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PubMed1987

Simultaneous determination of levodopa, carbidopa, 3-O-methyldopa and dopamine in plasma using high-performance liquid chromatography with electrochemical detection.

An analytical method is described which allows a fast, reliable and precise determination of levodopa and its metabolises 3-O-methyldopa and dopamine, as well as the peripheral aromatic amino acid decarboxylase inhibitor carbidopa, in a single 1 ml plasma sample of Parkinsonian patients. The compounds are quantitatively isolated on small Sephadex G-10 columns and determined by HPLC with electrochemical detection. Dihydroxybenzylamine or alpha-methyldopa are used as the internal standard. An example of therapeutic drug monitoring in a patient with fluctuations in motor performances is given. It is confirmed that interference with absorption of levodopa from the stomach by food can be partly responsible for these observed fluctuations.

Journal Article↗
PubMed1995

Bradycardia and asystole following atropine-neostigmine administration after caesarean section in a parturient receiving methyldopa for pregnancy-induced hypertension.

We report one case of bradycardia and asystole immediately after the administration of 1 mg atropine and 2 mg neostigmine after the completion of an urgent caesarean section. We attribute this adverse reaction to the treatment of pregnancy-induced hypertension with methyldopa, perhaps facilitated by other drugs employed. Similar reactions have been reported relating to beta-receptor antagonists and tricyclic antidepressants, but not to methyldopa.

Journal Article↗
PubMed2006

Modified high-performance liquid chromatography with electrochemical detection method for plasma measurement of levodopa, 3-O-methyldopa, dopamine, carbidopa and 3,4-dihydroxyphenyl acetic acid.

Plasma measurements of levodopa and its major metabolites including dopamine and 3-O-methyldopa have been limited by cumbersome methods and poor sensitivity within relatively narrow ranges of plasma levels. We now report a modification of an HPLC method that permits concomitant measurements of a wide range of concentrations of levodopa, dopamine (DA), carbidopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenyl acetic acid (DOPAC) from one HPLC injection. The recoveries ranged from 77 to 107% with an intra-day precision around 5% (CV) and inter-day CV's about 10-20%. This validated method will simplify pharmacokinetic studies of levodopa and its metabolites for mechanistic studies or therapeutic clinical monitoring which play a crucial role in development of strategies to prolong motor benefits from individual doses and reduce involuntary movements called dykinesias.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Simultaneous high-performance liquid chromatographic analysis of carbidopa, levodopa and 3-O-methyldopa in plasma and carbidopa, levodopa and dopamine in urine using electrochemical detection.

Two assay procedures are described for the analysis of levodopa, carbidopa and 3-O-methyldopa in plasma and levodopa, carbidopa and dopamine in urine. The methods are suitable for quantifying the analytes following therapeutic administration of levodopa and carbidopa. Both were based on reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and with methyldopa as the internal standard. Plasma samples were prepared by perchloric acid precipitation followed by the direct injection of the supernatant. Urine was prepared by alumina adsorption, and the analytes were desorbed with perchloric acid solution containing disodium EDTA and sodium metabisulfite prior to injection into the HPLC system. The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa.

Carbidopa↗
PubMed1977

Unusual alpha adrenergic receptor potency of methyldopa metabolites on melanocyte function.

Catecholamines possessing alpha adrenergic receptor agonist properties induce lightening or reverse melanocyte stimulating hormone darkening of frog skin in vitro. The capacity to activate this alpha receptor by the methyldopa metabolites methyldopamine and methylnorepinephrine was compared with the capacity of the naturally occurring dopa metabolites, dopamine and norepinephrine. Melanocyte stimulating hormone-induced darkening or dispersion of the granules was reversed by each of these metabolites. Methylnorepinephrine was 10 times as potent as norepinephrine, and methyldopamine was 30- to 100-fold more potent than the naturally occurring dopamine. These inhibitory effects on melanocyte stimulating hormone could be blocked or partially impaired using the alpha adrenergic blocker, phentolamine. They were not affected by pretreatment of frogs with the monoamine oxidase inhibitor pheniprazine (Catron) nor by the application of pheniprazine, angiotensin or serotonin in vitro. This neuroendocrine model has alpha adrenergic receptor relationships analogous to those described in the central nervous system for methyldopa metabolites.

Animals↗
PubMed1963

TREATMENT OF HYPERTENSION. AN EVALUATION OF ALPHA-METHYLDOPA.

