The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit.

AIM: To investigate the effect of diet upon liver function tests and serum lipids within the restricted environment of a Phase I unit. METHODS: An open randomized three-way crossover study was designed with subjects consuming three types of diet. The diets comprised, a balanced normal calorie diet, a high-carbohydrate high-calorie diet and a high-fat high-calorie diet. Each diet was consumed in a randomized sequence over 8 days with a recovery period of 14 days between periods. The blood concentrations of various laboratory parameters were measured at intervals throughout each dietary period and during the recovery periods. RESULTS: Blood transaminase activity and triglyceride concentrations increased significantly whilst subjects consumed a high-carbohydrate high-calorie diet but not when fed either a high-fat high-calorie diet or a balanced normal calorie diet. CONCLUSIONS: The rises in transaminases and triglycerides were caused by the carbohydrate content of the diet rather than its calorific value. Sucrose rather than starch was the carbohydrate which caused the rise in transaminases and triglycerides. The importance of controlling diet in Phase I studies is stressed.

Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo.

Troglitazone (TGZ), a 2,4-thiazolidinedione antidiabetic, causes hepatotoxicity in 1.9% of patients. TGZ is an inducer of, and substrate for, hepatic P450 3A. Microsomal metabolism yields a benzoquinone (TGZQ) and reactive intermediates. Kassahun et al. [Kassahun et al. (2001) Chem. Res. Toxicol. 14, 62-70] have trapped the intermediates as thioester, thioether, and disulfide conjugates of glutathione and found five conjugates in rat bile. The thioether was substituted in the chromane moiety. We have investigated the effect of the P450 3A inducer, dexamethasone (DEX), on metabolism of TGZ and TGZQ in rats and assessed the compounds' cytotoxicity. TGZ-glucuronide and sulfonate were confirmed as principal biliary metabolites of TGZ (50 mg/kg, iv). Bile from noninduced animals also contained a TGZ-glutathione thioether adduct (ML3) but it was substituted in the thiazolidinedione moiety. Pretreatment with DEX (50 mg/kg/day for 3 days) resulted in a 2-5-fold increase in the biliary concentration of ML3 and a 2-fold increase in the concentration of TGZQ, which was commensurate with the induction of hepatic P450 3A. Three of the known glutathione-conjugated metabolites were also found. TGZQ (50 mg/kg, iv) was metabolized to an analogue of one of the TGZ-glutathione thioesters and a glutathione adduct of TGZQ hydroquinone after DEX pretreatment. TGZ quinol glucuronide was a biliary metabolite of TGZ and TGZQ. Its formation would represent deactivation of TGZQ. TGZ was toxic to rat hepatocytes and Hep-G2 cells at concentrations exceeding 50 and 25 microM, respectively, after 24 h. In contrast, TGZQ was nontoxic to rat hepatocytes and toxic to Hep G2 cells only at concentrations exceeding 100 microM. Our results show that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation is enhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to either TGZQ or its metabolites.

Absence of a sertraline-mediated effect on digoxin pharmacokinetics and electrocardiographic findings.

UNLABELLED: The effects of oral administration of sertraline on the plasma concentration profile and renal clearance of digoxin were assessed in 20 healthy male subjects in a double-blind, randomized study. METHOD: All subjects first received digoxin 0.5 mg twice daily on Day 1, 0.25 mg twice daily on Day 2, and 0.25 mg daily thereafter. On Day 11, 10 subjects began concomitant sertraline administration with an initial dose of 50 mg/day that was titrated upward over 7 days to 200 mg/day, which was given over the remainder of the study period. The other 10 subjects received concomitant digoxin and placebo for 17 days beginning on Day 11. Trough plasma concentrations of digoxin were monitored daily beginning on Day 7. Blood samples and 24-hour urine collections were used to determine steady-state digoxin concentration and renal clearance before, during, and after sertraline coadministration. RESULTS: Sertraline had no effect on digoxin pharmacokinetics, except for a decrease in the time to reach the maximum plasma digoxin concentration (Tmax) compared with placebo (p = .0046), a finding thought to be of limited clinical significance. Side effects of mild-to-moderate severity were reported by 5 of 10 sertraline-treated subjects and by 6 of 10 placebo-treated subjects. CONCLUSION: The results of this study suggest that dosing adjustments of digoxin may not be necessary in patients receiving concomitant sertraline administration.

