Metabolism of (-) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit: a biochemical assessment

The urinary excretion of some important phenylethylamines, catecholamines, their metabolites, amphetamine, and methamphetamine were measured in parkinsonian patients on Sinemet (L-dopa plus carbidopa, a peripheral dopadecarboxylase inhibitor) and depressed patients after chronic (-) deprenyl treatment. Deprenyl was efficiently metabolized to amphetamine and methamphetamine. It increased the excretion of phenylethylamine and of m- and p-tyramine, and reduced the output of norepinephrine metabolites, but failed to alter the excretion of dopamine-deaminated metabolites. These changes were attributed more to amphetamine and methamphetamine than to inhibition of monoamine oxidase type B. Sinemet treatment alone increased the excretion of dopamine, 3-methoxytyramine, and their respective deaminated metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid. It is concluded that conversion of deprenyl to amphetamine and methamphetamine may contribute to some of the therapeutic benefits of deprenyl.     

The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats

Administration of L-dopa (L-3,4-dihydroxyphenylalanine) (200 mg/kg p.o.) to rats produced elevated plasma and muscle concentrations of both L-dopa and 3-O-methyldopa (3-OMD). This effect was potentiated by simultaneous administration of carbidopa (25 mg/kg p.o.). Both L-dopa and 3-OMD accumulated in muscle after administration of L-dopa with or without carbidopa. Elevated dopamine levels were detected in both muscle and plasma after treatment with L-dopa alone. Concurrent administration of carbidopa only diminished dopamine levels in plasma, and the duration of raised dopamine levels in muscle was increased. Carbidopa administration had no effect on the elevated plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) caused by L-dopa administration. In muscle, carbidopa treatment tended to prolong the duration of raised metabolite levels. Muscle appears to accumulate L-dopa at a site where decarboxylation is not totally prevented by concurrent carbidopa administration, and where dopamine is not degraded as actively as in other tissues. The muscle sink for L-dopa may influence the plasma profile of the amino acid, which has implications for the therapeutic response to L-dopa in Parkinson's disease.     

Effect of acute levodopa on brain catecholamines after selective MAO and COMT inhibition in male rats

Summary Interactions between a selective catechol-O-methyltransferase (COMT) inhibitor OR-462 and a monoamine oxidase (MAO)-A inhibitor clorgyline were studied measuring concentrations of L-dopa, dopamine and their metabolites in the rat hypothalamus and striatum after administration of levodopa/carbidopa (15/30 mg/kg i.p.). Part of the experiments were performed in rats pretreated with 6-OH-dopamine (6-OHDA) intracerebroventricularly (i.c.v.) to determine whether changes in dopamine metabolism occurred inside or outside catecholaminergic neurons. OR-462 was an effective COMT inhibitor at the doses 3 and 30 mg/kg i.p. Inhibition of 3-O-methyldopa (3-OMD) formation from L-dopa was reflected in the hypothalamus (45–81% decrease) and striatum (87–88% decrease), since 3-OMD penetrates the blood-brain barrier. Homovanillic acid (HVA) was decreased only in the striatum at 30 mg/kg of OR-462. Clorgyline (8 and 32 mg/kg i.p.) decreased 3,4-dihydroxyphenylacetic acid (DOPAC) formation in the hypothalamus and striatum by 61–91%. When given together, OR-462 and clorgyline elevated hypothalamic dopamine levels 3.2–4.6-fold, but striatal dopamine only 1.3–1.9-fold. The formation of 3-OMD and DOPAC remained suppressed and even brain HVA levels were decreased by 51–97%. 6-OHDA treatment decresed striatal and hypothalamic dopamine by 50% and noradrenaline by 75%. In these animals levodopa/carbidopa increased brain L-dopa 2.4–4-fold, those of 3-OMD 1.2–1.7-fold compared to intact animals, but the synthesis and metabolism of dopamine and the effects of COMT and MAO inhibitors were not significantly changed. Levodopa/carbidopa treatment decreased significantly prolactin and thyrotropin levels in serum but none of the additional treatments changed this action.     

