Presentation on theme: "ANTICANCER AND ANTI-HIV DRUGS DERIVED FROM AFRICAN AND OTHER PLANTS"— Presentation transcript:
1ANTICANCER AND ANTI-HIV DRUGS DERIVED FROM AFRICAN AND OTHER PLANTS Gordon Cragg, Ph.D.NIH Special VolunteerNatural Products BranchDevelopmental Therapeutics ProgramDivision of Cancer Treatment andDiagnosisNCI-FrederickFairview Center, Suite 206P. O. Box BFrederick, MD , U. S. A.Phone: ; fax:website:
2Traditional Medicine and Drug Discovery* 80% of the world population resides in developing countries80% of people in developing countries utilize plants to meet their primary health care needsGlobal pop. ca. 6.3 billion ca. 4 billion people utilize plants to meet their primary health care needs*Farnsworth NR, et al. Medicinal Plants in Therapy. Bull. W.H.O. 63: (1985)
4NATURE – THE SUPREME MOLECULAR ARCHITECT! Epothilone A docked in tubulin active siteEpothilone AIsolated from glidingbacteria (Myxobacteria)Nettles et al., "The Binding Mode of Epothilone A on a,ß-Tubulin by Electron Crystallography"Science, 6 August 2004, Vol. 305, pp (Copyright AAAS)
5PLANT-DERIVED ANTICANCER DRUGS IN CLINICAL USE OR DEVELOPMENT Vinblastine/Vincristine: Catharanthus roseus/Jamaica,Philippines (originally from Madagascar)Etoposide: Podophyllum species/ Eastern US, HimalayasPaclitaxel/Docetaxel: Taxus species/NW US, EuropeTopotecan/Irinotecan: Camptotheca acuminata/ChinaHomoharringtonine: Cephalotaxus harringtonia/ChinaFlavopiridol: Synthetic based on rohutikine fromDysoxylum binectariferum/IndiaCombretastatins: Combretum caffrum/S. Africa
6INTERNATIONAL COLLABORATION Prior informed consent/permits from Source CountryGovernment and stakeholders.Collaboration with Source Country Organizations.Training and technology transfer.Protection of environment and sustainable development.Plans for benefit-sharingDr. D. SoejartoU. Illinois at Chicago
7MICHELLAMINE B Potential Anti-AIDS Agent Discovery and Development 1987: Collected liana Ancistrocladus korupensis leaves.Korup National Park, Mundemba, S. West Cameroon.Dr. Duncan Thomas (MBG) and Mr. Ndembe (Forestry Dept.).New species (Thomas & Gereau, Novon, 1993, 3, ).1989: Michellamine B isolated. Active against a range of HIV-1and HIV-2 strains (Boyd et al., J. Med. Chem, 1994, 37, ).Sufficient isolated from fallen leaves for preclinical development.
11A. KORUPENSIS CULTIVATION STUDIES 1993: Contract for cultivation feasibility study awarded.All studies performed in Korup region involving local population.Extensive botanical and analytical survey:- Distribution: One liana per hectare.- Dried leaf analysis (N=>1,000): Up to 4% (w/w) MB.Nursery established at Mundemba. Cuttings of high-yieldingplants propagated.MB content of 1,5 year old seedlings: %
13DEVELOPMENT OF MICHELLAMINE B Formulation as diacetate salt.Toxicology: Rodents, dogs, primates.Toxic dose level close to anticipated effectiveantiviral dose (narrow therapeutic index).Development suspended.Possibility of lead development (Bringmann, Wurzburg).Novel antimalarial agents, the korupensamines, addfurther promise for A. korupensis.
