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RASOANAIVO ethnobotany based drug .pdf



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The 14th NAPRECA Symposium

“NATURAL PRODUCTS FROM AFRICAN BIODIVERSITY”
8-12 August, Nairobi, Kenya

Shifting the paradigm
to the ethnobotany-based drug discovery

Philippe Rasoanaivo
University of Antananarivo;
Institut Malgache de Recherches Appliquées

Outline
Key words speech:
speech evolution; adaptation

(Ethnobotany:
■ What I have learned from field work?
(Drug discovery today;
(The need to shift the paradigm:
■ Malaria,
■ Epilepsy
(R&D and commercialisation

Areas of research activities
( Tropical diseases
■ Malaria
■ Chikungunya (Phytochik project)

( Diseases affecting the brain
■ Hypoactive sexual desire disorders (HSSD);
■ Memory and cognitive dysfunction;
■ Convulsions;
■ Major depressive disorders (MDD);
■ Sleeping disorders.

Malaria epidemiology

1900

2007
Source: Nature 2010, 465, 342.

Life expectancy is increasing;
The world’s population is aging
Percent population aged 65 and over :

2008

Projection for 2040

Source: US Census Bureau, 2008

Increasing age-related diseases:
(degenerative and neurodegenerative diseases)
According to WHO in 2001, 450 Millions people have suffered
neurological, or behavioural problems.

Biodiversity and adaptive mechanisms
to survive in a stressful environment

Tsingy

Mangrove

We are living in a changing world

Evolution
■ Adaptive strategies
■ Detoxification

Natural selection
Evolving ecosystem
Climate change

“We experience ourselves,
our thoughts and feelings as
something separate from the
universe. Humanity is going
to need a substantially new
way of thinking if it is to
survive!"
Albert Einstein

Malaria : complex host-parasite interactions

Protective host
immune system

Insecticide
resistance

Immunopathology
Parasites escape the
host immune defence

Drugs

Drug resistance
Host expels rapidly
naturally-occurring drugs
(Lipinski’s rule of five)

Plasmodium

TOLERANCE?

Host

engaged in antagonistic co-evolution
in which evolution in the host defences
leads to counter-adaptations in the parasite
leading to endless non-equilibrium
evolutionary dynamics
Complex molecular interactions produce effects
that may not be achieved by single component:
SYNERGY, HOLISTIC APPROACH
P. Rasoanaivo, C. W. Wright, M. L. Willcox, B. Gilbert. Whole plant extracts versus
single compounds for the treatment of malaria: synergy and positive interactions
Malaria Journal 2011, 10(Suppl 1):S4 (15 March 2011).

Thinking on both sides of the coin
Inflammatory
HOST
process

PARASITES
Amino-acids

Cytokine
release

Haemoglobin
degradation

Heme (toxic)

Lymphocytes T

Dendritic cells

Hemozoin

Phagocytosis

Lymphocytes B

Antibodies

Evolving feature of science & technology
And drug discovery
Chronology

Data intensive

REDUCTIONIST
Virtual chemistry

in silico
Computational
in enzymo
in cellulo
in vitro
Theorical &
Laboratory

Combinatorial chemistry
Medicinal chemistry

in vivo
Isolation

Empirical

S&T

in homo

DD

Crude extract

HOLISTIC

From a traditional antimalarial plant
to malaria protection
A plant used to treat malaria
Ä Weak in vitro antimalarial effects in the isotopic microtest;
ÄModerate in vivo antimalarial effects (49% inhibition)
in the 4-day suppressive test.

BUT
Hidex Chameleon Reader

At Day 8:
Drastic drop of parasitemia (0.8%)

Lymphocytes

“Frozen” parasite

Going beyond the boundaries of
( standard antiplasmodial tests,
In the in vivo 4-day suppressive test:
D-1

D-4

Infestation

Curative

% parasite inhibition

100-90: very good to good
90-50: good to moderate
50-10: moderate to weak

Post 4th day events: Neglected
100% parasite inhibition never achieved
with nearly all plant extracts:
ÄParasite recrudescence,
ÄDrug resistance.

