Chapter 3

Capacity building in anthelmintic drug discovery

Michael Kron, Fouad Yousif & Bernadette Ramirez
Department

1. 2. 3. Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Lulea University Of Technology on 09/25/13 For personal use only. 4. 5.

Introduction Regional anthelmintic screening centres Productivity of established anthelmintic screening centres New screening centre opportunities Expert opinion

of Medicine, Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA

International collaboration in anthelmintic drug discovery holds special challenges compared with local or national discovery projects, and at the same time presents the opportunity to build capacity, forge long lasting interinstitutional relationships and strengthen infrastructure in multinational priority areas. This chapter discusses important issues that should be considered in the context of anthelmintic screening centre development and will give examples (Philippines and Egypt) of the productivity of developing country based screening centres. The positive outcomes of infrastructure building is realised in greater capacities for anthelmintic screening at institutions in the countries where the parasitic diseases are endemic and allows for optimum use of specialised resources for public health priority diseases that may be different from those in Western countries. Support for developing country based screening centres also can help countries optimise product development procedures and policies and can facilitate diffusion of desirable technology in corresponding global regions around the world.
Keywords: anthelmintic, Egypt TDR drug discovery, filariasis, Philippines, schistosomiasis Expert Opin. Drug Discov. (2007) 2(Suppl.1):S75-S82

1.

Introduction

In 2002, the University of Toronto Joint Centre for Bioethics reported the deliberations of an international panel of 28 scientists who addressed the question What are the top ten biotechnologies for the promotion of global health? [1]. This study responded to an April 2002 World Health Organization report, Genomics and World Health, which highlighted the importance of the growing biotechnology fields for improving health in developing countries and the existence of the 10/90 gap [2]. The so-called 10/90 gap refers to the fact that 90% of medical research is targeted at problems affecting only 10% of the worlds population. Thus, between the 10/90 gap and inequities in biotechnology research infrastructure, serious concerns were raised regarding the progression of the divide between North and South. The top 10 list included of molecular technologies for diagnosis of infectious diseases, vaccine development, drug and vaccine delivery systems, environmental improvement, pathogen genome projects, protection against sexually transmitted diseases, bioinformatics, genetically modified crops, recombinant technology to make therapeutic products and combinatorial chemistry for drug discovery. In light of these realities, one approach to narrowing the 10/90 gap is to promote true capacity building partnerships between countries that encourage the appropriate transfer of technology in order to fully use local personnel capacities, while at the same time making the most of local human and natural resources that can be used to address such topics as drug discovery. The benefit of such partnerships to developing country infrastructure is easy to envision, not the least of which are special needs viz a viz public health priorities, such as tropical helminthic disease, which are often unique to the developing country partner. The corresponding benefits to more industrialised partners lies in the opportunity to apply modern
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technologies and to gain insight into new scientific strategies using the traditional or biodiversity resources, which often reside within the same countries that are in need of scientific capacity building. A challenge for new partnerships is determining how to effectively establish such bilateral programmes while being mindful of national safeguards that are designed to protect genetic resources and intellectual property, and to promote biodiversity conservation if natural resources are indeed part of the partnership equations. In the context of drug discovery projects, true partnerships are evidenced by the successful transfer of technology (e.g., production of recombinant reagents and special analytical methods) that furthers drug discovery in the developing country by utilising its manpower and natural resources [3,4]. If natural products are taken outside the country for specialised testing, this is done so in a highly controlled fashion to minimise even the appearance of bio-piracy. In addition, lead compounds discovered elsewhere can be shared with external developing country researchers to help examine important anthelmintic properties.
2.

Regional anthelmintic screening centres

A number of regional anthelmintic screening centres have been active and scientifically productive in a variety of locations in Europe, Asia, Africa and North America. Measures of productivity include both occasional commercialisation of new products, but more frequently focus on the successful identification of natural products or strategies for anthelmintic drug discovery. For example, the Institute of Parasitic Diseases (IPD) in Shanghai, China, has collaborated with the Tropical Disease Research (TDR) Programme of WHO for > 20 years. In the context of research into malaria, schistosomiasis and filariasis, infrastructure development has also supported technical guidance to Chinese provincial institutes and graduate training programmes such as the Masters Research Program. In North Africa, the Theodor Bilharz Research Institute (TBRI) in Cairo, Egypt, has a long tradition of successfully identifying novel sources of anthelmintic, antischistosomal compounds. Not unexpectedly, more costly and manpower intensive medicinal chemistry follow-up on excellent ideas/new anthelmintic sources can be a rate limiting step in the long-term goal of new product and regional or global commercialisation. As additional country-specific screening centres are contemplated and organised, regional strengths can be identified while the lessons learned from other centres are internalized.
3.

