Effect Of Single Oral Dose Research Articles

Central effects of single oral doses of propranolol in man.

The central effects of propranolol, a lipophilic beta-adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.

Analgesic Efficacy of Dextropropoxyphene and Dextropropoxyphene-containing Combinations: a Review

Twenty years ago, as part of a review of the clinical pharmacology of mild analgesics (Beaver, 1965, 1966), I evaluated reports of those analgesic trials of dextropropoxyphene that appeared to satisfy the minimum methodologic requirements for a controlled clinical trial of analgesic efficacy. On reviewing reports of studies that have been published since then, I find little need to modify my evaluation of the efficacy of dextropropoxyphene that appeared in 1966, at least in respect to the effect of single oral doses: In summary, dextropropoxyphene (hydrochloride) is a mild oral analgesic which has proven superior to placebo in doses of 65 mg or more but which is of questionable efficacy in doses lower than 65 mg. The drug is definitely less potent than codeine: the best available estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately 1/2-2/3 as potent. Likewise, dextropropoxyphene in 32-65 mg doses is certainly no more, and possibly less, effective than the usually used doses of aspirin or A.P.C. (aspirin/phenacetin/caffeine). In the interim, the efficacy of dextropropoxyphene has been the subject of a number of other critical reviews (Miller et al., 1970; Miller, 1977), commentaries (Kiplinger & Nickander, 1971; Lasagna, 1976), and even congressional hearings (Beaver, 1979; Moertel, 1979). More importantly, new controlled clinical trials involving dextropropoxyphene hydrochloride or napsylate have been reported, and some of these use more sophisticated design and analysis than those available in 1966. I will therefore discuss the results of those newer studies of apparently suitable scientific design that meet at least the minimum criteria for a valid clinical assay of analgesic activity (Beaver, 1965; Houde et al., 1965,1966; Wallenstein & Houde, 1975; Beaver, 1983), and I will comment on only a few of the studies included in my previous review (Beaver, 1966).

The H1-antagonist mequitazine: studies on performance and visual function.

The effects of single oral doses of mequitazine (5 and 10 mg), terfenadine (60 mg) and triprolidine (10 mg) as active controls, and placebo were evaluated on visuo-motor coordination, digit symbol substitution, critical flicker fusion and dynamic visual acuity, and on subjective assessments of mood and well-being in six normal female volunteers. The study was double-blind. Mequitazine (5 mg) impaired visuo-motor coordination 7.5 h after ingestion (considered to be a chance result), but there was no effect on digit symbol substitution, critical flicker fusion threshold or dynamic visual acuity. Mequitazine (10 mg) impaired visuo-motor coordination and reduced the number of substitutions on the digit symbol substitution test. Terfenadine (60 mg) had no effect on performance or on subjective feelings. Triprolidine (10 mg) impaired visuo-motor coordination, reduced the number of substitutions on the digit symbol test, lowered the critical flicker fusion threshold and reduced dynamic visual acuity. Mequitazine (5 mg) and terfenadine (60 mg) are likely to prove acceptable H1 antagonists when sedation must be avoided.

Drug interaction between furosemide and indomethacin

The effect of single oral doses of furosemide(40mg) and indomethacin (50mg) on urine volume, urinary sodium, potassium and prostaglandin E(PGE) excretion and plasma renin activity(PRA) was investigated in 24 normal subjects. Urinary furosemide excretion was also examined. Furosemide increased urine volume, urinary sodium, potassium and PGE excretion and PRA. A good correlation was observed between urinary sodium and furosemide excretions (r=0.82). Indomethacin per se did not induce significant change in PGE excretion. However, it partially attenuated the natriuretic effect of furosemide and reduced the urinary furosemide excretion. The correlation between urinary sodium and furosemide excretions was not affected by indomethacin. In contrast to its partial attenuation in natriuresis, indomethacin almost completely inhibited the increase in PRA induced by furosemide. These results suggest that indomethacin, in the small dose which does not affect urinary PGE excretion, attenuates the furosemide-induced natriuresis by inhibiting the urinary furosemide excretion. It is also suggested that a mechanism other than sodium retention is involved in the complete suppression of PRA response to furosemide by indomethacin.

