Clinical advantages of COMT inhibition with entacapone - a review.

Two catechol- O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were developed during the 1990's to be used as adjuncts to levodopa (LD) - dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson's disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and entacapone are quite similar, and entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first entacapone dose. When LD is administered in several frequent daily doses, addition of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%. Based on studies with home diaries, entacapone increases the daily ON-time by an average of one to two hours, and reduces the daily OFF-time correspondingly in patients with PD with motor fluctuations. The daily LD dose has been reduced by 10 to 30%. These positive effects are sustained in long term use over several years. There is still scant information of the benefit of entacapone in patients without motor fluctuations. Entacapone can cause both dopaminergic and non-dopaminergic adverse events. Increased dyskinesias are most frequently recorded in patients with motor fluctuations. The dopaminergic adverse events can usually be diminished by reducing the LD dose. Non-dopaminergic adverse events are abdominal pain and diarrhea. Diarrhoea has led to discontinuation in 3 to 4% of the patients in clinical trials. Entacapone has not been connected to liver toxicity and there are no indications to follow laboratory safety during treatment. The benefit-risk ratio of entacapone is considered favorable.A triple LD/carbidopa/entacapone combination tablet has recently been developed. Three LD strengths (50, 100 and 150 mg) are available, each contains 200 mg of entacapone. The majority of the patients can be managed with these three LD strengths. Entacapone has today an established position in treatment of PD patients with motor fluctuations, either as a separate tablet or as the triple LD combination.

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 1week 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 1week treatment with either entacapone 200mg 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.

The effect of catechol-O-methyltransferase inhibition with entacapone on cardiovascular autonomic responses in L-Dopa-treated patients with Parkinson's disease.

We have compared the effects of entacapone, a peripherally acting catechol-O-methyltransferase (COMT) inhibitor, and placebo on cardiovascular autonomic responses in L-Dopa/dopa decarboxylase inhibitor-treated patients with Parkinson's disease (PD). In a double-blind, randomized, crossover study with two consecutive 1-week treatment periods, a battery of cardiovascular reflex tests (orthostatic, Valsalva, deep breathing, and isometric hand grip tests) was performed in a group of 15 patients with idiopathic PD. The first set of tests was performed after withholding L-Dopa overnight (control, "off" stage). The second and third sets of tests were performed in "on" stage after 1-week treatment with either entacapone 200 mg or placebo administered with each dose of L-Dopa/dopa decarboxylase (DDC) inhibitor. Valsalva, deep breathing, and orthostatic tests demonstrated no statistically significant differences in the ratio of the longest and shortest electrocardiographic R-to-R wave (R-R) intervals between entacapone and placebo or between study treatments and control. Blood pressure responses to both orthostatic challenge and prolonged isometric work (hand grip test) were similar between treatments. Systolic orthostatic hypotension was observed in only one patient during the control test, but it occurred more frequently after L-Dopa/DDC inhibitor, regardless of concomitant administration of either entacapone (n = 3) or placebo (n = 4). Peripheral COMT inhibition with entacapone does not significantly alter cardiovascular autonomic responses in L-Dopa-treated patients with PD.

Entacapone and selegiline with L-dopa in patients with Parkinson's disease: an interaction study.

Both the catechol-O-methyltransferase (COMT) inhibitor entacapone and the monoamine oxidase B (MAO-B) inhibitor selegiline are L-dopa extenders. Both are used, often simultaneously, as adjuncts to L-dopa/dopa decarboxylase (DDC) inhibitor treatment of Parkinson's disease (PD). Their possible interactions have not been previously studied in a double-blind manner.We studied clinical response, tolerability, haemodynamics and cardiac rhythm in 16 PD patients with end-of-dose-type motor fluctuations. The patients' individual L-dopa/DDC inhibitor treatment was stabilized before the experimental treatments. This was followed by three consecutive, randomized, double-blind 2-week treatment periods with entacapone (200mg with each L-dopa dose), selegiline (10mg o.d.) or both entacapone and selegiline with the L-dopa/DDC inhibitor medication. Clinical efficacy (L-dopa test with repeated motor and dyskinesia scoring) and safety (orthostatic test, 24-h ambulatory ECG, haematological and clinical chemistry variables and adverse events) evaluations were performed before each treatment (control) and at the end of each treatment period.All three treatments, entacapone, selegiline, and entacapone+selegiline as adjunct to L-dopa/DDC inhibitor improved (p<0.05) clinical disability compared to L-dopa only but they did not differ significantly from each other. Dyskinesias increased with all the treatments, statistically significantly (p<0.01) with entacapone+selegiline. No significant differences in haemodynamics were observed between control and any of the experimental treatments, or between the experimental treatments in the orthostatic test. One patient already had symptomatic orthostatism before experimental treatments (control). In two other patients orthostatism emerged after the introduction of selegiline, and in one after every experimental treatment. Twenty-four-hour ECG did not show any differences in supraventricular or ventricular extrasystoles or heart rate between treatments. No statistically significant differences were observed in adverse events or in haematology and clinical chemistry variables. One patient treated with entacapone+selegiline discontinued the study due to dizziness and insomnia. Our results suggest that co-administration of entacapone with L-dopa/DDC inhibitor, with or without selegiline, improves clinical disability, is safe, but may also enhance dopamine-related adverse events to some extent in PD patients with end-of-dose type motor fluctuations.

