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Dedication
In memory of my grandmother Renée Monllor,
To my mother Flora Monllor,
To my wife Shirley Pita,
To my son Christophe Pita-Wiart
Quote
If you see what needs to be repaired and how to repair it, then you have found a piece of the world that G-d has left for you to complete.
Rabbi Menachem Mendel Schneerson
Foreword
by Robert
Verpoorte
The present pandemic COVID-19 viral disease shows that despite all our advanced science, still nature is able to show us that we might think that we have all under control, but in fact that is not true. During the million years of evolution and development leading to the present day’s society, there has been many other pandemic diseases caused by viruses, microorganisms, and various parasites that hit humans. Some have been eradicated, some we have learned to control by prevention, and others by medication or the combination of both measures. Besides hygiene, vaccination is the major preventive medical treatment. But still many tropical diseases lack proper medicines.
Present day pharmaceutical development is mainly focused on chronic lifestyle-related diseases, requiring strict regimens for the patients of taking several medicines for the rest of their life to treat the symptoms of the disease, like hypertension, high cholesterol, and/or high glucose. The business model is clear, identifies all patients who have symptoms and then prescribes the medication to be taken every day for the rest of your life. The other business model for the big pharma is cancer treatments that concern a disease that is potentially killing the patient. To save the patient’s life, the society accepts high costs for medicines that cure, or at least give the patients some extra time to live. This is a business model that is based on very expensive medicines to stop the growth of cancer cells and preferably kill these cells. For both business models, costs of development will be similar, but the earnings should be in the first case on chronic treatments over many years, in the second case intensive treatments in short time. What are missing in these two models are the medicines to treat infectious diseases caused by
external organisms such as viruses, microorganisms, and parasites. For many of these illnesses, good medicines are available, like the antibiotics. But to develop novel drugs for these diseases, the business models mentioned do not work, as usually these illnesses are cured in a treatment of a week or so. That means the costs of developing a novel antibiotic or antiparasitic drug are difficult to earn back. Particularly for some of the more rare tropical diseases, big pharmaceutical companies do not have research programs for developing cures. The Nobel Prize 2015 shows two successful examples for parasitic diseases. This prize was for William C. Campbell and Satoshi Ōmura “for their discoveries concerning a novel therapy against infections caused by roundworm parasites” and the other half to Tu Youyou “for her discoveries concerning a novel therapy against Malaria.” The roundworms-caused diseases could be treated with a novel antibiotic Ivermectine that was developed and financed by the pharmaceutical company Merck. So why did I write this long introduction about the economics of drug development? Because this makes clear that the development of medicines against infectious diseases has stalled at the level of the pharmaceutical companies, because of too high costs to develop this sort of medicines for a small market. Despite the warnings of the SARS and MERS, no major efforts were developed for medicines against diseases caused by Corona viruses. The result of this omission is visible in 2020. The already mentioned Nobel Prize 2015 shows three things. First that nature is full of molecules that could be used to treat any disease, second that our ancestors already developed medicines for many diseases, and third that this sort of research can successfully be done at academic institutions and governmental research institutions. The type of research necessary for developing drugs that cure infectious diseases can be done in any lab with no need for highly specialized equipment and facilities. What you need is to be a good observer like Alexander Fleming who discovered by chance penicillin in 1928, though it took more than 10 years before Florey and Chain developed it into a medicine. The three of them received the Nobel Prize for Medicine in 1945.
The development of an antibiotic or antiparasitic drug is very different from drug research that is aiming at treating symptoms of lifestyle diseases, where a pharmacological interference in the human metabolism is required. Antiviral drugs are an in-between hybrid case. A virus is not a living organism, so per definition, you cannot kill it. A virus uses part of the cellular system to infect an organism, so it requires interference in the normal homeostasis of the host’s cells.
Coming now to the crux of this preface, why is this book so interesting? I mentioned already the importance of nature and the knowledge of our ancestors about the use of plants and other materials from their environment as medicines. Artemisinin was discovered as an antimalarial drug from Artemisia annua in the 1970s. The use of this plant to treat fever and malaria has its roots in ancient times and earliest record dates back to 200 BCE. Artemisia annua was already mentioned in a Chinese pharmacopeia in CE 340. In fact many of the therapies in Western medicine are derived from Eurasian medicinal plants. It thus makes sense that we analyze in depth the use of medicinal plants in different cultures and regions for treatments of infectious and parasitic diseases. The symptoms are clear of most infectious diseases, and also the effect of the treatment is easy to see, which makes that chances that our ancestors have found interesting plants are good. The present book is particularly suited to learn more about plants used in Asia as antiparasitic drug. The various pharmacological effects are mentioned for all the reported plants, as well as the type of compounds present in the plants, and if known, what are the active compounds. Gathering this information helps in discovering “hotspots” of chemodiversity that are of interest for further research on activity and eventually confirming activity by isolation and identification of the active compounds. So rather than screening all plants for activity, it makes more sense to first focus on what our ancestors already have achieved in terms of therapies. The book formulates briefly the scientific questions that need to be addressed.