Effects of orally administered Clenbuterol on oxytocin-induced uterine activity

Clenbuterol is a sympathicomimetic agent with a predominant effect on beta2-adrenergic receptors [6]. In addition to its bronchospasmolytic effect it inhibits uterine contractions and has been recommended for treatment of premature labor [6]. The results of pharmacokinetic studies in nonpregnant animals [4, 7] and in nonpregnant human individuals [8] indicate rapid absorption of an oral dose of Clenbuterol by the gastro-intestinal tract, resulting in relatively high plasma levels of the unchanged compound. Elimination of orally administered isotope-labelled Clenbuterol was shown to follow a biphasic curve with a half-life of 30— 35 hours in the second, slow phase [8]. If these pharmacologic properties would also be valid in pregnant women with uterine contractions, oral administration of Clenbuterol would appear to be an attractive approach to the treatment of premature labor. Therefore, the present study was designed to measure the effects of single oral doses of Clenbuterol on uterine activity as well as on variables of maternal and fetal cardiovascular function. The study was performed in term pregnant women with oxytocin-induced labor in order to obtain standardized uterine activity and to allow continuous measurement of in trauterine pressure and fetal heart rate.

Influence of sympatholytic drugs on the cardiovascular response to isometric exercise.

1. The effects of single oral doses of various sympatholytic drugs on the heart rate and blood pressure increases during isometric handgrip contraction were studied in six healthy subjects. 2. Bethanidine reduced both the systolic and diastolic increases in pressure. Clonidine reduced the systolic but not the diastolic increase. Oxprenolol alone or in combination with phentolamine or phenyoxybenzamine failed to influence the pressor response. 3. The increase in systemic blood pressure associated with sustained contraction of voluntary muscle appears to be relatively resistant to acute sympathetic adrenoreceptor blockade in man.

Depression of cyclic AMP and cyclic GMP in the cerebrospinal fluid of rats after acute administration of ethanol

The effect of single oral doses of ethanol on the levels of cyclic AMP and cyclic GMP in the cerebrospinal fluid was studied in rats. Ethanol markedly decreased the level of both cyclic nucleotides for at least 24 h. The decrease of cyclic nucleotides after medium and high doses (1.65 and 4.59 g/kg) was slower in onset but more pronounced than the decrease after a low dose (0.55 g/kg) of ethanol.

Immunosuppressive effects of low doses of glucocorticoids: effects on autologous and allogeneic mixed leukocyte reactions.

The effects of single oral doses of 10, 15, or 30 mg of prednisone on circulating mononuclear cells, autologous MLR, mitogen responses, and allogeneic MLR were studied in healthy volunteers. Doses as low as 10 mg were immunosuppressive, causing diminution of circulating T cells and monocytes, and significant reduction in autologous but not allogeneic MLR responses. These effects were maximal 6 hr after drug administration and gone by 24 hr. Autologous MLR responses were particularly sensitive to the effects of prednisone being significantly and consistently suppressed 2 hr after drug administration, before significant cell redistribution had occurred. Macrophage-enriched stimulating cells were more easily suppressed than responding T cells. Since the autologous MLR may be important in in vivo regulation of immune responses, its reduction by low-dose glucocorticoids may be of clinical relevance. This suppressive effect must be considered in studies of the autologous MLR in patients receiving glucocorticoid therapy.

Effect of single oral dose of DDT on the lipid metabolism of rhesus monkey

The effect of a single oral dose of DDT (150 mg/kg body wt) on the lipid metabolism of rhesus monkey has been investigated 48 hr after the administration of the drug. There was hypertriglyceridemia and increased triglyceride levels in adipose tissues of experimental animals. The increased triglyceride levels in plasma seemed to be due to their increased mobilization from the liver and decreased removal rate from plasma. However, postheparin plasma lipolytic activity (PHLA) of both protamine-sensitive and -resistant types increased in the plasma. Further, there was increased lecithin-cholesterol acyltransferase (LCAT) activity in DDT-treated animals which contributed to the increased esterified cholesterol in plasma. There was increased conversion of [ 14C] glucose into hepatic triglyceride but the lipid content did not change significantly in the tissue possibly due to the increased lipolytic activity and secretion into plasma.

