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PubMed2000

[Inhibition of catechol-O-methyltransferase. Optimizing dopaminergic therapy in idiopathic Parkinson syndrome with entacapone].

Registration of the inhibitor of the catechol-O-methyltransfersase (COMT) tolcapone has been stopped due to the possible relationship of tolcapone treatment to three cases of fatal hepatitis. As a result, strong uncertainty has emerged among neurologists about the principle of COMT inhibition itself. We review data, especially on the remaining COMT inhibitor, entacapone, with regard to pre-clinical and clinical efficacy and safety.

Antiparkinson Agents↗
PubMed1999

Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects.

The cerebral availability of the peripherally and centrally acting catechol-O-methyltransferase (COMT) inhibitor tolcapone is not known in humans. Therefore, we determined the concentration of tolcapone in cerebrospinal fluid (CSF) of 12 parkinsonian subjects 1-4 h after oral application of 200 mg of the drug. The mean concentration was 56.4+/-35.5 nmol/l (mean +/- SD). This concentration was calculated to cause 75.2+/-15% (mean +/- SD) inhibition of COMT in CSF. Thus, tolcapone efficiently inhibits COMT after crossing the blood-brain barrier in humans.

Administration, Oral↗
PubMed2004

Rapid determination of inorganic elements in airborne particulate matter by using acidified subcritical-water extraction and inductively-coupled plasma-optical-emission spectrometry.

A rapid and simple method has been developed for determination of inorganic elements in airborne particulate matter (PM10) by using acidified subcritical water and ICP-OES. Elements such as Al, As, B, Ba, Cd, Cu, Fe, Mn, Pb, Se, and Zn were rapidly and efficiently extracted from PM10 samples with a solution of 0.1 mol L(-1) HNO(3) under subcritical conditions. The method requires approximately 5% of the amount of acid used in the standard microwave extraction procedure. The material selected for the subcritical extraction manifold was poly ether ether ketone (PEEK), to avoid sample contamination with elements present in previously reported stainless-steel manifolds. The extraction temperature, time of static and dynamic extraction, and flow rate of acidified water were studied keeping the pressure controlled at about 1,500 psig. The efficiency of extraction of most of the analytes increased with temperature, tending to quantitative extraction at temperatures near 150 degrees C. After the extraction process the analytes were determined directly in the extract by ICP-OES. When the method was compared with the USEPA counterpart, the results indicate that under optimized conditions (static extraction time: 15 min, dynamic extraction time: 30 min, flow rate: 2 mL min(-1)) the analytes were extracted with recoveries between 73 and 158%. Alternatively, by using an extraction time of 15 min, the method could be used to screen for all the elements, with recoveries over 50%. The developed method was applied to the determination of inorganic elements in airborne particulate matter in the atmosphere of Santiago, Chile.

Acids↗
PubMed2001

Efficient flow injection and sequential injection methods for spectrophotometric determination of oxybenzone in sunscreens based on reaction with Ni(II).

Spectrophotometric determination of a widely used UV-filter, such as oxybenzone, is proposed. The method is based on the complexation reaction between oxybenzone and Ni(II) in ammoniacal medium. The stoichiometry of the reaction, established by the Job method, was 1:1. Reaction conditions were studied and the experimental parameters were optimized, for both flow injection (FI) and sequential injection (SI) determinations, with comparative purposes. Sunscreen formulations containing oxybenzone were analyzed by the proposed methods and results compared with those obtained by HPLC. Data show that both FI and SI procedures provide accurate and precise results. The ruggedness, sensitivity and LOD are adequate to the analysis requirements. The sample frequency obtained by FI is three-fold higher than that of SI analysis. SI is less reagent-consuming than FI.

Ammonia↗
PubMed2006

Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.