Productivity of established anthelmintic screening centres

In Egypt and most of Africa, anthelmintic drug screening has concentrated mainly on screening of plants. Many plants constitute important therapeutic agents in traditional medicine and healthcare practice [5]. Herbal medicine has
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produced some very effective treatments for malaria, such as quinine and recently artemisinin [6], but no similar success in the case of schistosomiasis [7]. In Egypt, schistosomiasis caused by Schistosoma mansoni and S. haematobium has remained endemic for 5000 years. Presently, 20 millions persons have the disease worldwide, perpetuated by the development of new irrigation and waterways that promote the distribution of intermediate host snails. Thus, anthelmintic screening of plants has focused on schistosomiasis and resulted in many leads from in vitro and in vivo (animal model) testing. For example, in vitro testing has shown a 90 100% mortality of Schistosoma worms using 4 g/ml goyazensolide, a component extracted from Eremanthus goyazensis [8]. Sparg et al. (2000) screened 21 species from South Africa against schistosomules of S. haematobium, where Berkheya speciosa (Asteraceae), Euclea natalensis (Ebenaceae) and Trichilia emetica (Meliaceae) were found lethal [9]. Molgaard et al. (2001) screened extracts of 23 species from Zimbabwe, and found that stem and root extracts from Abrus precatorius (Fabaceae) and stem bark extracts from Elephantorrhiza goetzei (Mimosaceae) have a good activity against schistosomules [10]. Robustic acid and an isoflavone compound from the seeds of the tree Millettia thonningii, extracts of Scilla natalensi and fresh Ledebouria ovatifolia possess in vitro antischistosomal activites [11]. Aqueous extracts of Scilla natalensis had activity against S. haematobium with a minimum inhibitory concentration (MIC) of 0.4 mg/ml. Aqueous extracts of fresh Ledebouria ovatifolia bulb material were found to be lethal to S. haematobium at a concentration of 1.6 mg/ml [12]. Yousif et al. (2007) carried out in vitro bioassay screening of 346 methanol extracts originated from 281 native and cultivated plant species growing in Egypt [13]. Strong antischistosomal activity was found in the extracts of 15 species (IC50 15 g/ml), viz Agave americana L.var. marginata Trel. (Agavaceae), A. lophantha Schiede (Agavaceae), Furcraea selloa C.Koch. (Agavaceae), Calotropis procera (Aiton) W.T.Aiton (Asclepiadaceae), Pergularia tomentosa L. (Asclepiadaceae), Asclepias sinaica (Boiss) Muschl. (Asclepiadaceae), Alkanna orientalis (L.) Boiss. (Boraginaceae), Khaya grandifoliola DC. (Meliaceae), Swietenia mahogani (L.) Jacq. (Meliaceae), Pimenta racemosa (Mill.) Pimenta racemosa (Mill.) J.W. Moore (Myrtaceae), Pinus canariensis C.Sm. (Pinaceae), Verbascum sinaiticum L. (Scrophulariaceae), Solanum elaeagnifolium Cav. (Solanaceae), S. nigrum L. (Solanaceae) and Brachychiton rupestris (Lindl.) K.schum. (Sterculiaceae). The Schistosome Biological Supply Centre (SBSC), Theodor Bilharz Research Institute (TBRI), in Cairo, Egypt, with support from the World Health Organization Tropical Disease Research Unit, investigated the schistosomicidal activity of 2407 compounds received from several commercial suppliers and reported that 73 were active against S. mansoni, 23 of which were highly active as defined by an IC50 value of 1 g/ml. Promising in vivo reports on antischistosomal plants are summarised in Table 1 [7,14-20].

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Table 1. In vivo examples of promising plants as sources of new anti-schistosomal compounds.

