NOMIFENSINE MALEATE

Toxicity

A likely cause of nomifensine toxicity is the aromatic amine group, as compounds containing this chemical substructure are notorious for producing toxic metabolites.

Description

Nomifensine is an inhibitor of norepinephrine (NE) and dopamine (DA) reuptake. It inhibits uptake of NE, DA, and serotonin (5-HT) in rat brain synaptosomes with IC₅₀ values of 6.6, 48, and 830 nM, respectively. It is selective for DA, NE, and 5-HT uptake inhibition over binding to dopamine D₂, α₁- adrenergic-, 5-HT₂, and muscarinic receptors (IC₅₀s = 43,000, 1,200, 3,800, and >13,000 nM, respectively, in rat brain membranes). Nomifensine is selective for inhibition of NE over DA uptake in vivo with minimal inhibitory doses of 28 and less than 57 μmol/kg, respectively. It decreases the time Wistar Kyoto, but not Sprague-Dawley, rats spend immobile in the forced swim test but also increases locomotor activity in the open field test in Wistar Kyoto and Sprague-Dawley rats when administered at a chronic dose of 10 mg/kg.

Originator

Alival,Hoechst,W. Germany ,1976

The Uses of NOMIFENSINE MALEATE

A novel antidepressant distinguished from existing tricyclic and tetracyclic antidepressants by its bicyclic structure.

Background

Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.

What are the applications of Application

Nomifensine is a norepinephrine-dopamine reuptake inhibitor

Definition

ChEBI: An N-methylated tetrahydroisoquinoline carrying phenyl and amino substituents at positions C-4 and C-8, respectively.

Manufacturing Process

A solution of N-(2-aminobenzyl)-1-phenyl-2-methylaminoethanol-1 was prepared by the reaction of α-bromo-acetophenone and (2nitrobenzyl)methylamine, followed by hydrogenation of the nitro group by means of nickel on diatomaceous earth at room temperature and reduction of the CO group by means of sodium borohydride. The intermediate thus produced was dissolved in 100 ml of methylene chloride and introduced dropwise into 125 ml of sulfuric acid at 10° to 15°C. After a short standing, the reaction mixture was poured onto ice and rendered alkaline by means of a sodium hydroxide solution. By extraction with ether, there was obtained 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-amino-isoquinoline. The base is reacted with maleic acid to give the maleate; melting point of the maleate 199° to 201°C (from ethanol).

brand name

Merital (Hoechst-Roussel);Anametrin;Caribium;Hoe 984;Hostalival;Merival;Musettamycin;Neurolene;Nomival;Psicronizer;Psyton.

Therapeutic Function

Psychostimulant

World Health Organization (WHO)

Nomifensine, an antidepressant indicated for the treatment of a wide range of depressive illness, was introduced in 1976. Subsequently rare cases of haemolytic anaemia - sometimes fatal - thrombocytopenia, hepatotoxicity and fever were associated with the use of the drug. Following discussions with regulatory authorities in the United Kingdom and the Federal Republic of Germany the major manufacturer withdrew all preparations containing nomifensine worldwide in January 1986.

Pharmacokinetics

Nomifensine is a dopamine reuptake inhibitor test-marketed in the United States by Hoechst AG (now Novartis) that increases the amount of synaptic dopamine available to receptors by blocking dopamine's re-uptake transporter. Nomifensine is now mainly used in scientific research, particularly in studies involving dopamine release in response to addiction.

Safety Profile

Poison by ingestion andintravenous routes. Human systemic effects by ingestion:diffuse hepatitis, hemorrhage and decrease in the numberof blood platelets (thrombocytopenia). When heated todecomposition it emits toxic fumes of NOx.

Metabolism

Not Available