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PubMed1987

Determination of methyldopa in plasma using high-performance liquid chromatography with electrochemical detection. Application to pharmacokinetic/bioavailability studies.

The problem of quantitatively measuring methyldopa (a-methyldopa) in biological matrices after applying therapeutic doses to humans is still challenging. Numerous methods have been published but most of them require a tedious, time-consuming sample preparation, are not specific enough or lack the necessary sensitivity. As the basis of conclusive human pharmacokinetic and bioavailability/bioequivalence studies is a validated analytical method, which is reliable, selective, sensitive and able to proceed hundreds or even thousands of samples in a limited time, an assay to fulfill these needs was developed. The present method employs a hiph-performance liquid chromatographic system consisting of a pump, an ODS column, an autosampler and an electrochemical detector. The assay is sensitive down to 50 ng/ml plasma, the calibration curves are linear in a range of 50-2000 ng/ml, the chromatographic peaks are well resolved and the precision and accuracy are excellent. The assay has been successfully used for the determination of very low methyldopa plasma levels during several clinical studies.

Biological Availability↗
PubMedDate not supplied

Colorimetric determination of sympathomimetic amines methyldopa and noradrenaline.

The chromogenic reagent p-dimethylaminocinnamaldehyde (PDAC) is introduced for the determination of the sympathomimetic amines methyldopa and noradrenaline. The method is based on measurement of the orange color developed when the alkaline solution of methyldopa and noradrenaline is allowed to react with PDAC at pH 5.0. The color developed obeys Beer's law in the concentration range 0.1-1.5 mL of 2 X 10(-3)M solution of noradrenaline and methyldopa. The results are compared with those obtained with another chromogenic reagent, p-dimethylaminobenzaldehyde (PDAB). Determinations on dosage forms of the drugs, using PDAC and PDAB reagents, agreed well with results of determinations by official pharmacopoeial methods.

Benzaldehydes↗
PubMed1976

Antihypertensive therapy with timolol and alpha-methyldopa. A double-blind trial in patients with moderately severe hypertension.

After 24 moderately severe hypertensive patients had been treated for 4 weeks with a placebo for timolol, alpha-methyldopa was added and titrated until control of the blood pressure or a total daily dose of 2 500 mg was achieved. At the 9th week, the dose of alpha-methyldopa was halved and either timolol or its placebo was titrated in double-blind fashion. Titration over a period of 4 weeks was followed by a further 5 weeks of stabilisation. In 22 patients whose responses were accepted for analysis, alpha-methyldopa caused a significant lowering of blood pressure, with a greater reduction in the upright posture and a reduction in pulse rate. The addition of timolol caused a highly significant further reduction in pulse rate and a significant reduction in blood pressure in 8 of 10 patients. Apart from a statistically significant increase in serum urea and creatinine with, however, retention of normal renal function, no other side-effects were attributable to timolol.

Adrenergic beta-Antagonists↗
PubMed1980

The antihypertensive effect of guanfacine compared with methyldopa.

Guanfacine (BS 100-141) (N-amidino-2-(2,6-dichlorophenyl)-acetamide hydrochloride) is a centrally acting alpha-adrenergic receptor agonist. A comparison of its anti-hypertensive effect with that of methyldopa was made in patients with essential hypertension. After a wash-out period of 8-10 days, 33 patients with hypertension of different degrees of severity were treated with guanfacine or methyldopa, both combined with clorexolone, in a randomized double-blind study extending over 8 weeks. Blood pressure was reduced significantly by both drug treatments, compared with the placebo. The incidence of side-effects with both drugs was low. Those that did occur decreased after adjustment of dosage. Guanfacine was clinically effective in all patients with various degrees of hypertension, but treatment with methyldopa was inadequate in 30% of patients even at maximum dosage. Up to 40 hours after abrupt drug withdrawal, no rebound hypertension was noted in the guanfacine group.

Adrenergic alpha-Agonists↗
PubMed1984

Methyldopa: an agent for the treatment of older patients with isolated systolic hypertension.

An open-label study was conducted to determine the effectiveness and tolerability of methyldopa in the treatment of 20 older patients (mean age, 67 years) with isolated systolic hypertension. After the two-week control period, during which 25 to 50 mg/day of hydrochlorothiazide was administered, the patients had a mean sitting blood pressure greater than or equal to 160/less than or equal to 95 mmHg. The patients were then treated for up to 16 weeks with a daily regimen of 25 to 50 mg of hydrochlorothiazide and 250 to 1,000 mg of methyldopa. The therapy controlled isolated systolic hypertension without orthostatic hypotension or adverse reactions. Clinically and statistically significant reductions (P generally less than 0.01) in mean sitting and standing systolic blood pressures occurred after as little as two weeks of treatment and were maintained throughout the 16-week study period. The findings suggest that methyldopa is suitable for use among older hypertensive patients.