In the coming years there will be a lot of interest for developing antiviral drugs, but this pandemic shows how vulnerable our
g p healthcare system is. New pandemics will occur, and worse, pathogenic microorganisms developing resistance against our major antibiotics and antiparasitic drugs is another major threat. In fact malaria is a major cause of death in the world (about 435,000 per year worldwide). Climate change will result in further spreading of (tropical) diseases. Ticks spreading Lyme disease and encephalitis, mosquitos spreading malaria in new areas, are just some other examples that should make us aware of the need to really make a major effort in developing novel drugs for this sort of diseases. So finally the question why nature as source and not synthesis? In Nature, all kind of organisms use chemistry to defend themselves against other organisms; thus nature is the place to find compounds that are able to selectively kill microorganisms or parasites and are not very toxic for humans. Chemical synthesis can then be of help to produce these compounds and make new analogues that might be more effective.
In conclusion, this book is at the basis of drug development from Nature and from our ancestors knowledge. The development of novel drugs to treat infectious and parasitic diseases is a major challenge for academic institutions and public research institutes. On the one hand, it will help to identify the locally known treatments that can be used safely and sort out those that have no activity at all, or/and are potentially toxic. Clinical trials will be an important tool in this. For the materials that have shown interesting activities, one can do further research on the active compound(s), which may result in leads for further drug development, and which can be used for standardizing local preparations. This book will be of great help to select the most promising plants for further research that may lead to novel drugs for some major killing diseases. So I want to congratulate Dr. Christophe Wiart for his excellent contribution to enable the further exploration of Asian traditional knowledge on medicinal plants for developing novel drugs.
Robert Verpoorte, Natural Products Laboratory, IBL, Sylvius Laboratory, Leiden University, Leiden, The Netherlands
Foreword by Bruno David
It gives me great pleasure to introduce this Medicinal Plants in Asia and Pacific for Parasitic Infections: Botany, Ethnopharmacology, Molecular Basis, and Future Prospects an essential contribution to our scientific knowledge of antiparasitic medicinal plants from that important part of the world. Dr. Wiart is a renowned expert in the phytochemistry of medicinal Asian-Pacific plants and already has a long list of excellent books to his name.
I have known Dr. Christophe Wiart for quite some time as I welcomed him at the end of his Pharmaceutical studies in 1995 for a 6-month internship at the Pierre Fabre Phytochemistry Research Laboratory near Toulouse (France). Christophe moved from his native Bri any to South-West France where Pierre Fabre has most of its facilities. Pierre Fabre Laboratories is a 60-year-old medium-sized French pharmaceutical company with 11,000 employees worldwide specialized in the development of plant-based ethical drugs and dermocosmetic products sold all over the world. Christophe impressed me so much and was so interested in the fields of phytochemistry and botany that I encouraged him to apply for a position of Pensiarah Pelawat at Malaya University (Petaling Jaya, Malaysia) as part of a collaboration with the French National Center of Scientific Research (CNRS). Since then, he has devoted his career and his life to the study of Malaysian plants and bioactive natural products from regions beyond South-East Asia. Since biodiversity together with associated traditional knowledge are disappearing everywhere at an alarming rate, and particularly in the Asia-Pacific region, it is vital to inventory, value and preserve this precious ethnobotanical know-how. The book’s presentation, based on botanical taxonomy, is a very relevant approach as it is
usefully correlated with the latest scientific information including pharmacology at molecular level.
Parasitic infections are a major socioeconomic issue in terms of public health. As the pharmaceutical industry is mainly profitdriven, scant a ention is paid to research and development of new parasitic agents. Such research is important since resistance has appeared in parallel to the long and continuous use of “old molecules.” The most successful approach historically, and still valid in antiparasitic research, is the bioguided isolation of bioactive natural products from genetic resources followed by optimization of therapeutic properties by medicinal chemistry.
