Absence of polymorphism of sparteine oxidation in the South African Venda.

1 This study has found no occurrence of poor metabolism of sparteine within a South African Venda population of 97 subjects. 2 On the basis of MR (metabolic ratio) the mean and distribution of the results are very similar to those found in Ghanaians. 3 The distribution is also similar to that for fast metabolizers in Caucasians. 4 It is concluded that different P450 cytochromes are responsible for immediate oxidation of debrisoquine and sparteine, but that both may be activated by the same P450 reductase.

Atropine and verapamil interactions in healthy volunteers.

The calcium antagonist falipamil, a chemical congener of verapamil, has anticholinergic properties. It was decided to study the interaction of verapamil with the anticholinergic drugs, atropine and pirenzepine, using healthy male volunteers. After atropine alone a significant tachycardia developed at 2 min and remained significant up to 90 min. Verapamil pretreatment followed by atropine administration resulted in a significantly greater tachycardia. Pirenzepine alone caused a bradycardic response which was accentuated after verapamil pretreatment. It is postulated that short term verapamil administration is accompanied by reflex activation of the sympathetic nervous system which does not manifest with a tachycardia owing to combined influence of verapamil and vagus on the sino-atrial node. Reduction of vagal tone with atropine treatment results in sympathetic overriding of the sino-atrial suppression, thus causing an additive tachycardia. The clinical use of atropine for prolonged verapamil-induced atrio-ventricular conduction is supported by these results.

The effect of verapamil on cardiac sympathetic function.

We have used systolic time intervals (STI) to measure inotrophy and chronotropy as indirect measures of the actions of noradrenaline, in order to ascertain whether the depletion of cardiac noradrenaline stores which has been shown to occur in laboratory rats after chronic verapamil treatment could be demonstrated in healthy volunteers. Placebo, verapamil, or atenolol were given by slow intravenous injection to 8 healthy volunteers and QS2I, LVETI, and PEP/LVET were measured. Verapamil pretreatment resulted in a positive inotropic state. Intravenous verapamil after oral pretreatment caused accentuated negative inotropic and chronotropic responses as compared with acute verapamil without pretreatment. We postulate that the observed initial inotropic effect may be in part due to an increase in the amount of noradrenaline available to the myocardium intrasynaptically, and that the accentuated negative response after intravenous or oral verapamil may result from a decrease in cardiac noradrenaline storage.

The effect of autonomic blockers on heart rate: a comparison between two ethnic groups.

The influence of autonomic blockers on the heart rate of ten Bushmen and eight White volunteers was studied. There were significant differences in heart rate response to atropine alone between the White's and Bushmen. However, after prior beta-adrenoceptor blockade, these differences were no longer significant. It is postulated that a varying pharmacogenetic sensitivity to autonomic blockers may result from inequality of vagal or sympathetic tone.

Inotropic effects of ranitidine.

The purpose of this controlled study was to study the effect of cimetidine and ranitidine on the myocardium of 8 healthy male volunteers using systolic time intervals. Ranitidine caused a significant decrease in the QS2I, as from 40 min indicating a positive inotropic effect. There were no significant changes in heart-rate or blood-pressure. It is postulated that ranitidine, differing structurally from cimetidine, may have a higher affinity for H2-presynaptic receptors at the sympathetic myocardial junction resulting in an increase in noradrenaline and an increased inotropic effect.

Paracetamol conjugation: an interethnic and dietary study.

To test whether dietary or hereditary factors affect paracetamol metabolism, two groups of Venda and a group of Caucasian medical students were investigated. The Venda groups were selected as traditionally living villagers and those who followed a Western life-style. Salivary concentrations of paracetamol and urinary amounts of the glucuronide and sulphate metabolites eliminated over 22 h were determined by HPLC. The metabolite formation rate constants and the percentage of the dose eliminated as each metabolite were calculated. No significant differences were found between the data for total Venda, rural Venda, westernized Venda and Caucasian students for the calculated metabolite parameters. Thus environmental effects showed no apparent influence on the sulphide and glucuronide conjugation of paracetamol, and no hereditary effect was evident between the Venda and Caucasians.

Antipyrine metabolism in the Venda.

The excretion of antipyrine metabolites over 48 h as percentage dose and the antipyrine kel and metabolite formation rate constants have been measured for 20 healthy Venda Africans. To allow comparison with published data from inter-ethnic studies with antipyrine, subjects were selected who had assumed a western life and diet. The values (mean +/- SE) for excretion of the metabolites, 4-hydroxyantipyrine (4OHA), norantipyrine (NORA) and 3-hydroxymethylantipyrine (3HMA) as percentage dose were 26.17 +/- 0.34, 7.44 +/- 0.34 and 13.28 +/- 0.31 respectively. The total of the three metabolites was 49.56 +/- 0.33. These results differ significantly from the values found for groups of Canadian students of Oriental and Caucasian backgrounds. The values (mean +/- SE) found for the antipyrine elimination rate constant and the metabolite formation rate constants of 4OHA, NORA and 3OHA were 6.56 (+/- 0.56) X 10(-2), 2.05 (+/- 0.24) X 10(-2), 0.60 (+/- 0.09) X 10(-2) and 1.06 (+/- 0.16) X 10(-2) respectively. Only the NORA formation rate constant showed any significant difference with the results obtained for Americans, although the Venda exhibited a wider distribution of the 3HMA data. The linearity of the probit plots obtained suggest that the subjects selected are homozygous for the oxidations investigated. The marked difference found in comparison with Caucasian and Oriental data on the one hand and American data on the other, also implies a marked difference between the Caucasian and Oriental data and the American data.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenergic blocking drugs and renal function.

A baboon model was used to investigate the effects of atenolol, nadolol, sotalol and labetalol on renal function. The glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, using radionuclides and a gamma camera, before and after 1 week's oral administration of these drugs. All the drugs caused an increase in the GFR, but this reached statistical significance only in the cases of sotalol (P less than 0,025) and labetalol (0,05 less than P less than 0,10). The RBF was not significantly changed, although it decreased in all cases.

Digoxin withdrawal in patients with sinus rhythm.

The need for maintenance treatment with digoxin was assessed in 10 elderly outpatients with sinus rhythm. Digoxin was withdrawn on the first day of the trial but any other treatment remained unchanged. The participants were seen once weekly on the same day for 5 consecutive weeks and assessed clinically, by the calculation of systolic time intervals and by M-mode echocardiography. In 2 patients the clinical condition deteriorated but in the rest digoxin was stopped without detrimental effects. Therefore, in the patient population selected, maintenance treatment with digoxin was deemed unnecessary in 90% of cases.