A REVIEW ON PHARMACOLOGY OF COMBINED EDARAVONE AND ARGATROBAN THERAPY IN ACUTE ISCHEMIC STROKE

Pharma Admission

Pharma courses

pharma admission

pharma courses

 

{ DOWNLOAD AS PDF }

ABOUT AUTHORS
Patel  Divya A*., Varodiya Priyanka S., Raj Hasumati A.
Department of Quality Assurance, Shree Dhanvantary Pharmacy College,
Kim, Surat, Gujarat, India
divyapatel388@gmail.com, drharaj@yahoo.com

ABSTRACT
This review article presents the pharmacology of combined edaravone and argatroban therapy especially in acute ischemic stroke. Edaravone (MCI-186) is a free radical scavenger, a novel neuroprotective agent. Argatroban  is a selective thrombin inhibitor.The antithrombotic agent was used in acute cerebral infarction. If the antithrombotic agent is administered in large quantities, the condition of patient become worse by occurrence of adeverse effect of cerebral haeorrhage. The use of edaravone in combination with antithrombotic agent has been proved to provide beneficial effect in acute ischemic stroke as edaravone has no influence to coagulation of blood and platelets aggregation. The combination therapy has fewer hemorrhagic  adeverse  effect. The mechanism of argatroban and edaravone is quite different. Argatroban, an anti-coagulant drug, directly improves the microcirculation of ischemic brain tissue while edaravone could indirectly attenuated brain edema by protection of endothelial cells damaged by free radicals generated after ischemic insult. The combination of both would have reciprocal and enhanced neuroprotective effects against ischemic insult. Both the drugs were approved by Japanese government and has been used in acute brain infarction in japan. The main objective of this review article is to provide pharmacological information of combined therapy of edaravone and argatroban to researcher in development of combined dosage form of this.

REFERENCE ID: PHARMATUTOR-ART-2269

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 11

Received On: 26/08/2014; Accepted On: 07/09/2014; Published On: 01/11/2014

How to cite this article: DA Patel, PS Varodiya, R Hasumati; A Review on Pharmacology of Combined Edaravone and Argatroban Therapy in Acute Ischemic Stroke; PharmaTutor; 2014; 2(11); 42-49

INTRODUCTION

Figure 1: Mechanism of stroke[1]

I) OXIDATIVE STRESS [1]
Oxidative stress is the pathogenesis of a number of neurological conditions including stroke. Oxidative stress is condition when the physiological balance between oxidants and antioxidants is disrupted. Oxidative stress leads to the formation of reactive oxygen species, reactive nitrogen species through multiple injury mechanisms, such as mitochondrial inhibition, Ca2+ overload, reperfusion injury, and inflammation. Most of ROS are generated during an acute ischemic stroke and that oxidative stress is an important mediator of tissue injury in acute ischemic stroke. Brain ischemia generates superoxide (O2-), which is the primary radical from which hydrogen peroxide is formed. Hydrogen peroxide is the source of hydroxyl radical (OH).  Thus, free radicals are regarded as an important therapeutic target for improving the condition ischemic stroke.

II) POST ISCHEMIC INFLAMMATION [1]
Microglia can transform  into phagocytes, after activation by ischemia, and they can release a variety of substances many of which are cytotoxic and cytoprotective. Microglia may exert neuroprotection by producing neurotrophic molecules such as brain-derived neurotrophic factor(BDNF), insulin- like growth factor I (IGF-I), and several other growth factors. The activated microglial cells in response to ischemia have the potential of  releasing several pro-inflammatory cytokines such as TNF- α, IL-1β, and IL-6, as well as other potential cytotoxic molecules including NO, ROS, and prostanoids.

Figure 2: Mechanism of oxidative stress [1]

EDARAVONE
Chemical name:- 3-methyl-1-phenyl-2 –pyrazolin-5-one. Also known as MCI-186.
A pyrazole derivative appears as white to off white crystalline powder. The drug is slightly soluble  in Distilled Water. (3 g/L). Freely soluble in methanol.

Edaravone melts at 127-131 ºC [2,3]

The pKa value of edaravone is 7.0.

Edaravone and its derivatives were synthesized by condensation of hydrazine and 3-oxopropionic acid esters in refluxed ethanol. 2-Pyrazolin-5- one was selected as the scaffold, (a) modification of the phenyl group at the 1-position, (b) introduction of substituents on the 1-phenyl moiety, (c) modification of the methyl group at the 3 position, and (d) introduction of substituents on the methylene moiety at the 4-position.

Figure 3: The chemical structure of edaravone [2]

This optimization suggested that compounds possessing lipophilic substituents were potent inhibitors of lipid peroxidation. The electronic properties of the substituents did not affect the activity of these compounds. The absence of inhibitory activity in 1-phenyl- 3,4,4-trimethyl-2-pyrazolin-5-one, which is not a subject to keto-enol tautomerization, [4]

Figure 4: Design of phenol like compound and its tautomerization [4]

Edaravone has three tautomeric forms: the amine, keto, and enol forms (Fig. 5). Approximately 50% of edaravone exist in an anionic form at physiological pH; this form may react strongly with reactive oxygen species in the brain. Compound which generate aromatic hydroxyl group by keto enol tautomerization would show radical scavenging and antioxidant activity and would not have toxicities of phenol.

Figure 5: Tautomeric forms of edaravone  [4]

i) IN VITRO PHARMACOLOGY:

Figure 6: In vitro pharmacology of edaravone [4]

An electron transfer from edaravone anion yields radical derived anion and edaravone radical, which reaction breaks the chain of oxidation of lipid. Edaravone radical is transformed in to 4,5-dione via edaravone peroxyl radical with reaction of molecular oxygen.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE


 

Pages

FIND MORE ARTICLES