Parkinson's disease selectively impairs preattentive auditory processing: an MEG study.

Auditory stimuli elicit auditory evoked magnetic fields (AEFs) called P50m and N100m, which index preconscious auditory processing in human. We investigated with a whole-head magnetometer whether Parkinson's disease (PD) impairs parallel preattentive auditory processing between the hemispheres. Stimulus blocks consisting of standard (80%) and deviant (20%) tones were monaurally presented in a passive condition to 11 PD patients with unilateral motor symptoms and to 11 age-matched healthy controls. The constant interstimulus intervals (ISIs) were 0.5 s and 2.5 s in separate blocks. The interhemispheric latency differences of the P50m and N100m were significantly lengthened in PD patients in the left-ear condition. This might be caused by the basal ganglia dysfunction in PD together with the simultaneous age-related neural degeneration predominant in the left auditory cortex.

Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease.

The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study. An L-Dopa test was performed on 3 study days. The first study day was with L-Dopa/benserazide only (control), the second after 14 days of treatment with 200 mg entacapone taken concomitantly with L-Dopa/benserazide in combination with either selegiline (10 mg daily) or placebo. After a 2-week washout period, selegiline and placebo treatments were switched, and the third study day was after 14 days of treatment. During the study days, clinical response was evaluated at 30-min intervals for 6 h, by using the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). In addition, repeated blood pressure measurements were made, and plasma samples were taken for analysis of L-Dopa, 3-O-methyldopa (3-OMD), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), dopamine, noradrenaline, and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Monoamine oxidase B (MAO-B) and COMT enzyme activities were measured from platelets and erythrocytes, respectively. Entacapone improved the clinical response to L-Dopa during both selegiline and placebo (p < 0.001) treatments. The improvement was more marked during combined selegiline and entacapone treatment than with entacapone alone (p < 0.01). Entacapone significantly increased plasma L-Dopa and DOPAC levels and decreased plasma 3-OMD and MHPG levels both with selegiline and placebo. Selegiline partially inhibited the entacapone-induced increase of plasma DOPAC. Plasma dopamine and noradrenaline levels did not change. Entacapone decreased erythrocyte COMT activity by > 35% (p < 0.001), and platelet MAO-B activity was almost completely inhibited by selegiline (p < 0.001). One patient withdrew because of diarrhea, dizziness, and loss of sleep when receiving selegiline treatment. Otherwise no differences in adverse events, mean daily blood pressures, or other safety parameters were observed between selegiline and placebo treatments. Our results suggest that entacapone can be safely administered together with L-Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.

Cerebrospinal fluid activity of tissue plasminogen activator in patients with neurological diseases.

AIM: To study cerebrospinal fluid (CSF) activity of tissue plasminogen activator (tPA) in patients with neurological diseases. METHODS: CSF tPA and urokinase (uPA) activities were studied using an immunocapture assay and zymography in 44 patients with neurological disease and 20 reference subjects. The patient group comprised three patients with meningitis, 21 with encephalitis, nine with acute lymphoblastic (n = 7) and myeloid (n = 2) leukaemia, seven with multiple sclerosis, three with facial paresis, and one with polyradiculitis. RESULTS: Raised tPA activities were observed in patients with multiple sclerosis, leukaemia and encephalitis. In contrast, there were no differences in the mean activities of tPA in patients with meningitis or other diseases compared with the reference subjects. The highest tPA activities were found in patients with multiple sclerosis. The mean activity in patients with leukaemia was higher than in those with meningitis and polyradiculitis, but not encephalitis and facial paresis. Although the CSF tPA activity correlated positively with age in reference subjects, no correlation was observed in patients. Samples were qualitatively screened for both tPA and uPA activity by zymography and positive samples were quantitated. Some of the samples had quantifiable levels of uPA activity: three of seven multiple sclerosis samples, 10 of 21 samples from patients with encephalitis and five of nine leukaemic samples. The highest activities were recorded in patients with leukaemia. uPA was not detected in the CSF of the patients with meningitis, facial paresis or polyradiculitis. CONCLUSIONS: Plasminogen activator activity can be measured reliably in CSF and the assessment of tPA activity may be useful for studying the pathogenesis of neurological diseases.