In a study utilizing an alternating double blind technique 15 patients were given alphamethyldopa in divided doses of 1 gram daily alone and in combination with a benzothiadiazine diuretic. The average blood pressure of patients receiving the drug alone was 157/90 mm of mercury, against the placebo control of 195/109 mm. The average blood pressure of patients receiving the drug in combination with a benzothiadiazine diuretic was 164/98 mm; in the control with placebo plus benzothiadiazine diuretic, it was 169/104 mm. Alpha-methyldopa appeared to be effective in reducing blood pressure in patients with benign essential hypertension.

Antihypertensive Agents↗
PubMed1963

TREATMENT OF HYPERTENSION. THE SPECIAL PLACE OF ALPHA-METHYLDOPA. A SHORT TERM STUDY.

Alpha-methyldopa in amounts of 750 mg twice daily is an effective antihypertensive agent, intermediate in potency between reserpine-thiazide combinations and ganglionic-sympathetic blocking drugs. Because it produces few undesirable side effects, it is well accepted by patients.It is useful for patients with moderate or severe hypertension not controlled by reserpine-thiazide combinations. Its favorable action on cardiac output and renal blood flow provides special advantages for patients with advanced hypertension aggravated by cardiac or renal combinations.

Antihypertensive Agents↗
PubMed1975

Antihypertensive drugs in combination: Effects of methyldopa on thiazide-induced changes in renal hemodynamics and plasma renin activity.

The rise in plasma renin activity (PRA) that accompanies thiazide diuretic therapy of hypertension may interfere with therapeutic effectiveness and contribute to hypokalemia. In an attempt to provide a basis for the previously empiric use of antihypertensive drugs, 20 hypertensive subjects were given a diuretic alone for three weeks and a diuretic plus methylodopa, which lowers PRA, for three weeks. The thiazide-induced rise in PRA was blunted by the methyldopa, while bl-od pressure fell even more and renal function was well maintained. The combination of a renin-lowering drug and a diuretic is rational and effective therapy for hypertension.

Adult↗
PubMed1978

Immunoblastic lymphadenopathy associated with methyldopa therapy: a case report.

The case of a 71-year-old woman who developed generalized weakness, lymphadenopathy, and a skin rash during methyldopa therapy is described. The prompt disappearance of symptoms following the discontinuation of the drug implicates it in the initial triggering of the abnormal lymphoid proliferation. Shortly thereafter, florid immunoblastic lymphadenopathy developed, and the patient subsequently responded to corticosteroid therapy. The frequent occurrence of immunoblastic lymphadenopathy during or shortly after the administration of various therapeutic medications is emphasized. The nature of the disorder and its differential diagnosis are discussed.

Adrenal Cortex Hormones↗
PubMed1992

Identification of O-methyldopa in the ventricular fluid of patients with Parkinson's disease.

A newly developed liquid chromatographic system with a multiple electrode detector was used for quantification of neurochemical substances in ventricular fluid of patients with Parkinson's disease. During the analysis, an unknown peak was observed at almost the same high-performance liquid chromatography retention time as 5-hydroxytryptophan. Through the use of ion suppression techniques, voltammographic analysis and fast atom bombardment mass spectrometry, the compound was identified as O-methyldopa, the major metabolite of L-dopa.

Cerebral Ventricles↗
PubMed1977

Fluorometric determination of methyldopa in biological fluids.

A fluorometric method for the analysis of methyldopa, based on the formation of a fluorophore after oxidation and rearrangement, is described. The drug is isolated from biological fluids by adsorption on alumina and elution with an organic solvent. Fluoresence is linear from 0.1 to 1.5 microgram of methyldopa/ml. The assay has a lower limit of sensitivity of 100 ng/ml and is suitable for pharmacokinetic studies following therapeutic doses in animals and humans.

Adsorption↗
PubMed2001

Effect of alpha-methyldopa on pentoxyresorufin O-dealkylation in liver microsomes from rats treated with phenobarbital.

Loss of pentoxyresorufin O-dealkylation (PROD) was observed when microsomes from PB-treated rats were preincubated in the presence of NADPH. PROD proved to be quite sensitive towards inactivation. Decrease in cytochrome P450 (CYP) dependent activity was accompanied by simultaneous formation of thiobarbituric acid reactive substances (TBARS) indicating the occurrence of lipid peroxidation. The presence of 50 microM alpha-methyldopa (AMD) during preincubation with NADPH resulted in complete protection against enzyme activity loss and the extent of lipid peroxidation was also diminished. Addition of ascorbate or GSH in combination with AMD reduced the protective effect of the drug on PROD. AMD probably exerts its effect by scavenging reactive oxygen species but chelation of ferric ions can also contribute to the protective effect of the drug on PROD activity.

