ISOCARBOXAZID (200 MG)

Absorption

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are readily absorbed by the GI tract, present a low bioavailability and reach peak concentrations in 1-2 hours.

Toxicity

Long-term toxicity studies to evaluate the carcinogenic, mutagenic and fertility impairment potential have not been conducted.

Chemical properties

Pale Yellow Solid

Originator

Marplan,Roche,US,1959

The Uses of ISOCARBOXAZID (200 MG)

Monoamine oxidase inhibitor. Antidepressant

The Uses of ISOCARBOXAZID (200 MG)

Isocarboxazid is a powerful MAO inhibitor. As with phenelzine, isocarboxazid is used for depressions that do not respond to other drugs.

Definition

ChEBI: 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide is a member of benzenes.

Indications

Isocarboxazid is indicated for the treatment of the enduring and debilitating symptoms of depression that have not responded to other antidepressant drugs. Depression is a common but serious mood disorder. The patient will present changes in its feelings, thoughts, and ability to handle everyday activities. For a mood disorder to be considered as depression, the symptoms should be present for at least two weeks.

What are the applications of Application

Isocarboxazid is a monoamine oxidase inhibitor

Background

Isocarboxazid has the formula 1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine-isocarboxazid. It is a monoamine oxidase inhibitor. It is used in the treatment of major depression, dysthymic disorder, atypical disorder, panic disorder and the phobic disorders. It was first introduced by Roche pharmaceuticals, further developed by Validus pharms Inc and first FDA approved as a prescription drug on July 1st, 1959.

Manufacturing Process

800 g of benzaldehyde was added to a hot solution (75°C) of 7 liters of ethanol containing 720 g of 5-methyl-2-isoxazole carboxylic acid hydrazide. The solution was stirred for ten minutes at which time the product began to crystallize. On cooling at 4°C for 14 hours, the solid was filtered off under vacuum and the solid filter cake was washed twice using 250 ml of ice cold ethanol for each washing. The lbenzylidene-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine was recrystallized from ethanol, MP 199°C to 200°C.
115 g of 1-benzylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was added portionwise over the period of an hour to 5 liters of anhydrous ether containing 18.5 g of lithium aluminum hydride. The reaction mixture was stirred for four hours and permitted to stand overnight. The excess lithium aluminum hydride was decomposed with 250 ml of ethyl acetate and 150 ml of water was added to decompose the complex. The solid was separated by filtration and the ether layer was concentrated to about 500 mi. 200 ml of benzene was added to dehydrate the solution. Concentration was continued until a solid remained. The 1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine was recrystallized from methanol, MP 105°C to 106°C.

brand name

Marplan (Oxford).

Therapeutic Function

Antidepressant

World Health Organization (WHO)

Isocarboxazid, a monoamine oxidase inhibitor (MAOI), was introduced in 1959 for the treatment of depressive illness. Subsequently concern regarding potentially serious interactions between MAOIs and foods containing tyramine inspired much restrictive regulatory action. However, MAOIs still retain a place in the treatment of serious depressive illness although there is no international consensus on which compounds should be preferred. Thus isocarboxazid remains available in several countries and is cited in the British National Formulary as a relatively safe example of this class of compound.

Pharmacokinetics

In vivo and in vitro studies demonstrated isocarboxazid-driven inhibition of MAO in the brain, heart, and liver. The reduced MAO activity, caused by isocarboxazid, results in an increased concentration of serotonin, epinephrine, norepinephrine, and dopamine in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. The increase of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors like isocarboxazid.

Synthesis

Isocarboxazid, 2-benzylhydrazid-5-methyl-3-isoxazolecarboxylate (7.2.6), can be synthesized from acetylacetone, which on nitrosation with nitrous acid gives 5- methyl-isoxazol-3-carboxylic acid (7.2.2). Esterification of this product gives the ethyl ester of 5-methyl-isoxazol-3-carboxylic acid (7.2.3). The synthesized ester (7.2.3) is further reacted with benzylhydrazine, to give isocarboxazide (7.2.6), or with hydrazine, which forms 5-methyl-isoxazol-3-carboxylic acid hydrazide (7.2.4). Reacting the latter with benzaldehyde gives hydrazone (7.2.5), which is further reduced to the isocarboxazide (7.2.6) [46,47].

Metabolism

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are rapidly metabolized by acetylation in the liver. As part of the metabolism, hippuric acid is a major metabolite.