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Biomedical subjects

J W Upward

Publications and source records attributed to J W Upward.

11 recordsLinked to original sources
PubMed1996

The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers.

OBJECTIVE: The pharmacokinetics of pranlukast, a leukotriene LTD4 antagonist, were studied in 48 young, healthy subjects after single and repeated oral doses (given every 12 h) ranging from 112.5 to 675 mg. The doses were administered 30 minutes after a light breakfast. RESULTS: Maximal drug concentrations generally occurred between 2 and 6 h after dosing, and there was some evidence of an absorption lag-time. Secondary peaks were observed in the plasma concentration vs. time profiles of many of the study subjects after both single and repeated doses, particularly during the period of maximum drug absorption. In general, after both single and repeated doses, there were related increases in the corresponding Cmax and AUC with a rise in dose, although the increase was diminished at doses above 450 mg. With repeated dosing of pranlukast the mean AUC was generally higher (up to 1.6-fold), and the higher plasma concentrations allowed characterisation of a longer mean t 1/2 than after single dose administration. The mean steady-state trough plasma concentrations attained after evening doses were considerably higher (up to 14-fold) than those obtained after the morning dose. CONCLUSION: The data suggested that the pharmacokinetics of pranlukast are influenced by the time of dosing. Based on analysis of urinary 6 beta-hydroxycortisol excretion, there was no evidence that pranlukast modified the metabolic activity of cytochrome P-450 3A isoenzymes.

Adolescent↗
PubMed1990

The pharmacokinetics of doxazosin in patients with hypertension and renal impairment.

1. The pharmacokinetics of doxazosin, following a single oral dose (1 mg) and chronic oral dosing (doubling doses up to a maximum of 16 mg day-1), were studied in 18 patients with mild to moderate hypertension and stable renal function varying from normal to severely impaired. In addition, the effect of chronic administration of doxazosin on renal haemodynamics was evaluated. 2. Significant accumulation of doxazosin occurred with chronic dosing, but comparison of dose-adjusted AUC after single and chronic dosing suggested that there was no change in clearance or bioavailability during chronic administration. 3. There was no significant relationship between plasma elimination half-life or the AUC for doxazosin and the degree of renal impairment. 4. Symptomatic postural hypotension occurred in six patients following the initial dose of 1 mg doxazosin. Systolic and diastolic blood pressure measured 24 h after the previous dose were significantly reduced during chronic administration of doxazosin by a mean of 12/6 mm Hg supine and 10/7 mm Hg on standing. 5. During chronic administration of doxazosin, there was a significant reduction of 13% in glomerular filtration rate compared with pre-treatment, but no change in effective renal plasma flow.

Adult↗
PubMed1990

The clinical pharmacology of granisetron (BRL 43694), a novel specific 5-HT3 antagonist.

Granisetron is a novel specific 5-HT3 receptor antagonist whose effects have been evaluated in an extensive programme of volunteer studies. Single intravenous doses of 2.5-300 micrograms/kg of granisetron over 30 min, and of 40-160 micrograms/kg, administered over 3 min, were very well tolerated. There were no serious adverse events. There were no consistent or clinically important effects on cardiovascular parameters (pulse rate, blood pressure, ECG). Single doses of 40-200 micrograms/kg (30 min infusion) or 160 micrograms/kg (3 min infusion) did not influence subjective state, psychomotor performance or EEG. The only adverse event reported consistently more frequently with granisetron than placebo was constipation; this generally subsided spontaneously after 24-72 h. In volunteers, granisetron was widely distributed and also rapidly eliminated, largely through non-renal mechanisms. Granisetron exhibited essentially linear kinetics over the dose range studied (30-300 micrograms/kg). There was considerable inter-subject variability in terminal phase half-life and total plasma clearance. Biological activity of granisetron, as evidenced by significant inhibition of cutaneous 5-HT-induced, axon-reflex flare, was still apparent 24 h after a single dose of 40 micrograms/kg. Repeated intravenous doses of granisetron (up to 160 micrograms/kg b.d. for 7 days) were also well tolerated. As in the single dose studies, constipation was the only adverse event reported consistently more with active treatment than with placebo, but in no case did this necessitate withdrawal from the study or administration of a laxative.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1988

Comparative effects of fluoxetine and amitriptyline on cardiac function.

1. The effects of fluoxetine and amitriptyline on the electrocardiogram (ECG) and systolic time intervals (STIs) were measured during a double-blind parallel-group study in depressed patients. 2. ECGs and STIs were measured after a 1 week placebo run-in, following 1 week's treatment with fluoxetine 40 mg daily or amitriptyline 100 mg daily, and then after 3 weeks' treatment with fluoxetine 60-80 mg daily or amitriptyline 150-200 mg daily. 3. Fluoxetine had no effect on the ECG or STIs at any dose. Amitriptyline 150-200 mg daily shortened the sinus cycle length by a mean of 12%, prolonged the PR interval by 8% and the QRS duration by 10%. Amitriptyline did not significantly alter the STIs.

Adult↗
PubMed1985

Electrophysiologic, hemodynamic and metabolic effects of intravenous bepridil hydrochloride.

