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At least 1,243 records · Page 69Linked to original sources
PubMed1992

Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study.

In vivo microdialysis was used to examine the effect of two new catechol-O-methyltransferase (COMT) inhibitors, Ro 40-7592 and OR-611, on extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum. The interactions of the COMT inhibitors with nomifensine, clorgyline and deprenyl were also studied. Ro 40-7592 (3-30 mg/kg, i.p.) decreased dose-dependently the efflux of HVA, increased that of DOPAC, and tended to increase that of dopamine. Higher doses of OR-611 (30-100 mg/kg, i.p.) also decreased the dialysate level of HVA, increased that of DOPAC, and tended to increase that of dopamine. Ro 40-7592 was about ten-fold as potent as OR-611. Neither of the COMT inhibitors changed dialysate levels of 5-HIAA. An OR-611 dose of 10 mg/kg i.p. had no significant effect, in contrast to Ro 40-7592, on any of the parameters studied; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. Both nomifensine (15 mg/kg, i.p.) and clorgyline (4 mg/kg, i.p.) alone elevated extracellular dopamine levels, and lowered those of DOPAC and HVA, though there were quantitative and temporal differences between the drugs. L-Deprenyl (1 mg/kg, i.p.) alone had no significant effect on any of the compounds measured. Ro 40-7592 (10 mg/kg, i.p.) potentiated the effect of nomifensine on dopamine efflux, and it tended to increase clorgyline-induced dopamine efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Administration, Oral↗
PubMed1993

Effects of three types of catechol O-methylation inhibitors on L-3,4-dihydroxyphenylalanine-induced circling behaviour in rats.

The effects of three new, selective inhibitors of catechol O-methylation were compared regarding their potentiation of L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa-induced contralateral circling behaviour in male rats. Some studies were also done with amphetamine, which causes ipsilateral turning. A peripherally acting compound, entacapone, a peripherally and centrally acting compound, tolcapone, and an atypical compound, CGP 28014 (3, 10 or 30 mg/kg) increased the effect of L-dopa/carbidopa (2/30 or 5/30 mg/kg) on contralateral circling by 2.0-6.1-fold. Addition of clorgyline (3 mg/kg) did not increase, but rather decreased, the entacapone (3 mg/kg) and L-dopa/carbidopa (2/30 or 5/30 mg/kg)-induced peak circling. Amphetamine (2.5 mg/kg)-induced ipsilateral circling behaviour was not affected by tolcapone (30 mg/kg). We conclude that L-dopa-induced circling behaviour is enhanced and prolonged by all types of catechol O-methyltransferase inhibitors regardless of their brain penetration. The results suggest that catechol O-methylation inhibitors may be beneficial as L-dopa adjuncts in the treatment of patients with Parkinson's disease.

Amidines↗
PubMed1993

Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase.

The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/kg), respectively. Additional metabolic effects of two inhibitors of catechol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake2 inhibitor (CGP 28014 (30 mg/kg)) were assessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The latter two effects were reversed by tolcapone and CGP 28014, but not by entacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances also decreased striatal HVA levels. Striatal 3-methoxytyramine levels were significantly lowered only by tolcapone. Our results show that enhanced central dopamine metabolism is modified by the inhibition of catechol O-methyltransferase even in the absence of L-3,4-dihydroxyphenylalanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltransferase.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats.

In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Beneficial effects of co-administration of catechol-O-methyltransferase inhibitors and L-dihydroxyphenylalanine in rat models of depression.

The administration of catechol-O-methyltransferase inhibitors alone changed neither the behavior of the rats in two animal models of depression, the forced swimming test (entacapone and tolcapone) or in the learned helplessness paradigm (tolcapone), nor the locomotor activity. L-Dihydroxyphenylalanine (L-DOPA) and carbidopa treatment as such decreased motility but did not improve the behavior in the antidepressant tests. Co-administration of catechol-O-methyltransferase inhibitors and L-DOPA/carbidopa increased the performance of rats in both tests without increasing locomotor activity. Catechol-O-methyltransferase inhibitors could be beneficial as adjunct drugs of L-DOPA not only in Parkinson's disease but also in the coincident depressive illness.

Analysis of Variance↗
PubMed1992

Determination of the catechol-O-methyltransferase inhibitor Ro 40-7592 in human plasma by high-performance liquid chromatography with coulometric detection.

A sensitive and specific high-performance liquid chromatographic method has been developed to measure the catechol-O-methyl-transferase (COMT) inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) in human plasma. The compound and the internal standard were extracted from plasma at pH 2 with n-butyl chloride-ethyl acetate (95:5, v/v). The extract was chromatographed on a reversed-phase column (Hypersil ODS, 5 microns) using a mixture of phosphate buffer (0.05 M, pH 2), methanol and tetrahydrofuran (45:55:5, v/v/v) as the mobile phase. Long-retained components were removed from the system by means of a simple column-switching system. Quantification of the catechol-O-methyltransferase inhibitor was performed by means of coulometric detection (0.1 V). The limit of quantification was about 1 ng/ml, using a 1-ml specimen of plasma. The recovery from human plasma was greater than 88%. The mean inter-assay precision was 5.3% in the range 2.5-1000 ng/ml. Linearity of the standard curve was obtained in the concentration range 2.5-500 ng/ml. The catechol-O-methyltransferase inhibitor was stable in human plasma when stored for six months at -20 degrees C and for 24 h at room temperature. The practicability of the new method was demonstrated by the analysis of more than 400 plasma samples from a tolerance study performed in human volunteers.