Animals↗
PubMed2001

Pharmacokinetic and pharmacodynamic alterations of methyldopa in rats with aortic coarctation. A study using microdialysis.

A pharmacokinetic-pharmacodynamic study of methyldopa (MD) was made in anesthetized sham operated (SO) and aortic coarctated (ACo) rats by using a vascular shunt probe for arterial microdialysis and simultaneous blood pressure recording. Anesthetized Wistar rats were used 7 days after aortic coarctation or sham operation. A vascular shunt probe was inserted into the carotid artery and a concentric probe was placed into the striatum or posterior hypothalamus. MD and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysates by HPLC-EC. MD (50 mg kg(-1)i.p.) induced an increase of heart rate in SO (Delta HR: 108 +/- 22 bpm, n= 6) and in ACo rats (Delta HR: 55 +/- 10 bpm, n= 6, P< 0.05, one way ANOVA). Moreover, MD also reduced the mean arterial pressure (MAP) of SO rats (Delta MAP: -10 +/- 4 mmHg, n= 6) and ACo animals (Delta MAP: -51 +/- 9 mmHg, n= 6, P< 0.05, one way ANOVA). Analysis of the arterial blood dialysates showed a lower half-life of MD in ACo rats (t(1/2): 1.5 +/- 0.3 h, n= 6, P< 0.05, 't' test) than in SO rats (t(1/2): 3.7 +/- 1.0 h, n= 6). A low accumulation and a fast decay of striatal MD levels were seen in ACo rats. However, peak levels of drug were greater in the hypothalamic dialysates of ACo rats than in SO animals samples. On the other hand, MD also induced an increase of DOPAC levels in the hypothalamic dialysates of ACo rats. In conclusion, the aortic coarctation modifies the pharmacokinetic and cardiovascular effect of MD in the rat. The action of this drug on dopaminergic neurotransmission is also altered in the ACo animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.

In a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt tablets containing 250 mg alpha-methyldopa (AMD) and Presinol film tablets with identical active ingredient content was examined in 24 healthy volunteers. Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) were evaluated statistically. Wilcoxon's nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0-infinity at the 90% probability level, the confidence interval was 0.883-1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt and Presinol tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt (test preparation) and Presinol (reference preparation) calculated from the AUC0-infinity values was 116.7+/-56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt and Presinol can be considered as bioequivalent preparations.

Adrenergic alpha-Agonists↗
PubMed1987

Cardiovascular role of A1 catecholaminergic neurons in the rabbit. Effect of chronic lesions on responses to methyldopa, clonidine and 6-OHDA induced transmitter release.

We confirmed the findings of previous investigators that bilateral anodal lesions of the A1 region were associated with hypertension, bradycardia, pulmonary edema and a high mortality. All these sequelae (except the bradycardia) no longer occurred after cathodal lesions and these were therefore used to investigate the role of the catecholaminergic (CA) neurons of the A1 region in circulatory regulation. Conscious rabbits were studied 2-4 weeks after A1 lesions or sham-operation, when resting mean arterial pressure (MAP) and heart rate (HR) were closely similar in both groups. We tested for differences in MAP and HR responses between lesioned and sham-operated groups: to intracisternal (i.c.) alpha-methyldopa (MD) and to clonidine; and to the acute effects of i.c. 6-hydroxydopamine (6-OHDA) which elicits central CA release. Since these tests depend on the integrity of the central CA neurons, response differences between lesioned and sham-operated groups denote participation by the CA neurons of the A1 region in the central circulatory pathways. The bradycardia responses in the above tests were all smaller in lesioned than sham-operated rabbits, but there were no differences in MAP responses. Electrical stimulation of the region under alfathesin anaesthesia produced depressor responses at low frequencies and pressor responses at high frequencies. From the results in conscious rabbits CA neurons of the A1 region mainly influence the pathways regulating HR, rather than blood pressure. The changes in MAP during electrical stimulation are thus probably mediated through non-CA neurons.

Animals↗
PubMed1989

Importance of spinal noradrenergic pathways in cardiovascular reflexes and central actions of clonidine and alpha-methyldopa in the rabbit.