Aged↗
PubMed1983

A comparison of acebutolol with methyldopa in hypertensive pregnancy.

Twenty pregnant women with mild to moderate hypertension were treated with either methyldopa or acebutolol, a beta-adrenergic blocking agent with cardioselectivity and intrinsic sympathomimetic activity, in a prospective open study. The two groups were comparable, although some selection bias may have been present. The dose of either drug was adjusted to attain a diastolic blood pressure of 80 mmHg or less, and 2 of the acebutolol group and 1 of the methyldopa group required the addition of hydralazine to achieve this. There were no still births or neo-natal deaths in either group. There was no difference discernible between the groups in duration of pregnancy, birth weight. Apgar score or placental weight, and no evidence of bradycardia, hypoglycaemia or respiratory difficulty in the babies born to mothers taking acebutolol. Fewer side-effects seemed to be present in the acebutolol group, and the mean period of hospitalization during pregnancy was 8 days in these patients compared with 14 days in the methyldopa group (p less than 0.01). The results of this pilot study suggest that acebutolol warrants further investigation as an effective and well-tolerated treatment of hypertension in pregnancy.

Acebutolol↗
PubMed1980

Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazine, and amiloride combination.

A multiclinic, double-blind, randomized study in 361 patients with essential hypertension compared Aldoretic, (Merck & Co., Inc., New Jersey), a combination of methyldopa, hydrochlorothiazide, and amiloride with the combination of hydrochlorothiazide and amiloride and with methyldopa alone. At the end of week 12, the proportion of patients who were classified as normotensive (diastolic less than or equal to 90 mm Hg) was 61% in the group treated with Aldoretic, which was statistically significantly greater than the 48% in the hydrochlorothiazide/amiloride group and the 35% in the methyldopa group.

Adult↗
PubMed1981

A comparison of chlorthalidone-reserpine and hydrochlorothiazide-methyldopa as step 2 therapy for hypertension.

Two fixed-combination drugs commonly used in the step 2 treatment of hypertension, chlorthalidone plus reserpine and hydrochlorothiazide plus methyldopa, were compared in an evaluation of efficacy and adverse reactions. Ninety-one percent of the chlorthalidone-reserpine group achieved diastolic blood pressures of 90 mmHg or lower compared with 55% of the hydrochlorothiazide-methyldopa group. The incidence of adverse reactions in the chlorthalidone-reserpine group was 31% compared with an incidence of 64% in the hydrochlorothiazide-methyldopa group.

Chlorthalidone↗
PubMed1981

Indapamide in ambulant treatment of hypertension: a comparative study with alpha-methyldopa.

Indapamide and methyldopa were compared in an open parallel study in patients with mild or moderate hypertension. Both drugs showed an antihypertensive effect significantly different from placebo but with indapamide the blood pressure response occurred sooner, after 2 weeks, as opposed to 4 weeks with methyldopa. Indapamide was better tolerated than methyldopa, producing fewer side effects.

Antihypertensive Agents↗
PubMed1994

A comparison of nifedipine with methyldopa in pregnancy induced hypertension.

OBJECTIVE: To compare nifedipine (group 1) with methyldopa (group 2) in the management of pregnancy induced hypertension (PIH). DESIGN: A prospective clinical trial. SETTING: Obstetric Unit, General Hospital, Peradeniya. PATIENTS: A total of 126 patients with PIH were allocated alternately to either group. The patients in group 1 received nifedipine 30 to 90 mg/day and in group 2 methyldopa 750 to 2000 mg/day. MEASUREMENTS: Blood pressure, the extra days added to the pregnancy, number of patients treated for acute hypertensive episodes, maturity of fetus at birth, mode of delivery, birth weight, intrauterine deaths, Apgar score, maternal side effects and complications. RESULTS: The two groups on admission to the study had similar periods of gestation (group 1, 33.6 + 5.9, group 2, 34.1 + 4.2), systolic blood pressure in mmHg (151 + 22, and 154 + 24) and diastolic blood pressure (108 + 12, and 108 + 12). The results showed no differences between the two groups, with respect to maturity of fetus at delivery (35.1 + 5.5, and 35.7 + 2.9), mode of delivery, number of intrauterine deaths, average systolic blood pressure in mmHg (148 + 14 and 152 + 16), average diastolic blood pressure (102 + 8 and 104 + 9), highest systolic blood pressure (169 + 24 and 167 + 30), highest diastolic blood pressure (115 + 12 and 116 + 11), birth weight in kg (2.015 + 0.957, and 1.922 + 0.660) and number of days added to the pregnancy (7 + 7, 9 + 11). The Apgar score for group 2 was better than in group 1, and less patients in group 2 required treatment for acute hypertension during the period of study. CONCLUSIONS: The results of our study indicate that nifedipine is as effective as methyldopa in the treatment of PIH.

