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At least 19 recordsLinked to original sources

PubMed1992

Motor function, graft survival and gliosis in rats with 6-OHDA lesions and foetal ventral mesencephalic grafts chronically treated with L-dopa and carbidopa.

In rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway, foetal ventral mesencephalic grafts implanted into the 6-OHDA-lesioned striatum produced a reduction in apomorphine-induced contralateral rotation, and complete abolition of (+)-amphetamine-induced ipsilateral rotation. The graft-induced reduction of apomorphine and (+)-amphetamine-induced rotation was not affected by chronic 27 week administration of L-DOPA and carbidopa to rats receiving foetal grafts. TH-immunohistochemistry revealed greater than 96% loss of dopamine cells in the substantia nigra ipsilateral to the 6-OHDA lesion in all animals, but cell loss in the ipsilateral ventral tegmental area was more variable (21-46% of the intact side). TH-positive cells in the intact substantia nigra and ventral tegmental area were not affected by chronic treatment with L-DOPA and carbidopa. In the lesioned striatum of rats receiving sham grafts, no TH-positive cells or fibres were seen. In the 6-OHDA-lesioned striatum of animals receiving foetal grafts, many TH-positive cells were seen in the grafts and chronic treatment with L-DOPA and carbidopa did not reduce cell survival. GFA-P immunohistochemistry revealed that a unilateral 6-OHDA lesion followed by a sham graft was not associated with a reactive gliosis reaction in the striatum at the time of study (38 weeks after lesion surgery and 30 weeks after sham-graft), and treatment of such rats with L-DOPA and carbidopa was also without effect on glia. In contrast there was a marked gliosis in the striatum surrounding foetal grafts which was unaffected by chronic treatment with L-DOPA and carbidopa. The grafts themselves were surrounded by a rim of glial cells, and the glial density within the grafts was higher in animals receiving chronic L-DOPA and carbidopa treatment. However, there was no obvious relationship between the number of TH-positive cells within the grafts, or graft volume, and glial cell density within the grafts. These results suggest that long-term treatment with L-DOPA and carbidopa does not impair either the behavioural recovery produced by foetal ventral mesencephalic grafts in rats or the long-term survival of grafts as revealed by TH-immunohistochemistry. The presence of a foetal graft is associated with a reactive gliosis in the implanted striatum, which was not altered by long-term treatment with L-DOPA and carbidopa. However such treatment did result in an increase in glial density within the grafts themselves.

Animals↗

PubMed1991

Peripheral pharmacokinetic handling and metabolism of L-dopa in the rat: the effect of route of administration and carbidopa pretreatment.

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

The effect of L-dopa and carbidopa treatment on the survival of rat fetal dopamine grafts assessed by tyrosine hydroxylase immunohistochemistry and [3H]mazindol autoradiography.

The effect of treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) and carbidopa for five weeks on the survival of rat fetal dopaminergic ventral mesencephalon cells implanted into the denervated striatum of rats with unilateral 6-hydroxydopamine nigrostriatal lesions was assessed. Rats receiving unilateral nigral 6-hydroxydopamine lesions followed by sham striatal grafts (Groups A and B) showed no recovery of (+)-amphetamine- or apomorphine-induced motor asymmetry. Rats in Group B (receiving treatment with L-DOPA and carbidopa) showed an increase in apomorphine-induced contralateral rotation and stereotypy. Animals receiving unilateral nigral 6-hydroxydopamine lesions followed by fetal striatal dopamine grafts (Groups C and D) showed complete recovery of (+)-amphetamine-induced rotation and a decrease of apomorphine-induced contralateral rotation. Treatment of animals in Groups B and D with L-DOPA (200 mg/kg per 24 h) and carbidopa (25 mg/kg per 24 h) by mouth for five weeks had no effect on the behavioural response to (+)-amphetamine. In the 6-hydroxydopamine-lesioned animals there was loss of tyrosine hydroxylase-immunoreactive cells in substantia nigra and ventral tegmental area of greater than 97% and to 66%, respectively, compared to the intact side. The number and morphology of tyrosine hydroxylase-immunoreactive cells in the intact substantia nigra and ventral tegmental area was not altered by treatment with L-DOPA and carbidopa. In the 6-hydroxydopamine-lesioned striatum of rats receiving a sham graft (Group A) or a sham graft and treatment with L-DOPA and carbidopa (Group B) there were no tyrosine hydroxylase-positive cells or fibres visible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

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.

