An overview of the pharmacokinetics of cilomilast (Ariflo), a new, orally active phosphodiesterase 4 inhibitor, in healthy young and elderly volunteers.

The oral pharmacokinetics of cilomilast (Ariflo) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for Cmax and t(1/2) were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily aftermeals were well tolerated following dose titration.

Insulin inhibits peroxisomal fatty acid oxidation in isolated rat hepatocytes.

Inhibition by insulin of long chain fatty acid oxidation in mitochondria is mediated in part by elevating malonyl-CoA levels, which inhibit carnitine palmitoyl-transferase I. Whether insulin alters peroxisomal oxidation has not been studied. We present data which show that insulin inhibits the oxidation of palmitic acid by peroxisomes (IC(50) = 8.5 x 10(-11) M) at hormone concentrations 100-fold less than those needed for mitochondrial inhibition (IC(50) = 1.3 x 10(-8) M). We used a purified peroxisome preparation to study the mechanism of insulin action. Insulin had a direct effect in the peroxisome preparations to decrease oxygen consumption, fatty acyl-CoA oxidizing system activity and acyl-CoA oxidase by approximately 40%, 30% and 15%, respectively. Since insulin degrading enzyme (IDE) is an insulin-binding protein known to be in peroxisomes, we studied the effect of an inhibitory anti-IDE antibody on the ability of insulin to inhibit the fatty acyl-CoA oxidizing system. The antibody eliminated the inhibitory effect of insulin. We conclude that insulin inhibits peroxisomal fatty acid oxidation by a mechanism requiring IDE.

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers.

AIMS: To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration. METHODS: Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed. RESULTS: Statistically significant (P < 0.05) increases were noted in AUC(o,t) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71-1.84). CONCLUSIONS: Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.

The pharmacokinetics of pranlukast in healthy young and elderly subjects.

Pranlukast is a novel LTD4 antagonist under development for the treatment of asthma. To assess the effect of age, the pharmacokinetics of pranlukast were studied in healthy young (9 females, 10 males, mean 30 years) and elderly subjects (9 per sex, mean 70.4 years). After an overnight fast volunteers were given 300 mg of pranlukast orally, 30 min after a light breakfast. Serial blood samples were collected for 24 hs, and the plasma was assayed by HPLC/UV. Pranlukast was well tolerated by the volunteers. The resultant mean plasma concentration vs. time data were very similar for both age groups. The estimated geometric mean AUCO-t and Cmax ratios (95% CI in parentheses) for elderly : young were 1.00 (0.71, 1.41) and 0.93 (0.66, 1.33), respectively. Median Tmax occurred at 4.5 h in both age groups. There were no significant differences observed in the pharmacokinetics of pranlukast between healthy young and elderly subjects. On stratifying the young and elderly data with respect to gender, no marked differences were observed between male and female subjects in the mean pharmacokinetic parameters of pranlukast, and the respective plasma concentrations profiles were very similar.

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.

Granisetron as antiemetic therapy in children with cancer.

The safety and efficacy of the new 5HT-3 antagonist granisetron as an antiemetic in children with cancer was evaluated in 40 children at a single dose of 40 micrograms/kg. No adverse affects attributable to the granisetron were noted. The overall major and complete response rate was 82.5% and this was highest in the younger children. Only 2 patients showed no response. Pharmacokinetic studies showed associations between some pharmacokinetic parameters and age which were no longer apparent after normalisation for body weight. Granisetron is an effective and very well-tolerated antiemetic and appears to be an important addition to the supportive care available for children with cancer.

Pharmacokinetics and tolerability of ascending intravenous doses of granisetron, a novel 5-HT3 antagonist, in healthy human subjects.

The pharmacokinetics and tolerance of granisetron, a novel 5HT3-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 micrograms.kg-1 to group 1; 150, 180, 200 and 230 micrograms.kg-1 to group 2 and 270 and 300 micrograms.kg-1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection. Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 micrograms.kg-1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186-264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l.h-1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.

Granisetron, a selective 5-HT3 receptor antagonist, for the prevention of radiation induced emesis during total body irradiation.

The antiemetic efficacy of granisetron was tested in an open trial in patients undergoing highly emetogenic treatment by single fraction total body irradiation. Thirty-two consecutive patients were entered. Results were both patient- and observer-rated. Following a single intravenous dose of granisetron 18 patients (56.3%) experienced total protection and a further 13 (40.6%) had major antiemetic protection with four of these patients experiencing nausea only. One patient experienced an anaphylactic reaction on infusion of monoclonal antibody-treated donor marrow 5 h after administration of the trial drug and vomited on multiple occasions. The reaction was associated with hypotension. A further patient experienced transient hypotension secondary to septicaemia 8 h after receiving granisetron. Three patients required a second dose. Headache was the most frequent side-effect occurring in three patients, but in to of these patients the test drug was not thought to be implicated. In conclusion granisetron is a highly effective agent in controlling radiation induced emesis with a favourable toxicity profile.

Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients.

In an open ascending-dose study, granisetron, a specific 5-HT3 receptor antagonist, was administered to 24 paediatric patients (17 male, 7 female, mean age 6.2, range 3-15 years) who were receiving moderately or highly emetogenic chemotherapy for malignant disease. Single doses of 10, 20 and 40 micrograms/kg were administered by intravenous infusion 1 h before chemotherapy. Each dose level was studied in a group of 8 patients. With the 40 micrograms/kg dose, 5 of 8 patients experienced no nausea or vomiting in the 24 h after granisetron treatment. With 20 micrograms/kg, a similar response was seen, but with 10 micrograms/kg only 2 of 8 patients experienced complete antiemetic protection despite additional prophylactic chlorpromazine in this group. Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram. It is concluded that granisetron was very well tolerated by paediatric patients. In addition, there was clear evidence of a major antiemetic effect for at least 24 h after a single intravenous dose of 20 or 40 micrograms/kg.

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.

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)

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.

Does atenolol improve physical and psychological function after coronary artery bypass surgery: a controlled study.

A double-blind prospective randomized trial of atenolol (100 mg once daily) was carried out on 88 patients (78 men) awaiting coronary artery bypass graft surgery. Standardized ratings of both psychiatric morbidity and functional capacity were made before, 3 months (n = 82) and 12 months (n = 81) after surgery. One year after surgery men in the atenolol group had a significantly shorter treadmill exercise time than those on placebo (7.21 +/- 0.28 min vs 8.32 +/- 0.40 min; p less than 0.05), but the frequency of reported anginal attacks during the year was similar in both drug groups. Improvement in functional capacity (measured in exercise time) in the 71 men following surgery was related to both physical and psychological variables assessed before the operation. Men with more severe occlusive disease, lower neuroticism and higher extraversion scores pre-operatively showed greater percentage improvement in exercise time after surgery. Women had significantly levels of psychiatric morbidity and shorter treadmill exercise time than men both before and after surgery. Of the psychiatric and psychological variables, only ratings of Type A behaviour fell significantly in the atenolol group (170.9 +/- 5.3 vs 163.0 +/- 5.2; p less than 0.05). This change, which is probably not clinically important, occurred independently of any reduction in either overall psychiatric morbidity score or ratings of somatic symptoms mediated by beta-adrenergic receptors. The atenolol group reported more side-effects of both psychological and physical symptoms than the placebo group. We do not recommend the routine use of atenolol after bypass graft surgery. Our findings failed to support the suggestion that Type A characteristics may reflect an underlying sympathetic nervous system reactivity.

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.