Transcript Towards an Integrated Research Policy in the Area of Drug

Towards an Integrated Research Policy
in the Area of Drug Discovery in the
Arab Countries
Including mechanisms to better utilization of
their terrestrial and marine wealth.
Bassem El-Menshawi
NEPAD Sci & Technol Regional Coordinator
for Northern Africa,
National Research Centre, Cairo, Egypt
DRUG DISCOVERY
TYPES OF RESEARCH LABORATORIES
NEEDED:
This depends on the therapeutic class
required
DRUGS TO BE DISCOVERED
FOR EXAMPLE: IF PRIORITY GIVEN TO:
-ANTITUMORS,
-ANTICARCINOGENIC,
-IMMUNOMODULATORY,
-ANTIVIRAL AGENTS
A CELL CULTURE LAB IS NEEDED
THE STATE
THE ART OF DRUG
ADVANTAGES
ANDOF
DISADVANTAGES
DISCOVERY:
In-Vitro Bioassays
-Rapid, less selective, but diagnostic, less expensive,
-suitable for minute amounts of materials,
for screening
number
of
• -suitable
THE USE
OF IN large
VITRO
BIOASSAYS
samples in Drug Discovery programs.
In-Vivo
• THE USE
OFBioassays
CELL LINES
More selective, expensive, mostly Time Consuming,
(e.g.model,
HUMAN
TUMOR
CELL
Animal
require
large amounts
of LINES)
material,
hardly could guide the fractionation of extracts or mixture
of compounds.
TYPES OF RESOURCES TO BE UTILIZED:
Natural Resources Line :
- Plants
- Microbes (bacteria, fungi)
- Marine Organisms
Synthetic Line:
- Novel Chemical Entities
- Generics
THE BASIC CHEMICAL LABS:
LAB FOR NATURAL PRODUCTS
(Isolation of Natural Compounds)
LAB FOR SYNTHESIS
(Rational Pharmacological, &
Computer Aided Drug Design)
IN ADDITION TO
- ANTI-VIRAL TESTING LAB
- PHARMACOLOGICAL PROFILE &
TOXICOLOGY LAB
FOR BIOTECHNOLOGICAL PRODUCTS
A BIOTECH / MOLECULAR BIOLOGY
FOR DISCOVERY OF ANTIBIOTICS:
A MICROBIOLOGY / FERMENTATION LAB
FOR ANTI-SCHISTOSOMIASIS:
PARASITOLOGY LAB
THERAPEUTIC NATURAL PRODUCTS
- ACTIVE COMPOUNDS
- ACTIVE EXTRACTS
- COMBINED ACTIVE EXTRACTS
METHODS OF DRUG DISCOVERY FROM
NATURAL PRODUCTS
How the Active Principle be
identified ?
-Phytochemical Approach
-Bio-Activity Approach
-High Throughput Screening
-Computer Aided HPLC/MS
EXISTING PROJECT MODEL:
AT THE NATIONAL RESEARCH CENTRE, EGYPT
A SEARCH FOR
SCHISTOSOOMICIDAL, ANTITUMOR,
ANTICARCINOGENIC,
IMMUNOMODULATORY,
AND ANTIVIRAL AGENTS
IN EGYPTIAN PLANTS
•
This is a drug discovery program
conducted at NRC
•
based on Egyptian plants,
•
utilizes universally accepted protocols
for bioactivity-guided fractionation
of plant extracts,
•
and in-Vitro Bioassays.
Under this project Egyptian plants
are Bio-assayed for specific
medicinal activities:
1.
2.
3.
4.
5.
Schistosomicidal
Antitumor
Cancer chemopreventive
[anticarcinogenic]
Immunomodulating
Antiviral
BIOACTIVITY APPROACH:
-Extracts are screened for a specific
medicinal activity (an in-vitro bioassay).
-Only BioActive extracts are
fractionated.
-Active fractions are further fractionated
to isolate the active compound(s) in
pure form.
-Characterization of its structure.
•
Only Bio-Active Extracts
are subjected to
Bioassay-Guided Fractionation, in 2
steps:
1.
2.
Initial Partitioning
Comprehensive Fractionation
for the isolation of their active
principles.
EX-VIVO BIOASSAY
• In-Vivo / In-Vitro
• Used for assaying the activity of compounds
isolated in limited amounts,
• untill additional materials could be obtained
sufficient for in-vivo bioassy.
• It detects the effect of in-vivo absorption and
metabolism on compounds that are active in-vitro.
Active compounds isolated are then
bioassayed in animal models
to confirm the bioactivity
and determine their therapeutic value
and toxicity profiles.