14POTENTIAL ANTI-HIV DRUG FROM HOMALANTHUS NUTANS : PROSTRATIN Dr. Paul Cox entered into a Covenant with healers ofWestern Samoan village of FalealupoCovenant signed with village chiefs and orators withconcurrence of Prime Minister and Parliament.Use of Homalanthus nutans by healers recordedby Dr. Cox: Treatment of “yellow” fever.$480,000 provided for schools, clinics, water supplies,trails, aerial walkways, etc.Endowment established for preservation of forest.P.A.Cox, Pharmaceutical Biology, 2001, 39 (Supplement ), 33-40
15Samoan Traditional Healers in Village of Falealupo
16Potent activator of HIV expression in latently- infected T-cells Licensed by NIH to the AIDS ReSearch Alliance of AmericaAgreement with Government of SamoaMilestone payments on completion of Phase I, II and III clinical trialsRoyalties totaling 20% of net revenuesDistribution between government, village community and healers’families
17Sarawak Biodiversity Center for in-country Calophyllum teysmannii var. inophylloide. Sustainable source of potential anti-AIDSdrug, calanolide B. Discovery from tree in Sarawak, Malaysia, promoted conservation and replanting of seedlings in clearcut regions, and led to establishment of theSarawak Biodiversity Center for in-countryresearch on drug discovery from local biodiversityD.D. Soejarto, University of Illinois at Chicago
18CALANOLIDES DEVELOPMENT 1995: Calanolides licensed to Medichem Research Inc.Synthesis of (+)-calanolide A supported by NCI SBIR grantNegotiation with Sarawak State Govt. required by LOC1996: Joint venture company, Sarawak MedichemPharmaceuticals formedPhase I trials of Calanolide-A completed/well toleratedPhase II trials in progressCalanolide B in preclinical development
19PARALLEL DEVELOPMENT OF HERBAL MEDICINES NOVEL CONVENTIONAL DRUGS AND THE DISCOVERY OFNOVEL CONVENTIONAL DRUGSBioassay-guided isolation and chemical characterizationof active principle(s)Provide markers for standardization of herbal productsProvide lead compounds for conventional drugdevelopment
20Basic PhilosophyAny herbal drug or botanical supplement to be considered for clinical trials must be botanically authenticated as well as chemically and biologically standardized.Dr. Norman Farnsworth, Director, UIC/NIH Center for Botanical DietarySupplements Research
21Steps Required Prior to Clinical Assessment of Herbal Drugs/Botanical Dietary Supplements Acquire plant materialVerify identity; taxonomic/microscopic/PCRCheck for pesticides; herbicides; heavy metalsEstablish/select appropriate bioassayBioassay several types of extractsIn vitroIn vivo (if possible/relevant)
22Steps Required (continued) Bioassay-guided isolation and chemical characterization of active principle(s)Prepare the biologically and chemically standardized dosage formConduct stability studiesIn vitro studies on standardized productMetabolism (including interactions with p450s)PharmacokineticsToxicityMechanism of Action
23Thank you for visiting this website, which is intended to be a network hub for allstakeholders in Africa’s natural plant products sector. Through knowledge-sharingand information-exchange via this site, ASNAPP (Agribusiness in SustainableNatural African Plant Products) seeks to create a knowledge community that willstrengthen the continent’s capacity to develop this sector.In the interests of developing successful natural product agribusinesses, and thushelping to reduce poverty in rural communities, ASNAPP promotes collaborationand knowledge sharing with research and academic institutions, government,private enterprises, non-profit organizations, the donor community and civilSociety.For this purpose, the ASNAPP website encourages information exchange in any of thefollowing areas:Applied research and technology transferQuality assurance and controlMarket linkages and developmentEnterprise and farmer association developmentNatural resource managementPolicy dialogue and advocacy
24Partner countries: Ghana, Rwanda, Senegal, South Africa, Zambia, USA These areas are the main thrust of ASNAPP’s activities for 2005, based on the followingthree new programmes funded by the United States Agency for International Development (USAID):The Partnership for Food Industry Development Program (PFID), managed byRutgers University’s New Use Agriculture and Natural Plants Products Program.The Rural Livelihoods Activity in Southern Africa programme, run by the MichiganState University Partnership for Food Industry Develop Program – Fruits andVegetables (MSU PFID – F & V) in conjunction with a consortium of partners.The Partnership for Sustainable Germplasm Development for Non-traditionalCrops, a collaborative project involving various academic and research institutionsas well as private enterprises in South Africa and Zambia.ASNAPP USARutgers University - Cook College Department of Plant Biology and Plant Pathology 59 Dudley Road, 381 Foran Hall New Brunswick, New Jersey 08901Professor Jim Simon Co-Principal Investigator and Quality Control Coordinator ASNAPP Program New Use Agriculture and Natural Plants Program Tel: Ext. 355/379 Fax: Website: Partner countries: Ghana, Rwanda, Senegal, South Africa, Zambia, USA
25Clinical Trials and Complementary and Alternative Medicine (CAM) While many CAM treatments have already been in use fora long time (sometimes for centuries), there is not the kindof scientific knowledge available about them that has beengained from studies of conventional medicine. Many peopleare already using CAM, and without this scientific knowledge,they may be at risk— for example, for serious effects fromtaking the wrong dose, using the treatment in the wrong way,or using it with another treatment with which it interacts.
26INTERNATIONAL AND REGIONAL COLLABORATION AFASSA: Africa, Asia and South AmericaCo-ordinates activities of networks involved in natural productresearch in Africa, Asia and South America.Founded at Intercontinental Symposium on Natural ProductsResearch in Montevideo in December, 1999.NAPRECA SYMPOSIUMADDIS ABABA 2003Next symposium:Antananarivo, MadagascarAugust 9-12, 2005Takelaka.dts.mg/rafita