Entacapone in combination with standard or controlled-release levodopa/carbidopa: a clinical and pharmacokinetic study in patients with Parkinson's disease.

We investigated clinical response and pharmacokinetics of levodopa when entacapone, a catechol O-methyltransferase (COMT) inhibitor, was administered concomitantly with either a standard (Std) or a controlled-release (CR) levodopa/carbidopa preparation to 12 patients with Parkinson's disease. An open cross-over study consisted of the initial study day without entacapone followed by two 10-day treatment periods with a study day at the end of each period. The patients who received entacapone (200 mg t.i.d. or q.i.d.) concomitantly with Std levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.) during the first period received subsequently entacapone with CR levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.), and vice versa. On the study days, the patients took the medication at 8 a.m. and the second dose 6 h later. We evaluated the disability before drug administration and then 1-h intervals for 8 h. Repeated blood samples were taken for analysis of plasma levodopa, 3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone. Entacapone decreased significantly the clinical disability with both Std and CR levodopa, slightly more with Std levodopa. The clinical response started earlier with Std levodopa whereas the "on"-time increased by about 1 h, equally with both levodopa preparations. Std levodopa produced 23% higher area under the curve (AUC) of levodopa than the CR preparation, but entacapone increased the AUC approximately equally, 33% with Std and 36% with CR levodopa. Entacapone slightly decreased Cmax of levodopa in combination with Std levodopa, whereas it increased that with CR levodopa. The AUC of 3-OMD was about 20% smaller after Std than after CR levodopa. Entacapone decreased the AUC of 3-OMD by 38-40% with both levodopa preparations. Entacapone did not modify the AUC levels of carbidopa although its bioavailability was less from CR levodopa than from Std levodopa. In three patients levodopa dosage was reduced when on Std levodopa because of nausea. Otherwise, the treatments were well tolerated. The study shows that entacapone is an effective COMT inhibitor when combined with either Std levodopa or CR levodopa.

Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients.

We studied the effect of entacapone, a selective catechol-O-methyltransferase inhibitor, on the bioavailability and clinical effect of levodopa in Parkinson's disease (PD). On day 1 (control day), nine patients received their own levodopa (plus benserazide) medication only; for the next 7 days they received 200 mg of entacapone with each dose of levodopa (tid or qid). We evaluated disability in the morning (8 AM) before drug administration and then at 1-hour intervals until 6 PM on days 1, 2, and 8, using a modified motor part of the Unified Parkinson's Disease Rating Scale. Repeated blood samples were taken before and during the 4 hours after the morning drugs for pharmacokinetic evaluation of entacapone and of levodopa and its metabolites. Added to the levodopa treatment, entacapone decreased clinical disability by about 16% (p < 0.05) from day 1 to day 8. The area under the curve (AUC) of levodopa increased by 38% (p < 0.01) after administration of a single dose of entacapone and by 40% (p < 0.05) after 7 days of multiple dosing with entacapone. Entacapone did not change the Tmax and Cmax values of levodopa. After 7 days of treatment with entacapone, the AUC of 3-O-methyldopa had decreased by 44% (p < 0.01) and of homovanillic acid by 26% (p < 0.05) as compared with treatment with levodopa alone. Four patients became slightly more dyskinetic during entacapone treatment than before it. The combination of entacapone and levodopa was well tolerated, judged by the lack of significant changes in hemodynamic and safety variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre- and postcentral cortical somatosensory evoked potentials in hemiparkinsonism.

We recorded cortical frontal, central, and parietal somatosensory evoked potentials (SEPs) in 9 patients with hemiparkinsonism and in a group of 25 healthy volunteers. No differences were observed in the SEPs recorded after stimulation of the asymptomatic and symptomatic sides in the patients. Likewise, comparison with the healthy controls did not reveal significant group differences or abnormal waveforms in the patients. Even frontal N30 deflection, which has been reported to be diminished in Parkinson's disease (PD), was normal and symmetric in the patients. Therefore, no evidence was found for altered sensory input to the motor or premotor and supplementary motor cortices in PD.

Suppression of magnetic mu rhythm during parkinsonian tremor.