Propranolol in angina pectoris: Duration of improved exercise tolerance and circulatory effects after acute oral administration

The duration of the effects of single oral doses of 80 and 160 mg of propranolol was studied in 11 patients with stable, exercise-induced angina pectoris. After administration of both doses, plasma propranolol levels peaked at 2 hours in 8 of the 11 patients and thereafter declined exponentially with an average plasma half-life of 3.98 hours (range 1.4 to 4.3) after the 80 mg dose and 4.28 hours (range 1.9 to 5.4) after the 160 mg dose. There was wide interindividual variation in plasma propranolol concentration at any given time after each dose. Treadmill walking time to the onset of angina, the total duration of exercise and the total external work performed were significantly greater by 1 hour after each dose of propranolol than after placebo. This improvement in exercise tolerance persisted unchanged for 8 hours ( P < 0.001) and was still significant although less marked at 12 hours ( P < 0.05). Improvement in exercise tolerance after propranolol was associated with a significant reduction in S-T segment depression during exercise. Both at rest and during exercise, heart rate, systolic blood pressure and rate-pressure product decreased after propranolol, and these circulatory effects persisted for 12 hours. Changes in walking time, heart rate and systolic blood pressure were similar after 80 and 160 mg of propranolol. Despite the increase in exercise duration and in total work performed after propranolol, the rate-pressure product at the onset of angina was lower after propranolol. In view of the prolonged effects of single oral doses of 80 and 160 mg of propranolol, it is suggested that administration of propranolol twice daily should be adequate in treating patients with stable angina pectoris. These studies also demonstrate that routine measurement of plasma propranolol levels is of little practical value in the management of patients with angina pectoris.

The effect of lisuride hydrogen maleate, an ergot derivative on anterior pituitary hormone secretion in man.

The effects of single oral doses of 0.2 mg of lisuride hydrogen maleate, a semisynthetic ergot derivative, on serum levels of prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol and blood glucose were studied in six normal males. Lisuride effectively inhibited basal PRL secretion as well as the PRL response to TRH given 3 h later. In addition, the drug raised basal GH levels and decreased basal and TRH stimulated TSH secretion. No significant differences between lisuride and control were observed in basal LH and FSH, LHRH stimulated gonadotrophins or in cortisol. Drowsiness was noted by all subjects, one became nauseated and another vomited, 60 and 90 min respectively after administration of lisuride. No changes were seen in pulse rate and blood pressure. The endocrine effects of lisuride were attenuated by the prior administration of the dopamine antagonist metoclopramide. These results suggest that lisuride acts as a long-acting dopamine agonist and that therefore this drug could be of therapeutic use in hyperprolactinaemic states and acromegaly.

Effect of beta‐blockers on exercise double product (systolic blood pressure x heart rate).

1 The effect of single oral doses of six beta-receptor antagonists on exercise-induced changes in double product (systolic blood pressure x heart rate) were studied in 25 human volunteers. 2 Three doses of propranolol, nadolol, oxprenolol, pindolol, timolol and atenolol were selected for study on the basis of in vivo beta-blocking potency. 3 Although all beta-blockers studied reduced the double product response to exercise, the pharmacodynamics of this effect differed markedly. 4 Pharmacodynamic half-lives, estimated for the drug tested, were 39 h for nadolol, atenolol 21 h, timolol 15 h, oxprenolol 13 h, propranolol 11 and pindolol 8 h. 5 These results suggest that the clinical choice of a beta-blocker with the least problems of compliance can be made on the basis of pharmacodynamics as well as pharmacological profile.

Comparison of pirbuterol and pirbuterol and hydroxyzine in patients with reversible airway obstruction

The effects of single oral doses of pirbuterol 10 mg plus hydroxyzine 10 mg, and of pirbuterol 10 mg plus placebo, were compared in a single-blind cross-over trial in 17 adult patients with reversible airway obstruction. The initial bronchodilator response after the two treatments was similar, but mean specific airway conductance at 3, 4, 6 and 8 h, and mean FEV1 and FVC after 3 and 4 hours, were significantly higher after pirbuterol + hydroxyzine than after pirbuterol + placebo. The mean thoracic gas volume measured at 3 and 4 h was lower after pirbuterol + hydroxyzine. Heart rate, blood pressure and a continuous ECG record did not differ after the two treatments. The findings suggest that the combination of pirbuterol and hydroxyzine brings about more prolonged bronchodilatation in patients with reversible airway obstruction than does pirbuterol alone.

