entacapone

entacapone
IUPAC name	(2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide
Width	200
CAS number	130929-57-6
DrugBank	DB00493
UNII	4975G9NM6T
ATC prefix	N04
ATC suffix	BX02

entacapone is a pharmaceutical agent classified as a catechol-O-methyltransferase inhibitor, utilized as an adjunct therapy in the management of Parkinson's disease. It is specifically co-administered with regimens containing levodopa and a peripheral decarboxylase inhibitor such as carbidopa, with the primary aim of prolonging the therapeutic effect of levodopa. By inhibiting the enzyme responsible for metabolizing levodopa in the periphery, it enhances the delivery of levodopa to the central nervous system, thereby improving motor function control in patients experiencing end-of-dose "wearing-off" phenomena.

Medical uses

It is indicated for use with levodopa/carbidopa to treat end-of-dose motor fluctuations in individuals with Parkinson's disease, a condition characterized by the degeneration of dopaminergic neurons in the substantia nigra. Clinical trials, such as those conducted by the Parkinson Study Group, have demonstrated its efficacy in reducing "off" time and increasing "on" time without troublesome dyskinesia. Its use is generally reserved for patients already on a stable regimen of levodopa who are experiencing predictable motor fluctuations, and it is not recommended for the treatment of drug-induced parkinsonism or other forms of atypical parkinsonism like progressive supranuclear palsy.

Adverse effects

Common adverse effects are often related to its potentiation of levodopa and include increased dyskinesia, nausea, and orthostatic hypotension. A distinctive, harmless side effect is the discoloration of urine to a reddish-brown color. More serious but rare risks include symptoms suggestive of neuroleptic malignant syndrome upon abrupt withdrawal and a potential for inducing severe diarrhea and hepatotoxicity, necessitating monitoring of liver function tests. Cases of rhabdomyolysis and fibrotic conditions such as pleural effusion have been reported in post-marketing surveillance by agencies like the Food and Drug Administration and the European Medicines Agency.

Pharmacology

As a selective, reversible inhibitor of the catechol-O-methyltransferase enzyme located peripherally, it acts primarily in the gastrointestinal tract, liver, and kidneys to prevent the conversion of levodopa to 3-O-methyldopa. This inhibition increases the bioavailability and plasma half-life of levodopa, allowing more to cross the blood-brain barrier for conversion to dopamine by aromatic L-amino acid decarboxylase in the striatum. Its pharmacokinetic profile shows rapid absorption, extensive first-pass metabolism, and high plasma protein binding, with elimination primarily via biliary excretion following glucuronidation.

Chemistry

It is a nitrocatechol derivative, chemically described as (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide. The compound exists as a geometric isomer, with the active form being the trans isomer. It is a yellow, crystalline powder that is sparingly soluble in water but soluble in dimethyl sulfoxide and methanol. Its molecular structure features a catechol moiety essential for binding to the active site of the catechol-O-methyltransferase enzyme, alongside a nitro group and a diethylamide chain that contribute to its potency and selectivity.

History

The development of entacapone originated from research at the Orion Corporation in Finland during the late 1980s, as part of a program to discover selective catechol-O-methyltransferase inhibitors to improve levodopa therapy. It followed the earlier, hepatotoxic inhibitor tolcapone. Key clinical development was led through international collaborations, including the NOMECOMT and the SECOMT studies. It received its first marketing authorization in the European Union in 1998 and was approved by the Food and Drug Administration in 1999, marketed under the brand name Comtan by Novartis.

Society and culture

It is available as a generic medication in many jurisdictions, significantly reducing costs for healthcare systems like the National Health Service and insurers. The drug has been the subject of formulary considerations and treatment guidelines issued by bodies such as the American Academy of Neurology and the Movement Disorder Society. Its development story is often cited in discussions on the evolution of adjuvant therapy for Parkinson's disease, and it has been featured in educational materials from the Michael J. Fox Foundation for Parkinson's Research.

Category:Drugs