Peripheral catechol-O-methyltransferase Research Articles

The relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset

Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg’s threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = −0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.

Stalevo® : A pioneering treatment for OFF periods in Parkinsons disease.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.

Developmental and behavioral toxicity assessment of opicapone in zebrafish embryos

The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 μM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.

Effects of a New Natural Catechol-O-methyl Transferase Inhibitor on Two In Vivo Models of Parkinson's Disease.

A tetrahydroisoquinoline identified in Mucuna pruriens ((1R,3S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid, compound 4) was synthesized and assessed for its in vitro pharmacological profile and in vivo effects in two animal models of Parkinson's disease. Compound 4 inhibits catechol-O-methyltransferase (COMT) with no affinity for the dopaminergic receptors or the dopamine transporter. It restores dopamine-mediated motor behavior when it is co-administered with L-DOPA to C. elegans worms with 1-methyl-4-phenylpyridinium-damaged dopaminergic neurons. In a 6-hydroxydopamine rat model of Parkinson's disease, its co-administration at 30 mg/kg with L-DOPA enhances the effect of L-DOPA with an intensity similar to that of tolcapone 1 at 30 mg/kg but for a shorter duration. The effect is not dose-dependent. Compound 4 seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound 4 further validates the traditional use of M. pruriens for the treatment of Parkinson's disease, and compound 4 can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.

Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

The inhibition of catechol O-methyltransferase and monoamine oxidase by tetralone and indanone derivatives substituted with the nitrocatechol moiety

The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson’s disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.

A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat

Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9–1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val158Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.

3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA.

BackgroundWe evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of l-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of l-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with l-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.ResultsThe number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by l-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-l-DOPA treatment (25 µM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 µM l-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 µM), and was enhanced by concomitant treatment with entacapone (0.3 µM). The uptake of l-DOPA into and the release of glutathione from striatal astrocytes after l-DOPA treatment (100 µM) were inhibited by simultaneous exposure to 3-OMD (100 µM).ConclusionsThese data suggest that l-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with l-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood–brain barrier, this reagent may enhance l-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of l-DOPA on dopaminergic neurons.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0289-0) contains supplementary material, which is available to authorized users.

Pharmacological Profile of Opicapone, a Third Generation Nitrocatechol COMT Inhibitor, in the Rat

In this study opicapone´s pharmacological properties were evaluated as well as its potential cytotoxic effects. The pharmacodynamic effects of opicapone were explored by evaluating rat catechol-O-methyltransferase (COMT) activity and levodopa pharmacokinetics, in periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg/kg up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not recovered control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with concomitant reduction of 3-OMD from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone upon brain catecholamines after levodopa administration were sustained up to 24 h post administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. In conclusion, opicapone is endowed with a prolonged inhibitory profile on peripheral COMT resulting in an extended bioavailability of levodopa without toxicity effects, presenting thus some improved properties over the current available COMT inhibitors.

Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat.

Catechol-O-methyltransferase (COMT) is an important target in the levodopa treatment of Parkinson's disease; however, the inhibitors available have problems, and not all patients benefit from their efficacy. Opicapone was developed to overcome those limitations. In this study, opicapone's pharmacological properties were evaluated as well as its potential cytotoxic effects. The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg⋅kg(-1) up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. Opicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors.

Possible treatment concepts for the levodopa-related hyperhomocysteinemia.

The saga of harmful levodopa (LD) in the treatment of Parkinson's disease (PD) resulted from outcomes of animal—and cell culture studies and the clinical observation of motor complication related to the short half life of LD. Further aspects of LD long term application, the LD associated homocysteine increase and its emerging consequences on progression, and onset of neuropsychiatric symptoms and of vascular disease are only partially considered. Therapeutic approaches for this LD-mediated neurotoxic homocysteine increase are vitamin supplementation or LD application with an inhibitor of catechol-O-methyltransferase (COMT). However, forcing central dopamine metabolism further down the methylation path by central blocking of COMT and MAO-B may reduce oxidative stress and homocysteine levels. But it may also increase N-methylation of tetrahydroisoquinolines to neurotoxic N-methylated tetrahydroisoquinolines. These compounds were observed in cerebrospinal fluid and plasma of long term LD-treated PD patients. Therefore LD application with peripheral COMT inhibition may be safer.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of a Novel, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.

BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of L-DOPA and Enhances Its Availability to the Brain

The present study aimes at determining the effects of the catechol-O-methyltransferase (COMT) inhibitor BIA 3-202 [1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in peripheral circulation (jugular vein), whole brain, and striatal microdialysates in rats orally treated with L-DOPA plus benserazide. A low dose (3 mg/kg) of BIA 3-202 was relatively selective to inhibit liver COMT, being devoid of major significant inhibitory effects upon brain COMT. By contrast, a high dose (30 mg/kg) of BIA 3-202 markedly inhibited liver and brain COMT. BIA 3-202 (3 and 30 mg/kg) reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation (jugular vein), brain tissue, and striatal dialysate, but failed to increase the levels of dopamine in striatal dialysates despite the increase in dopamine brain levels. However, the changes in brain levels of L-DOPA, 3-O-methyl-L-DOPA, and dopamine and in striatal dialysate levels of L-DOPA and 3-O-methyl-L-DOPA, obtained with 3 mg/kg BIA 3-202, were not different from those obtained with 30 mg/kg BIA 3-202. In conclusion, inhibition of peripheral COMT by BIA 3-202 may suffice to improve the availability of L-DOPA to the brain.

Effects of peripheral and central catechol- O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats

Tolcapone is a mixed (peripheral and central) catechol- O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of l-DOPA into 3- O-methyl-DOPA and thereby increase plasma and cerebral levels of l-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of l-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following l-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of l-DOPA and DA compared with saline. The levels of l-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.

Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.

A homologous series of novel nitro-catechol structures (7a-7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone) was found to exhibit the most potent and selective inhibition of peripheral COMT, with an inhibition profile more similar to entacapone 2 than tolcapone 1 (an equipotent peripheral and central inhibitor) but with much improved duration of action (7b, 70% inhibition and 2, 25% inhibition at 9 h after administration). The effects of structural modifications to 7b on COMT inhibitory profile were investigated, and it is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition. The introduction of the alpha-methylene group, the major structural difference between 7b and 1, would appear responsible for the observed enhancement in selectivity of peripheral COMT inhibition of 7b, which has more limited access to the brain than 1.

The effect of COMT inhibition with entacapone on cardiorespiratory responses to exercise in patients with Parkinson's disease

The inhibition of catechol- O-methyltransferase (COMT) may impair catecholamine clearance resulting in unwanted cardiac and hemodynamic events. We therefore studied the effects of entacapone, an inhibitor of peripheral COMT, on cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on respiratory muscle strength in l-dopa treated patients with Parkinson's disease (PD). A randomized, double-blind, cross-over study with two 1 week treatment periods was performed in 15 PD patients. The test battery included analysis of hemodynamics, gas exchange parameters and plasma NA during a maximal exercise test, assessment of maximal static airway pressures and pre- and post-exercise motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). The first test was done after withholding l-dopa overnight (‘run-in’ test, off-phase). The second and third tests were done in on-phase after 1 week treatment with either entacapone 200 mg or placebo given with each dose of l-dopa. No differences in maximal work load, plasma NA, or in cardiorespiratory responses to either maximal or work rate standardized submaximal exercise were observed between entacapone and placebo, except for O 2 pulse, which was slightly lower ( p<0.05) after entacapone at submaximal exercise level. Maximal airway pressures were similar between the study treatments and run-in. Exercise had no effect on motor UPDRS after either study treatment or during the run-in test. No serious adverse events were observed. The results of this study suggest that entacapone does not change the work capacity, work efficiency or respiratory muscle strength in l-dopa treated PD patients with mild to moderate disease severity, and that its use with l-dopa seems to be safe in conditions of maximal physical effort. However, data from the long-term use of COMT inhibitors are needed to confirm these findings.

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging.

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.

Comparative tolerability of the newer generation antiparkinsonian agents.

In recent years, the treatment of Parkinson's disease has undergone an immense amount of research, resulting in the development of multiple new medications. This has largely been fuelled by dissatisfaction over the development of motor complications secondary to long term levodopa therapy. Different treatment approaches are applied depending on the stage of Parkinson's disease. In early and mild Parkinson's disease, selegiline offers a limited symptomatic effect. Its neuroprotective effect, although at present theoretical, has questionable clinical relevance. Increased mortality associated with selegiline has been reported, although a meta-analysis of 5 different trials did not support this finding. The newer, non-ergoline dopamine agonists, pramipexole and ropinirole, have undergone extensive studies to evaluate their efficacy as monotherapy in early Parkinson's disease. These newer agonists are ideal initial symptomatic medications, primarily because they delay the onset of levodopa-induced motor fluctuations. Efficacy of the newer dopamine agonists in advanced disease seems to be comparable to that of the older agents, bromocriptine and pergolide. Adverse effects can be reduced by starting the medication at a very low dose and then slowly titrating upward. Catechol-O-methyl transferase (COMT) inhibitors are indicated for the treatment of motor fluctuations in advanced disease, particularly the 'wearing-off' phenomenon. Tolcapone, a peripheral and central COMT inhibitor, appears to be quite effective, producing a 47% reduction in 'off' time. Unfortunately, 3 deaths have been observed, which are presumably secondary to tolcapone therapy. The drug has been withdrawn in many countries, and liver enzyme testing is mandatory in the US. Entacapone, a purely peripheral COMT inhibitor with a lower potency than tolcapone, has also proved to be effective and has not been associated with liver damage, obviating the need for testing.

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.