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RASOANAIVO Chemosensitizers from medicinal plant .pdf



Nom original: RASOANAIVO_Chemosensitizers from medicinal plant.pdf
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Chemosensitizers
from medicinal plants
of Madagascar

Table of contents
1- Basic background of resistance;
2- Strategies to overcome drug resistance;
3- Chemosensitizers from plants of Madagascar;
4- Mechanism of chloroquine resistance
and its reversal;
5- Introducing the Institut Malgache
de Recherches Appliquées;

LIVING ORGANISMS
Reproductive system
BIRTH

DEATH

RESISTANCE

Bacterias, Fungi,
Parasites,Viruses,

Infectious diseases
Cancerous
Cells

Drug resistance
Vector resistance

Areas where drug-resistant malaria
has been reported (WHO, 1999)

World malaria situation
Resistance to Fansidar
Resistance to Chloroquine
Multi-drug resistance

Strategies to overcome drug resistance

New drugs
Mechanisms of
drug resistance
Vaccine

Medicinal plants

?

Integrated approach to antimalarial plants
- Chemosensitizers
- Prophylactic
- Cytotoxic
- Antiplasmodial

Anticancer agents
True antimalarials

Direct effects on parasite viability

ANTIMALARIAL PLANTS
Effects on host-parasite relationships
- Immunostimulants
- Antipyretic
- Unexpected mechanisms
Rasoanaivo P, Oketch H, Willcox M, Bodeker G. Fitoterapia 2001 (in press)

Chemosensitizers
for chloroquine resistant
malaria

Obituary: the Malagasy forester Abrahama
Journal of Ethnopharmacology 1999, 68, 1-2.

Medicinal plants used to enhance chloroquine action

Strychnos diplotricha
Strychnos myrtoides

Strychnos mostueoides

Hazomalania voyroni

Strychnopsis thouarsii
Spirospermum penduliflorum
Burasaia madagascarienis

Rasoanaivo P, Ratsimamanga S, Frappier F, Current Medicinal Chemistry 1996, 3, 1.

Preliminary investigation of Strychnos species
1.00

50
45

0.80

40
35

In vitro

0.60

30

In vivo

25
20

0.40

15
10
0.20

5
0
1

0.00
0.00

0.20

0.40

N

0.60

0.80

2

3

4

1.00

CH3
H

O
N

N
Ac

CO2CH3

N

H
O

Malagashanine

CH3

O

CH3 O

CH3

Strychnobrasiline

Rasoanaivo P, Ratsimamanga-Urverg S, Milijaona R, Rafatro H,
Galeffi C, Nicoletti M. Planta Medica 1994, 60, 13.

Traditional recipe

Clinical trials

Clinical observation
Pre-clinical investigations
Phytochemistry
Pharmacology
Toxicology
Pharmacokinetics

Opened clinical trials

Randomised, double blind
Clinical trial
Rasoanaivo P, Plenary lecture in the IDRC Meeting on « Valorisation de la Matière
Végétale », Québec, 7-9 August 2001.

Ankazobe

Research Initiative on Traditional Anti-Malarials
Methods (RITAM)

Peaceful coexistence ?
Resistance

Host

Pacific cohabitation ?

Parasites

Drugs

New directions ?

Is there a key structure requirement
for reversal activity
in drug resistant malaria and cancer ?

The 1,4-diamino unit hypothesis
.
Naturally-occuring chemosensitizers

Me
N

O

N
N
H

O

CH3

CH3

Strychnobrasiline

N
N
H

N
H
O

CH3

O

Malagashanine

Me

Me
N

Synthetic chemosensitizer

CO2Me

N
Cl

Chlorpheniramine

The 1-amino-4-phenyl unit hypothesis
MeO
MeO

CN
Me
N

N

Verapamil

Amitryptiline
OMe
OMe

R
N

N

patented chemosensitiser

Me
Me

Interaction chloroquine – diamines against

a chloroquine-resistant strain of Plasmodium falciparum
1.00

NH2
H2N
0.80

Fe
N

0.60

N
Fe

CH3

CH3
0.40

Fe
N
Fe

CH3

-(CH2)6

N
CH3

0.20

0.00
0.00

0.20

0.40

Rasoanaivo et al. (work in progress)

0.60

0.80

1.00

Key structure requirements ?

S
S
S = N, aromatic rings
CH3
HN
Cl

CH3
N

CH3

N

Chloroquine
Rasoanaivo P. Lead compounds from higher plants. Plenary lecture in the Meeting
of the Phytochemical Society of Europe, Lausanne, 12-14 September 2001.

MDR Resistance
OCH3

H3CO

OCH3
CH3
N
O

O
OCH3
OCH3

O
O

OCH3

Pervilleine series isolated from Erythroxylum pervillei
Silva GL, Cui B, Chavez D, You M, Chai HB, Rasoanaivo P, Lynn SM, O’Neill MJ,
Lewis JA, Besterman JM, Monks A, Farnsworth NR, Cordell GA, Pezzuto JM,
Kinghorn AD. J. Nat Prod. 2001 (in press).

Strychnobrasiline

malagashanine derivatives

O

O
CH3

N

O
N

[0]
N
H

CH3

N
O

CH3

O

O

Na-deacetyl-strychnobrasiline

CH3
CH3

O

N

HO
+
N

CH3

..N

N

O
O

CH3

O

O
H3CO

C
O

Trigalo F, Martin MT, Rasolondratovo B, Blond A, Rasoanaivo P, Frappier F.
Tetrahedron (submitted).

Other derivatives (confidential): patent in progress.

CONCLUSION
Medicinal plants
Phytomedicines
Leads
Biochemical tools
Messages

Drug discovery
Mechanisms
of action

Funding agencies
International Foundation for Science
Agence Universitaire de la Francophonie
Projet FAC
Projet VIHPAL
Projet CAMPUS
Netherland Foundation
International Development Research Centre

Introducing the Institut Malgache

de Recherches Appliquées

Production
& export

Rural communities

Patents
Funded projects
Publications
Research
& Development
Clinic

Collaborations

Phytochemistry Lab

Parasitology Lab

In vitro antiplasmodial tests

Cytotoxicity tests

Pharmacodynamics Lab

Diabetology Lab

Analytics


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