada Phone 530-756-4899 Fax 530-756-3805 Email jlo62@comcast.net

January 22 Minicourse on “Techniques for Handling Stallions in the Breeding Situation” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

January 23–24 Minicourse on “Reproductive Management of the Stallion” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

January 25–28 AAEP 11th Annual Resort Symposium Sheraton Mirage Resort South of Brisbane, Australia Phone 859-233-0147 Email aaepoffice@aaep.org Web aaep.org

January 26–27 Minicourse on “Reproductive Management of the Mare” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

January 28–30 3rd Congress of the European College of Equine Internal Medicine Hotel Sehrs Campus Cerdanyola del Valles Barcelona, Spain Web 3rdcongresseceim.com

January 29–31 Ontario Veterinary Medical Association Annual Conference and Trade Show

Oral Paste for Horses and Foals NADA 141-123, Approved by FDA Caution Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Description Chemical name: 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole.

Empirical formula: C17H19N3O3S. Molecular weight: 345.42. Structural formula:

Westin Harbour Castle Hotel Toronto, Ontario, Canada Phone 905-875-0756 Fax 905-875-0958 Email cneziol@ovma.org

H3C

OCH3 CH3 O

OCH3 H

How Supplied GASTROGARD® (omeprazole) Paste for horses contains 37% w/w omeprazole and is available in an adjustable-dose syringe. Each syringe contains 2.28 g of omeprazole. Syringes are calibrated according to body weight and are available in boxes of 7 units or 72 units.

Storage Conditions Store at 68°F – 77°F (20-25°C). Excursions between 59°F – 86°F (15-30°C) are permitted.

Indications For treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks of age and older.

Dosage Regimen For treatment of gastric ulcers, GASTROGARD Paste should be administered orally once-a-day for 4 weeks at the recommended dosage of 1.8 mg omeprazole/lb body weight (4 mg/kg). For the prevention of recurrence of gastric ulcers, continue treatment for at least an additional 4 weeks by administering GASTROGARD Paste at the recommended daily maintenance dose of 0.9 mg/lb (2 mg/kg).

Directions For Use • GASTROGARD Paste for horses is recommended for use in horses and foals 4 weeks of age and older. The contents of one syringe will dose a 1250 lb (568 kg) horse at the rate of 1.8 mg omeprazole/lb body weight (4 mg/kg). For treatment of gastric ulcers, each weight marking on the syringe plunger will deliver sufficient omeprazole to treat 250 lb (114 kg) body weight. For prevention of recurrence of gastric ulcers, each weight marking will deliver sufficient omeprazole to dose 500 lb (227 kg) body weight.

• To deliver GASTROGARD Paste at the treatment dose rate of 1.8 mg omeprazole/lb body weight (4 mg/kg), set the syringe plunger to the appropriate weight marking according to the horse’s weight in pounds.

• To deliver GASTROGARD Paste at the dose rate of 0.9 mg/lb (2 mg/kg) to prevent recurrence of ulcers, set the syringe plunger to the weight marking corresponding to half of the horse’s weight in pounds.

• To set the syringe plunger, unlock the knurled ring by rotating it 1/4 turn. Slide the knurled ring along the plunger shaft so that the side nearest the barrel is at the appropriate notch. Rotate the plunger ring 1/4 turn to lock it in place and ensure it is locked. Make sure the horse’s mouth contains no feed. Remove the cover from the tip of the syringe, and insert the syringe into the horse’s mouth at the interdental space. Depress the plunger until stopped by the knurled ring. The dose should be deposited on the back of the tongue or deep into the cheek pouch. Care should be taken to ensure that the horse consumes the complete dose. Treated animals should be observed briefly after administration to ensure that part of the dose is not lost or rejected. If any of the dose is lost, redosing is recommended.

• If, after dosing, the syringe is not completely empty, it may be reused on following days until emptied.

Replace the cap after each use.

Warning Do not use in horses intended for human consumption. Keep this and all drugs out of the reach of children. In case of ingestion, contact a physician. Physicians may contact a poison control center for advice concerning accidental ingestion.