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 C_max 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.     

Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with Sinemet CR

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.     

Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers

A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.     

Comparison between results achieved by administering L-dopa and Sinemet in parkinsonism in the light of our records]

On the basis of observations of 18 patients the authors evaluated clinically the action of Sinement preparation (Merch, Sharp and Dohme) containing L-dopa 250 mg and carbidopa 25 mg in the treatment of Parkinson's disease. In the evaluation particular attention was given to side effects. Therapeutic results of Sinemet and L-dopa alone were compared in patients receiving these drugs alternatively. The observations of authors indicate that Sinemet gives the same therapeutic results as L-dopa, but in much lower doses and with less frequent side effects. Sinemet, similarly as L-dopa exerts the best effect on bradykinesia and muscular rigidity and less on tremor.     

The effect of an increased ratio of carbidopa to levodopa on the pharmacokinetics of levodopa

ABSTRACT – A randomized, cross-over study was designed to compare the effects of an increased ratio (from 1:10 to 1:4) of carbidopa to levodopa on the fate of levodopa and carbidopa in 11 healthy subjects. Four combinations of carbidopa/levodopa (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg, 62.5/250 mg) were used. Plasma levodopa, carbidopa, dopamine and dopac concentrations as well as urinary excretions of levodopa and dopac were determined by a sensitive high-performance liquid chromatography with electrochemical detection after a single carbidopa/levodopa tablet. As the ratio of carbidopa to levodopa increased, there was a significant increase in apparent t_1/2 and AUC values of levodopa. At the same time the urinary excretion of levodopa increased and that of dopac decreased. The plasma ratios of levodopa/dopamine and levodopa/dopac and the urinary ratio of levodopa/dopac also increased. There were less subjective side-effects in the 1:4 groups than in the 1:10 groups. It is concluded that increasing the amount of carbidopa in relation to levodopa may be beneficial and further clinical studies are clearly indicated.     

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 (t _1/2) 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 andonce with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and oncewith 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 wasunaffected by tolcapone in all treatment groups and the maximum plasma concentration (C _max ) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60–90% and levodopa t _1/2 by 20–60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t _1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD C _max decreased by 80% and AUC by 70% with tolcapone. Thetolerability 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.     

Pharmacokinetic and clinical evaluation of liquid L-dopa/carbidopa in Parkinson's disease

The aim of the study was to assess the pharmacokinetic properties and clinical effectiveness of L-dopa/carbidopa solution treatment in patients with parkinsonian motor fluctuations. No significant difference in maximal L-dopa concentration, time to peak L-dopa concentration and area under curve was found in single dose studies which compared equivalent tablet and solution L-dopa/carbidopa doses in 9 patients. Seven out of 10 patients treated with hourly doses of liquid L-dopa/carbidopa were improved after switching from conventional tablet medication. Less 'off' time per day and less 'off' phase disability were the usual benefits. Six of these patients maintained this improvement and continued on long-term liquid medication. The benefits of this treatment do not relate to improved L-dopa delivery to the bloodstream. The ability of patients to fractionate the treatment into small, frequent doses which can be used more flexibly than tablets appears to confer the main advantages of liquid L-dopa/carbidopa in the management of parkinsonian motor fluctuations.     