Adult↗
PubMed1994

Effects of the antihypertensive drugs alpha-methyldopa and hydralazine on the performance of spontaneously hypertensive rats in the elevated plus-maze.

The effects of antihypertensive drugs on the performance of spontaneously hypertensive rats (SHR) in the elevated plus-maze were determined. Male SHR (3 months old) were submitted to long-term treatment (15 days) with alpha-methyldopa (alpha MD, 5 g/l, N = 10) and hydralazine (HYD, 100 mg/l, N = 10) given orally, diluted in water. After the drug treatment, the performance of the rats in the plus-maze was observed for 5 min in a single test and mean arterial pressure (MAP) and heart rate (HR) were then measured. The antihypertensive drugs reduced MAP significantly (mean +/- SEM: CON = 176.2 +/- 5.2, alpha MD = 157.8 +/- 4.6 and HYD = 150 +/- 4.4 mmHg) and only alpha MD increased HR significantly (mean +/- SEM: CON = 391.7 +/- 13.8, alpha MD = 453.3 +/- 14 and HYD = 368.8 +/- 18.9 bpm). The alpha MD group presented a lower total number of entries (mean +/- SEM: CON = 12.7 +/- 0.7, alpha MD = 8.7 +/- 0.9 and HYD = 12 +/- 0.9) and spent less time in the open arms than the CON (N = 10) and HYD groups (mean +/- SEM: CON = 0.69 +/- 0.04, alpha MD = 0.48 +/- 0.07 and HYD = 0.65 +/- 0.06 s). alpha-Methyldopa acts centrally and hydralazine acts peripherally. The behavioral change of SHR treated with alpha-methyldopa suggests that hypertension seems to be related to central nervous dysfunctions that are affected by an antihypertensive drug with central noradrenergic action.

Animals↗
PubMed1995

Effect of diltiazem and methyldopa on gestation-related renal complications in rats with adriamycin nephrosis. Relationship to glomerular prostanoid synthesis.

BACKGROUND: In the presence of pre-existing renal disease, occurrence of hypertension during pregnancy may compromise renal function and aggravate proteinuria. In pregnant rats with early adriamycin nephropathy, this is associated with an increase in the glomerular TxB2:PGE2 ratio. In the present study we evaluated the effect of blood-pressure control on renal function and its relationship with glomerular prostanoid synthesis. DESIGN OF THE STUDY: Pregnant Wistar rats with adriamycin nephropathy received diltiazem, 30 mg/kg/day or methyldopa, 400 mg/kg/day from mid-gestation. Mean arterial pressure (MAP), inulin clearance (CIN), urine protein excretion (UP) and glomerular prostanoid synthesis were measured. Results were compared with (i) untreated pregnant rats with adriamycin nephropathy, (ii) virgin rats with adriamycin nephropathy, and (iii) normal virgin or (iv) pregnant normal rats. RESULTS: MAP increased in untreated pregnant rats with adriamycin nephropathy (P < 0.01 versus virgin rats with adriamycin nephropathy), contrasting with the physiological decrease observed in normal pregnant rats. Diltiazem and methyldopa decreased MAP to normal values. In untreated pregnant rats with adriamycin nephropathy CIN decreased and proteinuria increased significantly at the end of gestation. Treatment with diltiazem and methyldopa augmented GFR, but only diltiazem decreased UP significantly. It was associated with an increased glomerular PGE2 synthesis. CONCLUSION: We conclude that in rats with adriamycin nephropathy, antihypertensive treatment improved GFR. Diltiazem also decreased urinary protein excretion, associated with a normalization of the glomerular TxB2:PGE2 ratio.

Animals↗
PubMed1995

Poisoning with anti-hypertensive drugs: methyldopa and clonidine.

Methyldopa and clonidine are anti-hypertensive drugs which are used less commonly nowadays. Experience of toxicity and self-poisoning with these drugs remains limited. This review examines the cases reported in the literature of overdosage or poisoning with methyldopa and clonidine, and the presenting symptoms and management in such cases. With supportive therapy, the prognosis following toxicity with methyldopa and clonidine is good. Although an initial presentation with drowsiness or coma is common, careful attention should also be directed to any cardiovascular complications.

Antihypertensive Agents↗
PubMed1977

Effect of alpha-methyldopa and alpha-methyl-m-tyrosine on the amount of noradrenaline in the heart and brain of irradiated rats.