Adult↗

PubMed1992

Effect of a macrolide (spiramycin) on the pharmacokinetics of L-dopa and carbidopa in healthy volunteers.

In one well-equilibrated parkinsonian patient treated with combined L-dopa and carbidopa (Sinemet), we have observed changes in treatment efficacy while receiving spiramycin (Rovamycine) for an intercurrent respiratory infection. A preliminary study of the pharmacokinetics of L-dopa and its main metabolites 3-O-methyldopa (3-OMD) and dihydroxyphenylacetic acid (dopac) in two parkinsonian patients treated with Sinemet has revealed a marked decrease in the AUC0-360 of these two metabolites after a 3-day course of Rovamycine. In order to confirm this interaction, we have studied the modifications of the pharmacokinetics of L-dopa, 3-OMD, dopac, and carbidopa in eight male healthy volunteers after a single dose of Sinemet 250 (L-dopa, 250 mg and carbidopa, 25 mg) before and after a 3-day course of Rovamycine. Our study confirms this interaction. After spiramycin, we observed a marked reduction in AUC0-360 for L-dopa (p less than 0.001), 3-OMD (p less than 0.001), and carbidopa (p less than 0.001), and an increase in AUC0-360 for dopac (p less than 0.01). The L-dopa elimination half-life was increased (p less than 0.012); differences in peak plasma concentrations did not attain statistical significance. We think that these modifications in L-dopa pharmacokinetics after spiramycin are due to nonabsorption of carbidopa secondary to modified gastrointestinal motility.

Adult↗

PubMed1991

Effect of dopamine, L-dopa, carbidopa and L-dopa/carbidopa on arthus and delayed hypersensitivity skin reactions in the rat.

This study deals with the effects of dopamine (DA), L-dopa, carbidopa and L-dopa/carbidopa on immuno-inflammatory skin reactions in the rat. For this purpose, male Wistar rats immunized with bovine serum albumin in Freund's adjuvant were treated subcutaneously with different doses of DA, L-dopa, carbidopa and L-dopa/carbidopa, for a period of 14 consecutive days or 3 days before skin-testing with BSA. An additional group of rats received 1 injection of a dopamine-related drug 4 hours before and 1 injection 4 hours after skin-testing. Corresponding controls were treated with saline. Arthus and delayed hypersensitivity skin reactions were read at 4 and 24 hours respectively. The results showed that repeated injections of DA, L-dopa and L-dopa/carbidopa significantly suppressed Arthus and delayed reactions. The highest suppression was recorded in rats treated with L-dopa plus carbidopa. Concerning the dose required for immunosuppression it appears that DA was the most effective. Carbidopa did not affect hypersensitivity skin reactions. These results suggest the in vivo relationship between dopamine-related compounds (L-dopa and DA) and immuno-inflammatory reactions. Most probably, L-dopa when is given alone converts into DA and this increase of DA content in periphery depresses immune reactions. However, L-dopa given together with carbidopa (an enzyme which prevents decarboxylation of L-dopa into DA, and enables the penetration of L-dopa into CNS) augments the content of DA in the brain and thus affects immune responses. It appears, therefore, that L-dopa and DA act both peripherally and centrally on immune responsiveness.

Animals↗

PubMed1979

Role of peripheral adrenoreceptors and vasopressin in the suppression of plasma renin activity by L-dopa in carbidopa-treated dogs.

