Artemether study

Mohanlal
15phm2007
MNP (Pharmacology)
INSTUTITE OF CHEMICAL TECHNOLOGY
mohanlalchoudhary1992@gmail.com

CONTENTS
Introduction
Preformulation Studies
Metabolic Profile In Body
Absorption Phenomena In Body-
transport Mechanisms
Absorption Window
Plasma Protein Binding
Interaction Phenomena
Pharmacological Models
In-vitro models
In-vivo models

INTRODUCTION
 It is an antimalarial for the treatment of uncomplicated
multiple drug-resistant strains of Plasmodium
falciparum malaria.
 The 2015 Nobel Prize in Physiology or Medicine is awarded
Professor Youyou Tu for her discoveries concerning a novel
therapy against Malaria.
 Youyou Tu searched ancient literature on herbal medicine in
her quest to develop novel malaria therapies. The plant
Artemisia annua , Tu developed a purification procedure,
which rendered the active agent, Artemisinin, a drug that is
remarkably effective against Malaria.
 Its combination with Lumefantrine has first been marketed
by Novartis under the brand names Riamet and Coartem.
 It is a methyl ether derivative of artemisinin, which is a
peroxide lactone isolated from the antimalarial plant Artemisia
annua (compositae) It is also known as dihydroartemisinin methyl

STRUCTURE OF ARTEMETHER
 Molecular formula - C16H26O5
 Molecular Mass- 298.374

CONTINUE
A sesquiterpene lactone with a
peroxide bridge [sesquiterpene = a
molecule formed from 3 isoprene
units; a lactone = a cyclical ester, R-
COO-R'].
Trioxane
The endoperoxide bridge (-O-O-) is
essential to the activity of the
molecule.

Principle areas of preformuation research
Bulk characterization:
1. Crystallinity & polymorphism,
2. Hygroscopicity,
3. Fine particle characterization,
4. Powder flow properties.
Solubility analysis:
1. Ionization constant –Pka
2. pH solubility profile,
3. Common ion effect-Ksp ,
4. Solubilization ,
5. Dissolution,
6. Partition co-efficient
Stability analysis:
1. Solution stability,
2. pH rate profile,
3. Solid state stability,
4. Bulk stability,
5. Stability in toxicology formulation

PREFORMULATION STUDY
1. Physicochemical property
 It is lipophilic in nature and prectically
insoluble in water.
 Patition coefficient (LogP) is approximatly
n-octanol/water =3.53.
 According to biopharmaceutical
classification it is classified in class-II (high
permeability and low solubility).
 It is white crytaline solid
 Spectroscopy analysis(IR & Mass )

Pharmacokinetics
Absorption
 It is absorbed by active transport mechanism.
 It is lipid-soluble and is administered orally or
i.m., but not i.v. injection.
 Oral absorption is slower taking 2-4 hours,
but is enhanced by food.
 Absorption improves considerably with
concurrent ingestion of grapefruit juice.
Plasma protein binding
Artemether has high plasma protein
binding approximately 95%

continue
Metabolism
It undergoes substantial first pass
metabolism and is converted to DHA.
Extensive
metabolism by CYP3A4 yields a
variable t1/2 of 3-10 hours.
Metabolism by oxidation and
glucuronide conjugation reaction.

Mechanism of action
These compounds have presence of
endoperoxide bridge .
Endoperoxide bridge interacts with
heme(Fe2+) in parasite .
Heme iron cleaves this endoperoxide
bridge.
There is generation of highly reactive
free radicals which damage parasite
membrane by covalently binding to
membrane proteins.
The enzyme P. falciparum adenosine
triphosphatase has been proposed as

Cont….
Ion-dependent alkylation is the likely
mode of action.

Antimalerial action
Artemisinin
Artemisinin
Conventional
Treatment

INTERACTION
 Terfenadine, Asternizole, Antiarrhythmics,
Tricyclic Antidepressants ,Phenothiazines
administered may administered concurrent with
artemether ,increase the risk of cardiac
conduction defects.
 Clarithromycin may significantly increase
the blood levels of artemether .
 Drugs which inhibitor of CYP 3A4 increase the
plasma drug concentration and enzyme inducer
reduces plasma drug conentration of artemether.