Interest in antiparasitic agents should be renewed at an international level in both academic and private research sectors as the global warming, tropicalization of temperate areas, the migrations that this generates, and the anthropic pressure on ecosystems are prone to the resurgence of old pathogens and emergence of new ones. The recent pandemic of SARS-CoV-2 is unfortunately a significant illustration of the recrudescence of parasitic infections in a fully globalized world. In addition to the obvious issue of global health in the tropical source countries of these diseases, globalization and rapid exchanges swiftly turn these pathologies into a mass phenomenon relevant for researchers and for the international pharmaceutical industry…
There is no doubt whatsoever that this new release, carefully composed and covering all aspects of the subject, will provide inspiration to anyone—from academic and industrial researchers to students, administrators, civil servants, conservationists, and NGOs interested in antiparasitic plants. We wish Dr. Wiart’s new book all the success that it deserves.
Bruno David Dr. , DPharm, PhD, HDR
Ex-Director
of Phytochemistry Research
Pierre Fabre Laboratories
Toulouse (France), June 2, 2020
Foreword by Maria de Lourdes Pereira and Veeranoot
Nissapatorn
Parasites, a group of infectious agents, cause a significant devastating impact on humans worldwide. Since parasites play a critical role in public health concerns, these tropical diseases have been reported to increase morbidity and mortality in developing countries, particularly in Africa and Asia. As of now, the impact of parasites can be witnessed in the high rate of infection and disease burden in marginalized people (adults and children) across the world.
Parasites are divided into two main groups: (1) protozoa which are vectors, food and/or water-borne parasites. Vector-borne includes blood sucking parasites, like Plasmodium spp. causing malaria, Trypanosoma spp. causing trypanosomiasis, and Leishmania spp. cause leishmaniasis while food and/or water-borne consists of Toxoplasma gondii (toxoplasmosis), free-living amoebae (e.g., Acanthamoeba spp. and Naegleria fowleri), Giardia lamblia (giardiasis), Cryptosporidium parvum (cryptosporiasis), and Entamoeba histolytica (amoebiasis). While helminths are divided into three groups: nematodes (roundworms) mainly involve soil-transmi ed helminths, cestodes (flatworms) are vertebrate parasites, with each species infecting a single definitive host or group of closely related host species, and trematodes (flukes) include internal parasite flatworms of molluscs and vertebrates, with a complex life cycle of at least two hosts. Parasite causes infectious, but some remain neglected diseases. Thus, malaria is considered the most common
killer disease followed by leishmaniasis found in the tropics. Among children, parasitic diseases like giardiasis, cryptosporidiosis, amoebiasis, and soil-transmi ed helminthiases are the main source of illnesses ranging from mild to moderate and severe conditions, depending on geographical areas, social contact, as well as behavioral practices.
Though drugs are currently available used in the form of single and/or combined therapy; however, the partial effective of treatment has been recorded in many parasitic diseases, such as cryptosporidiosis, toxoplasmosis, and acanthamoebiasis due to the thick wall of (oo)cysts. At the same time, drugs resistant has been constantly emerged and has caused a remarkable economic and public disaster, especially related to noneradicable diseases, as is always seen among all, like malaria and leishmaniasis. Furthermore, novel drugs are also in the pipeline to combat the long-standing parasitic diseases, like Chagas disease or sleeping sickness. Unfortunately, there is limited funding for discovery, development, and delivery (3D) of new therapeutic agents for parasitic diseases. In fact, chemotherapy is the major modality considered not only for the treatment, but also for the control of these parasitic diseases in the infected individuals, especially in areas with endemicity. There is no doubt that these modern drugs are periodically reported on the adverse side effects, low efficacy, high toxicity, long-course treatment regimen, induction of parasite resistance, and cost effectiveness. Therefore it is timely that an alternative therapy based on natural products is considered as the other opportunity to play its role in the therapeutic advance of antiparasitic diseases. Plant-based therapy has long been used as folklore and traditional healer as far back the human ancient civilization.
This book Medicinal Plants in Asia and Pacific for Parasitic Infections: Botany, Ethnopharmacology, Molecular Basis, and Future Prospects underscores several aspects on the use of medicinal plants in AsiaPacific region that are useful in treating parasitic diseases. Prof. Christophe Wiart, an expert in vivid and enigmatic plants in Asia, is the author of several books related the medicinal plants used in Asia and the Pacific for antimicrobial activities. He has again penned
g p down this book with all his vast knowledge and efforts to investigate how the effectiveness of plant-based therapy can help to reduce the suffering among affected individuals. This book covers all medicinal plants used for the treatment of parasitic infections in a geographical zone ranging from Turkey to Pacific islands. The plant is described, uses given local names, and pharmacological effects against amoeba, protozoa, nematodes, and helminths. Therefore it is highly appreciated the efforts of Prof. Wiart to compile this historical and scientific document in a systematic manner, which I am sure that this book will be useful for students, teachers, researchers, and all users of natural and traditional medicine to experience deeper to their therapeutic potentials.