BACKGROUND: Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson's disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed. METHODS: We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d. RESULTS: Plasma levels of SAH [day 1: 48.32+/-22.52, 23.92-98.25 (mean+/-SD, range; micromol/l); day 3: 37.72+/-15.84, 23.4-61.89; p = 0.01] and tHcy (day 1: 13.88+/-5.62, 7.63-24.81; day 3: 11.38+/-4.44, 5.98-20.45; p = 0.04) significantly reduced. Plasma levels of levodopa did not significantly (p = 0.17) increase, whereas 3-OMD concentrations significantly (p = 0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p = 0.22). CONCLUSION: Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.

Aged↗
PubMed1996

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects.

OBJECTIVE: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. METHODS: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone; its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long halflife of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. CONCLUSION: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson's disease.

Aged↗
PubMed1998

Catechol-O-methyltransferase: variation in enzyme activity and inhibition by entacapone and tolcapone.

OBJECTIVE: The aim of this investigation was to study the variation of catechol-O-methyltransferase (COMT) activity in the human liver, duodenal mucosa and renal cortex, and to investigate the inhibition of COMT by entacapone and tolcapone. This study included 87 samples of human liver, 94 samples of the duodenum and 72 samples of the renal cortex. RESULTS: The activity of COMT was measured with 3,4-dihydroxybenzoic acid (242 micromol x l(-1)), the methyl acceptor substrate, and adenosyl-L-methionine (44 micromol x l(-1)), the methyl donor substrate. The hepatic activity of COMT activity was significantly higher in men than in women, whereas it was not sex-dependent in the duodenum or renal cortex. The activity of COMT varied 4.4-fold in the liver of men, 2.6-fold in the duodenum and 5.3-fold in the renal cortex. The median estimates of COMT activity were 577, 499, 103 and 159 pmol x min(-1) x mg(-1) in the liver of men and women, in the duodenum and in the renal cortex, respectively. CONCLUSION: Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P = 0.008), respectively, in the liver; consistent results were obtained with the other tissues.

Adult↗
PubMed1998

Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson's disease therapy.

OBJECTIVE: To evaluate fully the pharmacokinetics and pharmacodynamics of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT), after oral and intravenous administration. METHODS: Sixteen healthy male volunteers were given tolcapone in single doses of 200 mg orally and 50 mg intravenously, separated by a washout period of 7 days or more, in a single-center, open-label, randomized, cross-over study. Pharmacokinetic parameters were calculated using both compartmental and non-compartmental methods; pharmacodynamics were evaluated from erythrocyte COMT activity. RESULTS: After an initial lag time of 0.5 h, tolcapone was rapidly absorbed (peak plasma concentrations were reached within approximately 2 h) following either zero- or first-order absorption kinetics. The absolute bioavailability of an oral dose was approximately 60%. The volume of distribution was approximately 9 1, and the total clearance was approximately 71.h-l, resulting in a mean plasma half-life of 1.8 h. The degree of erythrocyte COMT inhibition was closely related to tolcapone plasma concentration; a rebound in COMT activity was observed after tolcapone withdrawal. Both oral and intravenous tolcapone were well tolerated. DISCUSSION: Because of its relatively low systemic clearance, tolcapone exhibits only a small degree of first-pass metabolism and a relatively good oral bioavailability, which explains the higher plasma concentrations and stronger COMT inhibition observed with tolcapone compared with entacapone, another COMT inhibitor. The pharmacokinetic and pharmacodynamic profile of tolcapone obtained in this study underlines the potential of the agent to be used as an adjunct to levodopa in the treatment of Parkinson's disease.

Administration, Oral↗
PubMed2000

Polymer production by two newly isolated extremely halophilic archaea: application of a novel corrosion-resistant bioreactor.