Effects of oral terbutaline in children with bronchial asthma

The cardiopulmonary effects of single oral doses of terbutaline were evaluated in children with chronic bronchial asthma. Fifteen children, 6 to 13 yr of age and weighing 22.3 to 51.8 kg, were treated with 1.25, 2.5, 3.75 and 5.0 mg of terbutaline using a double-blind crossover vs placebo design. Before treatment and at intervals up to 420 min following treatment, measurements were made of lung volumes, vital capacity, FEV 1, maximum expiratory flow volume curves, airway resistance (R aw), and specific airway conductance (G aw/V L). Heart rate, systolic and diastolic blood pressures, and electrocardiograms were also obtained. The most consistent and sensitive indicators of pulmonary function were G aw/V L and FEV 1, both of which showed significant improvement after all doses, The peak improvement of these parameters was proportional to the dose of terbutaline. Cardiovascular effects of terbutaline consisted of small increases in systolic blood pressure or transient EKG changes and were clinically unimportant. Other side effects such as headache, tremor, dizziness, and nausea, although proportional to the dose of terbutaline, were mild and transient. The dose of 2.5 mg terbutaline produced the most improvement in pulmonary function in relation to the number of side effects.

Human pharmacology studies with a new, orally active stimulant of cardiac adrenergic beta-receptors

The effects of single oral doses of 5, 10, and 20 mg. of a new cardioselective β-stimulant, preparation C 50,005 A-Ba , were tested and compared with the response to placebo in eight healthy volunteers (four aged 23 to 26 years and four aged 49 to 55 years). The compound induced a doserelated increase in myocardial contractility (reduction of 17 to 24 msec. in PEP c) and in heart rate, which was accelerated by 8 to 20 beats/minute by comparison with the placebo values. The rise in systolic pressure observed in response to C 50,005 A-Ba was both dose-related and dependent on the age of the subjects; in the younger group there was an increase of 16 to 31 mm. Hg and in the older group an increase of 7 to 21 mm. Hg. A slight decrease in diastolic pressure was noted, which was likewise more prominent in the younger subjects. These changes were ascribed to a decrease due to aging in the responsiveness of the adrenergic β-receptors to stimulation. The effects of the compound set in quickly, reached their maximum within 30 to 60 minutes, and persisted for about 4 hours. The only side effects observed were slight palpitations. Depression of the ST segment was noted in one 55-year-old subject and was interpreted as a manifestation of latent coronary disease. In view of this finding, it seems possible that the preparation could be used as a diagnostic agent for a simple test of coronary function. Continuous E.C.G. recordings over a period of 5 3 4 hours , including three ergometer tests at submaximum effort, showed that by comparison with placebo, C 50,005 A-Ba caused a slight increase in the frequency of isolated ventricular and supraventricular premature contractions, and also in the incidence and intensity of sinus arrhythmias not due to respiration. Essentially the same changes in cardiac rhythm were observed in four young volunteers during continuous E.C.G. recordings over a period of 9 hours in response to the repeated administration of C 50,005 A-Ba in a dosage of 15 mg. three times a day on two consecutive days. The differences from the corresponding placebo values were, however, not statistically significant. C 50,005 A-Ba is thus an orally active cardiostimulant agent with a high degree of β 1-receptor selectivity and with only a very slight arrhythmogenic potential. It is well tolerated and could afford beneficial effects in the treatment of heart failure or as a countermeasure in therapy with β-blockers.

Comparison of ocular hypotensive effects of acetazolamide and atenolol.

