Doses Of Carbidopa Research Articles

Oral carbidopa has no effect on the renal response to angiotensin II in normal man

1. The effect of inhibition of intrarenal dopamine synthesis by carbidopa on the renal response to angiotensin II infusion was studied in six healthy salt-loaded volunteers. 2. Subjects received an infusion of angiotensin II at two doses (0.5 and 1.0 ng min-1 kg-1) on two occasions. Before one study they took a single dose of carbidopa (100 mg) by mouth. 3. The plasma concentrations of angiotensin II produced by the infusion were similar on both study days. Angiotensin II infusion reduced urinary dopamine excretion on the control day. Urinary dopamine excretion was undetectable at all times after carbidopa, but carbidopa did not change the basal excretion rate of sodium. Despite inhibition of renal dopamine synthesis, the reductions in both absolute and fractional sodium excretion during the angiotensin II infusion were not different from those seen in the control study. 4. The reductions in glomerular filtration rate and effective renal plasma flow which occurred during angiotensin II infusion were not modified by pretreatment with carbidopa. 5. The renal response to angiotensin II is not modulated either wholly or in part by endogenous intrarenal dopamine levels. The fall in urinary dopamine excretion which occurs during angiotensin II infusion is consistent with a modulatory role for tubular reabsorptive capacity in the regulation of proximal tubular dopamine synthesis.

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.

Randomized Double-Blind Cross-Over Study of Sinemet-Controlled Release (CR4 50/200) versus Sinemet 25/100 in Parkinson’s Disease

Sinemet-controlled release (CR4) consisting of 50 mg carbidopa/200 mg levodopa was compared with Sinemet 25/100 in 24 Parkinson's disease (PD) patients during a 16-week double-blind cross-over study. The mean age of the patients was 66.2 years, their mean duration of PD was 9.3 years. All of the patients had response fluctuations consisting mainly of the 'wearing-off' phenomenon. Some of the patients also experienced the 'on-off' phenomenon. All patients were evaluated using the unified Parkinson disease rating scale. The following significant differences were noted on Sinemet CR4. More patients noted a decrease in dyskinesias and response fluctuations; more patients experienced a decrease in stage when 'on'; more patients were 'on' longer during the day, and more patients were globally improved. The mean number of doses per day were significantly less on Sinemet CR4 (mean 5.0, range 3-8) than on Sinemet 25/100 (mean 6.2, range 4-11 doses/day). The mean dose of levodopa in Sinemet CR4 was 1,186 +/- 458 mg and the mean dose of carbidopa was 797 +/- 115 mg. The mean dose of levodopa in Sinemet 25/100 was 873 +/- 304 mg and the mean dose of carbidopa was 218 +/- 76 mg. This study indicates that Sinemet CR4 is a useful addition for patients with response fluctuations.

Increased dosage of carbidopa in parkinsonian patients on low carbidopa-levodopa regimen. Effect on levodopa bioavailability.

The effect of a 2.5-fold increase in daily carbidopa intake on the bioavailability of levodopa was studied in six patients with Parkinson's disease on a low chronic regimen of carbidopa-levodopa (Sinemet) at the fixed ratio of 1:10. The extent of levodopa absorption, expressed as the area under the 11-h plasma levodopa concentration-time curve (AUC0-11 h), was not enhanced by the higher carbidopa dose. A significant increase in the AUC was found for the levodopa metabolite 3-O-methyldopa at the higher carbidopa intake. Clinical performances of individual patients were identical with both carbidopa-levodopa ratios. From these data, an adequate inhibition of peripheral decarboxylation and hence a good bioavailability of levodopa may be expected in patients taking low doses of carbidopa-levodopa, using currently available commercial preparations.

The effects of carbidopa dose and time and route of administration on systemic L-dopa levels in rats.