When extracerebral dopa decarboxylase is inhibited by carbidopa, L-dopa lowers plasma renin activity (PRA). The present study was designed to determine whether this suppression of PRA is mediated by the sympathetic nerves, and to identify the peripheral adrenergic receptor types involved. All experiments were performed in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were minimized by means of a suprarenal aortic clamp. Neither alpha adrenoreceptor blockage with phenoxybenzamine nor beta adrenoreceptor blockade with propranolol was by itself sufficient to block the suppression of PRA by L-dopa with carbidopa. However, combined alpha and beta adrenoreceptor blockade lowered PRA and completely prevented any further suppression of PRA by L-dopa with carbidopa. It was also observed that phenoxybenzamine decreased PRA by 48% when administered to propranolol-treated animals. Taken together, these data indicate that L-dopa with carbidopa suppresses PRA by decreasing sympathetic nerve stimulation of both alpha and beta adrenoreceptors. Plasma vasopressin concnetration was significantly decreased by L-dopa with carbidopa both in the control group and in animals with combined alpha and beta adrenoreceptor blockade. Because plasma vasopressin levels decreased after L-dopa, vasopressin is unlikely to play a causative role in the suppression of PRA.

Animals↗

PubMed1976

[HGH secretion after oral application of L-dopa and L-carbidopa (author's transl)].

The stimulatory effect of L-Dopa and L-Carbidopa (Nacom) on HGH secretion was determined in 12 children of normal height aged from 6 to 14 years. Each child received a standard dose of 250 mg L-Dopa and 25 mg L-Carbidopa p.o. HGH concentration in the serum was determined at standard intervals. All subjects showed a sufficient increase of HGH. The mean value was 19.6 ng/ml. According to the maximum values of the HGH concentration the sample can be divided into two groups; the first group reached the highest values after 20--40 min, the second one after 60--90 min. On evaluation of the curve of the mean values it appears that 2 blood samples taken 40 and 90 min after the ingestion of L-Dopa and L-Carbidopa are sufficient in order to exclude HGH deficiency. The theoretical background for HGH secretion after stimulation by L-Dopa and L-Carbidopa is discussed.

Administration, Oral↗

PubMed1976

Enhancement of the anti-hypertensive effect of methyldopa and other anti-hypertensive drugs by carbidopa in spontaneously hypertensive rats.

1. A peripheral inhibitor of L-aromatic amino acid decarboxylase, carbidopa [(-)-L-alpha-hydrazino-3,4-dihydroxy-alpha-methylbenzenepropanoic acid monohydrate], at doses up to 25 mg/kg intraperitoneally or 30 mg/kg orally had no effect on directly recorded arterial pressure of spontaneously hypertensive rats derived from the Wistar/Okamoto strain. It enhanced, however, the anti-hypertensive effects of methydopa, hydrallazine, guanethidine and clonidine, and, to a lesser extent, reserpine and hydrochlorothiazide. The mechanism of this enhancement is presently unkonwn, but biochemical studies support the assumption that carbidopa is likely to reduce sympathetic nervous system activity. 2. The conversion of [3H]tyrosine (given intraperitoneally) to dopa (3,4-dihydroxypheylalanine) and catecholamines was measured in the hearts and adrenals of control rats and animals pretreated with carbidopa (100 mg/kg, intraperitoneally). Carbidopa significantly decreased the accumulation of 3H-labelled catecholamines in both organs and increased their total tyrosine content and the specific radioactivity of tyrosine.

Animals↗

PubMed1977

Long-term therapy of myoclonus and other neurologic disorders with L-5-hydroxytryptophan and carbidopa.

We evaluated the therapeutic effect of L-5-hydroxytryptophan (L-5HTP), the precursor of serotonin (5-hydroxytryptamine), combined with carbidopa, a peripheral decarboxylase inhibitor, in patients with intention myoclonus and examined the serotonin metabolites in spinal fluid, blood and urine before and during therapy. In 18 patients with intention myoclonus due to anoxia or other brain damage, 11 derived more than 50% overall improvement during treatment with L-5HTP and carbidopa. Spinal-fluid 5-hydroxyindoleacetic acid was 35% lower in patients with intention myoclonus than in controls (P less than 0.05). Therapy with L-5HTP and carbidopa increased the concentration of serotonin metabolites in urine and spinal fluid. We postulate that a deficiency of brain serotonin is causally related to intention myoclonus and that the therapeutic effect of L-5HTP and carbidopa may be due to the repletion of serotonin in regions of the brain where serotoninergic neurons have degenerated.

