Effect of methyldopa treatment on cardiac function and myocardial blood flow in mongrel dogs.

Administration of methyldopa (100 mg/kg, orally twice daily for a period of 3 days) to mongrel dogs produced significant reductions in blood pressure and heart rate. The hypotensive effect of the drug was due to a reduction in peripheral resistance. Methyldopa treatment also produced a significant decrease in coronary vascular resistance. Studies on the left ventricular function indicated that treatment with methyldopa does not compromise the ability of the myocardium to respond to an increased work load. Thus, the beneficial effect of this agent on the myocardial circulation, together with its lack of any detrimental effect on the cardiac function suggest that methyldopa may be an effective agent for the control of hypertension.     

Interaction between Levodopa and Methyldopa

The interaction between methyldopa and levodopa was studied in 18 patients with Parkinsonism. Together they produced a fall in blood pressure in doses which when given alone had no effect or only a slight hypotensive effect. Severe hypotension never occurred. It is reasonable to give methyldopa to hypertensive patients on levodopa but the regimen should be initiated in hospital.     

Effect of phenobarbitone on the nucleocytoplasmic transport of ribonucleic acid in vitro.

The transport of nucleic acids from the nucleus to the cytoplasm is a potential site for modification of normal cellular processes by drugs and hormones. In this study the effect of phenobarbitone on nucleocytoplasmic transport of ribosomes was measured in an assay system in vitro. The transport of radioactive ribosomes from isolated rat hepatic nuclei to unlabelled post-microsomal supernatant was measured in rats treated with 80 mg of phenobarbitone/kg body wt. or saline 3h before death. With either treatment, transport was linear with time, and dependent on temperature and the presence of ATP. However, phenobarbitone treatment increased transport of ribonucleoproteins over saline-treated animals nearly twofold. The effect of phenobarbitone was mediated through the cytosol, but was not the result of altered stability of the RNA transported to the cytosol. Cycloheximide (5 mg/kg body wt.) given 3.5 h before death inhibited the stimulation of transport by phenobarbitone. The data indicate that phenobarbitone increased the transport of RNA by stimulating the synthesis of cytosol factors that regulate transport of RNA from the nucleus.     

Characterization of alpha-adrenoceptors involved in central thermoregulation in rabbits

Intracerebroventricular (icv) injection of methyldopa induced body temperature changes in the rabbits. The dose of 100 micrograms/kg did not produce any significant change on body temperature whereas 250 micrograms/kg of the drug induced hyperthermia. Higher dose of 500 micrograms/kg produced initial hypothermia which was followed by hyperthermia. On further increase of the dose to 1 mg/kg, consistent hypothermia was evident. Prazosin, a specific post-synaptic alpha 1 adrenoceptor blocker, induced hypothermia whereas piperoxan (presynaptic alpha 2 antagonist) produced hyperthermia. The pretreatment with prazosin, blocked the hyperthermic response of methyldopa. The initial hypothermia by 500 micrograms/kg of methyldopa was also potentiated. The pretreatment with piperoxan completely blocked the hypothermia but had no effect on hyperthermic response of methyldopa. Pretreatment of rabbits with both prazosin and piperoxan completely blocked the hypothermia as well as hyperthermic response of methyldopa. Thus it appeared that both presynaptic alpha 2 and postsynaptic alpha 1 adrenoceptors are involved in central thermoregulation in rabbits.     

Methyldopa and propranolol or practolol in moderate hypertension.

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.     

Pretreatment with phenobarbitone modifies suppressant effect of cyclosporine on wound healing

Cyclosporine has been reported to suppress the tensile strength of healing incision wound. Prednisolone, an inducer of hepatic microsomal enzymes, abolished the tensile strength suppressant effect of cyclosporine. Cyclosporine is metabolized by the hepatic cytochrome P-450 enzymes. Induction of microsomal enzymes with phenobarbitone was evaluated for its effect upon the wound healing suppressant effect of cyclosporine. Pretreatment of male rats with phenobarbitone (75 mg/kg/day, ip) for 3 days resulted in alleviating the tensile strength suppressant effect of cyclosporine (5 mg/kg/day, po for 10 days). Phenobarbitone, per se, did not affect the tensile strength. That phenobarbitone prevents cyclosporine induced nephrotoxicity without affecting the humoral immunosuppressant action of cyclosporine has recently been reported. The possibility of modulating microsomal enzymes with phenobarbitone offers another approach in preventing cyclosporine-associated toxicities during immunosuppression.     

Atenolol,methyldopa, and chlorthalidone in moderate hypertension.