Pharmacological screening
models
In vitro methods for screening antimalarial compounds
1. 3H Hypoxanthine uptake method
2. Giemsa stained slide method
3. Isobologram analysis
4. Micro-test (Mark III)
5. Other in vitro methods(Flow cytometry and measurement of LDH
activity of Plasmodium falciparum)
In vivo methods for screening antimalarial compounds
Rodent models:
a) Plasmodium berghei 4 day suppression test
b) Hill's test for causal prophylaxis and residual activity
c) Sporonoicidal activity testing
Avian models
Primate models
Plasmodium cynomolgi rhesus model

3H Hypoxanthine uptake
method
Purpose and Rational
1. 3H Hypoxanthine uptake is a standardized model to
determine the level of Plasmodium falciparum growth
inhibition.
2. Radiolabelled hypoxanthine uptake by parasite is an
indicator of its growth and multiplication
Procedure
1. Paracite are growth in different concentration of test
compound in medium containing reduced
concentration of hypoxanthine.
2. 3H Hypoxanthine is added for an additional incubation
period before cell harvesting and measurement of
radioactivity by a 1205 Betaplate reader.
3. Mean counts per minute (cpm) are generally in the
range of 20,000-60,000, with the acceptable minimum
of 10,000

continue
Evalution
% reduction = (mean cpm of test samples) 3H Hypoxanthine X
100
Percent reductions are used to plot percentage inhibition of growth as a
function of drug concentration.
IC 50 are determined by linear regression analyses.
Advantages of in vitro methods
1. Precise and efficient
2. Rapid
3. Large number of compounds can be evaluated at the same time
4. Synergism or antagonism with drug combinations can be studied
5. Better assessment of intrinsic activity of a drug.

RODENT MODEL for in vivo
Purpose and rational
The efficacy of a compound is assessed by comparison of blood parasitemia and mouse
survival time in test and control mice.
Methodology
 Species and strain: Swiss Albino mice 25 g
 Sex: Male/Female
 five animals are used for each treatment group and control
Procedure:
 Noval Medical Research Institute mice free from Eperythrozoon coccoides are
maintained 220C at 50-70% humidity, fed with diet containing p -aminobenzoic acid
45 mg/kg body wt.
 Mice is then contaminated with Eperythrozoon coccoides survive infection
with Plasmodium speces.

Cont…
 Clean the infection and 4 days continue injection of anti
malerial drug by IP.
 On day 0, mice are injected with 0.2 ml of
aliquot Plasmodium berghei intravenously or
intraperitoneally .
 Vehicle treated mice (control group) is compared with the test
drug treated group.
 On days 1 to 3, the experimental groups are treated again
with the same dose and same route as on day 0.
Evalution:
 Carefully evalute 0 to 4 hr. after injection and after this in 4
hr. interval for 1 day and after this 12 hr. interval both test and
control group.

REFERENCES
 Indian Journal of Pharmaceutical Education and research.
 Range H. P, Dale M. M, Ritter J M, Moore P K, “Pharmacology”.
Elsevier Science,5th, 2003,679.
 Tripathi K D, “Essentials Of Medical Pharmacology”.Jaypee
Brother Medical Publisher; 6th, 2008; 780-796.
 www.wjpps.com(World Journal of Pharmacy and Pharmaceutical
Sciences)
 www.ajphr.com
 Falad Catharine and Manyando Christine, “Safety Profile Of
Coartem The Evidence Base”. Malaria Journal. 2009; 8 :1475-2875
 Indian pharmacopoeia 2010(vol.-2) ,836 to 837.
 www.drug.com
 Lachman Leon And Liberman “theory and prectical of industrial
pharmacy varghese publication, dadar bombay ,3rd edition ,1990 ,
page no. 185- 187.
 Arnold, K. Qinghaosu and derivatives in treatment of malaria - a
personal review. J. Hong Kong Med. Assoc. 45,189-196.

Artemether study

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