Absence of a sertraline-mediated effect on the pharmacokinetics and pharmacodynamics of carbamazepine.

UNLABELLED: A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers to assess the effects of sertraline on the pharmacokinetics and pharmacodynamics of carbamazepine. METHOD: Subjects received carbamazepine 200 mg once daily for 2 days and every 12 hours thereafter. On Days 16 to 32, subjects also received either sertraline or placebo daily. The dose of sertraline was increased from 50 to 200 mg daily over 7 days; the 200-mg dose was given for 10 days. Samples for pharmacokinetic analyses were obtained on Days 15 and 32; trough plasma concentrations of carbamazepine and its principal metabolite, carbamazepine-10, 11-epoxide (CBZ-E), were determined daily beginning on Day 13. Cognitive function testing was performed on Day 1 before carbamazepine dosing (baseline), Day 15 (carbamazepine alone), and Day 32 (carbamazepine plus sertraline or placebo). RESULTS: There were no significant differences between the sertraline and placebo groups in any of the pharmacokinetic parameters for carbamazepine or CBZ-E. Carbamazepine alone impaired cognitive function. The addition of sertraline did not potentiate these effects. Side effects were reported by 2 subjects in each group, but none were severe. CONCLUSION: These findings indicate that sertraline does not affect the pharmacokinetics of carbamazepine or its principal metabolite and does not potentiate the cognitive effects of carbamazepine.

Absence of effect of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin.

UNLABELLED: A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin in 30 healthy male volunteers. METHOD: All subjects received phenytoin throughout the study. The dose of phenytoin was 100 mg three times daily; steady-state trough plasma phenytoin concentrations were determined on Day 6. Concurrent treatment with sertraline (16 subjects) or placebo (13 subjects) was initiated on Day 8 and continued throughout the study in those subjects whose trough plasma phenytoin concentrations were between 5 and 20 micrograms/mL. The dose of sertraline was increased from 50 to 200 mg/day over 7 days; the 200-mg dose was then administered for 10 days. The plasma phenytoin concentration-time profile was determined on Day 7 before the start of sertraline or placebo dosing and at the end of dosing on Day 24. Psychometric testing was done before and after dosing on Days 0, 7, and 24. RESULTS: There were no significant differences between the sertraline group and the placebo group in the pharmacokinetic parameters of phenytoin. In addition, there was no indication that administration of phenytoin alone or concomitant administration of phenytoin and sertraline impaired cognitive function. Treatment-related side effects, primarily headache and nausea, were reported in 8 of 16 sertraline subjects and in 5 of 13 placebo subjects. Two subjects in the sertraline group withdrew because of side effects (rash), and 3 subjects in the placebo group withdrew because of side effects (rash and headache). CONCLUSION: High dosages of setraline did not affect the pharmacokinetics or the pharmacodynamics of phenytoin in ths study performed in healthy volunteers.

Absence of effect of sertraline on time-based sensitization of cognitive impairment with haloperidol.

UNLABELLED: This double-blind, randomized, placebo-controlled study evaluated the effects of haloperidol alone and haloperidol plus sertraline on cognitive and psychomotor function in 24 healthy male subjects. METHOD: All subjects received placebo on Day 1 and haloperidol 2 mg on Days 2 and 25. From Days 9 to 25, subjects were randomly assigned to either sertraline (12 subjects) or placebo (12 subjects); the sertraline dose was titrated from 50 to 200 mg/day from Days 9 to 16, and remained at 200 mg/day for the final 10 days of the drug administration period. Cognitive function testing was performed before dosing and over a 24-hour period after dosing on Days 1, 2, and 25. RESULTS: Impairment of cognitive function was observed 6 to 8 hours after administration of haloperidol on Day 2 but was not evident 23 hours after dosing. When single-dose haloperidol was given again 25 days later, greater impairment with earlier onset was noted in several tests in both treatment groups, suggesting enhancement of this effect. There was no indication that sertraline exacerbated the impairment produced by haloperidol since an equivalent effect also occurred in the placebo group. Three subjects (2 on sertraline and 1 on placebo) withdrew from the study because of side effects. Ten subjects in each group reported side effects related to treatment. The side effect profiles of sertraline and of placebo were similar. CONCLUSION: Haloperidol produced a clear profile of cognitive impairment that was not worsened by concomitant sertraline administration.

