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PubMed1985

Antihypertensive treatment in pregnancy: analysis of different responses to oxprenolol and methyldopa.

One hundred and eighty three hypertensive pregnant women were randomly assigned to antihypertensive treatment with oxprenolol (96 women) or methyldopa (87 women). Control of hypertension was equivalent in both treatment groups, and in 64 (35%) cases hydralazine had to be added to the treatment to achieve the therapeutic goal (diastolic blood pressure below 85 mm Hg). Five perinatal deaths occurred, one in the oxprenolol group and four in the methyldopa group. Detailed analysis confirmed a previous report of greater fetal growth in the group treated with oxprenolol; this trend was present regardless of severity of hypertension and parity. With increasing duration of treatment the differences between the two groups diminished, and there was no difference after 10 weeks of treatment, a finding that may explain some of the reported discrepancies among therapeutic studies. As hypertension in pregnancy may pursue an accelerated course, necessitating urgent delivery, and there is no satisfactory method of predicting the duration of treatment in individual patients fetal benefit is most likely to be achieved by treatment with oxprenolol, provided that there is no maternal contraindication to treatment with beta blockers.

Adult↗
PubMed1971

Enhancement of methyldopa metabolism with barbiturate.

The spurious increase in serum catecholamine levels associated with methyldopa treatment can be reduced by the simultaneous administration of phenobarbitone. This accelerating effect of phenobarbitone on methyldopa metabolism has been demonstrated in relation to both adrenaline and noradrenaline, and investigations suggest that it is due to the effect of barbiturate on the activity of metabolizing enzymes.

Catecholamines↗
PubMed2003

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy volunteers.

The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C(max) 1.99 vs. 0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18 mg x h x l-1). The respective values after multiple doses (day 8) were: C(max) 1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96 mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C(max) within a predefined range of 80-125 and 70-143%, respectively. In conclusion, the observed differences in C(max), t(max) and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.

Adult↗
PubMedDate not supplied

Collagen metabolism and reversal of aortic medial hypertrophy in spontaneously hypertensive rats treated with methyldopa.

Collagen synthesis, content, and concentration were determined in the hypertrophied intima media of thoracic aortas from 10-, 15-, and 20-week-old spontaneously hypertensive rats (SHR). Although the rates of aortic collagen synthesis declined with age, the dry weight of the intima media and the total collagen content increased proportionally. Collagen concentration thus remained unchanged. Methyldopa was administered orally to SHR when they were 12 to 15 weeks of age, when their body weight were identical to the untreated group. Blood pressure and the degree of aortic medial hypertrophy, judged by medial dry weight per kilogram body weight, were significantly lower compared with untreated SHR. Collagen synthesis was likewise decreased to a mean rate not significantly higher than age-matched normotensive Wistar-Kyoto controls. This reduction in collagen synthesis, however, was not sufficient to decrease measurably the total collagen content of the aortas compared with untreated SHR. Since medial dry weights were lower in the treated rats, collagen concentration in aortas from SHR given methyldopa for 3 weeks was actually increased. The increase in collagen concentration also suggests that medial hypertrophy was reversed.

Aging↗
PubMedDate not supplied

Antihypertensive metabolites of alpha-methyldopa.

alpha-Methyldopa acts through a metabolite in the central nervous system. Of the three metabolites most prominently considered as potential mediators of alpha-methyldopa hypotension--alpha-methyldopamine, alpha-methylnorepinephrine (MNE), and alpha-methylepinephrine (ME)--ME is the most potent depressor agent following intravenous infusion into rats, following injection into the lateral ventricle, and following injection into the solitary tract nucleus (NTS). The depressor effect of ME in the NTS is attenuated as effectively by timolol as by yohimbine, while the combination of both timolol and yohimbine completely abolishes the pharmacological activity of ME in the NTS. ME is approximately eightfold more potent than MNE in the NTS and also has a greater susceptibility to timolol attenuation.

Animals↗
PubMedDate not supplied

Fifteen-year survival of patients beginning treatment with methyldopa between 1962 and 1966.

