Transcript plant-derived drugs

ANTICANCER AND ANTI-HIV DRUGS DERIVED FROM
AFRICAN AND OTHER PLANTS
Gordon Cragg, Ph.D.
NIH Special Volunteer
Natural Products Branch
Developmental Therapeutics Program
Division of Cancer Treatment and
Diagnosis
NCI-Frederick
Fairview Center, Suite 206
P. O. Box B
Frederick, MD 21702-1201, U. S. A.
Phone: 301-846-5387; fax: 301-846-6178
e-mail: [email protected]
website: http://dtp.nci.nih.gov;
http://dtp.nci.nih.gov/branches/npb/index.html
Traditional Medicine and
Drug Discovery*
• 80% of the world population resides in
developing countries
• 80% of people in developing countries utilize
plants to meet their primary health care needs
• Global 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. 63:965-981 (1985)
PLANT-DERIVED DRUGS
• Analgesics: Aspirin: Salix species/Europe
Morphine, Codeine;Papaver somniferum/
Mesopotamia (Iran, Iraq)
• Cardiotonic: Digitalin: Digitalis purpurea/UK-Europe
• Malaria: Quinine: Cinchona spp./Amazonia
Artemsinin: Artemisia annua/China
• Antihypertensive: Reserpine: Rauwolfia
serpentina/India
• Memory enhancement: Physostigmine: Physostigma
venenosum/West Africa
Muscle relaxant: Tubocurarine:Chondrodendron spp./
Amazonia
NATURE – THE SUPREME MOLECULAR ARCHITECT!
Epothilone A docked in tubulin active site
Epothilone A
Isolated from gliding
bacteria (Myxobacteria)
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Nettles et al., "The Binding Mode of Epothilone A on a,ß-Tubulin by Electron Crystallography"
Science, 6 August 2004, Vol. 305, pp. 866-869 (Copyright AAAS)
PLANT-DERIVED ANTICANCER DRUGS
IN CLINICAL USE OR DEVELOPMENT
• Vinblastine/Vincristine: Catharanthus roseus/Jamaica,
Philippines (originally from Madagascar)
• Etoposide: Podophyllum species/ Eastern US, Himalayas
• Paclitaxel/Docetaxel: Taxus species/NW US, Europe
• Topotecan/Irinotecan: Camptotheca acuminata/China
• Homoharringtonine: Cephalotaxus harringtonia/China
• Flavopiridol: Synthetic based on rohutikine from
Dysoxylum binectariferum/India
• Combretastatins: Combretum caffrum/S. Africa
INTERNATIONAL COLLABORATION
• Prior informed consent/permits from Source Country
Government and stakeholders.
• Collaboration with Source Country Organizations.
• Training and technology transfer.
• Protection of environment and sustainable development.
• Plans for benefit-sharing
Dr. D. Soejarto
U. Illinois at Chicago
MICHELLAMINE 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, 494-498).
• 1989: Michellamine B isolated. Active against a range of HIV-1
and HIV-2 strains (Boyd et al., J. Med. Chem, 1994, 37, 1740-45).
• Sufficient isolated from fallen leaves for preclinical development.
MICHELLAMINE B COLLABORATION: CAMEROON
FEASIBILITY STUDY
CULTIVATION OF A. KORUPENSIS
National Cancer Institute
Gordon Cragg
Purdue University
Center for New Crops and Plant Products
James Simon
University of
Yaounde
Johnson Jato
World Wildlife
Fund
Paul Symonds
Missouri
Botanical
Garden
James Miller
Oregon State
University
Duncan Thomas
A. 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-yielding
plants propagated.
• MB content of 1,5 year old seedlings: 0.07-0.73%
DEVELOPMENT OF MICHELLAMINE B
• Formulation as diacetate salt.
• Toxicology: Rodents, dogs, primates.
Toxic dose level close to anticipated effective
antiviral dose (narrow therapeutic index).
• Development suspended.
• Possibility of lead development (Bringmann, Wurzburg).
• Novel antimalarial agents, the korupensamines, add
further promise for A. korupensis.
POTENTIAL ANTI-HIV DRUG FROM HOMALANTHUS
NUTANS : PROSTRATIN
• Dr. Paul Cox entered into a Covenant with healers of
Western Samoan village of Falealupo
• Covenant signed with village chiefs and orators with
concurrence of Prime Minister and Parliament.
•Use of Homalanthus nutans by healers recorded
by 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
Samoan Traditional Healers in Village of Falealupo
Potent activator of HIV
expression in latentlyinfected T-cells
• Licensed by NIH to the AIDS ReSearch Alliance of America
• Agreement with Government of Samoa
• Milestone payments on completion of Phase I, II and III clinical trials
• Royalties totaling 20% of net revenues
• Distribution between government, village community and healers’
families
Calophyllum teysmannii var. inophylloide.