Effect of tenidap sodium on digoxin pharmacokinetics in healthy young men.

1. The effects of tenidap sodium and placebo on digoxin pharmacokinetics were compared in 14 healthy young men, in a double-blind, parallel-group study lasting for 24 days. 2. Subjects were administered digoxin alone for the first 10 days and digoxin plus tenidap 120 mg day-1 or placebo for the remaining 14 days. 3. Changes in the means between day 10 (digoxin monotherapy) and day 24 (combined therapy) for renal clearance, area under the plasma concentration-time curve during the dosing interval, and the minimum and maximum plasma digoxin concentrations did not differ significantly between the tenidap and placebo groups. There was a small but statistically significant increase (0.5 h) in the time taken to reach maximum plasma digoxin concentration following 14 days' continuous tenidap co-administration compared with placebo, but this was not considered to be clinically meaningful. 4. Co-administration of tenidap and digoxin was well tolerated. No subject withdrew from the study during combination treatment. Treatment-related adverse events were of mild to moderate severity and were reported by four subjects on digoxin monotherapy, four on tenidap and digoxin, and by two on digoxin and placebo. Those reported by the tenidap group predominantly affected the gastrointestinal system and were mild in severity. There were no reports of laboratory test abnormalities or cardiovascular abnormalities related to combined digoxin and tenidap administration. 5. The results of this study indicate that, in healthy young men, co-administration of tenidap with digoxin does not have any apparent clinically significant effects on the pharmacokinetic profile of digoxin, and the treatment is well tolerated.

The effect of tenidap on the anti-hypertensive efficacy of ACE inhibitors in patients treated for mild to moderate hypertension.

1. A randomised, placebo controlled, double-blind, parallel group study was conducted to assess the effect of tenidap sodium, a novel cytokine modulating drug, on the stable hypotensive response to the angiotension converting enzyme (ACE) inhibitor enalapril in subjects with mild to moderate, uncomplicated, essential hypertension. 2. Twenty-four male and female hypertensives, aged 33-77 years, received either 120 mg tenidap sodium or matched placebo daily for 22 days concomitantly with enalapril. 3. Mean endpoint supine and standing, systolic and diastolic pressures remained within 10% of baseline in each treatment group. However, the endpoint values were marginally above baseline during double-blind treatment with tenidap and marginally below baseline in the group receiving placebo. The increases in supine and standing systolic pressures in the tenidap group differed significantly from the changes in the placebo group. There were no significant differences between groups in changes in pulse rate. 4. Gastrointestinal side effects of mild to moderate severity attributed to treatment with tenidap were experienced by five subjects, one of whom was withdrawn during the third week of treatment. One subject receiving placebo was withdrawn because of a moderate headache attributed to study treatment. 5. The results of this study suggest that treatment with tenidap may interfere with the anti-hypertensive efficacy of ACE inhibitors. It is recommended that blood pressure should be monitored when tenidap is administered concomitantly with an ACE inhibitor.

The effect of tenidap on the anti-hypertensive efficacy of thiazide diuretics in patients treated for mild to moderate hypertension.

1. This randomised, placebo-controlled, double-blind, parallel-group study was conducted to assess the effect of tenidap sodium 120 mg, a novel anti-arthritic cytokine modulating drug, on the hypotensive efficacy of the thiazide diuretics hydrochlorothiazide or bendrofluazide. 2. Twenty-three male and female patients, aged 41-78 years, with mild to moderate, uncomplicated, essential hypertension controlled with thiazide diuretic therapy, received either a single daily dose of tenidap sodium 120 mg or matched placebo for 22 days in addition to their diuretic therapy. Changes between baseline and endpoint in supine and standing systolic and diastolic pressures and pulse rate were compared between treatment groups. 3. Daily treatment with tenidap reduced the anti-hypertensive efficacy of the thiazide diuretics. Blood pressure tended to increase marginally and the increase in mean standing diastolic pressure observed with tenidap was significantly greater than the change in the placebo group. All pressures tended to decrease in the placebo group and all endpoint measurements were within 7 mm Hg of baseline in both groups. 4. Treatment-related side effects of mild to moderate severity were reported in two subjects receiving tenidap, but in neither case was treatment discontinued. Two subjects receiving placebo also experienced side effects considered to be treatment-related and both were withdrawn from the study. 5. The results of this study suggest that tenidap may be given to patients treated for mild to moderate essential hypertension controlled with thiazide therapy; however, the patient's blood pressure should be regularly monitored.