Bepridil, a fast and slow channel blocking drug, was administered intravenously over 5 minutes in a dose of 3 mg/kg body weight to 19 patients. Ten patients received intravenous bepridil during electrophysiologic study, performed for the investigation of known or suspected cardiac arrhythmias. Sinus cycle length increase from 764 +/- 56 to 886 +/- 62 ms (p less than 0.002). AH interval increased from 101 +/- 6.9 to 137 +/- 11.9 ms (p less than 0.01). HV and QRS durations were not significantly affected. QTc interval increased from 395 +/- 13 to 423 +/- 13 ms (p less than 0.001). Atrial effective refractory period increased from 211 +/- 8 to 242 +/- 8.7 ms (p less than 0.005), and atrioventricular nodal effective refractory period increased from 299 +/- 26 to 366 +/- 30 ms (p less than 0.02). Right ventricular effective refractory period increased from 233 +/- 9.3 to 259 +/- 8.1 ms (p less than 0.001). In an additional 9 patients with coronary artery disease, a hemodynamic and metabolic study was performed. A transient mean decrease dP/dt max from 1,646 +/- 164 to 1,506 +/- 238 mm Hg/s (p less than 0.05) and a mean increase of 2.6 mm Hg (p less than 0.05) in left ventricular end-diastolic pressure were observed. Both values had returned to control levels 15 minutes after drug infusion. Blood pressure, cardiac output, coronary sinus blood flow and myocardial lactate extraction ratio did not change significantly. This profile of powerful electrophysiologic and minor hemodynamic changes indicates a potentially useful role for bepridil in the acute management of supraventricular arrhythmias and, possibly, ventricular arrhythmias.

Adolescent↗
PubMed1985

Oral labetalol in the management of stable angina pectoris in normotensive patients.

The efficacy of labetalol, an alpha and beta receptor antagonist, was evaluated in 12 normotensive patients with stable angina pectoris in a single blind dose ranging study. After a two week period of placebo treatment, labetalol was given in doses of 100, 150, 200, and 300 mg twice daily, each for two weeks. Frequency of angina attacks decreased from 9.4 (SEM 2.3)/week in the control period to 7.3 (2.8), 5.2 (2.6), 3.8 (1.8), and 3.3 (1.9)/week in the four successive treatment periods. In the same periods the number of glyceryl trinitrate tablets consumed decreased from 7.0 (2.6)/week to 5.8 (3.3), 3.9 (2.9), 2.7 (1.8), and 2.6 (2.1)/week. Maximal symptom limited treadmill exercise tests were performed three and 12 hours after dosage at each dose. Exercise tolerance (expressed as seconds of the Bruce protocol) increased from 266 (44) with placebo to 306 (44), 369 (50), 396 (48), and 413 (51) in the four treatment periods. This improvement was accompanied by a significant blunting of the heart rate and blood pressure responses to exercise. Trough point exercise tolerance did not differ significantly from that at three hours after dosage. Thus labetalol is effective as an antianginal agent at doses of 150-300 mg twice daily and is well tolerated by the normotensive patient with angina.

Adult↗
PubMed1984

A study to compare the efficacy, plasma concentration profile and tolerability of conventional mexiletine and slow-release mexiletine.

In order to evaluate and compare slow-release mexiletine 360 mg 12 hourly and conventional mexiletine 200 mg 8 hourly, twelve patients with symptomatic ventricular arrhythmias have been studied. Ambulatory electrocardiographic monitoring was performed before treatment and at the end of two, two week long treatment periods during which slow-release mexiletine and conventional mexiletine were administered in random order. On the last day of each treatment period frequent blood samples for drug assay were collected during a dosage interval. Each formulation produced greater than 70% suppression of ventricular ectopic beats in 55% of patients. The variation between pre-dose and observed peak plasma concentration was 29.6% with slow-release mexiletine and 71.6% with mexiletine (P less than 0.01). The time from pre-dose to observed peak concentration was 4.0 h (+/- 1.6 SD) with slow-release mexiletine and 2.0 h (+/- 1.8 SD) with conventional mexiletine (P less than 0.05). Three patients were withdrawn from the study in the first treatment period because of central nervous system or gastric adverse effects. Overall, side-effects were marginally fewer on therapy with slow-release mexiletine. We conclude that, in the nearest equivalent dosage, the slow-release formulation is as effective as conventional mexiletine and at least as well tolerated. The fluctuations in plasma mexiletine concentration are less marked on the slow-release preparation despite the longer dosage interval, which allows effective oral therapy with a twice daily dosage.

Administration, Oral↗
PubMed1983

The appropriate dosage regime for the transition from intravenous lignocaine to oral tocainide after acute myocardial infarction.

To define the appropriate regime for the transition from intravenous lignocaine to oral tocainide after uncomplicated acute myocardial infarction, 43 patients received lignocaine to steady state. Each patient then received a tocainide dosage schedule. Plasma concentration of lignocaine and tocainide was measured frequently until the third peak plasma tocainide level. Tocainide 400 mg 8 hourly starting 4 h before cessation of lignocaine and tocainide 400 mg 4 hourly starting at the end of the infusion produced therapeutic plasma tocainide concentration (3.5-9 mg/l) only after the second dose. Tocainide 600 mg 12 hourly starting 6 h before cessation of lignocaine and tocainide 600 mg 6 hourly starting at the end of the infusion quickly achieved therapeutic plasma tocainide concentration which declined to give subtherapeutic first dose troughs of 2.42 mg/l (+/- 0.28 SEM) and 2.79 mg/l (+/- 0.27 SEM) respectively. Consistently therapeutic plasma tocainide concentrations were achieved by both of these regimens after the second dose. The short plasma half-life of lignocaine which for these regimes was 3.71 h (+/- 0.25 SEM), resulted in subtherapeutic lignocaine concentrations before consistently therapeutic plasma tocainide concentrations had been achieved. On the basis of these results, the 600 mg 6 hourly tocainide dosage schedule was studied with cessation of lignocaine infusion either two or six h after the first tocainide dose. With the former regime only three of 5 patients had therapeutic lignocaine at the subtherapeutic tocainide trough.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