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/carbidopa

This study investigated the tolerability and the pharmacokinetic and pharmacodynamic interactions between single oral administration of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg), a novel catechol-O-methyltransferase (COMT) inhibitor, and standard carbidopa/levodopa 25 mg/100 mg (Sinemet 25/100) in healthy adult volunteers. This was a single-center, double-blind, placebo-controlled, randomized, crossover study with 5 single-dose treatment periods with a washout period of 2 weeks between doses. During each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Sinemet 25/100. Tolerability was assessed by recording adverse events, vital signs, continuous EKG, and clinical laboratory parameters. Pharmacokinetic parameters of levodopa and 3-O-methyl-levodopa (3-OMD) were determined. The activity of soluble COMT in erythrocytes was also measured. Eighteen subjects (10 men and 8 women) participated in the study. The drug combination was well tolerated, with the adverse events reported being transient and generally mild in severity. Mean levodopa Cmax values were attained at 0.8 to 1.8 hours postdose. Thereafter, plasma levodopa levels declined with a mean t1/2 that increased in a manner that depended on the dose of BIA 3-202. The increase in systemic exposure to levodopa (AUC0-infinity) occurred at all doses of BIA 3-202, attaining its maximum at 200 mg BIA 3-202 (95% conficence interval, 1.43-1.73). The mean Cmax and AUC0-infinity values of 3-OMD decreased dose proportionally in BIA 3-202-treated subjects, with differences being statistically significant for all the doses tested. Maximum COMT inhibition occurred between 0.8 and 2.0 hours postdose, and ranged from 56 (50 mg) to 85% (400 mg). Time to return to baseline COMT activity ranged from 6 (50 mg) to 18 hours (400 mg), following the same dose-dependent tendency. In conclusion, the novel COMT inhibitor BIA 3-202 increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard levodopa/carbidopa.     

Comparison of Sinemet CR4 and standard Sinemet: double blind and long-term open trial in parkinsonian patients with fluctuations

"Wearing-off" effect, the most common form of levodopa-induced fluctuations, seems to be related to the short plasma half-life of the drug. More sustained plasma levodopa levels may be achieved with a new controlled-release formulation of carbidopa/levodopa, Sinemet CR4. We studied 20 patients, 12 men and 8 women, with Parkinson's disease complicated by "wearing-off" phenomenon. Mean age was 61.1 +/- 8.1 years, duration of symptoms 8.3 +/- 2.4 years, and the Hoehn-Yahr stage 3.0 +/- 0.9. In a 12-week double-blind study, the average number of tablets administered per day decreased from 5.7 +/- 1.2 to 3.8 +/- 0.7 when Sinemet CR4 (50/200) was substituted for the standard Sinemet (25/100) (p less than 0.001). However, this was at the expense of reducing the "on" time (without dyskinesia) from 9.3 +/- 4.6 to 7.5 +/- 4.3 (p less than 0.05), although the total "on" time did not significantly change. In a long-term follow-up of 18 patients, the "on" time with dyskinesia and morning dystonia significantly increased (p less than 0.05). There was no significant change in the total daily dosage of levodopa, but the daily number of doses and tablets significantly decreased (p less than 0.001). Despite increased dyskinesia, most patients preferred taking fewer tablets and have elected to continue taking Sinemet CR4 instead of standard Sinemet. Sinemet CR4 seems to offer a new and effective strategy for the management of levodopa-related fluctuations.     

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

Summary. Inhibition of the catechol-O-methyltransferase (COMT) is an effective treatment for end-of-dose fluctuations in advanced Parkinson's disease. The aim of the present investigation was to analyse the consequences of subsequent alterations in levodopa metabolism under common treat-ment conditions when the levodopa dose is adjusted due to the occurrence of dyskinesias after initiation of the COMT-inhibitor. Ten patients with advanced Parkinson's disease (Hoehn & Yahr stage IV) were medicated with tolcapone. Prior to and five to ten days after the initiation of tolca-pone 300 mg/d, serum level profiles of levodopa and its metabolites (3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) were performed. The mean daily levodopa dose was reduced from 894 ± 248 mg to 646 ± 252 mg (p = 0.003). There was a significant increase in the area under the curve (AUC) of DOPAC during COMT-inhibition compared to the baseline profile (p = 0.009). There were significant decreases of the AUC of HAV (p = 0.001) and the ratios of the AUC HVA / AUC DOPAC (p = 0.0001) and AUC 3-OMD / AUC levodopa (p = 0.0001). Conclusion: The elevation of DOPAC and the decrease of HVA and HVA / DOPAC reflect a shift of the levodopa metabolism towards the MAO-B dependent oxidative pathway. This might contribute to production of hydroxyl radicals and induction of oxidative stress. Received July 9, 2001; accepted September 28, 2001     

Dopaminergic responsivity during cocaine abstinence: a pilot study.