A novel corrosion-resistant bioreactor composed of polyetherether ketone (PEEK), tech glass and silicium nitrite ceramics was constructed and applied for the cultivation of two newly isolated, extremely halophilic archaea producing poly(gamma-glutamic acid) (PGA), or poly(beta-hydroxy butyric acid) (PHB), respectively. These bacteria were isolated from hypersaline soil close to Aswan (Egypt). The isolate strain 40, which is related to the genus Natrialba, produced large amounts of PGA when cultivated on solid medium. Culture conditions were optimised applying the corrosion-resistant bioreactor. PGA production was dependent on NaCl concentration and occurred about at 20% (w/v) NaCl in the medium. A maximum cell density of about 1.6 g cell dry matter/l was obtained when the bioreactor was stirred and aerated in a batch fermentation process using proteose-peptone medium. The supernatant was monitored with respect to PGA formation, and after 90 h a maximum of 470 mg/l culture volume was detected by HPLC analysis. Culture conditions were optimized for the isolate 56, which accumulated PHB as intracellular granules. Batch fermentations in the stirred and aerated bioreactor applying acetate and n-butyric acid as carbon sources led to cell density of 2.28 g cell dry matter/l and a maximum PHB accumulation contributing to about 53% of cellular dry weight. About 4.6 g PHB were isolated from 10.6 g dried cells of strain 56, which exhibited a weight average molar mass of 2.3 x 10(5) g mol(-1) and a polydispersity of about 1.4.

Archaea↗
PubMed2003

The relevance of preclinical studies for the treatment of Parkinson's disease.

An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).

Antiparkinson Agents↗
PubMed1998

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/ carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg and once with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and once with placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa was unaffected by tolcapone in all treatment groups and the maximum plasma concentration (Cmax) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60-90% and levodopa t1/2 by 20-60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD Cmax decreased by 80% and AUC by 70% with tolcapone. The tolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.

Administration, Oral↗
PubMed2005

Dopamine is metabolised by different enzymes along the rat nephron.

The purpose of this study was to determine the basal levels of dopamine (DA) and to examine the enzymes involved in DA metabolism in different microdissected nephron segments from rat kidneys. Segments were incubated with DA (50 nM) or DA plus monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT) inhibitors. Basal DA levels were higher in the proximal convoluted tubule (PCT, 10.8+/-3.7 pg/mm) and in the medullary collecting duct (MCD, 10.9+/-4.0 pg/mm) than in the medullary thick ascending limb of Henle's loop (MTAL, 4.9+/-0.9 pg/mm) (P<0.05). The percentage of exogenously added DA that was not metabolised was similar in both PCT (67+/-13%) and MCD (65+/-5%) and lower in MTAL (35+/-7%), suggesting that MTAL is a major site of DA metabolism. Inhibition of MAO (pargyline 1 mM) significantly increased the basal content of DA and the percentage of the added non-metabolised DA (to 95+/-10%) in PCT but had no effect on MTAL or MCD. Conversely, inhibition of COMT (nitecapone or Ro-41-0960, both 1 mM) slightly increased the basal levels of DA only in MTAL, whereas the percentage of added DA not metabolised rose to 97+/-10% in MTAL and to 91+/-15% in MCD. COMT inhibition had no effect in PCT. In conscious rats pargyline (50 mg/kg) increased urinary DA from 680+/-34 to 1,128+/-158 ng/d/100 g BW (P<0.01) while nitecapone (40 mg/kg) produced a slight non-significant increment. Our results show that DA is present all along the rat nephron and that renal DA is metabolised continuously and predominantly by MAO in proximal segments, and by COMT in the more distal ones.

Animals↗
PubMed2005

The long-term mechanical integrity of non-reinforced PEEK-OPTIMA polymer for demanding spinal applications: experimental and finite-element analysis.

Polyetheretherketone (PEEK) is a novel polymer with potential advantages for its use in demanding orthopaedic applications (e.g. intervertebral cages). However, the influence of a physiological environment on the mechanical stability of PEEK has not been reported. Furthermore, the suitability of the polymer for use in highly stressed spinal implants such as intervertebral cages has not been investigated. Therefore, a combined experimental and analytical study was performed to address these open questions. A quasi-static mechanical compression test was performed to compare the initial mechanical properties of PEEK-OPTIMA polymer in a dry, room-temperature and in an aqueous, 37 degrees C environment (n=10 per group). The creep behaviour of cylindrical PEEK polymer specimens (n=6) was measured in a simulated physiological environment at an applied stress level of 10 MPa for a loading duration of 2000 hours (12 weeks). To compare the biomechanical performance of different intervertebral cage types made from PEEK and titanium under complex loading conditions, a three-dimensional finite element model of a functional spinal unit was created. The elastic modulus of PEEK polymer specimens in a physiological environment was 1.8% lower than that of specimens tested at dry, room temperature conditions (P<0.001). The results from the creep test showed an average creep strain of less than 0.1% after 2000 hours of loading. The finite element analysis demonstrated high strain and stress concentrations at the bone/implant interface, emphasizing the importance of cage geometry for load distribution. The stress and strain maxima in the implants were well below the material strength limits of PEEK. In summary, the experimental results verified the mechanical stability of the PEEK-OPTIMA polymer in a simulated physiological environment, and over extended loading periods. Finite element analysis supported the use of PEEK-OPTIMA for load-bearing intervertebral implants.