The ocular hypotensive effect of single oral doses of (a) atenolol (50 mg), (b) acetazolamide (500 mg), (c) atenolol (50 mg) and acetazolamide (500 mg) in combination, and (d) vehicle (inert tablets) were compared in 8 patients with glaucoma. In this single-dose, double-masked trial the combination was observed as most effective in reducing ocular tension. Both the combination and atenolol performed markedly better than vehicle. That acetazolamide did not reduce ocular tension significantly more than vehicle is probably explained by relatively low initial ocular tensions. There was no evidence of interaction between atenolol and acetazolamide in this study. Acetazolamide probably remains the first-choice oral medication for glaucoma. It is cautiously suggested that beta-blocking drugs may have a future therapeutic role, but longer-term studies on larger numbers will be required to establish this.

Antiarrhythmic and electrocardiographic effects of single oral doses of disopyramide

Ten patients with various heart diseases and ventricular arrhythmia received a single oral dose of disopyramide (DE) 200 mg. The ECG was recorded continuously for about 50 h from 2-4 h before drug administration. A statistically significant reduction in the number of ventricular ectopic beats (VEBs) was seen 1.0-3.5 h after drug intake; the average number of VEBs per 30 min decreased from 317 during the control period to 92 by 1.0-3.5 h after treatment and if one patient who did not respond is excluded, the corresponding figures were 272 and 14, respectively. Consecutive VEBs were seen in seven patients before DE was given and decreased significantly (p less than 0.05) 1.5-5.5 h after drug administration. There was no change in the PQ interval, the QRS interval showed a slight increase, whereas the QT interval was prolonged 0.5-4 h after administration of DE. A specific gas chromatographic method was used for DE assay in plasma and urine. Absorption was rapid in all patients. Urinary excretion during the first 48 h after drug intake varied between 35 and 75%. The lowest effective antiarrhythmic concentration estimated in six patients ranged from 1.4 to 7.0 mug/ml. beta-Phase half-life in five patients was between 10.3 and 22.1 h.

The effects of propranolol, practolol and metoprolol on exercise-induced tachycardia in relation to plasma levels in man.

1. The effects of single oral doses of propranolol, practolol and a new cardioselective beta-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74-3 (s.e.m. = 6-8) to 153-8 (s.e.m. = 9.8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluorometrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1-5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50-60 ng/ml (half-life 2-75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050-1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140-150 ng/ml (half-life 1-7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting beta-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.

Effect of single oral doses of benzbromarone on serum and urinary uric acid.

AbstractThe effects of various single oral doses of micronized benzbromarone on serum and urinary uric acid and urinary oxypurines were studied in 5 healthy volunteers and in 5 patients with gout. There was an effective, unequivocal, and dose‐related reduction in serum uric acid levels in both groups. The simultaneous increased excretion of urinary uric acid but not of oxypurines suggests the mechanism of effect is uricosuria. The prolonged duration of action up to 48 hours after dosing is advantageous as the drug need be taken only once a day. The data presented favor a protracted trial of benzbromarone in patients with gout and hyperuricemia.

Persistent electroencephalographic changes in rhesus monkeys after single doses of pentobarbital, nitrazepam and imipramine

The immediate and persistent effects of single oral doses of sodium pentobarbital 20 mg/kg, nitrazepam 25 mg/kg and imipramine 25 mg/kg, were compared on behavioural patterns as well as on quantitative aspects of diurnal EEG patterns in rhesus monkeys. Consecutive pre-drug EEG recordings on agar treated monkeys, showed no significant variations in day to day EEG levels of wakefulness, drowsiness, sleep and the REM state. Both the sedative-hypnotic agents, sodium pentobarbital and nitrazepam, significantly reduced wakefulness and the REM state and increased slow wave sleep. They reduced the latency to onset of slow wave sleep but significantly increased the latency to onset of the REM state. The antidepressant agent imipramine, did not influence any of the EEG parameters to a significant extent. Significantly enhanced REM levels persisted during the 7-day post-drug period after cessation of medication of all three psychoactive agents. The effect on the macaque EEG of an increase in slow wave sleep with concomitant decreased levels of wakefulness and REM with respect to baseline levels, provides a quantitative basis for comparing sedative-hypnotic agents in monkeys. Residual drug-induced EEG changes, reflected by enhanced REM levels, may prove a sensitive indicator of persistent drug effects in subhuman primates.