The overall accomplishments After 3 years of the
project’s life are as follows:
1. Plant
Collection
1625 plant samples collected
2. Preparation of
Plant
Extracts
1787 plant organs dried and
1350 powdered
1149
(Corresponding to 958 species:
534 wild, and 424 cultivated
species).
alcoholic extracts prepared
water extracts prepared
3. In-Vitro Bioassays
3.A. Schistosomicidal
bioassay
1796 extracts bioassayed
1196 alcoholic
600 aqueous
3.B. Antitumor
bioassay:
(i) Brine Shrimp
Bioassay
2118 extracts bioassayed
1268 alcoholic
850 aqueous
(ii) Ehrlich Ascites
Carcinoma
1447 extracts bioassayed
951 alcoholic
496 aqueous
3.C. Anti-carcinogenic
activity
·
Micronucleus bioassay
10 Extracts bioassayed
·
Antioxidant prescreen
200 Extracts bioassayed
3.D. Immunomodulatory
activity
Murine LymphoprolIferative
153 Extracts bioassayed
3.E. Antiviral Activity
· Foot & Mouth
Disease virus
·Hepatitis-A virus
·Herpes Simplex
259 Extracts bioassayed
80 Extracts bioassayed
372 Extracts bioassayed
342 Extracts have been classified as “Promising Bioactive” in all
the bioassayys. Are as follows:
176 lcoholic extracts possessed 100% activity at 100ppm as
Schistosomicidals.
24 alcoholic extract possessed >100% at 50ppm (Brine Shrimp).
44 extracts gave > 75% at 100 ppm as Antitumor (Ehrlich).
Anticarcinogenic.
Micronucleus: Activity is under investigation
14 extracts with 90% activity (% of inhibitory activity of
radicle production) at 25 μg / ml as Antioxidant.
3 extracts showed activity as Immunosuppressant.
1 extract showed acivity as immunostimulant
55
alcoholic extracts with activity higher than 80% at 30 and
40μg /ml (43 contain tannins, and 12 without tannins) as
25 water extracts with activity higher than 80% at 40 μg /ml as
Antivirals.
4. Initial
Fractionation
157 “Most Active” plant extracts in the bioassays
were selected for fractionation and
confirmatory testing.
30 active in schistosomicidal bioassay
27 active in the Brine Shrimp lethality bioassay
20 active in the Ehrlich ascites carcinoma
bioassay
80 active in the antiviral bioassay (44 of them
are of 2nd priority due to their tannin
contents)
50
22
14
5
9
Results:
Out of the above 157 extracts were
fractionated and bioassayed:
active in the Schistosomicidal bioassay
active in the Brine Shrimp Lethality bioassay
active in the Ehrlich ascites carcinoma
bioassay
active in the antiviral activity against HSV
type I
5. Bioactivity–Guided
Fractionation
5 Extracts of the above were
subjected to comprehensive
fractionation (completed)
6. Structure
determination
5 Compounds were isolated
3 of them were identified
3 other compounds are in
isolation steps.
7. Bioassay In-Vivo
8. Toxicity in
Animals
7 Extracts
4 Fractions
were tested in ex-vivo
bioassay, prior to testing
them in-vivo
25 Extracts were studied for
their toxicity in animals.
Patenting and Discoveries :
Bioactive
Compounds
Under Patenting
Bioactive
Extracts/Fractions
under Patenting
4 Antitimors, and 1
schistosomicidal
157
In three bioactivities
(Schistosomicides,
Antitumors, and
antivirals.
Conclusions
-Screening Large Number of
Natural Species
-Using In Vitro Bioassays
-For 5-10 Medicinal Activities
•Conclusions:
-Integrates Arab Natural
wealth
-Optimizes Arab IPR
-Enhance the Invention in a
Strategic Area
Conclusions
- 1-3 Central Joint Research Lab
(under one strategy, one
mechanism, one protocol, and one
leader).
- Nodes in each country
- Joint Surveying of Biodiversity
-Joint Ownership of Products
- Networking
Conclusions
- Arab Meeting for Strategic
Planning of Drug Discovery
- Role of Bibliotheca
Alexandrina
ALL THE PRAISES AND
THANKS BE TO
ALLAH
RESEARC TEAM
Prof. Dr. Fouad Youssif
NRC Principal
Investigator
TBRI
Prof. Dr. Abdel-Monem Osman
NCI/Cairo Univ.
Prof. Dr. Laila Emara
NRC
Assoc. Prof. Dr. Mohamed Aly
NRC
Prof. Dr. Karima Mahrous
NRC
Prof. Dr. Bassem El-Menshawi
•
• THIS PROJECT IS FUNDED BY THE
ACADEMY OF SCIENTIFIC RESEARCH AND
TECHNOLOGY, CAIRO, EGYPT, UNDER THE
PROGRAM OF BIOTECHNOLOGY 1998.