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response.

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist.

Twenty patients receiving a variety of emetogenic cytotoxics (including cisplatin in 5) were given a single i.v. infusion of 40 micrograms kg-1 of BRL43694 (as the hydrochloride salt) in successive groups of 3-4 patients between 0-6 hours after chemotherapy. Eleven patients were completely protected from vomiting; 9 had mild to moderate nausea and vomiting, but none severe enough to require alternative anti-emetic 'rescue'. In 4 of the patients in whom BRL43694 was delayed until 4-6 h after chemotherapy, vomiting had already begun; in each case immediate termination of vomiting occurred when BRL43694 was infused. No adverse effects attributable to the anti-emetic were observed. Mean pharmacokinetic parameters in 14 patients in whom plasma assay data are available were: Maximum observed concentration = 30.7 ng ml-1; terminal phase half-life = 8.96 h; total body clearance = 0.376 (1 h-1) kg-1; apparent volume of distribution = 2.85 l kg-1. This study shows BRL43694 to be an effective and well tolerated anti-emetic. Further studies aimed at defining an optimal dose and schedule for use against the most emetogenic cytotoxics are in progress.

Clinical pharmacokinetics of allopurinol.

Allopurinol is a widely used drug in the management of hyperuricaemia. It is rapidly and extensively absorbed following oral administration. The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. Up to 80% of allopurinol is recovered in the urine within 24 hours, mainly in the form of oxypurinol. Allopurinol is negligibly absorbed after rectal administration. In animals, allopurinol is found in highest concentrations in vascular tissue, blood, liver, intestine and heart. It is negligibly bound to plasma proteins. Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. Allopurinol inhibits the metabolism of 6-mercaptopurine and azathioprine, which require dosage modifications. The interaction of allopurinol with oral anticoagulants and phenytoin has not been clearly established in clinical practice.

The effects of serum, lithium, ethacrynic acid, and a low external concentration of potassium on specific [3H]-ouabain binding to human lymphocytes after incubation for 3 days.

We have quantified specific [3H]-ouabain binding sites in normal human lymphocytes, and have measured the changes in the numbers of those sites which occur in response to various stimuli. We have confirmed previous findings that incubation for 72 h in the presence of fetal calf serum causes an increase in [3H]-ouabain binding, and that this does not occur if the cells are incubated in fetal calf serum which has first been dialysed. During incubation of the lymphocytes for 3 days in the presence of dialysed fetal calf serum each of the following stimuli caused an increase in specific [3H]-ouabain binding: addition of ethacrynic acid (1 mumol l-1), addition of lithium (1 mmol l-1), and reduction of the external potassium concentration (to 0.75 mmol l-1). By analogy with the similar results in HeLa cells reported by others, we suggest that the increase in [3H]-ouabain binding may, in the case of ethacrynic acid and the reduction of the external potassium concentration, be initiated by an increase in the intracellular sodium concentration. The mechanisms whereby fetal calf serum and lithium cause an increase in [3H]-ouabain binding are not clear.

Clinical pharmacokinetics of bretylium.

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of intractable neurogenic pain with carbamazepine.

Sixteen patients with previously intractable neurogenic pain were treated with carbamazepine (CBZ) for a period of six weeks. CBZ initial daily dosage of 400 mg was increased by a similar amount every second week to a maximum of 1,200 mg. Single dose kinetic studies prior to initiating CBZ therapy showed that these patients metabolised the drug similarly to healthy controls. Side effects, including rash (3) and ataxia (3), necessitated discontinuation of treatment in six patients. A further three patients withdrew because of lack of effect. Of the seven patients who completed the protocol, five showed a significant fall in pain score at all dosage increments with a maximum effect at the highest dose (p less than 0.01). In the seven patients for whom data was available at all three CBZ dosages, there was a significant correlation between sedation scores and CBZ concentrations (p less than 0.005). CBZ may be of value in the management of chronic neurogenic pain. Further controlled studies are indicated.