STUDY OF ARTEMETHER

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

CONTENTS IntroductionPreformulation StudiesMetabolic Profile In BodyAbsorption Phenomena In Body-transport

MechanismsAbsorption Window Plasma Protein Binding Interaction PhenomenaPharmacological ModelsIn-vitro modelsIn-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 ether.

STRUCTURE OF ARTEMETHER Molecular formula -

C16H26O5 Molecular Mass- 298.374

CONTINUEA sesquiterpene lactone with a

peroxide bridge [sesquiterpene = a molecule formed from 3 isoprene units; a lactone = a cyclical ester, R-COO-R'].

TrioxaneThe 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 STUDY1. 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 )

IR SPECTRA of ARTEMETHER

MASS SPECTRA

PharmacokineticsAbsorption 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%

Metabolic profile

continueMetabolismIt 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 actionThese 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 the primary target for this class of molecules.

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 modelsIn vitro methods for screening antimalarial compounds1. 3H Hypoxanthine uptake method2. Giemsa stained slide method 3. Isobologram analysis4. 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 compoundsRodent models:a) Plasmodium berghei 4 day suppression testb) Hill's test for causal prophylaxis and residual activityc) Sporonoicidal activity testingAvian models Primate modelsPlasmodium cynomolgi rhesus model

3H Hypoxanthine uptake method

Purpose and Rational1. 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

Procedure3. Paracite are growth in different concentration of test

compound in medium containing reduced concentration of hypoxanthine.

4. 3H Hypoxanthine is added for an additional incubation period before cell harvesting and measurement of radioactivity by a 1205 Betaplate reader.

5. Mean counts per minute (cpm) are generally in the range of 20,000-60,000, with the acceptable minimum of 10,000

continueEvalution% 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 vivoPurpose 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.

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