Adverse Reactions In efficacy trials, when the drug was administered at 1.8 mg omeprazole/lb (4 mg/kg) body weight daily for 28 days and 0.9 mg omeprazole/lb (2 mg/kg) body weight daily for 30 additional days, no adverse reactions were observed.

Precautions The safety of GASTROGARD Paste has not been determined in pregnant or lactating mares.

Clinical Pharmacology Mechanism of Action: Omeprazole is a gastric acid pump inhibitor that regulates the final step in hydrogen ion production and blocks gastric acid secretion regardless of the stimulus. Omeprazole irreversibly binds to the gastric parietal cell’s H+, K+ ATPase enzyme which pumps hydrogen ions into the lumen of the stomach in exchange for potassium ions. Since omeprazole accumulates in the cell canaliculi and is irreversibly bound to the effect site, the plasma concentration at steady state is not directly related to the amount that is bound to the enzyme. The relationship between omeprazole action and plasma concentration is a function of the rate-limiting process of H+, K+ ATPase activity/turnover. Once all of the enzyme becomes bound, acid secretion resumes only after new H+, K+ ATPase is synthesized in the parietal cell (i.e., the rate of new enzyme synthesis exceeds the rate of inhibition).

Pharmacodynamics: In a study of pharmacodynamic effects using horses with gastric cannulae, secretion of gastric acid was inhibited in horses given 4 mg omeprazole/kg/day. After the expected maximum suppression of gastric acid secretion was reached (5 days), the actual secretion of gastric acid was reduced by 99%, 95% and 90% at 8, 16, and 24 hours, respectively.

Pharmacokinetics: In a pharmacokinetic study involving thirteen healthy, mixed breed horses (8 female, 5 male) receiving multiple doses of omeprazole paste (1.8 mg/lb once daily for fifteen days) in either a fed or fasted state, there was no evidence of drug accumulation in the plasma when comparing the extent of systemic exposure (AUC0-∞). When comparing the individual bioavailability data (AUC0-∞, Cmax, and Tmax measurements) across the study days, there was great inter- and intrasubject variability in the rate and extent of product absorption. Also, the extent of omeprazole absorption in horses was reduced by approximately 67% in the presence of food. This is evidenced by the observation that the mean AUC0-∞ values measured during the fifth day of omeprazole therapy when the animals were fasted for 24 hours was approximately three times greater than the AUC estimated after the first and fifteenth doses when the horses were fed hay ad libitum and sweet feed (grain) twice daily. Prandial status did not affect the rate of drug elimination. The terminal half-life estimates (N=38) ranged from approximately one-half to eight hours.

Efficacy Dose Confirmation: GASTROGARD® (omeprazole) Paste, administered to provide omeprazole at 1.8 mg/lb (4 mg/kg) daily for 28 days, effectively healed or reduced the severity of gastric ulcers in 92% of omeprazole-treated horses. In comparison, 32% of controls exhibited healed or less severe ulcers. Horses enrolled in this study were healthy animals confirmed to have gastric ulcers by gastroscopy. Subsequent daily administration of GASTROGARD Paste to provide omeprazole at 0.9 mg/lb (2 mg/kg) for 30 days prevented recurrence of gastric ulcers in 84% of treated horses, whereas ulcers recurred or became more severe in horses removed from omeprazole treatment.

Clinical Field Trials: GASTROGARD Paste administered at 1.8 mg/lb (4 mg/kg) daily for 28 days healed or reduced the severity of gastric ulcers in 99% of omeprazoletreated horses. In comparison, 32.4% of control horses had healed ulcers or ulcers which were reduced in severity. These trials included horses of various breeds and under different management conditions, and included horses in race or show training, pleasure horses, and foals as young as one month. Horses enrolled in the efficacy trials were healthy animals confirmed to have gastric ulcers by gastroscopy. In these field trials, horses readily accepted GASTROGARD Paste. There were no drug related adverse reactions. In the clinical trials, GASTROGARD Paste was used concomitantly with other therapies, which included: anthelmintics, antibiotics, non-steroidal and steroidal anti-inflammatory agents, diuretics, tranquilizers and vaccines.

Diagnostic and Management Considerations: The following clinical signs may be associated with gastric ulceration in adult horses: inappetence or decreased appetite, recurrent colic, intermittent loose stools or chronic diarrhea, poor hair coat, poor body condition, or poor performance.

