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PubMed2003

Modifications of plasma and platelet levels of L-DOPA and its direct metabolites during treatment with tolcapone or entacapone in patients with Parkinson's disease.

We compared--retrospectively--the effects of a 3-month therapy with catechol- O-methyltransferase (COMT) inhibitors tolcapone (100 mg, t.i.d.) and entacapone (200 mg, t.i.d.), on L-DOPA metabolism in two groups of parkinsonian patients with motor fluctuations. Plasma and platelets concentrations of L-DOPA and its direct metabolites, dopamine and 3- O-methyldopa (3-OMD), were measured before starting treatment, after two weeks and at the end of treatment. Patients treated with tolcapone showed significant increases in plasma and platelet L-DOPA levels and marked reduction of plasma and platelet 3-OMD levels, both at short- and long-term. Entacapone did not modify L-DOPA levels, while inducing a less marked reduction of plasma and platelet 3-OMD concentrations, with respect to tolcapone, at both time points. Both drugs were similarly effective in increasing plasma and platelet levels of dopamine. These results confirm the different profiles of activity of the two drugs, with tolcapone proving more effective on both the intra- and extra-cellular levels of L-DOPA and 3-OMD.

Age Factors↗
PubMed2000

Tolcapone increases maximum concentration of levodopa.

No significant increase of the maximum concentration (Cmax) of levodopa after addition of catechol-O-methyltransferase inhibitor tolcapone occurred in previous pharmacokinetic studies predominantly on healthy volunteers. We compared pharmacokinetics of levodopa in plasma before and after addition of tolcapone in 13 treated parkinsonian subjects under standardized conditions. We found a significant increase of Cmax of levodopa after the addition of tolcapone. This may represent one cause for the occurrence of dyskinesia previously early in the course of treatment with tolcapone.

Aged↗
PubMed1998

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960.

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.

Animals↗
PubMed1999

Inhibition of catechol-O-methyltransferase (COMT) in the brain does not affect the action of dopamine and levodopa: an in vitro electrophysiological evidence from rat mesencephalic dopamine neurons.

In order to study whether the membrane hyperpolarization and firing inhibition caused by dopamine and levodopa on rat midbrain dopamine cells are affected by the inhibition of brain catechol-O-methyl-transferase (COMT), intracellular electrophysiological recordings were made from these neurons maintained in vitro. Here we report that a treatment of the cerebral tissue with tolcapone, a central and peripheral inhibitor of COMT, does not change the membrane responses of midbrain dopamine neurons to dopamine and levodopa. The lack of modification of the dopaminergic effects by tolcapone suggests that the pharmacological inhibition of intracerebral COMT does not have detectable action on dopamine neurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's disease, might be dependent on the reduction of COMT activity in the extracerebral tissue.

Animals↗
PubMed2001

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in L-DOPA/carbidopa treated rats.

Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Animals↗
PubMed2002

Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

Comparison of 0.1% bromfenac sodium and 0.1% pemirolast potassium for the treatment of allergic conjunctivitis.

PURPOSE: We compared the efficacy of a new nonsteroidal antiinflammatory drug (NSAID) eye drop, 0.1% bromfenac sodium (Bromfenac), with that of an antiallergic agent, 0.1% pemirolast potassium (Pemirolast), in the treatment of seasonal allergic conjunctivitis in Japanese patients. METHODS: Twenty-two subjects with seasonal allergic conjunctivitis were enrolled in the study. One eye was treated with Bromfenac eye drops and the contralateral eye was treated with Pemirolast eye drops for 1 week. Subjective ocular symptoms and objective ocular signs evaluated by slit-lamp examination were scored and recorded before and after treatment. RESULTS: Both drugs significantly decreased ocular signs after 1 week, but not symptoms. No significant differences in subjective symptoms or objective signs were observed between the two drugs. Ten patients (45.5%) selected Bromfenac as more effective, nine patients (40.9%) selected Pemirolast, and three patients found no difference in efficacy between the two drugs. CONCLUSION: Bromfenac sodium is as safe and effective for the treatment of allergic conjunctivitis as pemirolast potassium.

Adolescent↗
PubMed2005

Response of primary fibroblasts and osteoblasts to plasma treated polyetheretherketone (PEEK) surfaces.

Polyetheretherketone (PEEK) is a synthetic polymer with suitable biomechanical and stable chemical properties, which make it attractive for use as an endoprothetic material and for ligamentous replacement. However, chemical surface inertness does not account for a good interfacial biocompatibility, and PEEK requires a surface modification prior to its application in vivo. In the course of this experimental study we analyzed the influence of plasma treatment of PEEK surfaces on the cell proliferation and differentiation of primary fibroblasts and osteoblasts. Further we examined the possibility of inducing microstructured cell growth on a surface with plasma-induced chemical micropatterning. We were able to demonstrate that the surface treatment of PEEK with a low-temperature plasma has significant effects on the proliferation of fibroblasts. Depending on the surface treatment, the proliferation rate can either be stimulated or suppressed. The behavior of the osteoblasts was examined by evaluating differentiation parameters. By detection of alkaline phosphatase, collagen I, and mineralized extracellular matrix as parameters for osteoblastic differentiation, the examined materials showed results comparable to commercially available polymer cell culture materials such as tissue culture polystyrene (TCPS). Further microstructured cell growth was produced successfully on micropatterned PEEK foils, which could be a future tool for bioartificial systems applying the methods of tissue engineering. These results show that chemically inert materials such as PEEK may be modified specifically through the methods of plasma technology in order to improve biocompatibility.