Compound/source Artemether (Artemisia annua) Mirazid Mirazid Nigella sativa Ferula assafoetida
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Animal model Human Human Human Mouse Mouse Mouse

Effective doses/forms 6 mg/kg 10 mg/kg x 3 6 days Ineffective Oil Oil and powder Fruit mesocarp 200 mg/kg

Reported by Utzinger et al. Massoud et al. (2001) Abo-Madyan et al. (2004) Botros et al. (2004) Barakat et al. (2005) Mahmoud et al. (2002) Ramadan et al. (2004) Koko et al. (2005)

Reference
[7] [14,15]

(Commiphora molmol)

[16,17]

[18] [19] [20]

Balanities aegyptiaca

4.

New screening centre opportunities

Awareness of a countrys unique biodiversity resources is often seen as an opportunity for new drug discovery efforts applied to the full spectrum of human, animal and plant diseases. For example, the Philippines is one of the worlds 12 mega diversity countries at the junction of 3 bio-geographic zones. The combination of extraordinary terrestrial and marine biodiversity and widespread endangering conditions places the Philippines in the worlds top five high priority conservation hotspots [101]. While the Philippines has been a collaborator with many international drug discovery research groups, development of its own dedicated screening centres has been slow to occur. To aggressively protect and explore its national biodiversity resources, the Philippines developed arguably one of the most advanced systems of environmental legislation in the region. In particular President Ramoss 1995 Executive Order defined critical regulations for national and international groups involved in bio-discovery. Full compliance with EO247 is a necessary and very challenging component to natural products research in the Philippines (Figure 1) [21,22]. Thousands of species of medicinal plants have been reported in the Philippines and it is widely believed that indigenous herbalists have knowledge of hundreds or thousands more. Compendia of medicinal plants (marine and terrestrial) unique to different geographic zones in the Philippines and other natural products used in traditional medicines are being compiled by academic, government and local indigenous groups, with the long-term goals of: i) identifying natural products for sustainable development; and ii) addressing intellectual property claims by different indigenous groups and research organisations. The Philippine Department of Science and Technology (DOST) and the Philippines Council for Health Research and Development (PCHRD) through the National Integrated Research Programme on Medicinal Plants, help regulate medicinal plant utilisation. Because the commercial markets are well defined, understanding the structure and diversity of active components in medicinal plants is a national priority. To facilitate medicinal plant discovery, specific indigenous groups have agreed to work

with the University of the Philippines (UP) and carefully chosen external collaborators, to share their knowledge of medicinal plants. In order to implement safeguards against taking advantage of sensitive populations, the Philippine government established a National Commission for Indigenous People (NCIP). The mission of the NCIP is to provide independent and objective oversight to groups seeking to collaborate with indigenous groups. But concern over intellectual property rights and motivation of international partners delayed awards of NCIP certificates of compliance until 2004. In that year, the NCIP issued its first certificate of compliance to a joint US-UP team with funding from the US National Institutes of Health International Collaborative Biodiversity Group Programme (ICBG). A key component to such an effort is transparency in dealing with sensitive populations a globally important, delicate and controversial issue. To maintain oversight of ongoing activities, the NCIP requires extensive evidence of free and prior informed consent (FPIC) that documents the methods and outcomes of negotiations. Plans to commercialise any product requires its own set of regulations that not only safeguard the national participants of the country itself, but also the environment in the event of unforeseen negative outcomes of the biodiscovery process. Two major Filipino public health problems in need of new anthelmintiic therapies are schistosomiasis and lymphatic filariasis. Approximately six million people are at risk of S. japonicum and two million are considered directly exposed to the parasite [23]. The stool of infected mammals (e.g., water buffaloes, domestic animals; considered as reservoir hosts) contain infective eggs that contaminate freshwater sources that harbour the intermediate host snails (Oncomenalia hupensis quadrasi). At present, the treatment of schistosomiasis in the Philippines relies on a single drug of choice, praziquantel. While relatively safe to use in whole communities for mass treatment programmes, concerns are raised as to the possible development of drug resistance in the future. Similar concerns exist for drugs used to treat filariasis. Lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi is endemic throughout most of the southern
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Capacity building in anthelmintic drug discovery

PIC concerned entity

Applicant Letter of intent IACBGR forms

Technical secretariat Initial screening

IACBGR

Ministry concerned

Research proposal public notification Issues certificate after 60 days

Requests for additional document Refers documents to appropriate agency

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PIC certificate PIC certificate

Initial review and evaluation Final evaluation Approval

Field research activities can commence, but without survey knowledge of indigenous people. Collection permit