Benzophenones↗
PubMed2005

The in vitro stabilising effect of polyetheretherketone cages versus a titanium cage of similar design for anterior lumbar interbody fusion.

UNLABELLED: This biomechanical study was performed to test the primary segmental in vitro stabilising effect of a standard and large footprint radiolucent poly-ether-ether-ketone (PEEK) box cage versus a titanium box cage for anterior lumbar interbody fusion. Eighteen L2-L3 and sixteen L4-L5 cadaveric motion segments were divided into three groups and received a titanium cage or a radiolucent PEEK cage with standard or large footprint. All specimens were tested in three testing conditions: intact, stand-alone anterior cage and finally with supplemental translaminar screw fixation. Full range of motion and neutral zone measurements were determined and anterior cage pull out force was tested. The titanium design was significantly more effective in reducing the range of motion only in axial rotation. The larger footprint radiolucent cage did not increase stability as compared to the standard footprint. The titanium cage pull out force was significantly (P=0.0002) higher compared to both radiolucent cage constructs. CLINICAL RELEVANCE: Supplemental posterior fixation is strongly recommended to increase initial stability of any anterior interbody fusion cage construct. Although the biomechanical stability necessary to achieve spinal fusion is not defined, the radiolucent designs tested in this study, with a standard footprint as well as with a larger footprint, may be insufficiently stabilised with translaminar screws as compared to the titanium implant. Supplemental pedicle screw fixation may be required to obtain adequate stabilisation in the clinical setting.

Benzophenones↗
PubMed2005

Anterior cervical fusion with polyetheretherketone (PEEK) cages in the treatment of degenerative disc disease. Preliminary observations in 36 consecutive cases with a minimum 12-month follow-up.

STUDY DESIGN: Retrospective analysis of 36 cases of degenerative disc disease treated by interbody fusion with polyetheretherketone (PEEK) cages. OBJECTIVE: To determine the safety and efficiency of PEEK cages for anterior cervical fusion (ACF). SUMMARY OF BACKGROUND DATA: ACF with autologous bone has been reported since over 50 years ago. The recent development of cages housing materials inducing osteogenesis simplifies the technique of interbody fusion. The main purposes of bone substitutes for ACF are immediate biomechanical support, osteo-integration of the graft, and elimination of local side effects at the donor site. This report shows our results using PEEK cages. MATERIALS AND METHODS: During an 18-month period, 36 consecutive patients had cervical fusions at 43 levels between C3 and C7. All operations involved one or two disc spaces for degenerative disc disease. We implanted all disc spaces with PEEK cages (Stryker Corporation, Kalamazoo, MI) containing granulated coralline hydroxylapatite (Pro-Osteon 200, Interpore Cross International, Irvine, CA) or deantigenated pig bone in a gel solution (Gen-Os, Tecnoss, Torino, Italy). RESULTS: About 97% of patients had a good to excellent outcome; the result in one myelopathic patient was fair. The cervical fusion rate was 16.7% at 3 months, 61.1% at 6 months, and 100% at one year. CONCLUSIONS: PEEK cages appear to be safe and efficient for ACF. In order to confirm our preliminary impressions studies on larger series with long term follow-up are warranted.

Adult↗
PubMed2002

Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.

The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.

Animals↗