Maria de Lourdes Pereira, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
Veeranoot Nissapatorn, School of Allied Health Sciences, Walailak University, Thammarat, Thailand
Foreword by Vu Thi Thom
Mother nature is a source of plants that have been used by humans since time immemorial for food and medicines. Vietnam is a tropical country with plenty of parasitic infections such as malaria, fasciolosis, hookworm, Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Enterobius vermicularis, Strongyloides stercoralis, Fasciolopsis buski, Fasciola hepatica, Clonorchis sinensis, and Paragonimus westermani. It is found in community studies that more than 80% of stool samples contained at least one parasite species and the most common species were hookworm, Trichuris trichiura, and Ascaris lumbricoides. Vietnamese traditional medicine recommends plants with potentials of antiparasitic infection such as Diospyros mollis, Cyrtomium fortune, Mallotus philippinensis, Punica granatum, Areca catechu, Combretum quadrangulare, Chenopodium ambrosioides, Cucurbita pepo, Stemona tuberosa, Artemisia annua, Dichroa febrifuga, Tinospora crispa, and Aglaia merostele. This traditional knowledge has been mentioned in the present book wri en by Christophe Wiart who has dedicated his life to the study of medicinal plants in Asia. It is my belief that the present book will be an uncontournable reference and a precious tool for the discovery of lead antiparasitic compounds from medicinal plants in Asia-Pacific.
Vu Thi Thom, PhD, Department of Science & Technology, International Cooperation, Vietnam, Department of Basic Science in Medicine and Pharmacy, School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam
Preface
The intention behind the writing of this book is to offer a comprehensive set of interrelated botanical, ethnopharmacological, phytochemical, and molecular data to students, scholars, and researchers looking forward to discovering antiparasitic agents from the medicinal plants of Asia and the Pacific. This book is a simple and humble a empt to grasp and understand a very vast, yet fascinating, topic. It is becoming more and more apparent over the years that a logic exists behind pharmacological activities of medicinal plants. In simple words, the botanical classification of a plant is correlated with certain classes of natural products which themselves have the tendency to have either antiamoebic, antiplasmodial, antileishmanial, antitrypanosomal, or anthelminthic properties. The same is true for other activities including antimicrobial, anticancer, etc., but these are not treated here.
This book consists of chapters corresponding to the major angiosperm clades as per the Angiosperm Phylogeny Group classification III (Angiosperm Phylogeny Group, 2009. An update of the Angiosperm Phylogeny Group classification for the orders and families of flowering plants: APG III. Botanical Journal of the Linnean Society, 161(2), pp. 105–121). Within each major clade, medicinal plants are presented according to the order and families they belong to. For each plant is given its scientific name, subfamily and tribe (if relevant), synonyms, local names, detailed botanical description (to allow the reader to recognize it), as well as medicinal uses, pharmacological properties, and commentaries. Thousands of carefully selected publications are cited and self-made botanical plates available. It is my dear hope that this book will contribute to
further antiparasitic evaluation of medicinal plants leading to the isolation of drugs.
This book could not have been wri en without the moral support of my mother, my wife Shirley, and my dear friends Khoo Teng Jin, Thomas Maul, Mohammed Rahmatullah, Christopher Jesudason, Hazem Demrdash, Frederic Weber, Neil Russel Mennie, Blandine Louapre, Pierre Monnier, Alejandro Estudillo, and Marc Archer.
Christophe Wiart, Kuala Lumpur, Malaysia
March 31, 2020
C H A P T E R 1
Antiparasitic Asian medicinal plants in the Clade
Protomagnoliids
Abstract
Medicinal plants in Asia and the Pacific in the Clade Protomagnoliids are few and mainly used for the treatment of malaria and dysentery. Most of these plants have not been examined for their antiparasitic properties in vitro and in vivo. Plants in this Clade are sisters of all the other Clades of Angiosperms. They produce tannins, lignans, and sesquiterpenes.
The family Nymphaeaceae consists of 5 genera and 75 species of ancient and often magnificent aquatic herbs. The leaves are simple, spiral, stipulate or exstipulate, floating, cordate, or peltate. The petiole is long and spongy. The flowers are showy and solitary. The calyx comprises four sepals. The corolla consists of up to 70 petals.