The 15-year survival of a group of 205 patients who started treatment in the period 1962 through 1966 and who received methyldopa for two-thirds or more of the time has been investigated. At entry these patients had severe hypertension with an average pretreatment pressure of 216/126 mm Hg. Twenty-one percent had retinal hemorrhages, cotton-wool spots, or papilledema. Blood pressure showed a large fall in the first year, followed by a small, progressive, further fall up to the sixth year. After 5 years of treatment the blood pressure averaged 144/90 mm Hg in men and 151/91 mm Hg in women. The average daily dose of methyldopa was approximately 1500 mg and changed little over the 15-year period. Survival was analyzed by life tables. Approximately 81% of men and women aged 30 to 49.9 years at entry were still alive 10 years later. In the age group 60 to 69.9 years, 53.8% of men and 63.2% of women were still alive 10 years later. Seventy-nine of the patients died during the follow-up period, 89% from cardiovascular or renal disease. Ischemic heart disease (40%) was the major cause of death, followed by stroke (19%). No patients died from drug toxicity.

Adult↗
PubMed1978

A randomized crossover comparison of acebutolol and methyldopa in the treatment of mild to moderate essential hypertension.

In a randomized crossover comparison between acebutolol and methyldopa for the treatment of mild to moderate essential hypertension in 30 patients, acebutolol, a cardioselective beta-one-adrenergic blocker, at 400 to 800 mg daily was found to be significantly better (p less than 0.002) than 500 to 1000 mg methyldopa daily in reducing both systolic and diastolic blood pressures and pulse rate. Patient compliance with therapy was excellent, and there were no side-effects on acebutolol, whereas patients on methyl-dopa reported a significant number of side-effects (p less than 0.002). The potassium-sparing effect due to acebutolol was significant (p less than 0.005) and this has not been reported before. This may be beneficial in diuretic-induced hypokalaemia in the hypertensive patient.

Acebutolol↗
PubMed1984

The correlation of changes in systolic blood pressure with regional anatomical regression of hypertensive left ventricular hypertrophy in patients on chronic antihypertensive therapy (greater than 1 year): alpha-methyldopa compared to propranolol.

Twenty patients with mild to moderate hypertension and evidence of left ventricular hypertrophy (relative wall thickness greater than or equal to 0.45), who previously had not received either alpha-methyldopa or propranolol, were allocated at random to treatment with one or other of these drugs as monotherapy after a 2-week baseline period on no medication. Dosage was titrated until normotension was attained and patients were then maintained on this treatment for a year. Analysis of blood pressure measurements and echocardiograms taken before and during maintenance therapy showed that there were significantly correlated changes in systolic blood pressure and heart rate with left ventricular cavity and regional wall changes during chronic drug administration. In the alpha-methyldopa group there were significant correlations between changes in erect and supine systolic blood pressure and the posterior wall index, and in erect systolic blood pressure and left ventricular mass. In the propranolol group, there were significant correlations between changes in supine systolic blood pressure and interventricular septal thickness, and in erect heart rate and supine systolic blood pressure with the percentage change in internal diameter of the left ventricle. It is suggested that these observations may have important therapeutic implications for hypertensive patients with documented left ventricular hypertrophy.

Adult↗
PubMed1981

Systemic lupus-like syndrome induced by methyldopa therapy.

Pleural pericarditis, fever, and a positive reaction for antinuclear antibody developed in a 50-year-old white woman while she was receiving methyldopa (500 mg daily). After withdrawal of the drug, there was complete resolution of the clinical signs and symptoms, as well as normalization of the patient's antinuclear antibody titer. To our knowledge, this is the first reported case of a clinical lupus-like syndrome induced by therapy with methyldopa.

Antibodies↗
PubMed1981

Morphologic alterations in patients with alpha-methyldopa-induced liver damage after short- and long-term exposure.

Alpha-methyldopa-induced histologic alterations were investigated in 21 patients with hepatic injury after short- and long-term exposure. Seven patients developed liver injury within 6 months and 24 after several years (mean, 5 years) of exposure. Histologic findings and clinical and biochemical data differed significantly in the two groups. Morphologic analysis of the short-term-treated group revealed marked parenchymatous degeneration, focal, confluent and massive necrosis, and inflammation. Fatty accumulation and increased fibrous trabeculae were characteristic for the patients treated for long term. All patients in the short-term-exposed group had acute and severe hepatitis. Four of them had icterus. Two patients died of hepatic coma. Patients in the long-term-treated group had for several months initially mild but increasing discomfort, dyspepsia, nausea, and colics. Liver function tests in these groups revealed differences in serum albumin, bilirubin, and transferase levels. No changes were observed in alkaline phosphatase and Thrombotest. Fat accumulation and fibrous trabeculae suggest that the alterations precede the clinical symptoms and biochemical signs of hepatitis. The findings show that alpha-methyldopa may induce hepatocellular injury after short- and long-term exposure.

