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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 217 records · Page 12Linked to original sources
PubMed1981

Propranolol and sotalol as antagonists of isoproterenol-enhanced physiologic tremor.

Six normal subjects were studied after graded bolus injections of isoproterenol. Log dose-response curves for increases in both heart rate (mostly beta 1), and amplitude of physiologic tremor (beta 2) were constructed for each subject in the control state and 2 hr after 10 or 40 mg propranolol, 200 mg sotalol, or placebo. All heart rate curves were shifted to the right in an approximately parallel fashion by all active treatments (40 mg propranolol greater than 200 mg sotalol greater than 10 mg propranolol). The tremor curve was also shifted to the right by 10 mg propranolol in an approximately parallel fashion and to the same extent as the heart rate curve (both dose-ratios = 6.1), but the tremor curves after both 40 mg propranolol and 200 mg sotalol appeared to be flattened as well as shifted laterally. We conclude that whereas it may be possible that 10 mg propranolol acts as a competitive antagonist of isoproterenol at beta 2-sites in skeletal muscle, 40 mg propranolol and 200 mg sotalol must have additional actions in reducing isoproterenol tremor. The possibilities are discussed.

Administration, Oral↗
PubMed1981

Effect of atenolol, metoprolol, and propranolol on isoproterenol-induced tremor and tachycardia in normal subjects.

The effect of single oral doses of atenolol (100 mg), metoprolol (100 mg), propranolol (40 mg), and placebo on exercise tachycardia and on heart rate and finger tremor responses to graded injections of isoproterenol was investigated in six normal subjects. Propranolol was more potent than atenolol and metoprolol in suppressing the increase in heart rate and tremor amplitude produced by isoproterenol, even though at the dose used it was the least effective of all three drugs in decreasing exercise tachycardia. Although these data are consistent with the hypothesis that the suppression of isoproterenol-induced tremor is mediated by antagonism of peripheral beta 2-adrenergic receptors, the possibility that a separate action other than beta-blockade may contribute to the tremorolytic action of propranolol cannot be excluded. The potential usefulness of examining the effect of beta-adrenoceptor blocking drugs on isoproterenol-induced tremor and tachycardia in cardioselectivity studies is discussed.

Adult↗
PubMed1981

Metoprolol and propranolol in essential tremor: a double-blind, controlled study.

Single oral doses of propranolol (120 mg), metoprolol (150 mg) and placebo were given in a randomised, double-blind fashion to 23 patients with essential tremor. Both beta blockers were significantly more effective than placebo in reducing the magnitude of tremor. The decrease in tremor produced by metoprolol (47, sem 9%, n = 23) was not significantly different from that observed propranolol (55, sem 5%, n = 23). Tachycardia on standing was antagonised by both drugs to a similar extent. These findings suggest that metoprolol may represent a valuable alternative to propranolol in the treatment of essential tremor. The data is consistent with the hypothesis that the tremorolytic effect of beta blockers in these patients may be unrelated to peripheral beta-2 adreno-receptor blockade, being possibly mediated by other central or peripheral modes of action of these drugs. However, it cannot be excluded that at the dose used, metoprolol had lost its relative cardio-selectivity and that the reduction in tremor was mediated by competitive antagonism at beta-2 receptor sites in skeletal muscle.

Adult↗
PubMed1981

Altered drug binding to serum proteins in pregnant women: therapeutic relevance.

The binding of diazepam, phenytoin and valproic acid to serum proteins in vitro has been compared in pregnant women of different gestational ages and in controls. The unbound fraction of each of three drugs was elevated during pregnancy (particularly during the last 8 weeks) probably due, at least in part, to a fall in serum albumin concentration. These findings may provide a partial explanation for the increase in the clearance of certain drugs during pregnancy and need to be taken into account when interpreting serum drug levels in clinical practice.

Adult↗
PubMed1981

Drug interactions with phenytoin.

Drug interactions with phenytoin are a frequent occurrence, although their clinical relevance has often been overemphasised. Probably the most important of such interactions are those resulting in inhibition of phenytoin metabolism: due to the saturable nature of phenytoin biotransformation even minor degrees of inhibition can produce disproportionate changes in both steady-state serum concentration and the magnitude of pharmacological effect. Phenytoin has marked enzyme-inducing properties and can stimulate the metabolism of many concurrently administered drugs, thereby reducing their therapeutic efficacy. Clinically important examples of such interactions include a reduction of the anticoagulant effect of dicoumarol, a decrease in the prophylactic efficacy of the contraceptive pill and failure of response to various corticosteroid agents when administered therapeutically or diagnostically. Unless complicated by additional mechanisms, plasma protein binding interactions with phenytoin are seldom of clinical significance. However, they may alter considerably the relationship between serum drug concentration and clinical response, a possibility which needs to be taken into account when interpreting serum phenytoin levels in clinical practice.