The effects of carbidopa dose and time and route of administration on systemic plasma levels of parenterally and nonparenterally administered L-dopa were examined in rats. Intravenous coadministration of L-dopa + carbidopa resulted in significant (P less than 0.05) carbidopa-dependent increases in both the area under the plasma L-dopa concentration versus time profile (AUC; +27%) and the plasma L-dopa half-life (t1/2; +35%). Simultaneous duodenal or rectal carbidopa administration did not alter the L-dopa i.v. pharmacokinetic profile. Carbidopa pretreatment significantly increased the i.v. L-dopa AUC (+38 and +82% for i.v. and duodenal pretreatments, respectively) compared to simultaneous administration. Both i.v. and duodenal carbidopa increased duodenal L-dopa AUC to a similar extent (+282 and +239% for i.v. and duodenal administration, respectively). Rectal studies indicated poor absorption of both L-dopa and carbidopa, with no demonstrable effect on plasma L-dopa. The results indicate that the timing and route of carbidopa and L-dopa administration are important in determining the extent of i.v. or duodenal L-dopa systemic availability. The rat model affords results similar to those reported in human studies and may be useful for more extensive evaluation of L-dopa and carbidopa interactions.

Effect of supplemental carbidopa on bioavailability of L-dopa.

The effect of doubling carbidopa intake on single dose bioavailability of L-Dopa was examined in five parkinsonian patients. Increasing carbidopa from a mean of 145 to 290 mg/day caused a mean increase in peak plasma Dopa concentrations from 1,893 +/- 476 to 2,733 +/- 607 ng/ml and area under the Dopa plasma concentration versus time curve of 24.6 +/- 10.0%, as well as a decrease in the time to peak plasma concentration to 0.7 +/- 0.2 versus 1.2 +/- 0.3 h. Increasing the within-dose ratio of carbidopa to L-Dopa, even in patients receiving "maximally effective" doses of carbidopa, further increases bioavailability of L-Dopa, presumably by inhibiting "first pass' metabolism in the gut.

Drugs Five Years Later

Bromocriptine, a specific dopamine receptor agonist, has been used for the treatment of various hyperprolactinemic conditions and as adjunctive therapy for acromegaly (with or without concomitant hyperprolactinemia) and Parkinson's disease. Bromocriptine is extremely effective in suppressing prolactin secretion regardless of the cause, in restoring gonadal function and fertility, and in decreasing the size of prolactin-secreting pituitary tumors. Most patients with acromegaly have clinical improvement with this drug. When bromocriptine is added to a regimen of levodopa or carbidopa, patients with Parkinson's disease frequently have additional clinical improvement and, in most patients, the levodopa or carbidopa dose can be reduced. Withdrawal of bromocriptine therapy is associated in most patients with reversal of its beneficial effects--return of hyperprolactinemia, return of excess growth hormone secretion, and exacerbation of Parkinson's disease.

Dose and sex related effects of aromatic aminoacids decarboxylase inhibitors on serum prolactin in humans.

Single doses of carbidopa and benserazide, two inhibitors of aromatic aminoacids decarboxylase, have been given orally to healthy women and men aged 19 to 32 years. Serum prolactin levels increased in respect to baseline levels when 80, 125 or 250 mg of carbidopa and 10, 20, 30, 50, 80 or 125 mg of benserazide were given. The carbidopa doses of 20 and 50 mg were ineffective. Carbidopa induced the enhancement of serum prolactin at a later time and over a longer time span than benserazide. The effect on serum prolactin is dose dependent for both drugs. The hyperprolactinaemia obtained with 250 mg of carbidopa and with 125 mg of benserazide is significantly larger in women than in age matched men. The observed prolactin increase fits with the hypothesis that a diminution of the inhibitory effect of dopamine at the pituitary and/or at the median eminence levels may occur in connection to the pharmacologically impaired monoamine synthesis. An effect of serotonin cannot, however, be excluded.

Carbidopa elevates hypothalamic dopa and serum prolactin in rats

The administration of carbidopa (MK-486, α-methyl-L-dopa hydrazine; 100–200 mg/kg, intraperitoneally) causes several-fold increases in hypothalamic dopa and serum prolactin levels in male rats within 2 hours; these changes are not reversed by the administration of pyridoxine. These observations suggest that high doses of carbidopa can affect catecholamine synthesis within the hypothalamus.