Clinical signs in foals may include: bruxism (grinding of teeth), excessive salivation, colic, cranial abdominal tenderness, anorexia, diarrhea, sternal recumbency or weakness. A more accurate diagnosis of gastric ulceration in horses and foals may be made if ulcers are visualized directly by endoscopic examination of the gastric mucosa.

Gastric ulcers may recur in horses if therapy to prevent recurrence is not administered after the initial treatment is completed. Use GASTROGARD Paste at 0.9 mg omeprazole/lb body weight (2 mg/kg) for control of gastric ulcers following treatment. The safety of administration of GASTROGARD Paste for longer than 91 days has not been determined.

Maximal acid suppression occurs after three to five days of treatment with omeprazole.

Safety • GASTROGARD Paste was well tolerated in the following controlled efficacy and safety studies.

• In field trials involving 139 horses, including foals as young as one month of age, no adverse reactions attributable to omeprazole treatment were noted.

• In a placebo controlled adult horse safety study, horses received 20 mg/kg/day omeprazole (5x the recommended dose) for 90 days. No treatment related adverse effects were observed.

• In a placebo controlled tolerance study, adult horses were treated with GASTROGARD Paste at a dosage of 40 mg/kg/day (10x the recommended dose) for 21 days. No treatment related adverse effects were observed.

• A placebo controlled foal safety study evaluated the safety of omeprazole at doses of 4, 12 or 20 mg/kg (1, 3 or 5x) once daily for 91 days. Foals ranged in age from 66 to 110 days at study initiation. Gamma glutamyltransferase (GGT) levels were significantly elevated in horses treated at exaggerated doses of 20 mg/kg (5x the recommended dose). Mean stomach to body weight ratio was higher for foals in the 3x and 5x groups than for controls; however, no abnormalities of the stomach were evident on histological examination.

Reproductive Safety In a male reproductive safety study, 10 stallions received GastroGard Paste at 12 mg/kg/day (3x the recommended dose) for 70 days. No treatment related adverse effects on semen quality or breeding behavior were observed. A safety study in breeding mares has not been conducted.

For More Information Please call 1-888-637-4251 and please visit our web site at www.gastrogard.com.

Marketed by: Merial Limited Duluth, GA 30096-4640

February 7–9 Equine Lameness Days Buenos Aires, Argentina Email contact@agpferd.de Web cicade.info Web agpferd.com

February 13 Minicourse on “Embryo Recovery and Transfer in the Mare” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

February 16 Minicourse on “Reproductive Ultrasonography in the Mare” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

February 17–20 “Individual Experience with Ultrasounding In-House Mares” Equine Reproduction Concepts, LLC Amissville, Virginia Phone 540-937-9832 Email info@equinereproduction.com

May 16–17 Equine Purchase Days Naestved, Denmark Email contact@agpferd.de Web cicade.info Web agpferd.com.

July 18–24 31st Bain Fallon Memorial Lectures Twin Waters Resort Sunshine Coast Queensland, Australia Phone 02 9280 0922 Fax 02 9211 7601 Email eva@infosalons.com.au Web eva.org.au

Merial Limited, a company limited by shares registered in England and Wales (registered number 3332751) with a registered office at PO Box 327, Sandringham House, Sandringham Avenue, Harlow Business Park, Harlow, Essex CM19 5QA, England, and domesticated in Delaware, USA as Merial LLC. US Patent: 4255431 and 5708017 Copyright © 2005 Merial Limited.

All rights reserved. Rev. 08-2005

Compiled by Benjamin Hollis; send listings to bhollis@vetlearn.com

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®GASTROGARD is a registered trademark of the AstraZeneca Group of Companies.

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The Final Diagnosis ❯❯ Ronald E. Gill, DVM, Gill Veterinary Clinic, West Salem, Illinois

Just Another Unusual Day

I

’ve been fortunate to spend my entire me shudder. The welding bead was still on career in rural mixed animal practice. each end of the rod.