Combined treatment with low doses of different drugs is widely used for moderate hypertension. The effects of atenolol and methyldopa at two dose levels and in combination at the lower doses were studied in patients with moderate hypertension on continuous treatment with moderate hypertension on continuous treatment with chlorthalidone. The mean reduction in standing blood pressures obtained with atenolol 150 and 300 mg/day was about 27/17 mm Hg and with methyldopa 750 and 1500 mg/day about 28/14 mm Hg. Combined treatment with atenolol 150 mg/day and methyldopa 750 mg/day for four weeks resulted in a reduction of 38/25 mm Hg. No difference was observed between the two doses of methyldopa. The lower dose of atenolol was better than the lower dose of methyldopa in reducing lying and standing diastolic blood pressures. These findings show that in patients on continuous treatment with chlorthalidone the addition of atenolol alone or methyldopa alone or of atenolol and methyldopa in combination is effective in the treatment of moderate hypertension.     

Phenobarbitone-induced stimulation of protein synthesis in liver of diabetic rat.

The effect of phenobarbitone on liver weight, on the rate of protein synthesis and on the sedimentation profiles of polyribosomes from livers was studied in diabetic rats. The rate of protein synthesis by isolated postmitochondrial supernatants from diabetic rats is lower than that from normal animals. The analysis of polyribosome profiles and the effect of Sephadex chromatography on protein synthesis demonstrated that the reduction was dependent in part on polyribosomal disaggregation and in part on the presence in the cytosol of low molecular weight inhibitor(s). Phenobarbitone administration had the same effect in either diabetic or normal rats in that it increased, (a) the degree of polyribosomal aggregation, (b) the rate of protein synthesis by the isolated postmitochondrial supernatants, (c) liver weight and (d) the activity of the inducible enzyme, NADPH-cytochrome c reductase. Both polyribosomal and soluble factors appear to be involved in the phenobarbitone effect. As the diabetic rats do not secret insulin the results suggest that insulin is not involved in the control of protein synthesis by phenobarbitone. It is suggested that the intracellular redox state has a major influence on the rate of protein synthesis.     

Effects of methyldopa on prolactin and growth hormone.

The effects of administration of methyldopa on serum prolactin and growth hormone (GH) concentrations in hypertensive patients were studied. Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In patients treated with methyldopa for two to three weeks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive patients. In contrast, patients treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal.     

Methyldopa Liver Damage

Twenty patients are described in whom liver damage appeared to be directly related to the administration of methyldopa. Sixteen had hepatitic syndromes from which they recovered on stopping methyldopa; four of these patients had recurrences of jaundice after a second course of the drug. Features suggestive of active chronic hepatitis were found in two patients. There were two deaths attributed to methyldopa, one of these being in a patient with pre-existing undiagnosed macronodular cirrhosis.     

The effect of phenobarbitone on protein synthesis by liver polyribosomes in fed and starved rats.

1. The effect of phenobarbitone on the rate of protein synthesis and on the sedimentation patterns of various liver subcellular fractions containing ribosomes was studied in rats. 2. Phenobarbitone treatment increased the incorporation of [114C]leucine into protein by all preparations, provided they had not been subjected to preliminary treatment with Sephadex G-25. The phenobarbitone-induced effect on incorporation was associated with a gain in liver weight and a higher degree of polyribosomal aggregation. 3. Preparations that were treated with Sephadex G-25 incorporated more radioactivity into protein, but did not show the response to phenobarbitone treatment. 4. When the influence of starvation and phenobarbitone was studied separately on membrane-bound and membrane-free polyribosomes, it was shown that whereas both classes of polyribosomes were affected by starvation, apparently only the former class was susceptible to phenobarbitone stimulation of protein synthesis. 5. The decreased capacity for protein synthesis of polyribosomes from starved rats was independent of their association with the membranes of the endoplasmic reticulum, but resulted from polyribosomal disaggregation, from an intrinsic defect of the polyribosomes themselves and from changes in composition of the cell cap. 6. The results are discussed in relation to the problem of the control of protein biosynthesis and of the functional separation of membrane-bound and membrane-free polyribosomes.     

Cytochrome P-450 inducer/inhibitor effects on cell cultures of Catharanthus roseus

Cytochrome P-450 inducers phenobarbitone and β-naphthoflavone and cytochrome P-450 inhibitor ketoconazole were examined for their effect on Catharanthus roseus. Treatment was during growth on medium M3 which supports alkaloid synthesis. The inhibitor ketoconazole was found to inhibit serpentine accumulation prior to an effect on growth, while the inducers inhibited growth and in the case of phenobarbitone increased serpentine accumulation. No direct evidence of induction or inhibition of plant cytochrome P-450 is shown and the results are discussed in relation to possible effects on geraniol hydroxylase and other plant cytochromes P-450.     