This preliminary study investigated dopamine (DA) function in six hospitalized cocaine-dependent subjects (DSM-III-R) who received 1.5 mg/kg of active cocaine by mouth, t.i.d., for 3 days followed by 9 days of placebo cocaine. During early and late abstinence from cocaine, plasma growth hormone (GH), homovanillic acid (HVA), prolactin, and 3-methoxy-4-hydroxyphenethyleneglycol responses to the placebo-controlled administration of oral L-dopa 250 mg/carbidopa 25 mg (Sinemet) were measured. Sinemet caused significantly greater placebo-corrected increases in GH and HVA during early as compared with late abstinence. Acute abstinence from cocaine may be associated with increased DA responsivity, which normalizes over time.     

Are high doses of carbidopa a concern? A randomized, clinical trial in Parkinson's disease

Recommended doses of carbidopa are 75-200 mg/day. Higher doses could inhibit brain aromatic amino-acid decarboxylase and reduce clinical effects. We compared 4-week outpatient treatments with carbidopa (75 and 450 mg/day) administered with L-dopa on the subjects' normal schedule. After each treatment phase, subjects had two 2-hour L-dopa infusions. The first infusion examined the effects of carbidopa doses administered the preceding 4 weeks, and the second infusion determined the acute effects of the two dosages of carbidopa. The antiparkinsonian effects and L-dopa and carbidopa plasma concentrations were monitored during the infusions. Twelve subjects completed the study. Carbidopa concentrations were eight times higher after the high-carbidopa phase. Area under the curve (AUC) for clinical ratings did not differ for the four L-dopa infusions, although AUC for plasma L-dopa was modestly increased with 450 mg of carbidopa. Nine subjects reported that the high-carbidopa outpatient phase was associated with greater response to L-dopa. Doses of 450 mg/day of carbidopa did not reduce the responses to L-dopa infusion, extending the safe range of carbidopa to 450 mg/day.     

Glial cell line–derived neurotrophic factor–levodopa interactions and reduction of side effects in parkinsonian monkeys

Glial cell line–derived neurotrophic factor (GDNF) stimulates the nigrostriatal dopaminergic pathway and improves motor functions in animal models of parkinsonism. Sinemet is currently the most widely used drug for treating Parkinson's disease. The present study has evaluated GDNF–Sinement interactions in parkinsonian rhesus monkeys. Both GDNF and Sinemet, when given alone, significantly improved total parkinsonian scores. The response to Sinement did not change after intracerebroventricular vehicle injections. In contrast, there was a functional interaction between GDNF and levodopa. When comparing the levodopa dose response before and after GDNF treatment, significant behavioral improvements were seen after trophic factor administration at every levodopa dose level except 500 mg. Adverse responses to Sinemet treatment alone in parkinsonian animals included vomiting, dykinesias, dystonias, and stereotypic movements. Combined GDNF–Sinemet treatment significantly reduced the occurrence of these levodopa-induced side effects, with a >90% decrease in adverse responses seen at the mid-Sinemet (250 mg levodopa–25 mg carbidopa) dose level. The only side effect from GDNF treatment was a transitory weight loss. Thus, combined GDNF–Sinemet treatment could be of therapeutic value in treating parkinsonism, by producing a greater functional response and by mitigating adverse responses to Sinemet treatment.     