Animals↗
PubMed2006

Optimal design for multivariate response pharmacokinetic models.

We address the problem of designing pharmacokinetic experiments in multivariate response situations. Criteria, based on the Fisher information matrix, whose inverse according to the Rao-Cramer inequality is the lower bound of the variance-covariance matrix of any unbiased estimator of the parameters, have previously been developed for univariate response for an individual and a population. We extend these criteria to design individual and population studies where more than one response is measured, for example, when both parent drug and metabolites are measured in plasma, multi-compartment models, where measurements are taken at more than one site, or when drug concentration and pharmacodynamic data are collected simultaneously. We assume that measurements made at distinct times are independent, but measurements made of each concentration are correlated with a response variance-covariance matrix. We investigated a number of optimisation algorithms, namely simplex, exchange, adaptive random search, simulated annealing and a hybrid, to maximise the determinant of the Fisher information matrix as required by the D-optimality criterion. The multiresponse optimal design methodology developed was applied in two case studies, where the aim was to suggest optimal sampling times. The first was a restrospective iv infusion experiment aimed to characterise the disposition kinetics of tolcapone and its two metabolites in healthy volunteers. The second was a prospective iv bolus experiment designed to estimate the tissue disposition kinetics of eight beta-blockers in rat.

Adrenergic beta-Antagonists↗
PubMed2005

Effect of betaTCP filled polyetheretherketone on osteoblast cell proliferation in vitro.

Non-resorbable thermoplastic polymers have become more important for reconstructive surgery due to their excellent chemical and physical properties. Polyetheretherketone-beta-tricalcium phosphate (betaTCP-PEEK) composites were developed as alternative materials for load-bearing applications. This study presents the effect of polyetheretherketone (PEEK) specimens incorporated with 5, 10, 20 and 40 wt% beta-tricalcium phosphate (betaTCP) and processed by injection molding on cultivated osteoblast cells. Normal human osteoblast (NHOst) cells were seeded onto polymer discs to evaluate cell viability and proliferation after 24, 72 and 120 h of cultivation by employing the WST-1 assay. Standard tissue culture plastic was used as a control. The osteoblast cells were found to be viable in all PEEK groups, while the cell proliferation was progressively inhibited due to the incorporated beta-tricalcium phosphate. BetaTCP-PEEK showed concentration independent decrease of cell proliferation compared to the unfilled PEEK and the control group. In summary, this study confirms the non-toxic nature of pure PEEK, whereas this could not definitely be verified for betaTCP-PEEK as a composite material in chosen concentrations of beta-tricalcium phosphate in vitro.

Benzophenones↗
PubMed2002

COMT-inhibition increases serum levels of dihydroxyphenylacetic acid (DOPAC) in patients with advanced Parkinson's disease.

UNLABELLED: Inhibition of the catechol-O-methyltransferase (COMT) is an effective treatment for end-of-dose fluctuations in advanced Parkinson's disease. The aim of the present investigation was to analyse the consequences of subsequent alterations in levodopa metabolism under common treatment conditions when the levodopa dose is adjusted due to the occurrence of dyskinesias after initiation of the COMT-inhibitor. Ten patients with advanced Parkinson's disease (Hoehn & Yahr stage IV) were medicated with tolcapone. Prior to and five to ten days after the initiation of tolcapone 300 mg/d, serum level profiles of levodopa and its metabolites (3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) were performed. The mean daily levodopa dose was reduced from 894 +/- 248 mg to 646 +/- 252 mg (p = 0.003). There was a significant increase in the area under the curve (AUC) of DOPAC during COMT-inhibition compared to the baseline profile (p = 0.009). There were significant decreases of the AUC of HAV (p = 0.001) and the ratios of the AUC HVA / AUC DOPAC (p = 0.0001) and AUC 3-OMD / AUC levodopa (p = 0.0001). CONCLUSION: The elevation of DOPAC and the decrease of HVA and HVA / DOPAC reflect a shift of the levodopa metabolism towards the MAO-B dependent oxidative pathway. This might contribute to production of hydroxyl radicals and induction of oxidative stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Optical spectra and kinetics of reactions of prostaglandin H synthase: effects of the substrates 13-hydroperoxyoctadeca-9,11-dienoic acid, arachidonic acid, N,N,N',N'-tetramethyl-p-phenylenediamine, and phenol and of the nonsteroidal anti-inflammatory drugs aspirin, indomethacin, phenylbutazone, and bromfenac.

A combination of cyclooxygenase activity assays, rapid spectrophotometry and pre-steady-state, steady-state, and transient-state kinetics is used to characterize further the properties of prostaglandin H synthase. 13-Hydroperoxyoctadeca-9-11-dienoic acid is used as oxidizing substrate and the effects of the following compounds are examined: arachidonic acid, N,N,N',N'-tetramethyl-p-phenylenediamine, phenol, diethyldithiocarbamate, and the nonsteroidal anti-inflammatory drugs aspirin, indomethacin, phenylbutazone, and Bromfenac. The order of reactivity of four of these substrates, predominantly with compound II of prostaglandin H synthase, is N,N,N',N'-tetramethyl-p-phenylenediamine greater than phenol greater than indomethacin approximately phenylbutazone. Aspirin exhibits no effect. Arachidonic acid causes inactivation. Diethyldithiocarbamate acts as a reducing substrate for the oxidized forms of prostaglandin H synthase. Bromfenac appears to act both as a protective agent and inhibitor.

Animals↗