Effect of morphine on rotational behavior of unilaterally brain-lesioned mice and rats: morphine withdrawal and development of tolerance.

1. The effect of acute morphine administration on the rotational behavior of unilaterally brain-lesioned mice and on the amphetamine-induced rotational behavior of unilaterally brain-lesioned rats was studied. 2.

Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers.

Objective: To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise.

Background: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant.

Simultaneous inhibition of catecholamine-O-methylation by entacapone and neuronal uptake by imipramine: lack of interactions.

Objective: We have evaluated the effects of simultaneous inhibition of catechol-O-methyltransferase (COMT) by entacapone and of neuronal monoamine reuptake by imipramine on haemodynamics and catecholamine metabolism, and the safety and tolerability of the drug combination in healthy women.

Methods: In a randomized, single-dose, single-blind, cross-over study, 12 healthy women were given placebo, entacapone (200 mg), imipramine (75 mg) or entacapone and imipramine in combination. Heart rate, blood pressure, systolic time intervals, and plasma concentrations of catecholamines and their metabolites were measured at rest and during exercise.

COMT inhibition by entacapone does not affect growth hormone or prolactin secretion in healthy volunteers.

We studied the effects of entacapone, a novel inhibitor of the enzyme catechol-O-methyltransferase (COMT), on spontaneous and levodopa (LD) modulated secretion of growth hormone (GH) and prolactin (PRL) in 12 healthy male volunteers. The study had a double-blind, cross-over design with two experimental settings. In the first setting the subjects received a single oral dose of 400 mg of entacapone or matching placebo in a randomized order.

Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan.

The role of cardiac troponin C (cTnC) as a target protein for the calcium sensitization by levosimendan, pimobendan, MCI-154 and EMD 53998 was evaluated using purified recombinant human cTnC. For determination of calcium- and magnesium-dependent binding of the compounds to cTnC a new type of cTnC-HPLAC column was used. Furthermore, dansylated cTnC was utilized to study the effect of the calcium sensitizing compounds on calcium-induced conformation of cTnC.

The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine.

Background: Entacapone is a potent, selective catechol-O-methyltransferase (COMT) inhibitor. Entacapone could potentiate the hemodynamic effects of exogenously administered catecholamines, which are substrates of the COMT enzyme.

Design And Methods: Originally, the study was to follow a placebo-controlled, randomized crossover design.

Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation.

Levosimendan is a novel positive inotropic drug targeted to increase contraction force of the heart through its calcium-dependent binding to troponin C (cTnC). We investigated the calcium-sensitizing effect of levosimendan on contractile proteins as well as its positive inotropic and lusitropic effects in paced guinea pig papillary muscle. We also studied the effect on energy consumption of myosin-actin crossbridges in a myosin ATPase assay.

Effect of entacapone, a COMT inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of controlled-release levodopa-carbidopa in volunteers.

We studied the effect of entacapone, a catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of a controlled-release (CR) levodopa-carbidopa preparation (Sinemet CR) in an open, randomized trial in 12 healthy male volunteers. The inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured. Single graded doses of entacapone (100-800 mg) were administered concomitant with a single oral dose of CR levodopa, or CR levodopa was given without entacapone (control treatment), at least 1 week apart.

COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise.

We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.

The effects of the COMT inhibitor entacapone on haemodynamics and peripheral catecholamine metabolism during exercise.

1. Catechol-O-methyltransferase (COMT) inhibition might be assumed to potentiate the effects of circulating catecholamines, particularly under conditions of enhanced catecholamine release. 2.

Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog.

Metabolites of entacapone, (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl) propenamide, a potent inhibitor of catechol-O-methyltransferase, were isolated from dog urine. After hydrolysis of glucuronides and sulfates, 5 metabolites were identified in addition to unchanged entacapone by HPLC with diode-array UV detection, electron ionization mass spectrometry and IR spectroscopy. The (Z)-isomer of entacapone was the most abundant phase I metabolite while less abundant metabolites were formed through cleavage or reduction of the side chain carbon-carbon double bond, hydrolysis of the amide bond or through hydration of the nitrile group.

