Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The combinations of benserazide and levodopa (1:4, Madopar) and of carbidopa and levodopa (1:10 and 1:4, Sinemet) are currently the most effective treatment of Parkinson's disease. In the present comparative study some effects of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa administered alone or in combination with levodopa by the oral route were investigated in two animal species (rat and mouse) and in healthy volunteers. Benserazide is about 10 times more potent than carbidopa as inhibitor of peripheral AADC both in animals and man. Even at relatively high doses (up to 60 mumol/kg p.o.) benserazide is shown in animals to inhibit the decarboxylation of levodopa only in the extracerebral tissues, thus permitting the formation of dopamine in the striatum and in the hypothalamus. As benserazide is the most potent peripheral AADC inhibitor presently available, is well tolerated and relatively nontoxic even when used chronically, it appears to be the peripheral AADC inhibitor of choice for the development of controlled-release formulations in which Dopa is combined with a peripheral AADC inhibitor. When administered to healthy subjects the pharmacokinetics of the new drug delivery system named Madopar HBS (hydrodynamically balanced system) was characterized by lower and delayed plasma peak concentrations but a longer-lasting concentration of Dopa than after Madopar standard. Therefore, this new controlled-release system may reduce the clinical fluctuations occurring in patients with 'wearing-off' and 'on-off' phenomena.
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PMID:Inhibition of decarboxylase and levels of dopa and 3-O-methyldopa: a comparative study of benserazide versus carbidopa in rodents and of Madopar standard versus Madopar HBS in volunteers. 312 42

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the "tyramine effect," may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the "on" state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p less than 0.01 for each parameter). No significant improvement occurred in the objective quality of the "on" state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.
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PMID:Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease. 312 50

The pattern visual evoked potential (PVEP) and pattern electroretinogram (PERG) were studied in 5 cynomolgus monkeys before and during the development of a parkinsonian syndrome induced by MPTP. The stimuli were vertical bars of four spatial frequencies (0.5, 1.2, 2.5 and 3.5 cycles/degree (cpd) modulated at temporal rates of 1, 4, 6, and 8 Hz. Following MPTP administration, all monkeys developed parkinsonian signs accompanied by changes in the amplitude and latency of the PVEP and PERG. Sinemet L-dopat carbi olopa administration produced temporary recovery of both PVEP and PERG. Two of the monkeys were followed for a prolonged period: 30-40 days after MPTP, the parkinsonian signs showed partial recovery; the PVEP latency and amplitude to 2.5 and 3.5 cpd stimuli and the latency to 1.2 cpd showed improvement but remained abnormal. The latencies of PERGs were normal, but the amplitudes were significantly reduced when stimuli of 2.5 and 3.5 cpd were used. Both PVEP and PERG to 0.5 cpd stimuli returned to normal. No further modifications were seen in the recordings performed 6 months and 1 year later. This study demonstrates (1) that spatial frequency-dependent electrophysiological abnormalities occur in the MPTP-treated monkey, a result previously found in human Parkinson's disease, and (2) that dopamine has a specific function in neurotransmission in the visual system of primates.
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PMID:Spatial frequency-dependent abnormalities of the pattern electroretinogram and visual evoked potentials in a parkinsonian monkey model. 325 50

The first phase of a longitudinal multicenter study comparing bromocriptine and L-dopa (as Sinemet) as de novo therapy for Parkinson's disease using a double-blind randomized design has recently been completed. Over a period of 5.5 months, bromocriptine and L-dopa were equipotent in reducing functional and neurological disability. These observations complement and extend earlier studies and suggest a role for bromocriptine as de novo therapy of Parkinson's disease.
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PMID:A double-blind study of bromocriptine and L-dopa in de novo Parkinson's disease. Short-term results. 328 77