A Within-patient Comparison of Debrisoquine and Methyldopa in Hypertension

In a titrated dose cross-over trial of debrisoquine and methyldopa in 38 hypertensive patients neither drug was superior in lowering supine or standing diastolic pressure with a minimum of side effects. Methyldopa caused significantly greater reduction of supine (P<0·001) and standing (P<0·02) systolic pressure but caused intolerable side effects in two patients. Tiredness was the most characteristic and troublesome side effect with methyldopa and postural hypotension was prominent in patients while on debrisoquine.     

Change of toxic and antineoplastic properties of ftorafur by means of action on nonspecific microsomal oxidase]

The inducers of microsomal hydroxylases, phenobarbitone and methylcholanthrene, inhibited the development of neurotoxic shock provoked by high doses of ftorafur in mice, but stimulated the animal mortality on the 4th-8th day after the drug administration. The opposite effect on both toxicity manifestations has been obtained under the action of the inhibitor SKF 525-A. Pretreatment of the animals with phenobarbitone or phenobarbitone-methylcholanthrene combination markedly increased the antineoplastic activity of ftorafur determined by a loss of the spleen weight in mice infected with Rauscher's leukemia.     

Anticonvulsants and thyroid function.

Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3.     

Pituitary responsiveness to gonadotrophin-releasing and thyrotrophin-releasing hormones in children receiving phenobarbitone.

The effect of long-term treatment with phenobarbitone on pituitary responsiveness to gonadotrophin-releasing hormone and thyrotrophin-releasing hormone was studied in 20 boys being treated with the drug to prevent febrile convulsions. Baseline concentrations of luteinising and follicle-stimulating hormones were reduced as well as the responses of these hormones to stimulation with gonadotrophin-releasing hormone. Baseline prolactin concentrations were raised in comparison with those in normal children. The response of prolactin to thyrotrophin-releasing hormone, however, was impaired only in the children who had been receiving the drug for a long time. Phenobarbitone had no effect on the secretion of growth hormone. Further studies should be carried out to ascertain how long these effects on pituitary function last after phenobarbitone is withdrawn and whether this interference with pituitary function modifies the child''s subsequent development.     

A novel support for laccase immobilization: cellulose acetate modified with ionic liquid and application in biosensor for methyldopa detection

A material based on cellulose acetate (CA) and the room temperature ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (BMI·N(Tf)(2)) was developed and characterized by scanning electron microscopy, electron dispersive spectroscopy and infrared analysis. Laccase (Lac) from Aspergillus oryzae was immobilized in this material to investigate the behavior of methyldopa by square-wave voltammetry. Under optimized conditions, the Lac biosensor based on CA/BMI·N(Tf)(2) exhibited an excellent electrocatalytic performance: the analytical curve showed good linear range for methyldopa concentrations from 34.8 to 370.3 μM with a detection limit of 5.5 μM. This sensor demonstrated acceptable stability (ca. 60 days; at least 350 determinations), good repeatability and reproducibility (relative standard deviations of 1.5 and 4.3%, respectively). The recovery study of methyldopa in pharmaceutical formulations ranged from 94.1 to 105.9%. The determination of this substance using the biosensor compared favorably with that using a spectrophotometry procedure at the 95% confidence level, and indicated potential application to methyldopa determination in pharmaceutical samples.     

Evaluation of mutagenic effect of the antihypertensive drug methyldopa (Aldomet) on mammalian systems in vivo and in vitro and on Allium cepa

The antihypertensive drug methyldopa (Aldomet) was tested for possible clastogenic activity on normal and hypertensive rats and on human lymphocyte cultures and for its influence on the cell cycle of Allium cepa. The drug had no clastogenic effect on rat bone marrow cells but showed a toxic effect on A. cepa root tip cells and significantly increased the frequency of sister-chromatid exchanges in lymphocyte cultures, without any effect on the frequency of chromosome aberrations.     

Randomised comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy.

Fifty-three pregnant women with moderately severe hypertension were randomly allocated to treatment with methyldopa or oxprenolol. There were no significant differences between the groups in age, height, weight, parity, or stage of gestation at the start of treatment. The outcome of pregnancy was better in the group treated with oxprenolol, with greater maternal plasma volume expansion and placental and fetal growth. No intrauterine deaths occurred in either group, and antepartum fetal distress, detected by oxytocin challenge testing, was evident in only one patient, who received methyldopa. This infant, and one other in the methyldopa group, died in the neonatal period. No neonatal deaths occurred in the oxprenolol-treated group. Even in this small number of patients these results were considerably better than those in untreated women with hypertension of similar severity. Apgar scores in both groups were equivalent at birth, while blood sugar concentrations were higher in the oxprenolol group. Oxprenolol appears to be safe and effective in controlling hypertension during pregnancy. There was no evidence of harmful effects on the fetus, and oxprenolol may offer a selective advantage over methyldopa for fetal growth and wellbeing in utero.