Anticonvulsants↗
PubMed1980

The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy.

In a group of 5 women on long-term anticonvulsant and oral contraceptive therapy, the plasma ethynylestradiol (EE) concentration on 50 microgram EE daily was 11.1 +/- 4.5 pg/ml. These values were at the lower end of the range found in normal women in this laboratory taking 30 microgram EE daily (6-190 pg/ml). Four women have been studied prospectively for 3 months, over 1 cycle before and 2 cycles during phenobarbital 30 mg b.i.d. therapy. Significant falls in the plasma EE concentration were seen in two women (from 104.8 +/- 13.4 to 37.7 +/- 2.0 pg/ml and from 125.6 +/- 23.8 to 34.8 +/- 6.7 pg/ml p less than 0.01) and breakthrough bleeding was seen in both women. No changes in plasma concentrations of follicle stimulating hormone, progesterone, norethindrone or norgestrel were seen. There was a significant increase in the sex hormone binding globulin capacity from 100.7 +/- 5.8 to 133.3 +/- 1.2 nmoles/1 (p less than 0.05). These changes are consistent with the known microsomal enzyme inducing effect of phenobarbital.

Adolescent↗
PubMed1980

Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects.

The effect of sodium valproate (400 mg three times daily) on the disposition kinetics of intravenous phenytoin (250 mg) was investigated in seven normal subjects. After valproate, the free (unbound) fraction of phenytoin in serum rose from 9.6 +/- 0.9% (SD) to 15.6 +/- 1.4% on average (p < 0.001). The effect was associated with an increase in systemic clearance and apparent volume of distribution of total drug. There was a strong positive correlation between percent increment in each of these parameters and percent increment in unbound drug in serum. Free phenytoin concentration in serum and phenytoin concentration in saliva increased during valproate administration. As a result, both the clearance and the apparent volume of distribution of free drug were reduced. There was an increase in the renal excretion of unchanged phenytoin during valproate administration, but the effect was too small to have an appreciable influence on the overall clearance of the drug. There were no consistent changes in the excretion of the major metabolite 5, p-hydroxyphenyl, 5-phenyl, hydantoin (pHPPH), in the urine. These results suggest that valproic acid may have two separate and opposing effects on phenytoin disposition: (1) displacing phenytoin from plasma protein binding sites, thereby enhancing the systemic clearance of total drug, and (2) inhibiting phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

Adult↗
PubMed1980

Quality control in drug measurement.

Therapeutic drug monitoring of serum concentrations has become a rapidly expanding area of clinical pharmacology and is likely to remain an important growth area in the future, despite that the evidence for the efficacy of such monitoring is inconclusive except for a handful of drugs and findings that the reliability of much drug assay work is far from optimal. Nonetheless, in view of the likelihood that the use of routine monitoring will increase, the institution of quality control programs seems not only desirable, but necessary. We describe the design of Bartscontrol (formerly known as St. Bartholomew's Hospital Quality Control Scheme for Antiepileptic Drugs) and discuss the experience of this program. Although the feedback provided to the participants of such a program seems to encourage an overall increase in precision, our findings also indicate that some laboratories perform consistently badly. While the data generally do not reveal that variations in precision are due to analytical method employed, a scheme such as the one described can occasionally make the important finding that a particular technique is inappropriate, as was found for the case of spectrophotometry for phenytoin.

Anticonvulsants↗
PubMed1980

A comparative study of antipyrine and lignocaine disposition in normal subjects and in patients treated with enzyme-inducing drugs.

1 The disposition kinetics of lignocaine and antipyrine were compared in eight normal subjects and in eleven patients receiving chronic therapy with antiepileptic drugs. The urinary excretion of D-glucaric acid (D-GA) was measured in 16 subjects. 2 In patients treated with antiepileptic drugs antipyrine clearance and D-GA excretion were significantly increased, whereas lignocaine biovailability was significantly reduced. 3 When all the subjects included in the study were considered, a significant positive correlation could be found between the apparent oral clearance of lignocaine (Dose/area under the blood concentration curve) and both antipyrine clearance (r = 0.73) and D-GA excretion (r = 0.74). 4 When normal subjects and epileptic patients were considered separately, a significant positive correlation could be confirmed between the apparent oral clearance of lignocaine and both antipyrine clearance (r = 0.71) and D-GA excretion (r = 0.76) in normal subjects, and between antipyrine clearance and D-GA excretion (r = 0.75) in epileptic patients. 5 These results suggest that the reduction of the oral availability of lignocaine in epileptic patients is secondary to induction of first-pass metabolism of the latter drug.

Adolescent↗