3-OMD and homocysteine plasma levels in parkinsonian patients

Summary. One main metabolizing pathway of levodopa is O-methylation to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). Since COMT requires Mg²⁺ and S-adenosylmethionine as methyl donor for this transmethylating process, COMT converts S-adenosylmethionine to S-adenosylhomocysteine and subsequent homocysteine. Objective of this study was to demonstrate relations between plasma levodopa, 3-OMD and total homocysteine in treated parkinsonian subjects. We measured homocysteine, levodopa and 3-OMD by HPLC. We compared plasma homocysteine in two groups of treated parkinsonian subjects subdivided according to their 3-OMD level. Homocysteine was significantly (p = 0.002) elevated in the group with higher 3-OMD concentrations and positively (r = 0.52, p = 0.0006) correlated to 3-OMD. Homocysteine induces vascular disease. Previous studies showed an increase of ischaemic heart- and cerebrovascular disease in treated parkinsonian patients. Received November 20, 2000; accepted September 26, 2001     

Effect of nitecapone and clorgyline, given intracerebro-ventricularly on L-dopa metabolism in the rat brain.

A new COMT inhibitor, nitecapone (OR-462) or clorgyline, a MAO-A inhibitor, was infused into the 3rd brain ventricle (i.c.v.) of conscious male rats. None of the enzyme inhibitors given alone alter hypothalamic or striatal levels of L-dopa, dopamine or their metabolites. Most of the rats were pretreated with levodopa/carbidopa (LD/CD, 15/30 mg kg-1 intraperitoneally). Now, the action of nitecapone is localized in the hypothalamus since homovanillic acid (HVA) is decreased there, not in the striatum. The levels of 3-O-methyldopa (3-OMD) are not changed in either brain region, suggesting a lack of the peripheral leakage of nitecapone. Clorgyline (3 and 10 micrograms rat-1) elevates hypothalamic and dopamine levels. Nitecapone and clorgyline decrease prolactin (PRL) levels below those reduced by LD/CD treatment.     

Validation of a rodent model of Parkinson's disease: Evidence of a therapeutic window for oral Sinemet

Behavioral measures of parkinsonism that are more clinically relevant than rotometry have been developed for rats with severe unilateral dopamine depletions, and the validity of these measures is supported by reports that these parkinsonian symptoms are attenuated by drugs that are effective in the clinical setting. Although the therapeutic gold standard, l-DOPA:carbidopa (Sinemet), effectively attenuates parkinsonian symptoms, the beneficial effects of this drug are limited by the dyskinesias that it produces at higher doses. The range of effective doses, from the minimum dose that produces beneficial effects to the dose that produces intolerable dyskinesias, is referred to as the “therapeutic window”. It would be extremely valuable to assess, preclinically, the effects of novel treatments on the therapeutic window for Sinemet. The results of the present study support the validity of nondrug-induced measures of parkinsonian symptoms in dopamine-depleted rats. Neurological measures revealed large behavioral deficits in the affected forelimb analogous to the deficits exhibited in Parkinson's disease patients, and these deficits were significantly attenuated with some doses of oral Sinemet (30–40 mg/kg). These drug effects on measures of parkinsonism were specific to performance with the affected limb. At slightly higher doses (50 mg/kg), the rats were untestable due to severe dyskinesias. The results of the present study suggest that it is possible to investigate the therapeutic potential of novel treatments as well as their effects on the therapeutic window of oral Sinemet in this rodent model of Parkinson's disease.     

Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations.

The safety and efficacy of Sinemet CR, a controlled-release formulation of carbidopa/levodopa, were investigated in a three year, open-label trial involving 18 parkinsonian patients with fluctuating motor response. The average daily levodopa dosing frequency did not change significantly during long-term treatment. Efficacy measures generally revealed a gradual progression of parkinsonian disability. Patient diaries of motor fluctuations revealed relative stability of time "on" but with a tendency toward increased time "on with dyskinesias" over the 36 month follow-up period. There were no adverse laboratory results deemed to be related to Sinemet CR and no unexpected side effects were observed.