We recorded spontaneous magnetoencephalographic (MEG) activity and somatosensory-evoked fields (SEFs) with a 24-channel planar SQUIDgradiometer in five patients with hemiparkinsonism. The SEFs of the patients were within normal limits. During tremorless periods, the spontaneous activity over the somatomotor cortex had a frequency peak at approximately 10 Hz in all five patients and another at approximately 20 Hz in three. Tremor dampened the 10-Hz activity in all patients; in three the effect was bilateral. Tremor did not increase MEG activity at the tremor frequency. The suppression of the mu rhythm by the parkinsonian tremor resembled that occurring during voluntary movements in healthy subjects.

Diffusion of contrast media in cerebrospinal fluid: comparison of iohexol, iopamidol and iotrolan in vitro.

Diffusion of iohexol (300 and 240 mgI/ml), iopamidol (300 and 200 mgI/ml), and iotrolan (300 and 240 mgI/ml) in the cerebrospinal fluid (CSF) of 16 patients was studied in vitro. Test tubes containing CSF were kept in a waterbath at 37 degrees C. Contrast medium was injected along the wall into the tubes, and diffusion of contrast media in the tubes was followed with repeated computed tomography for 5 h. The contents of the tubes were then mixed by shaking, and the tubes were scanned immediately and 8 h later. The contrast media first settled in the bottom of the tubes and then diffused upwards. Iotrolan diffused more slowly than the other media, but the difference was only significant at a concentration of 300 mgI/ml. The difference between iohexol and iopamidol was minimal. In general, diffusion was slower in CSF samples with an elevated protein content, but the difference in the diffusion of contrast medium in normal and pathological CSF was seldom statistically significant, perhaps owing to the small number of samples (5) with an elevated protein content. All contrast medium-CSF mixtures remained homogeneous after mixing. These experiments showed measurable differences in the diffusion of contrast media in CSF, but it does not seem very likely that these would be significant in clinical practice.

CQA 206-291: a novel dopamine agonist in the treatment of Parkinson's disease.

The antiparkinsonian efficacy and tolerability of CQA 206-291, a novel ergoline derivative with potent dopamine agonist properties, were studied during 2 months of treatment in 72 parkinsonian patients. In 36 de novo patients (patients who have not previously been treated with levodopa or dopamine agonists), CQA 206-291 was studied in an open design, while in 36 levodopa-treated patients, CQA 206-291 was studied in a randomized, double-blind, parallel-group, placebo-controlled design. CQA 206-291 induced in both groups a significant antiparkinsonian effect with an effective dose range of 5-30 mg/day. The spectrum of adverse events was similar to what is commonly observed with dopamine agonists. Further studies are required to assess the putative therapeutic advantages of CQA 206-291 when compared to other antiparkinsonian drugs.

Animal models of parkinsonism.

The discovery of profound dopamine depletion of basal ganglia in patients with Parkinson's disease and the development of antiparkinsonian drug therapy were largely based on animal models. The behavioural changes caused by cholinergic drugs, reserpine and related agents, and unselective neuronal lesions were the first widely used animal models for Parkinson's disease. The crucial breakthrough was the observation of the circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model still is one of the basic animal models of Parkinson's disease. It is suitable for the screening of new potential antiparkinsonian agents with the classic spectrum. The parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and the monkey is the latest and the best animal model for Parkinson's disease. Especially when given to the monkey, MPTP causes biochemical, behavioural and neuropathological changes which largely mimick those of Parkinson's disease in man. The MPTP-induced parkinsonism in the monkey can be used for the study of the neurobiology and new forms of drugs therapy of Parkinson's disease. However, because the MPTP monkey model is expensive and laborious, it is not particularly convenient for the screening of new drugs. Recently, a new approach in the treatment of Parkinson's disease is to develop drugs which might prevent or retard the disease progression. The prevention of behavioural changes of aged rodents is used as an animal model and promising results with selegiline have been obtained.

Selegiline in Parkinson's disease.

Twenty patients with Parkinson's disease were treated with the MAO-B inhibitor selegiline (l-deprenyl) and placebo without levodopa (L-dopa) in a randomized double-blind clinical cross-over study to analyze relative importances of dopamine (DA) synthesis and metabolism. The daily dose of selegiline was gradually increased to a maximum of 30 mg in all patients. The clinical neurological disability (Columbia score) was about 10% less on selegiline (30 mg/day) than on placebo. This difference was neither statistically nor clinically significant. The results are compatible with the possibility that treatment with selegiline without concomitant L-dopa does not significantly increase DA concentration which remains low and is determined mainly by tyrosine hydroxylase activity. At low DA levels the DA re-uptake mechanism recaptures most of the released DA and DA deamination is of minor significance. The pathway of DA oxidation becomes more important only at higher DA concentrations, accomplished by bypassing the rate limiting step of tyrosine hydroxylation using L-dopa.