Effect of pyridoxine on the depletion of tissue pyridoxal phosphate by carbidopa

One or two hours after rats received a single dose (100 or 800 mg/kg, intraperitoneally) of carbidopa (MK-486; α-methyl-L-dopa hydrazine), pyridoxal-5′-phosphate (PLP) concentrations were significantly depressed in peripheral tissues (serum, liver, and muscle) and in hypothalami, but not in whole brains. Repeated administration of carbidopa (three 100 mg/kg doses per day for 3 days) lowered PLP concentrations in serum, liver, and muscle (by 88%, 51%, and 18%, respectively) among rats killed 2 hr after the final injection. PLP levels in brain and hypothalamus were also reduced significantly (by 22% and 18%, respectively) after this treatment. The activity of aromatic L-amino acid decarboxylase (AAAD) in hypothalamic homogenates (assayed in vitro) exhibited a parallel small decline; its activity in brain homogenates, however, was not significantly changed. Administration of pyridoxine·HCl (200 mg/kg/day for 3 days) in addition to carbidopa blocked the fall in hypothalamic AAAD activity. Pyridoxine administration did not affect the inhibition of peripheral AAAD by carbidopa in vivo; it failed to interfere with carbidopa's blockade of decarboxylation of exogenous L-dopa (100 mg/kg, given intraperitoneally 1 hr before sacrifice). These findings suggest that large doses of carbidopa can, by depleting tissues of PLP, cause potentially undesirable nonspecific changes in pyridoxine-dependent enzymes. However, the coadministration of pyridoxine with carbidopa can maintain tissue PLP levels and protect against such enzyme changes.

L-DOPA reversal of hyperdopaminergic behaviour

Rats, made behaviourally supersensitive to apomorphine by reserpine, were successfully desensitized after 4 days of high L-DOPA: Carbidopa doses. This reversal, observed on apomorphine-induced sniffing behaviour, suggests that the treatment may be of some benefit in tardive dyskinesia.

Effect of carbidopa (MK-486) on the metabolic fate of L-3,4-dihydroxyphenylalanine (L-dopa). I. Effect of carbidopa on the tissue dopa decarboxylase and on the L-dopa-2-14C uptake by the brain in rats.

The inhibitory effect of Carbidopa (MK-486) on L-3, 4-dihydroxyphenylalanine (DOPA) decarboxylase in various tissues including the brain was investigated as well as the distribution of Carbidopa-14C in rats. The increase in the brain uptake of radioactive L-DOPA by Carbidopa was demonstrated. Carbidopa, highly distributed in the kindney, lung, and liver, strongly inhibited DOPA decarboxylase activity in the main tissue except the brain in a dose dependent fashion. In spite of a rapid elimination of Carbidopa itself, the inhibitory effect appeared to retain for a long period, i.e., more than 24 hr. With a high dose of Carbidopa, the activity in the brain appeared to be inhibited appreciably. It was proved, however, that this was due to the drug contained in the cerebral blood by the determination of decarboxylase activity or radioactive Carbidopa in the brain perfused with saline, confirming that Carbidopa is a peripheral inhibitor. Carbidopa-14C was found to be distributed highly in the aorta walls which was presumed to be due to a non-specific binding to elastine in the tissue. Carbidopa enhanced the brain uptake of radioactive L-DOPA linearly to the dose of L-DOPA. The effect depended upon the proportion of oral Carbidopa to L-DOPA, and the mixing ratio around 1 : 10 was suggested to be the most efficient combination to elevate the brain uptake of L-DOPA.

A YEAR'S COMPARISON OF TREATMENT OF PATIENTS WITH PARKINSON'S DISEASE WITH LEVODOPA COMBINED WITH CARBIDOPA VERSUS TREATMENT WITH LEVODOPA ALONE

Forty patients were treated with levodopa combined with the selective extracerebral dopa-decarboxylase inhibitor carbidopa (MK 486). Once stabilised on optimum levodopa dosage with a fixed dose of carbidopa (50 mg. four times a day), they were randomly allocated either to continue this combined treatment for a year or to switch to levodopa plus placebo for a year. The clinical response of all patients to combined treatment was rapid, with a significant reduction in total disability within 2 weeks. Optimum levodopa dose was obtained within 4-20 weeks, and the greater part of the clinical improvement was seen in that time, in contrast to the slow increase in dose and delayed appearance of benefit seen with treatment with levodopa alone. After this initial period of combined treatment, patients on levodopa plus carbidopa fared better over the year of the trial than those on levodopa alone. They had much less nausea and vomiting and a slightly better clinical response, although they showed more abnormal involuntary movements, and three patients developed the "on/off" effect. The benefits of combined treatment indicate that this is now the therapy of choice for patients with Parkinson's disease who require levodopa.