5-Hydroxytryptophan↗

PubMed1979

Levodopa with benserazide or carbidopa in Parkinson disease.

Plasma levodopa and therapeutic responses to treatment with levodopa in combination with benserazide or carbidopa were studied in 49 patients with Parkinson disease not previously treated with levodopa in a blind randomized crossover trial. The treatment periods were 12 weeks; similar dosage schedules were used, with doses that induced equal levels of plasma levodopa in both combinations. In pretrial studies of plasma levodopa responses, 200 mg of levodopa and 50 mg of benserazide was equal to 250 mg of levodopa combined with 25 mg of carbidopa. Equal plasma levodopa responses to both combinations were also found during the trial. There was no significant difference between the treatment groups in beneficial effects on parkinsonian disability and individual symptoms or in the frequency of involuntary movements. However, nausea and vomiting occurred significantly more often during treatment with levodopa and carbidopa than during treatment with levodopa and benserazide. This difference was probably due to inadequate inhibition of peripheral decarboxylase inhibitor by the 1:10 ratio of carbidopa to levodopa.

Benserazide↗

PubMed1992

The effects of carbidopa administration on 6-[18F]fluoro-L-dopa kinetics in positron emission tomography.

Carbidopa (L-alpha-hydrazino-alpha-methyl-b-(3,4-dihydroxyphenyl) propionic acid is a known inhibitor of aromatic amino acid decarboxylase. In both humans and monkeys, we studied the effects of carbidopa on plasma and brain kinetics of 6-[18F]fluoro-L-DOPA (FDOPA), an analog of L-DOPA used for PET studies of the central dopaminergic system. Pretreatment with carbidopa resulted in increases in the plasma levels of FDOPA and 3-O-methyl-6-[18F]fluoro-L-DOPA (3-OMFD). Total striatal and cerebellar activities measured with PET were also increased. Furthermore, increases observed in the specific striatal activity (striatum minus cerebellum total activity) were correlated with increases in the plasma FDOPA curve. Carbidopa pretreatment did not affect the influx rate constant (K) for FDOPA from plasma to striatum in humans as determined by Patlak graphical analysis. Thus, an increase in measured striatal tomographic activity was secondary to the increase in plasma FDOPA levels rather than as a result of changes in the FDOPA influx rate constant.

Adult↗

PubMed1978

Effects of apomorphine and apomorphine-L-dopa-carbidopa on alcohol post-intoxication symptoms.

In a randomised double-blind clinical trial on 58 gamma-alcoholics, the effect of apomorphine given orally in individual subemetic doses was compared with apomorphine-L-dopa-carbidopa and with placebo. No positive effects of treatment with apomorphine, or with the combination apomorphine-L-dopa-carbidopa, on alcohol consumption or post-intoxication symptoms could be demonstrated. In the group which received the combination apomorphine-L-dopa-carbidopa, the post-intoxication symptoms lasted significantly longer than in the other two groups.

Adult↗

PubMed1977

The effect of carbidopa administration on urinary sodium excretion in man. Is dopamine an intrarenal natriuretic hormone?

1 Carbidopa, a known inhibitor of the peripheral conversion of dopa to dopamine, was given to six normal volunteers to examine the effect of interference with dopamine synthesis on urinary sodium excretion. 2 On the first day of administration, carbidopa caused a significant fall not only in urinary dopamine excretion (P less than 0.01) but also in urinary sodium excretion (P less than 0.05). 3 A highly significant correlation was also found between mean sodium excretion and mean dopamine excretion in the days prior to and during carbidopa administration (r = 0.617, P less than 0.001; 4 = 0.764, P less than 0.001 respectively). 4 The significance of these findings is discussed and it is proposed that dopamine may be an important intrarenal natriuretic hormone.

Adult↗

PubMed1992

Spectrophotometric method for the determination of carbidopa using neotetrazolium chloride.