Protection by nitecapone against sodium taurocholate-induced damage to cultured gastric cells.

The goal of this study was to observe if nitecapone protected against taurocholate-induced damage in primary cultured rat gastric mucosal cells, as well as in a well-differentiated human gastric epithelial cell line (MKN 28). Prostaglandins were measured to analyze the protection mechanism. In primary rat gastric mucosal cell culture, nitecapone 125-250 microM protected the cells significantly against damage induced by sodium taurocholate, increasing cell viability by 31-38%.

Identification of major metabolites of the catechol-O-methyltransferase inhibitor nitecapone in the rat and dog.

Metabolites of nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], a potent catechol-O-methyltransferase inhibitor with gastroprotective and antiulcerogenic effects, were isolated by extraction and HPLC from dog and rat urine after enzymatic hydrolysis and as glucuronic acid and sulfate conjugates. Eight and 10 nonconjugated metabolites and unchanged nitecapone were found in hydrolyzed dog and rat urine, respectively, and identified by HPLC with diode-array UV detection, electron ionization mass spectrometry, and IR spectroscopy. In both species the main phase I metabolic pathways were: 1) reduction of the side chain carbon-carbon double bond and carbonyl groups and 2) cleavage of the side-chain double bond, giving an aromatic aldehyde that was partly oxidized to the corresponding carboxylic acid.

Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans.

Metabolites of entacapone [(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide++ +], a potent inhibitor of catechol-O-methyltransferase, were isolated from human and rat urine. After hydrolysis of glycosides and sulfates, four human and eight rat metabolites were identified, in addition to unchanged entacapone by HPLC with diode-array UV detection, electron ionization mass spectrometry, and IR spectroscopy. In man 10% of an oral dose was excreted in urine during 8 hr.

Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone.

Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes.

Liquid chromatographic determination of a new catechol-O-methyltransferase inhibitor, entacapone, and its Z-isomer in human plasma and urine.

Assay procedures for analysis of entacapone, (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)-propenamide++ +, and its Z-isomer in human plasma and urine are described. The methods were based on reversed-phase liquid chromatography with amperometric detection. Entacapone and its Z-isomer were extracted with n-hexane-ethyl acetate mixtures after acidification with hydrochloric acid.

Expression of recombinant soluble and membrane-bound catechol O-methyltransferase in eukaryotic cells and identification of the respective enzymes in rat brain.

The rat and human recombinant soluble and membrane-bound catechol O-methyltransferase (S- and MB-COMT, respectively) were expressed using mammalian and baculovirus vectors. Low levels of rat and human S-COMT polypeptides were detected by immunoprecipitation in K-562 cell lines transfected with the S-COMT vectors. From K-562 cells transfected with the rat MB-COMT construct, both S- and MB-COMT recombinant proteins were detected by a rat COMT-specific anti-serum.

PLS modelling of structure-activity relationships of catechol O-methyltransferase inhibitors.

Quantitative structure-activity analysis was carried out for in vitro inhibition of rat brain soluble catechol O-methyltransferase by a series (N = 99) of 1,5-substituted-3,4-dihydroxybenzenes using computational chemistry and multivariate PLS modelling of data sets. The molecular structural descriptors (N = 19) associated with the electronics of the catecholic ring and sizes of substituents were derived theoretically. For the whole set of molecules two separate PLS models have to be used.

Role of gastric mucosal eicosanoid production in the cytoprotection induced by nitecapone.

Nitecapone (3-100 mg/kg orally) dose-dependently (40-97%) decreased the macroscopic gastric lesions induced by ethanol, NaOH, or HCl in the rat. The duration of protection was long, being still 70% at 6 h after dosing. Nitecapone (10-100 mg/kg orally) induced at 1 h after dosing a significant and dose-dependent increase in gastric mucosal prostaglandin E2 release.