Adult↗
PubMed1977

Lithium carbonate and methyldopa: apparent interaction in man.

An experimental subject with a stable serum level of lithium experienced symptoms of lithium toxicity when he ingested methyldopa. Physicians prescribing either or both of these drugs should be aware of this apparent interaction between lithium and methyldopa.

Adult↗
PubMed1976

Bilateral renal calculi in patients receiving methyldopa.

Two patients with bilateral kidney stones had been taking methyldopa for 8 years and 10 years respectively. Their urine contained a brown pigment which darkened and precipitated on standing. This substance was identified as methlydopa. No other cause for stone formation was found, so it is suggested that the methyldopa, because of its poor solubility, provided a nidus for stone formation.

Adult↗
PubMed1977

Less common side effects of methyldopa.

A patient with methyldopa-induced hyperpyrexia who also developed positive antinuclear factors, LE cells and ocular disturbance is described. These side effects disappeared when the drug was withdrawn. The incidence of these side effects is reviewed. Methyldopa should be withdrawn when these side effects appear, as less troublesome antihypertensive drugs are now readily available.

Aged↗
PubMed1986

Methyldopa: an often overlooked cause of fever and transient hepatocellular dysfunction.

The clinical features and laboratory findings of 78 cases of methyldopa fever are reported. This drug reaction masqueraded as a variety of acute infectious diseases including septicaemia, meningitis, hepatitis and gastroenteritis, occurred within five weeks of starting the drug and appeared to be unrelated to its dosage. Eosinophilia and skin rashes were conspicuous by their absence. In the majority of patients, symptoms were relieved within 48 hours of the withdrawal of the drug. Sixty-one per cent of patients had biochemical evidence of liver damage but jaundice was uncommon. This pattern of mild hepatotoxicity in patients with early febrile reactions to methyldopa contrasts with the later more serious viral hepatitis-like illness due to the drug.

Adult↗
PubMed1975

Efficacy of an antihypertensive agent. Comparison of methyldopa and hydrochlorothiazide in combination and singly.

In a double-blind evaluation, the efficacy of a combination of methyldopa with hydrochlorothiazide was compared with that of its components, methyldopa and hydrochlorothiazide. The combination was found to be more efficacious than either of its components. It reduced the arithmetic mean of the pressures of all patients from 170/116 to 133/95 mm Hg in four weeks. Despite the greater effect of the combination, side effects were mild.

Adult↗
PubMed1976

Some side-effects of alpha-methyldopa.

Three different regimens of drug treatment for hypertension were compared with regard to the development of undesirable side-effects in a group of 53 patients attending a hypertension clinic. The combination of alpha-methyldopa and chlorthalidone produced the highest incidence of side-effects. Weakness and impotence were most frequently encountered. In contrast, the combination of chlorthalidone, hydralazine and propranolol, and chlorthalidone alone, produced fewer side-effects. It is recommended that alpha-methyldopa should not be a first choice in the treatment of hypertension.

Adult↗
PubMed1977

[The problems of adverse effects to the liver of alpha-methyldopa].

In 20 patients who were treated with alpha-methyldopa since at least one year the bilirubin content, the activities of aspartate and alanine-aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase as well as the retention of bromsulphalein were determined. In altogether 10 patients pathological findings of laboratory examinations were the result. The gamma-glutamyl transpeptidase activity proved to be particularly sensitive. By means of biopsy in 3 of these patients a fatty degeneration of the liver in stage I and in 4 of them a fatty degeneration of the parenchyma cell of minor degree were proved. A connection between duration and dosage of the treatment with alpha-methyldopa and these hepatological findings could not be ascertained statistically.

Adolescent↗
PubMed1990

Methyldopa, intravascular haemolysis and renal disease. A case report.

A 74-year-old man, who was receiving methyldopa to control systemic hypertension, presented to hospital in biventricular cardiac failure. He was found to be severely anaemic and jaundiced as a result of acute intravascular haemolysis with prominent haemoglobinuria. The cardiac failure and anaemia were initially refractory to fluid restriction and diuretics, but responded to red cell transfusion. Renal failure supervened, probably on the basis of hypoperfusion as a consequence of diuresis and hypotension. The patient died suddenly, possibly from myocardial infarction. Acute intravascular destruction of red cells in association with methyldopa appears not to have been previously reported.

Acute Kidney Injury↗