Biochemistry and pharmacology of catechol-O-methyltransferase inhibitors.

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of catechol structured compounds such as catecholamines, catecholestrogens, and L-dopa. When combined with decarboxylase inhibitor L-dopa is the most efficacious treatment for Parkinson's disease. Bioavailability and efficacy of L-dopa treatment can be enhanced greatly by the use of COMT inhibitors.

Introductory remarks: Catechol-O-methyltransferase inhibition--an innovative approach to enhance L-dopa therapy in Parkinson's disease with dual enzyme inhibition.

Catechol-O-methyltransferase (COMT) enzyme and its inhibition have been closely related to the treatment of Parkinson's disease (PD) patients with motor fluctuations needing enhancement of their levodopa (L-dopa) therapy (L-dopa/dopa decarboxylase inhibitor), this indication being so far the only clinical application of COMT inhibitors. L-dopa treatment has remained the most effective therapy for PD, but its further development has been quite a challenge mainly due to the effective metabolism of L-dopa in the human body by multiple pathways, decarboxylation and O-methylation being the two most important of them. The introduction of clinically effective and safe COMT inhibitors has greatly increased the usefulness of L-dopa therapy, but how to utilize the full potential of L-dopa is still unsolved leaving a need for more potent COMT inhibitors.

Orazipone inhibits activation of inflammatory transcription factors nuclear factor-kappa B and signal transducer and activator of transcription 1 and decreases inducible nitric-oxide synthase expression and nitric oxide production in response to inflammatory stimuli.

Orazipone [OR-1384; 3-[4-(methylsulfonyl)benzylidene]pentane-2,4-dione] is a novel sulfhydryl-modulating compound that has anti-inflammatory properties in experimental models of asthma and inflammatory bowel disease. In inflammation, inducible nitricoxide synthase (iNOS) generates NO, which modulates the immune response. Compounds that inhibit iNOS expression or iNOS activity possess anti-inflammatory effects.

Antieosinophilic activity of simendans.

Simendans are novel agents used in the treatment of decompensated heart failure. They sensitize troponin C to calcium and open ATP-sensitive potassium channels and have been shown to reduce cardiac myocyte apoptosis. The aim of the present study was to evaluate whether simendans reduce pulmonary eosinophilia and regulate eosinophil apoptosis.

Antieosinophilic activity of orazipone.

Orazipone is a novel sulfhydryl-reactive compound that has been previously shown to reduce lung eosinophilia in guinea pigs and rats and to inhibit degranulation in mast cells and cytokine production in monocytes and T-cells. However, the effects of orazipone on granulocyte longevity are unknown. Orazipone and its derivative 3-(4-chloro-3-nitro-benzylidene)-pentane-2,4-dione (OR-2370) reversed interleukin-5-afforded survival of human eosinophils by inducing apoptosis.

Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition.

In order to clarify the mechanisms of the positive inotropic actions of levosimendan and its optical isomer, dextrosimendan, we compared their concentration-dependent effects in intact papillary muscles, permeabilized cardiomyocytes and in purified phosphodiesterase enzyme preparations of guinea-pig hearts. In papillary muscles twitch tension increased with EC50 values of 60 nM and 2.8 microM for levosimendan and dextrosimendan, respectively.

Novel sulfhydryl-reactive compounds orazipone and OR-1958 inhibit cytokine production and histamine release in rat and human mast cells.

Orazipone (OR-1384) and OR-1958 are novel anti-inflammatory sulfhydryl reactive compounds with potential applications in the treatment of chronic obstructive lung disease and colitis. Mast cells are potent immune system cells which can be found in abundant numbers in mucosa of lung and gut. We have studied whether the anti-inflammatory effect of these compounds could be mediated through inhibition of the function of mast cells and compared their effects with the glucocorticoid budesonide.

Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice.

Catechol-O-methyltransferase (COMT) enzyme is a widely distributed enzyme that catalyses O-methylation of catecholamines and other compounds having a catechol structure. Because there has been some concern about the consequences of a low COMT activity in the development of oestrogen-dependent cancers and because one of the COMT inhibitors, tolcapone, has caused serious liver injuries in Parkinsonian patients, the histopathology and clinical chemistry of Comt-gene-disrupted mice were studied at the age of 12 months. Owing to the high COMT activities in liver and kidney and the role of COMT in the metabolism of catechol oestrogens, special emphasis was given to the histology of the liver, kidney and oestrogen-dependent organs such as mammary glands and uterus.

Effects of entacapone and tolcapone on mitochondrial membrane potential.

Catechol-O-methyl transferase (COMT) inhibitors, entacapone and tolcapone, are used as an adjunctive treatment to L-dopa in Parkinson's disease. Based on their catechol structure, both inhibitors are potential uncoupling agents, but only tolcapone shows this effect in vitro at clinically relevant concentrations. This study was designed to evaluate the direct uncoupling effects of the two COMT inhibitors in vitro and in vivo.

Differential effect of tetracaine and bupivacaine on catecholamine and 5-hydroxytryptamine turnover.

The effect of the local anesthetics, tetracaine and bupivacaine, on monoamine oxidase (MAO) activity of rat brain and on the major steps of catecholamine and 5-hydroxytryptamine (5-HT) turnover was examined. The IC50 of tetracaine for MAO-A and MAO-B inhibition was 1.2 microM and 19.