We have examined in conscious rabbits the chronic effects of 6-hydroxydopamine (6-OHDA)-induced local lesions of the spinal noradrenaline (NA) pathways on (i) resting mean arterial pressure (MAP) and heart rate (HR), (ii) the nasopharyngeal pressor response, (iii) the sympathetic component of the baroreceptor-heart rate reflex (iv) the acute responses to intracisternal (i.c.) clonidine and alpha-methyldopa (alpha-MD), and (v) the acute NA release response produced by i.e. 6-OHDA. One month after injection of 6-OHDA (40 nmol in 4 microliters) into the first cervical spinal cord segment (C1), the NA content was reduced to 29% in C2, 45% in T4 and 61% in L3 with little non-specific damage. Basal MAP was 14% higher (P less than 0.05) than in sham-operated rabbits suggesting increased vasoconstrictor tone. Basal cardiac sympathetic tone was enhanced, but a corresponding increase in cardiac vagal tone resulted in little net effect on resting HR in the spinal NA-depleted group. Spinal NA lesions attenuated the nasopharyngeal pressor reflex by 27% in baroreceptor-intact rabbits and by 38% in sino-aortically denervated (SAD) animals. The lesion did not affect HR range, gain and BP50 of the sympathetic baroreflex. In SAD rabbits, the acute MAP responses to i.c. 6-OHDA (early hypotension, late hypertension) were not affected by spinal NA depletion, but the early fall in HR (cardiac sympathetic inhibition) was abolished. The hypotension produced by i.c. clonidine or alpha-MD was not affected by the lesion, probably because many of the NA terminals in the lower thoracic and upper lumbar cord were still intact. Our results suggest that intraspinal NA fibers have a tonic inhibitory action on spinal preganglionic vasoconstrictor and cardiac motoneurons. The spinal NA neurons affecting vasomotor tone (but not cardiac sympathetic tone) are in turn inhibited by higher vasomotor centers receiving projections from the arterial and trigeminal afferents and thereby participate in vasoconstrictor reflexes.

Animals↗
PubMed1991

Contribution of forebrain noradrenaline innervation to the central circulatory effects of alpha-methyldopa and 6-hydroxydopamine.

We studied the circulatory effects of chronic lesions of the ascending noradrenergic (NA) projections to the forebrain on the acute effects of intracisternal (i.c.) alpha-methyldopa (alpha-MD) and 6-hydroxydopamine (6-OHDA) on mean arterial pressure (MAP) and heart rate (HR) in conscious rabbits with arterial baroreceptors either intact or denervated (sinoaortic denervation, SAD). Both drugs acutely release neurotransmitter from central NA neurons. I.c. 6-OHDA produced acute hypertension and bradycardia while i.c. alpha-MD produced acute hypotension and bradycardia. The responses are qualitatively similar in SAD rabbits except that after 6-OHDA, HR increased. In another group we studied the effects of the drugs 3-4 weeks after localised injections of 6-OHDA in the midbrain dorsal and ventral NA bundles. Local 6-OHDA depleted forebrain regions of NA by 44-76%, and had no effects on basal values of MAP or HR. The pressor and depressor effects, of 6-OHDA and alpha-MD respectively, were little affected by the lesions in either intact or SAD rabbits. By contrast, in rabbits with intact baroreceptors, the lesion abolished the bradycardia produced by i.c. alpha-MD and 6-OHDA. The latter drug now produced a late tachycardia. In SAD rabbits, however, there was no effect on the alpha-MD-induced bradycardia, but the 6-OHDA tachycardia was enhanced. Since the major effects of the lesions were confined to the rabbits with intact baroreceptor afferents, it suggests that the ascending NA pathways are important for the cardiac responses dependent on baroreceptor input. In intact animals, both drugs produce bradycardia through facilitation of the vagal component of the baroreceptor-heart rate reflex. In SAD rabbits, almost all the changes to HR are mediated through the cardiac sympathetic and the lesions have little effect on HR.

Animals↗
PubMed1989

Correlation between fall in blood pressure and in vivo amine release after alpha-methylDOPA.

Blood pressure (BP), hypothalamic tissue concentrations and the in vivo overflow of endogenous and alpha-methylated catecholamines were measured in urethane anaesthetised rats after alpha-methylDOPA (mDOPA) administration (200 mg/kg i.p.). Four hours after mDOPA, BP fell to its lowest value, 60% of control, and slowly returned towards control levels by 24 h. This was closely correlated with the evoked overflow of alpha-methylnoradrenaline (mNA, r = 0.9) and noradrenaline (NA, r = 0.7) but not dopamine (DA) or alpha-methyldopamine (mDA). However, the tissue content of mNA rose much more gradually and was not maximal until after 12 h while mDA content followed the development of the hypotension. The results provide direct evidence for a false transmitter role for mNA in the brain, and suggest that the release of newly synthesised mNA is responsible for the hypotensive effect of mDOPA. Differences in the time course of overflow and storage of NA and mNA suggest the presence of separate transmitter storage and releasable pools.

Animals↗