Even after 33 years, I still enjoy this I immediately sedated the mare and type of practice setting and will never forget removed one end of the rod from the fence some cases, such as the following. panel, which had temporarily trapped her in The call came at about 5:00 AM one spring the back of the stall. The owner asked what morning. (A ringing phone still immediately we were going to do, and I said that we wakes me no matter how deeply I am sleep- needed to cut the rod. Having no electricity ing.) The caller said, rather matter-of-factly, there, the owner brought a portable genera“We have a mare with a rod through her head.” tor to the pen. We hooked up his brandI quickly got dressed and began to con- new saw and, after a few attempts, were sider the possible causes of the injury and able to cut the rod. I instructed the owner what equipment and medications I should to take my position and steady the mare’s take with me. I went to the clinic, grab- head while I retracted the piece of metal bing everything from from the mare.

I could see a 10-ft piece of sur ger y packs and It appeared that tranquilizer to euthathe rod had entered sucker rod stuck completely the back left side nasia solution and syringes. of the head, behind through the mare’s head.

After the 20-mile the mandible and trip, I found the mare with an approximately below the left ear, and exited about halfway 1-week-old foal standing in the back of a between the eye and the nose on the right dark lean-to shed with no lights or electricity. side of the head. I imagined significant damThe owner had fashioned a gate using oil- age to the pharyngeal area or the esophagus field pipe and sucker rods, which are com- as well as the frontal sinuses. After cutting monly used for making gates in my area. As the rod, I carefully pulled the piece out from it became light, I could see a below the ear. The mare began to bleed pro10-ft piece of sucker rod stuck fusely, prompting the owner to expect her TO LEARN MORE completely through the mare’s to bleed to death. Fortunately, the bleeding head. I suspected that the mare soon subsided and then stopped. had been trying to reach the I gave the owners instructions regarding the green spring grass by pushing mare’s treatment. Amazingly, they reported The Final Diagnosis gives readers on the homemade gate, even- complete healing, and the mare continues to a chance to share their wondrous, weird, or legendary cases. Email tually breaking one end of the be in the herd and is doing well. submissions (no more than 1500 rod loose and suddenly impalThis story illustrates how even patients words) to jmoore@uga.edu. ing herself with the free end in serious condition can often do well and of the rod. Imagining how the completely recover. One of the things I enjoy mare was able to break the about mixed animal practice is that there’s CompendiumEquine.com entire piece loose still makes never an average day!

48

Compendium Equine: Continuing Education for Veterinarians® | January/February 2009 | CompendiumEquine.com

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Order today at VLSstore.com or call 800-426-9119 Publisher of Compendium Equine and other trusted veterinary resources

EQ8APE

FPO The best treatment for EGUS may be a dose of reality.

Equine Gastric Ulcer Syndrome (EGUS) caan easily become a reality for today’s horse. In fact, the majority of your clients’ racing and non-racing competittive horses could already be sufffering in silence with gastric ulcers.1,2 Clients come to o you for knowledge and tools they can’t get anywhere else. Training.

Experience. Diagnosis. Approved treatment. You havee the power to make the solution n for EGUS this simple.

Unique respon nse. Only GASTROGARD® (omeprazole) is FDA-approved to treeat gastric ulcers.

Unique ability.. Only you have the ability to prrovide diagnoses and GASTTROGARD. For information and EGUS educational tools, taalk with your Merial Sales Represeentative today. Or call 1-888--MERIAL-1.

Response.Ability.

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. GASTROGARD is indicated for the treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks and older. In efficacy trials, no adverse reactions were observed. Safety in pregnant or lactating mares has not been determined. DO NOT USE IN HORSES INTENDED FOR HUMAN CONSUMPTION. KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Mitchell RD. Prevalence of gastric ulcers in hunter/jumper and dressage horses evaluated for poor performance. Association for Equine Sports Medicine. September 2001.

Murray MJ. Endoscopic appearance of gastric lesions in foals: 94 cases (1987-1988). J Am Vet Med Assoc 1989;195(8):1135-1141.

1

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®GASTROGARD is a registered trademark of the AstraZeneca Group of Companies. ©2008 Merial Limited. Duluth, GA. All rights reserved. EQUIGGD901-A (10/08)

See Page 45 for Product Information Summary

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