Recommendation and draft of research agreement

Recommendation

Signed research agreement

Figure 1. Application process for biodiversity collection permits under Philippine law.
Permit is granted by Department of Environment and Natural Resources (DENR) after approval by the regional Protected Area Management Board (PAMB). Figure adapted from [GTZ Newsletter, 2000.] IACGGR: Interagency committee on biological and genetic resources; PIC: Prior informed consent.

half of the Philippine archipelago [24]. Analysis of cumulative prevalence data on filariasis indicates the persistence of filariasis in each of the three major island groups, Luzon, Visayas and Mindanao, including 45 out of 77 provinces, with 20 million persons living in areas with active transmission. In 1997, the Philippines established a National Filariasis Control Programme with a mission to provide mass combination chemotherapy to all endemic communities, a highly ambitious and logistically complex initiative given the span of an archipelago containing 7100 islands. In collaboration with US based investigators, in vitro worm-killing assays have been established to screen natural products and synthetic compounds for antifilarial or antischitosoma activity. Assays for S. japonicum adult worm killing as well as schistosomula killing have been adapted successfully and modified from previous protocols developed for use in S. mansoni (Figure 2 and Figure 3). Design of screening assays in the laboratory is logistically more complex in S. japonicum than in S. mansoni. First, access to a significant quantity of infected oncomelanid snails (source of cercariae, which are the starting material for transformation into schistosomula) is quite limited, while lab-rearing of infected snails is possible (although admittedly, the lab-culture of oncomelanid snails is not as easy and straightforward as with the intermediate
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hosts of S. mansoni). To address this technical limitation, scientists at UP obtain field-infected snails from freshwater habitats found in highly-endemic communities. UP presently has a library of some 16,000 Philippine terrestrial plant extracts already classified in terms of general cytotoxicity using cancer cell lines that were originally collected in the search for new cancer chemotherapies. The majority of these crude extracts remain unscreened for anthelmintic activity. Historically, antifilarial drug screens have been established using the intraperitoneal jird infection model of Brugia malayi (Figure 4) [25], but similar screening could also be conducted using endemic species of animal filaria, such as those found in water buffalo (carabao), hookworm and other geohelminths amenable to in vitro cultivation.
5.

Expert opinion

The creation, support and maturation of new collaborations in anthelmintic drug discovery hold great promise for all partners in terms of new products and infrastructures. Beyond the realm of product development, new infrastructure can be shared with educational and service programmes, legal and social science initiatives. However, a set of key issues should be identified that endeavour to promote new

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100 90 80 70 % Survived 60 50 40 30 20 10 Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Lulea University Of Technology on 09/25/13 For personal use only. 0 0 12 24 36 48 Time (hours) 60 72

Neg Cont with RBC Neg Cont w/out RBC DMSO w/RBC Comp1 Comp2 Comp3 Comp4 Comp5 Comp6 Comp7 Comp8

Figure 2. Survival of Schistosoma japonicum adult worms at various time points following culture with different puried natural plant products. Control worms in media supplemented with red blood cells (top curve) retain excellent viability in contrast to those cultured in media without red blood cells (bottom curve).

Percentage of cercariae survived at various observation periods at drug concentration 0.0001 mg/ml 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Time (hours) 7 8 9 10 Compound 1 Compound 2 Compound 3 Compound 4

Figure 3. Comparison of four novel synthetic anthelmitics for their ability to kill Schistosoma japoinicum cercaria. Note that although the viability of cercaria often can be followed only in terms of hours, the effect of lead compounds still can be accurately compared.

Observation period (hours)

% Survival

24

48

72

96

120

144

168

192

216

288

Notes Controls 100% viable at 21 days

Media control Albendazole 2 M (positive control) JBH01 150 nM JBH01 1.5 M LCM02 120 nM LCM02 1.2 nM X X X X

Figure 4. The effects of four structurally related synthetic natural compounds on adult female Brugia malayi. Note that the symbol X denotes the time in hours at which 100% of parasites are killed.
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Capacity building in anthelmintic drug discovery

Box 1. Issues for organisation of international collaborative anthelmintic screening programs.