Protective

Parameters for consideration
h Number of days of mice survival;
h % inhibition at D-6, 8, 10;
h Appearance/proliferation of lymphocytes;

Going beyond the boundaries of
( Current drug combination concept
Current Drug combination:
= Curative + Curative (ACTs)
Getting “outside the box”:
= Curative + Protective

Appropriate antimalarial + polyactive extract

Chloroquine
Sub-therapeutic doses

+

Aqueous extract

Proliferation of lymphocytes;
Parasites clearance;
No mice death at 60th day.
Serum of treated mice
Positive passive immunity transfer

Results were confirmed in Leuven (Belgium)
Laboratory of Molecular Immunology,
University of Leuven, Belgium

(No death in treated mice;
(Lymphocytes proliferation;
(Tolerance.
“Nature does noting without purpose,
or uselessly” Aristotle

Ä Extract:
-in vivo anti-inflammatory effects;
-antioxidant effects;
-inhibited MMP9.

The road map
► Further investigate:
Tolerance and protection;
Passive immunity transfer.
►Pursuing structure elucidation
of minor secondary metabolites.

Essential Oils and Brain Behaviour:
Review of the literature
Essential Oils
Ä Depression;
Ä Anxiety;
Ä Mood;
Ä Memory;
Ä Cognitive performance;
Ä Convulsions, epilepsy.

The brain will be one challenging problem of 21st century

Source:
L’EXPRESS, 1998

The resurrection plant Myrothamnus moschatus
Myrothamnaceae family/ one genus/ 2 species: Southern Africa, Madagascar

Rainy season

Lack of water: desiccation-tolerance

Anticonvulsant effects
The essential oils, at 100mg/kg, were able to prevent
convulsions in chemically-induced seizure models,
namely:
Pentylenetetrazole (PTZ), and picrotoxin (PIC),

Essential oils composition of Myrothamnus moschatus

trans‐pinocarveol  
(35.6%,)

α‐pinene 
(10.5%, )
pinocarvone 
(20.0%,)

p‐cymene 
(1.6%)

limonene 
(2.3%)

O

perillyl acetate 
trans‐p‐mentha‐1(7),8‐dien‐2‐ol 
(6.0%)
(3.3%)

β‐selinene 
(8.5%)

cis‐p‐mentha‐1(7),8‐dien‐2‐ol
(2.1%)

P. Rasoanaivo, B. Ralaibia, F. Maggi, M. Nicolleti, N. Vittori. Essential oils of Myrothamnus moschatus,
Journal of Essential Oils Research 2011, (in press)

Essential oils composition from naturally dry and green materials

trans‐pinocarveol
trans‐pinocarveolo
pinocarvone
pinocarvone
β‐selinene
β‐selinene

α‐pinene
perillyl acetate

α‐pinene

perillyl acetato

trans‐pinocarveolo

α‐pinene
pinocarvone
β‐selinene

perillyl acetato

Effects on neurites outgrowth

The way forward
(HeadSpace Solid Phase MicroExtraction
(HSSPME).
(Further behavioural tests:
Anticonvulsant
versus
improving the functioning of the brain

The hidden face of biodiversity and
indigenous knowledge

“ The most important production of knowledge is ignorance”
David Gross, Nobel Laureate in Physics

R&D and Business
Research

Development

► Basic research
► Applied research

► Experimental development
► Advanced development

The process of generating
new knowledge

Scientific production,
Publications
Business

The process of translating
new or existing knowledge
into products

Invention (IPRs)
Innovation
Process of turning an invention
into a marketable product

Knowledge

Acknowledgements
Dr Françoise Gueritte, Institut de Chimie des
Substances Naturelles, CNRS (France).
Prof M. Nicoletti, Università degli Studi
di Roma “La Sapienza”.
Dr Filippo Maggi, School of Pharmacy,
University of Camerino, Italy.
Drs P. Lyessen and P. Van den Steen, Rega
Institute, Leuven University, Belgium.
IFS/PRISM project for the donation
of the Hidex Chameleon Reader.

The baobab messages

Thank you for
Your attention


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