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Biomedical subjects

M D Rawlins

Publications and source records attributed to M D Rawlins.

At least 235 records · Page 13Linked to original sources
PubMed1976

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension. I. Relationship between plasma concentration and adrenergic beta-receptor blockade.

Mean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 - 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r = 0.80, p less than 0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the beta-blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r = 0.79, p less than 0.001).

Adrenergic beta-Antagonists↗
PubMed1976

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension. II. Relationship to its effect on blood pressure and plasma renin activity.

The kinetics of alprenolol, in relation to its effect on blood pressure and plasma renin activity, have been studied in sixteen patients. A within-patient comparison was made between therapy for six weeks with placebo or alpronolol 200 mg thrice daily. Thirteen patients responded to alprenolol by a signoficant fall in blood pressure. In three other patients treatment did not lower blood pressure. In the group as a whole there was no significant correlation between the fall in systolic, diastolic or mean blood pressure, and the steady-state plasma alprenolol concentration, renin status, or degree of beta blockade. However, the thirteen responsive patients showed a significant relationship (p less than 0.05 - 0.001) between the log mean steady-state plasma alprenolol concentration and the hypotensive response.

Adult↗
PubMed1976

Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses.

A gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorathidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n = 10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those preducted from the single oral dose studies in healthy volunteers.

Adult↗
PubMed1976

Pharmacokinetics of pancuronium in patients with normal and impaired renal function.

Plasma concentrations of pancuronium were measured using a fluorimetric method in six patients with normal renal function and seven patients in chronic renal failure. A tow-compartment open model was used in the pharmacokinetic analysis of the data. With this model, the clearance of pancuronium was found to be reduced significantly in the patients with renal failure, and in these individuals the volume of the central (distribution) compartment was increased significantly. The clinical implications of these findings are discussed.

Adult↗
PubMed1975

Antinuclear antibodies during procainamide treatment and drug acetylation.

Acetylator capacity was determined in two groups of patients who had received procainamide for more than three months. In seven patients antinuclear antibodies (A.N.A.) were detected during treatment, and these changes disappeared (in six patients) or were less pronounced (one patient) after withdrawal of the drug. These patients tended to have faster acetylation rates, and five were phenotypically "rapid" acetylators. Five patients who did not develop A.N.A. during treatment had less rapid (P less than 0.05) rates of acetylation, and four were "slow" acetylators. We suggest that the immunological changes which may occur during procainamide treatment may be associated with the acetylated metabolite of procainamide rather than the parent compound and that it might be possible to identify patients at risk.

Acetylation↗
PubMed1975

Plasma concentration of alpha-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester.

The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.

Administration, Oral↗
PubMed1975

Distribution and elimination kinetics of carbamazepine in man.

Carbamazepine (2.7-3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1-7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 1/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2-3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.

Administration, Oral↗
PubMed1974

Variability in response to drugs.

Variability in the response to drugs is due to three principal components-the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.

Acute Disease↗
PubMed1974

The effects of intraventricular 6-hydroxydopamine on body temperature and arterial blood pressure in cats and rabbits.

1 In unanaesthetized cats, the administration of 6-hydroxydopamine (6-OHDA), 750 mug, via the lateral cerebral ventricle produced a pronounced fall in rectal temperature but only a slight fall when repeated 7 days later. At this time hypothalamic noradrenaline concentration had diminished to 4% of control.2 In these animals, the hypothermic response to exogenous noradrenaline, 100 mug, given via the same route was uninfluenced by pretreatment with 6-OHDA.3 In unanaesthetized rabbits, intraventricular noradrenaline, 100 mug, produced a rise in rectal temperature and a biphasic effect on arterial pressure, a rise lasting 30 min followed by a fall.4 Intraventricular 6-OHDA, 750 mug, in unanaesthetized rabbits produced a rise in body temperature and a rise in arterial pressure. The same dose given to rabbits depleted of central noradrenaline with central 6-OHDA produced rises in body temperature and arterial pressure of similar magnitude, but of slower onset.5 These results suggest that intraventricular 6-OHDA releases noradrenaline from central neurones and that these neurones subserve thermoregulatory functions in both species. In the rabbit, central noradrenergic neurones can raise arterial pressure.

Animals↗