Familiarity and administrative condence in partnerships -multipurpose afliation agreements and memoranda of understanding Compliance and enforcement of national and international law Respect for International Conventions on Biodiversity and national regulations on biodiversity management
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Intellectual property management and legislative reform Transparency in benet sharing negotiations: Inter-institutional requirements, expectations of funding organisation Expectations and operating procedures in industry versus academia Special issues related to participation of indigenous peoples and access to traditional medicine knowledge Role of funding agencies to oversee business practices Prioritisation and evaluation of product development by industry experts:disclosure of proprietary, nancial and economic market variablesrole for WHO-TDR Leadership

equitable collaborations in the face of complex nationalistic, proprietary and industry priorities (Box 1). Conceptualisation of new laws for biodiversity management and resource utilisation must also be cognizant of factors that could lead to exclusivity. While in any nation, scientific expertise and infrastructure may be unequally distributed between institutions and cities, participation in drug discovery should not be limited only to those with the greatest political connections. In countries where foreign investigators are involved in bioprospecting, allegations of misuse of natural resources is an all too common complaint from local stakeholders. In wealthier Western countries, the pharmaceutical industry may devote immense sums to protecting patent rights; there are relatively few resources in the developing world devoted to protection of scientific discoveries or to pursue allegations of improper activity. Technical loopholes in patent law must be addressed upfront to address such one-sided lucrative arguments that a new commercial product might be chemically so far modified/remote from a bioactive natural compound that the country of origin should not be entitled to compensation. Whether or not funding agencies

themselves should also be held accountable for the professional activities and outcomes of its recipients work remains controversial. The primary mission of the pharmaceutical industry is to create profit. Barely 10 years ago, a representative of a leading major international pharmaceutical company reported to a WHO advisory committee that unless there was potential for a billion dollar market, they were not interested. However, times and consumer markets may be changing in a way to positively impact that sentiment. Creative marketing of anthelmintic products for human consumption might be combined with veterinary medicine applications and agricultural biological control efforts to make the industry more economically inclined to collaborate in the discovery of anthelmtics for use in humans who reside in the developing world. There is no doubt that developing country based screening centres can identify sources of interesting anthelmintics. Furthermore, the commonality of multiple helminth infections in different rural populations around the world does support the simultaneous search for broad spectrum anthelmintics effective against combinations of trematodes, cestodes, nematodes or even protozoa. The role of developing country-based screening centres as critically important national intermediaries between communities and commercialisation must be supported. But what is often lacking is the technical capacity (e.g., high tech analytical equipment) and experience to begin the next phases of drug discovery. Specifically, prioritisation of leads from natural products has no general template to guide investigators within and between nations. Therefore, international organisations such as the WHO could provide important leadership to help standardise and organise screening methods (parasite strains), provide cost-effective advice on the timing of expensive in vivo experimentation and experienced advisory boards would review leads in terms of medicinal chemistry/drugability, chemical engineering, pharmacokinetics, cytotoxicity testing, as well as preliminary critical commercial market assessments. Financial investment in needed infrastructure support for developing country-based screening centres would thus facilitate the acquisition of a self sustaining expertise in appropriate areas.

Acknowledgements
M Grotli, Department of Chemistry, Goeteborg University, Sweden, J Morris, Department of Chemistry, University of Adelaide, Australia, and M Nair, Bioactive Natural Product Laboratory, Michigan State University, East Lansing, Michigan, USA, each provided synthetic compounds for anthelmintic screening in the Philippines.