Sustainable source of potential anti-AIDS
drug, calanolide B. Discovery from tree in
Sarawak, Malaysia, promoted conservation
and replanting of seedlings in clearcut
regions, and led to establishment of the
Sarawak Biodiversity Center for in-country
research on drug discovery from local
biodiversity
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(+) - Calanolide A
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(-) - Calanolide B
D.D. Soejarto, University of Illinois at Chicago
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CALANOLIDES
DEVELOPMENT
 1995: Calanolides licensed to Medichem Research Inc.
 Synthesis of (+)-calanolide A supported by NCI SBIR grant
 Negotiation with Sarawak State Govt. required by LOC
1996: Joint venture company, Sarawak Medichem
Pharmaceuticals formed
 Phase I trials of Calanolide-A completed/well tolerated
 Phase II trials in progress
 Calanolide B in preclinical development
PARALLEL DEVELOPMENT OF HERBAL MEDICINES
AND THE DISCOVERY OF
NOVEL CONVENTIONAL DRUGS
Bioassay-guided isolation and chemical characterization
of active principle(s)
• Provide markers for standardization of herbal products
• Provide lead compounds for conventional drug
development
Basic Philosophy
Any 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 Dietary
Supplements Research
Steps Required Prior to Clinical Assessment of
Herbal Drugs/Botanical Dietary Supplements
1.
Acquire plant material
•
Verify identity; taxonomic/microscopic/PCR
•
Check for pesticides; herbicides; heavy metals
2.
Establish/select appropriate bioassay
3.
Bioassay several types of extracts
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In vitro
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In vivo (if possible/relevant)
Steps Required (continued)
4.
Bioassay-guided isolation and chemical
characterization of active principle(s)
5.
Prepare the biologically and chemically
standardized dosage form
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6.
Conduct stability studies
In vitro studies on standardized product
•
Metabolism (including interactions with p450s)
•
Pharmacokinetics
•
Toxicity
•
Mechanism of Action
http://www.asnapp.org/
Thank you for visiting this website, which is intended to be a network hub for all
stakeholders in Africa’s natural plant products sector. Through knowledge-sharing
and information-exchange via this site, ASNAPP (Agribusiness in Sustainable
Natural African Plant Products) seeks to create a knowledge community that will
strengthen the continent’s capacity to develop this sector.
In the interests of developing successful natural product agribusinesses, and thus
helping to reduce poverty in rural communities, ASNAPP promotes collaboration
and knowledge sharing with research and academic institutions, government,
private enterprises, non-profit organizations, the donor community and civil
Society.
For this purpose, the ASNAPP website encourages information exchange in any of the
following areas:
Applied research and technology transfer
Quality assurance and control
Market linkages and development
Enterprise and farmer association development
Natural resource management
Policy dialogue and advocacy
These areas are the main thrust of ASNAPP’s activities for 2005, based on the following
three new programmes funded by the United States Agency for International Development (USAID):
The Partnership for Food Industry Development Program (PFID), managed by
Rutgers University’s New Use Agriculture and Natural Plants Products Program.
The Rural Livelihoods Activity in Southern Africa programme, run by the Michigan
State University Partnership for Food Industry Develop Program – Fruits and
Vegetables (MSU PFID – F & V) in conjunction with a consortium of partners.
The Partnership for Sustainable Germplasm Development for Non-traditional
Crops, a collaborative project involving various academic and research institutions
as 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: +732 932-9711 Ext. 355/379
Fax: +732 932-9377
Email: [email protected]
Website: www.nuanpp.org
Partner countries: Ghana, Rwanda, Senegal, South Africa, Zambia, USA
Clinical Trials and Complementary
and Alternative Medicine (CAM)
While many CAM treatments have already been in use for
a long time (sometimes for centuries), there is not the kind
of scientific knowledge available about them that has been
gained from studies of conventional medicine. Many people
are already using CAM, and without this scientific knowledge,
they may be at risk— for example, for serious effects from
taking the wrong dose, using the treatment in the wrong way,
or using it with another treatment with which it interacts.
INTERNATIONAL AND REGIONAL COLLABORATION
AFASSA: Africa, Asia and South America
• Co-ordinates activities of networks involved in natural product
research in Africa, Asia and South America.
• Founded at Intercontinental Symposium on Natural Products
Research in Montevideo in December, 1999.
NAPRECA SYMPOSIUM
ADDIS ABABA 2003
Next symposium:
Antananarivo, Madagascar
August 9-12, 2005
Takelaka.dts.mg/rafita
THANK YOU
http://dtp.nci.nih.gov