Benzophenones↗
PubMed1989

Antibodies to cyclosporine A (CsA) by a novel route and their use to monitor cyclosporine levels by radioimmunoassay (RIA).

Anti-cyclosporine antibodies were generated in rabbits, using an antigen derived from CsA. CsA was linked to carrier proteins by means of a photoactive cross-linking reagent, 4-benzoylbenzoic acid (BBa), an alpha, beta-unsaturated ketone. In the presence of CsA, photolysis of BBa results in hydrogen abstraction and random insertion into the cyclosporine molecule, generating a population of CsA with carboxyl groups at various positions. Immunization with CsA-BBa-bovine serum albumin gave rise to high affinity antibodies to CsA, with Kd = 9.8 +/- 2.8 x 10(-11) M, as determined by Scatchard analysis. Specificity was determined by competition experiments in a radioimmunoassay (RIA), using a panel of six cyclosporine derivatives, substituted at different positions. The derivatives could be arranged into three groups according to their affinities. One derivative with the lowest affinity had a bulky O-t-butyl-D-serine in place of D-alanine in position 8. Serum CsA levels in 25 transplant patients were measured by RIA, and compared to levels determined with a commercially available polyclonal antibody, which is routinely used clinically. The rabbit antiserum gave values that correlated well with the results using the commercial antibody.

Animals↗
PubMed1991

Thick filter neutrophil chemotaxis performed in the absence of albumin.

Migration through a filter is a technique widely used for the study of cell chemotaxis. Since the original description of the technique by Boyden in 1962 (J. Exp. Med. 115, 453) using neutrophils and thick filters prepared from cellulose nitrate, albumin has been required in the incubation medium to support chemotaxis. However, the binding to albumin of compounds affecting chemotaxis can reduce their free concentration. We developed two procedures for studying neutrophil chemotaxis under reduced or albumin-free conditions. In one, cellulose nitrate filters were pretreated with albumin by a novel procedure and chemotaxis was carried out in albumin-free medium. As tested with the chemoattractant LTB4 and human neutrophils, the procedure resulted in full chemotaxis, measured by the number of cells crossing the filter, with an EC50 of 0.43 nM for LTB4. The LTB4-receptor antagonist LY 223982 inhibited the chemotactic action of LTB4 with a Ki of 62 nM in the albumin-pretreated filter system, thus showing 58 times greater potency than in medium containing 0.5% albumin. The second procedure makes use, for the first time, of a relatively new filter (Hydrophilic Durapore). This filter has the same dimensions and pore rating of the cellulose nitrate filter but did not require pretreatment with albumin to support chemotaxis in the albumin-free medium. LTB4 stimulated neutrophil chemotaxis across this filter with an EC50 of 0.29 nM. LY 223982 had a Ki of 11 nM, thus exhibiting a potency even greater than in the albumin-pretreated cellulose nitrate filter system. fMLP and C5a also stimulated chemotaxis in the absence of albumin. These results suggest that albumin is not obligatory for neutrophil chemotaxis through thick filters. The role of albumin in the chemotaxis assay using cellulose nitrate filters may be to counteract the adherence of cells or chemotactic agents to the filters.

Albumins↗
PubMed1996

Mapping catechol-O-methyltransferase in vivo: initial studies with [18F]Ro41-0960.

Ro41-0960 is a potent, fluorine containing COMT inhibitor which has be en reported to cross the blood brain barrier and to inhibit COMT in the brain. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in Parkinson's disease. Positron emission tomographic (PET) studies in baboon using F-18 labeled Ro41-0960 demonstrated a negligible uptake in the brain both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The brain to plasma ratios of F-18 averaged about 0.025. Region of interest analysis of the brain tissue area suggests that most of F-18 in the brain was due to the blood in the brain and not the brain tissue itself. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT activity. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as unchanged [18F]Ro41-0960 and that it could be displaced with unlabeled Ro41-0960. The fact that the average brain to blood ratio for mice (n=12) was 0.04, and that similar HPLC metabolite patterns were observed for brain and blood, provides consistent evidence that nearly all the F-18 in the brain represents F-18 in the cerebral blood vessels. These studies raise the question of whether the central pharmacological effects of Ro41-0960 are due to its presence in the brain. They also provide the first example of a positron emitter labeled radiotracer for COMT, and provide initial encouraging evidence that [18F]Ro41-0960 may be used to examine COMT in peripheral organs in vivo.

Animals↗
PubMed1990

Characterization of short-fibre reinforced thermoplastics for fracture fixation devices.

This study focuses on determining the effects of clinically relevant procedures on the flexural and fracture toughness properties of three short-fibre thermoplastic composites for potential application as fracture fixation devices. The procedures included sterilization, heat contouring and saline soaking. The three materials tested were polysulphone, polybutylene terephthalate and polyetheretherketone, all reinforced with 30% short carbon fibres. The polysulphone composite showed significant degradation in mechanical properties due to saline soaking. The polybutylene terephthalate exhibited significant degradation of mechanical properties following both contouring and saline soaking. The polyetheretherketone composite, however, exhibited no degradation in mechanical properties. The results demonstrated that flexion and fracture toughness testing were effective for determining the response of the composites to different applied conditions and demonstrated the stability of polyetheretherketone subjected to these treatments. Scanning electron microscopy demonstrated the most effective fibre-matrix bonding to be in the polyetheretherketone.

Benzophenones↗