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Schistosome parasites. Curr. Med. Chem. (2001) 8:1841-1860. Status report on questionable value of artemether for Schistosomiasis. BARTH LR, FERNANDES AP, RIBEIRO-PAES JT, RODRIGUES V: Effects of goyazensolide during in vitro cultivation of Schistosoma mansoni. Mem. Inst. Oswaldo. Cruz. (1997) 92(3):427-429. Anti-schistosomal effects of a compound isolated from Eremanthus goyazensis. SPARG SG, VAN STADEN J, JAGER AK: Efciency of traditionally used South African plants against schistosomiasis. J. Ethnopharmacol. (2000) 73:209-214. Survey of South African medicinal plant activity against Schistosoma mansoni. MOLGAARD P, NIELSEN SB, RASMUSSEN DE, DRUMMOND RB, MAKAZA N, ANDREASSEN J: Anthelmintic screening of Zimbabwean plants traditionally used against schistosomiasis. J. Ethnopharmacol. (2001) 74(3):257-264. Review of traditional plant medicines from Zimbabwe. LYDDIARD JR, WHITFIELD PJ, BARTLETT A: Antischistosomal bioactivity of isoavonoids from Millettia thonningii (Leguminosae). J. Parasitol. (2002) 88(1):163-170. Report of isoavenoid activitiy against S. mansoni. SPARG SG, VAN STADEN J, JAGER AK: Pharmacological and phytochemical screening of two Hyacinthacease species: Scilla natalensis and Ledebouria ovatifolia. J. Ethnopharmaco. (2002) 80(1):95-101. Summary of novel anthelmintic activities from Hyacinthacease sp. YOUSIF F, HIFNAWY MS, SOLIMAN G et al.: Large -scale in vitro screening of Egyptian native and cultivated plants for schistosomicidal activity. J. Pharm. Biolog. (2007) 45(6):501-510. Authoritative and most up to date review of antischistosomal activity in Egyptian medicinal plants. MASSOUD A, SHEIR Z, NASR AA et al.: A safe, effective, herbal antischistosomal therapy derived from myrrh. Am. J. Trop. Med. Hyg. (2001) 65(6):700-704. Reports one side of the argument for studying antischistosomal activity of myrrh. ABO-MADYAN AA, MORSY TA, MOTAWEA S: Efcacy of Myrrh in the 16.

treatment of schistosomiasis (haematobium and mansoni) in Ezbet El- Bakly, Tamyia Center, El- Fayoum Governorate, Egypt. J. Egypt Soc. Parasitol. (2004) 34(2):423-446. Additional supportive evidence for myrrh as antischistosomal treatment. BOTROS S, WILLIAM S, EBEID F, CIOLI D, KATZ N DAY TA, BENNETT JL: Lack of evidence for an antischistosomal activity of myrrh in experimental animals. Am. J. Trop. Med. Hyg. (2004) 71(2):206-210. Opposing arguments for the use of myrrh in schistosomiasis. BARAKAT R, EL-MORSHEDY H, FENWICK A: Efcacy of Myrrh in the treatment of human Schistosomiasis mansoni. Am. J. Trop. Med. Hyg. (2005) 73(2):365-367. Report on the potential efcacy of myrrh in human trials. MAHMOUD MR, EL-ABHAR HS, SALEH S: The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice. J. Ethnopharmacol. (2002) 79(1):1-11. Interesting immunomodulatory activity of N. sativa oil in schistosomal liver granulomas. RAMADAN NI, ABDEL-AATY HE, ABDEL-HAMEED DM et al.: Effect of Ferula assafoetida on experimental murine Schistosoma mansoni infection. J. Egypt. Soc. Parasitol. (2004) 34(3 Suppl.):1077-1094. In vivo effects of a plant extract in murine S. mansoni. KOKO, WS, ABDALLA HS, GALA IM, KHALID HS: Evaluation of oral therapy on Mansonial Schistosomiasis using single dose of Balanites aegyptiaca fruits and praziquantel. Fitoterapia (2005) 76(1):30-34. Human trial of a fruit plus praziquantel in S. mansoni infection. DALTON R: Natural resources: bioprospects less than golden. Nature (2004) 429(10):598-600. Independent review of the successes and failures of the US international cooperative biodiversity group program. GTZ NEWSLETTER: German-Philippines cooperation: implementing biodiversity (2000). Update on the complexity of biodiversity law in the Philippines.

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Website
101. http://www.biodiversityhotspots.org Conservational International Hotspots (2003). Highlights global range of international biodiversity zones and endangered areas.

2Scientic

Afliation
Michael Kron1 MD MS, Fouad Yousif 2 PhD & Bernadette Ramirez3 PhD Author for correspondence 1Professor and Director, Programme in International Health, Department of Medicine, Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA Tel: +1 414 456 5613; Fax: +1 414 456 6568; E-mail: mkron@mcw.edu

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Director, Schistosome Biological Supply Center, Theodor Bilharz Research Institute, El Nil Road, Warrak El-Hadar, Imbaba, Egypt 3Professor, Department of Biochemistry & Molecular Biology, College of Medicine, and Director, Institute of Biotechnology and Molecular Biology, National Institutes of Health, University of the Philippines-Manila, 547 Pedro Gil Street, Ermita, Manila 1000 Technical Ofcer, Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, 1211 Geneva 27, Switzerland

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