Effect of alpha-methyldopa and alpha-methyl-m-tyrosine on the amount of noradrenaline in the heart and brain of rats irradiated with 850 R was investigated. It was established that the application of alpha-methyldopa to the animals irradiated with 650 R caused significant decrease of noradrenaline stores in the heart and brain. Meanwhile, when alpha-methyldopa was applied to the animals irradiated with 850 R, there was no further decreasing of noradrenaline. The different effects may be tentatively explained: in animals irradiated with 650 R the processes of biosynthesis are still going on, while after the dose of 850 R, biosynthesis of catecholamine is badly damaged and the further inhibition of decarboxilase is probably impossible. Alpha-methyl-m-tyrosine caused, also, the strong discharge of noradrenaline storage in the heart and brain of irradiated animals. It is interesting to note there is no significant difference in inhibitory effect on animals irradiated with 650 and 850 R, respectively.

Animals↗
PubMed1996

Quality of life in normotensives compared to hypertensive men treated with isradipine or methyldopa as monotherapy or in combination with captopril: the LOMIR-MCT-IL study.

Quality of life (QOL) measures were assessed in a multi-center, double-blind, case-controlled trial of 1 year's duration. A total of 368 hypertensive male patients were randomly assigned to monotherapies of either isradipine, methyldopa or placebo. If normotension was not achieved, captopril was added. QOL assessments in the hypertensives and in 155 normotensives included a self-structured scale to measure the subjective perception of QOL, the severity, desirability and controllability of recent critical life events, semantic memory, physical dysfunction, sleep disorders, sexual difficulties, depression and work-related stress. The overall withdrawal rate during the trial was 19%, mainly due to lack of efficacy and adverse experiences. At baseline, and at the end of the trial, the normotensives as compared to hypertensive patients, had significantly better scores in most QOL measures. Patients treated with the combination of isradipine and captopril reported more favorable changes in the subjective measure of QOL (P < 0.03) and in semantic memory (P < 0.001) than patients treated with any of the monotherapies or with methyldopa in combination with captopril. There were no statistically significant differences among treatments for changes of other indices of QOL. In most QOL measurements, normotensives rated better then hypertensives. Patients treated on long-term therapy with the combination of isradipine and captopril showed improvement in self-structured QOL measures and semantic memory, compared to patients treated either with methyldopa or placebo.

Adult↗
PubMed1976

Methyldopa-induced liver injury. Rapid progression to fatal postnecrotic cirrhosis.

A 55-year-old woman developed symptoms suggestive of hepatitis 12 weeks after first receiving methyldopa for hypertension. Liver biopsy showed chronic aggressive hepatitis with subacute hepatic necrosis. Methyldopa was discontinued, but after exhibiting transient clinical improvement, the patient's condition progressively deteriorated until she died of hepatic failure, in spite of therapy with massive doses of corticosteroids and other nonspecific measures. During the terminal stage, a considerable decrease in the size of the liver was observed. At autopsy, the liver was found to be small, shrunken, and scarred; histological sections demonstrated postnecrotic cirrhosis. Such a rapid and relentless progression of methyldopa-induced liver injury is undoubtedly rare, but it may be prevented by careful supervision of patients who exhibit liver function abnormalities early in the course of therapy.

Adrenal Cortex Hormones↗
PubMed1991

Continuous intravenous monitoring of levodopa and 3-O-methyldopa by microdialysis and high-performance liquid chromatography with electrochemical detection.

Microdialysis, in association with ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection, was applied in vitro for the determination and quantification of levodopa and 3-O-methyldopa in blank spiked plasma and blood. The method presented gave accurate results; the calibration graphs for plasma were linear over the range of the expected values for both compounds. When using a dialysis probe with a membrane length of 1.6 cm at a 5 microliters min-1 perfusion speed, the recovery rate in plasma for levodopa was 30.1% and 68.5% for 3-O-methyldopa. However, less reproducible results were obtained for plasma levodopa levels in the range of 0.5 microliter ml-1 and lower. The microdialysis technique was subsequently successfully applied for the continuous intravenous monitoring of levodopa and 3-O-methyldopa in a levodopa-treated dogs.

Animals↗
PubMed1980

Methyldopa. Mechanisms and treatment 25 years later.

Methyldopa, an adrenergic-inhibiting compound, has been used for over 25 years as a safe and effective antihypertensive agent. The postulated mechanisms for the antihypertensive action of this compound have been varied and parallel our broadening knowledge of the role of the adrenergic nervous system in controlling arterial pressure. This review outlines the mechanisms of adrenergic control of the circulation and how the proposed mechanisms of action of methyldopa (ie, dopa decarboxylation, false neurotransmission, inhibition of renin release, and stimulation of alpha receptor sites in the brain) seem to account for the depressor action of the drug. Physiologic effects as well as immunologic and other clinical effects are also discussed.

Carboxy-Lyases↗