Sixteen patients with advanced Parkinson's disease (PD) and motor fluctuations were evaluated throughout 12 months of open label therapy on CR4-Sinemet. Reduced dosage frequency and significant motor improvement with reduced fluctuation occurred and were maintained with CR4-Sinemet compared with baseline on Sinemet. In a double-blind protocol using CR4-Sinemet in 20 stable PD patients, CR4-Sinemet was given twice daily and compared with Sinemet given four times daily. Patients remained stable without improvement or deterioration when the long-acting drug was substituted at 50% frequency. Plasma levodopa levels with CR4-Sinemet were smoother than with Sinemet. Although some patients receiving CR4-Sinemet found they functioned more slowly in the morning, the easier dosing schedule and improved amount of "on" time in fluctuators suggest that this formulation may become increasingly useful in managing PD.
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PMID:Controlled-release carbidopa/levodopa (CR4-Sinemet) in Parkinson's disease patients with and without motor fluctuations. 329 Jul 6

We evaluated 32 patients with Parkinson's disease in a double-blind, parallel group, placebo-controlled study with ciladopa (a troponylpiperazine derivative). The dosages administered were 5 mg b.i.d. and 15 mg b.i.d. Significant improvement was found in the gait scores and in the total disability scores in the high dose group (p less than 0.05). In addition, there was a trend toward improvement, though not significant, in the bradykinesia and rigidity scores in the high dose group and in the disability scores in the low dose group. Four patients in the low dose group and five patients in the high dose group decreased their Sinemet doses while no patients increased their Sinemet dose. There were no adverse effects observed in this study. These findings suggest that ciladopa may be an efficacious agent in Parkinson's disease. The low incidence of adverse effects with this agent suggests that higher doses may be utilized and may prove to be more effective.
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PMID:A double-blind evaluation of ciladopa in Parkinson's disease. 333 14

Five patients with advanced Parkinson's disease and fluctuations in therapeutic response to levodopa participated in, and four completed, an open label study of the efficacy of Sinemet CR5. Reductions in the number of daily doses and "off" periods as well as the increase in interdose interval and percent "on" time versus standard Sinemet were comparable to those achieved with Sinemet CR4 in these same patients. As compared with Sinemet CR4, there was a greater delay in the occurrence of peak plasma levodopa concentrations, and relative bioavailability was reduced. Sinemet CR5 appears to offer no advantages over Sinemet CR4 in the treatment of response fluctuations in Parkinson's disease.
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PMID:Controlled-release levodopa/carbidopa. III: Sinemet CR5 treatment of response fluctuations in Parkinson's disease. 337 25

To clarify the influence of gastric emptying on levodopa-related motor fluctuations in Parkinson's disease, we assessed mobility and plasma levodopa concentrations in 10 patients during five modes of levodopa administration: (1) standard intermittent oral (SIO), (2) intermittent duodenal (ID), (3) continuous duodenal infusion (CDI), (4) continuous gastric infusion (CGI), and (5) controlled-release Sinemet (CR-4). The rank order from greatest to least for both percentage of time "on" and average mobility score was CDI, CGI, ID, CR-4, and SIO. The rank order for variance of means, a measure of fluctuation, from least to greatest for mobility was CDI, CGI, CR-4, ID, SIO, and for plasma levodopa concentrations was CDI, CGI, ID, SIO, and CR-4. The results demonstrate that it is possible to produce very steady plasma concentrations of levodopa with a corresponding reduction in motor fluctuations by continuous intraduodenal administration of the drug. This mode of delivery is an ideal model for the development of optimal continuous-release preparations of levodopa. Other enteral routes have produced a more variable plasma levodopa concentration and clinical response.
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PMID:Duodenal and gastric delivery of levodopa in parkinsonism. 340 40

In this open study patients with advanced Parkinson's disease, who experienced pronounced fluctuations in symptoms while on standard L-dopa, were switched from Madopar/Sinemet to Madopar HBS. The dosage was adjusted until optimal response was obtained. The effect was unsatisfactory in 4 cases and side effects intervened in another 2. The remaining 16 patients exhibited substantial and frequently significant improvements with regard to both akinetic and dyskinetic phenomena. L-Dopa dosage was increased in all cases, and addition of standard L-dopa was required in one third of the cases. These benefits continued in the majority of patients.
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PMID:Madopar HBS: slow-release levodopa and benserazide in parkinsonian patients presenting marked fluctuations in symptoms on standard L-dopa treatment. 342 10

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.
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PMID:Chronic alterations in jejunal myoelectric activity in rats due to MPTP. 350 Dec 48


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