A new high-sensitive spectrophotometric method for the determination of microquantities of carbidopa is described. The method is based on the reduction of neotetrazolium chloride by carbidopa in an alkaline ethanolic medium. The formazan formed exhibits an absorption maximum at lambda = 507 nm, with an apparent molar absorptivity of epsilon = 6.63 x 10(4) M-1 cm-1 and a corresponding Sandell's sensitivity of 3.68 ng cm-2. Beer's law is obeyed over the range of 0.10-6.0 micrograms mL-1 while the optimum concentration range is 0.125-5.0 micrograms mL-1. The regression line equation was calculated as: A = 0.271C + 0.0023 with a correlation coefficient of 1.0000 (n = 28). The accuracy and the precision of the method were considered as very satisfactory. The results obtained from the determination of carbidopa using both the described procedure and the corresponding USP. XXII and BP 1988 clinical methods were statistically compared by means of Student's t-test as well as by the variance ratio F-test, and no significant difference was observed.

Carbidopa↗

PubMed1992

Effects of long-term infusions of dopa and carbidopa on renin and steroid secretion in the rat.

Plasma, kidney, and adrenal catecholamine concentrations were varied by infusing rats with L-dopa and/or carbidopa for 2 weeks. L-Dopa infusion (300 micrograms/day) increased dopamine concentrations in plasma, adrenal zona glomerulosa, and kidney by 140%, 74%, and 224%, respectively: the dopamine content of the adrenal inner cortex plus medulla was not increased. Infusion of carbidopa alone had no detectable effect upon endogenous dopamine concentrations. Concomitant infusion (300 micrograms/day) of carbidopa with L-dopa blocked the rise in plasma and adrenocortical dopamine caused by L-dopa alone. Plasma aldosterone and plasma and kidney active renin concentrations were unaffected by L-dopa administration but plasma corticosterone and deoxycorticosterone (DOC) were significantly elevated (P < 0.05); increases in DOC appeared greater than those of corticosterone. These data cast doubt on the theory that dopamine is a physiological tonic inhibitor of aldosterone synthesis in rats. However, in the rat, stimulatory effects of L-dopa on plasma concentrations of precursors of aldosterone might be of physiological significance since DOC is a potent mineralocorticoid.

Adrenal Cortex↗

PubMed1978

Carbidopa inhibits the growth hormone- and prolactin-suppressive effect of L-dopa in acromegalic patients.

The plasma GH, PRL, TSH, and dopamine (DA) responses to an infusion of L-dopa were examined in six acromegalic patients before and after pretreatment with carbidopa, a drug which inhibits the peripheral conversion of L-dopa to DA. Carbidopa neither modified baseline DA nor induced changes in baseline GH, PRL, or TSH levels. The drug instead markedly reduced the L-dopa-induced DA rise, an effect which was concomitant to a striking reduction of the suppressive effect of L-dopa on plasma GH and a partial inhibition of the suppressive effect of L-dopa on plasma PRL. TSH levels did not change either after L-dopa alone or L-dopa plus carbidopa. These data demonstrate that in "responder" acromegalics, L-dopa inhibits GH secretion through its peripheral conversion to DA and not via activation of central DA neurotransmission. For the effect of L-dopa on PRL secretion, in addition to a peripheral dopaminergic component, a central component cannot be disregarded.

Acromegaly↗

PubMed1977

The effect of a peripheral decarboxylase inhibitor (carbidopa) on monoamine and neuroendocrine function in man.

Carbidopa, a selective extracerebral decarboxylase inhibitor, was given to 10 normal volunteers to determine its effects on endogenous catecholamine, indoleamine, and endocrine function. Tryptamine, which is largely extracerebral in origin, was inhibited markedly (80 percent) by the carbidopa; 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenolglycol (MHPG) excretion also were inhibited by the drug but not to the same degree as tryptamine. These differential results may be due partly to the higher central nervous system origin of the 5-HIAA and MHPG but also to a peripheral "stores" effect. In addition, carbidopa resulted in significant increases in plasma prolactin and a small but significant decrease in plasma glucagon.

Adult↗