Steady-state pharmacokinetics of carvedilol and its enantiomers in patients with congestive heart failure.

Carvedilol is a relatively new drug with beta- and alpha 1-receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple-dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(-)-carvedilol, R(+)-carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice-daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose-proportional increases in steady-state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady-state plasma concentrations of the active metabolites also increased in a dose-proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25-50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.

The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline.

The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 micrograms/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.

Effect of age and gender on the pharmacokinetics of eprosartan.

AIMS: To compare the pharmacokinetics of eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of eprosartan. There were approximately two fold higher AUC and Cmax values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food.

Eighteen healthy males received a single 300 mg oral dose of eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. eprosartan (mean +/- S.D.) were characterized by a low systemic plasma clearance (131.8 +/- 36.2 mL min(-1)) and a small steady-state volume of distribution (12.6 +/- 2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5-7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, eprosartan may be administered without regard to meal times.

Eprosartan does not affect the pharmacodynamics of warfarin.

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.

Fenoldopam, a selective dopamine-1 receptor agonist, raises intraocular pressure in males with normal intraocular pressure.

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.

The effects of eprosartan, an angiotensin II AT1 receptor antagonist, on uric acid excretion in patients with mild to moderate essential hypertension.

The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of eprosartan on uric acid excretion were evaluated in 57 male patients with mild-to-moderate essential hypertension in a double-blind, randomized, placebo-controlled, repeated dose, dose-rising, two-period, period-balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of eprosartan dose regimens of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FEua), urine uric acid excretion, urine uric acid to creatinine (Uua/Ucr) ratios, or serum uric acid concentrations after single or repeated doses of eprosartan. Mean Uua/Ucr ratios for eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FEua values and Uua/Ucr ratios for eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild-to-moderate essential hypertension.

Use of topical corticosteroid pretreatment to reduce the incidence and severity of skin reactions associated with testosterone transdermal therapy.

Local skin reactions at the application site are the most common adverse events associated with the testosterone transdermal delivery (TTD) systems used to treat postpubertal hypogonadism in males. This open-label, controlled pilot study was conducted to determine whether topical pretreatment with triamcinolone acetonide 0.1% cream might be useful in reducing the incidence and/or severity of chronic skin irritation when used in healthy volunteers receiving TTD systems. Adult male volunteers wore three topical systems, which were applied to the upper back daily (Monday through Friday) for 6 weeks: (1) TTD with no pretreatment of application site; (2) TTD with pretreatment of application site using triamcinolone acetonide 0.1% cream; and (3) an inactive occlusive dressing (control). On Monday through Thursday, systems were removed 24 hours after application. Patches applied on Friday were worn continuously for 72 hours until their removal on Monday. Skin reactions were graded on a scale from 0 to 4 (0 = none, 4 = severe) and were assessed daily by research personnel, beginning at the time of system removal (assessment 1) and on the two subsequent clinic visits (assessments 2 and 3). All skin irritation scores of all subjects were totaled for each treatment regimen to obtain a cumulative score per treatment regimen. The cumulative scores were also analyzed by assessment time and study week (weeks 1-6). Eighty-two subjects were enrolled in the study, and 65 completed the 6-week treatment course. Mean age of subjects was 24 years (range, 18-69 years), and mean weight was 79.0 kg (range, 58.9-127.3 kg). All subjects were white males. At assessment 1, pretreatment with triamcinolone acetonide 0.1% cream (compared with no pretreatment) was associated more often with scores of 0 (no erythema), with comparable occurrences of mild skin irritation, and with fewer occurrences of moderate erythema. At all three assessments, more subjects had lower cumulative scores with pretreatment than without pretreatment. At every assessment and in each week of the study, total weekly cumulative skin irritation scores were also lower with pretreatment than without pretreatment. No adverse experiences other than skin irritation were reported. Results of this study suggest that in patients using TTD systems, the incidence and severity of skin irritation at application sites may be reduced through pretreatment with triamcinolone acetonide 0.1% cream.

A dose proportionality study of eprosartan in healthy male volunteers.

The present study investigated the proportionality of exposure after single oral doses of 100, 200, 400, and 800 mg of eprosartan, a nonpeptide, nonbiphenyl angiotensin II receptor antagonist, in 23 healthy young men. Eprosartan was safe and well tolerated. Exposure to eprosartan increased with dose but in a less than proportional manner. For each two-fold dose increase, area under the concentration--time curve (AUC) increased an average of 1.6 to 1.8 times and maximum plasma drug concentration (Cmax) increased an average of 1.5 to 1.8 times. For both parameters, the greatest difference from the dose multiple was observed between the 400- and 800-mg doses. Dose proportionality of eprosartan, as assessed by an equivalence-type approach using the 100-mg dose as the reference and a 30% acceptance region (0.70, 1.43), was achieved for the 200- and 400-mg doses for AUC and the 200-mg dose for Cmax. The observed changes in the pharmacokinetics of eprosartan suggest slight saturation of absorption of eprosartan over the 100- to 800-mg dose range, most likely due to the physicochemical properties of the drug (pH-dependent aqueous solubility and lipophilicity).

Bioequivalence assessment of a single 5 mg/day testosterone transdermal system versus two 2.5 mg/day systems in hypogonadal men.

A novel, nonscrotal, transdermal delivery system for testosterone therapy has been marketed for treatment of hypogonadal men. The usual dose of this system is two 2.5 mg/day systems applied daily. A new system has been developed that administers a dose of 5 mg/day using a single patch rather than two patches. A randomized, steady-state, four-period, replicate-design, open-label, crossover study was conducted to assess the bioequivalence of the two testosterone transdermal delivery systems in postpubertal, hypogonadal men: two 2.5 mg/day patches as the reference regimen (R) and one 5 mg/day patch as the test regimen (T). 21 men were enrolled, and 20 completed the study. Each subject was randomly assigned to one of four sequences (R1-R2-T1-T2, T1-T2-R1-R2, R1-T1-T2-R2, T1-R1-R2-T2), such that each subject received each regimen during two study sessions. Two subjects were inadvertently treated according to the sequence T1-R1-T2-R2. Patches were applied to the upper arm, thigh, and back in the evening on days 1, 2, and 3, respectively, of each study session. Serial blood samples were obtained for pharmacokinetic analysis of testosterone for 24 hours after patch application on day 3 of each study session. The two formulations would be considered bioequivalent if the 90% confidence intervals (CI) for the ratios of the adjusted geometric means for T:R for both area under the concentration--time curve from 0 to 24 hours (AUC0-24) and maximum concentration (Cmax) were completely contained in the interval (0.80, 1.25). Mean values for AUC0-24 and Cmax were similar for the two formulations. The T and R formulations were found to be bioequivalent based on both AUC0-24 (90% CI 0.96, 1.08) and Cmax (90% CI 0.92, 1.07). The median time to Cmax was also similar, indicating comparable rates of testosterone absorption for both formulations. Based on this analysis, the testosterone transdermal system 5 mg/day patch is bioequivalent to two of the 2.5 mg/day patches. Both systems were safe and well tolerated in hypogonadal men.

A dose-response study to assess the renal hemodynamic, vascular, and hormonal effects of eprosartan, an angiotensin II AT1-receptor antagonist, in sodium-replete healthy men.

STUDY DESIGN: The effects of orally administered eprosartan on changes induced by angiotensin II in blood pressure, renal hemodynamics, and aldosterone secretion were evaluated in healthy men in this double-blind, randomized, single-dose, placebo-controlled crossover study, which was conducted in three parts. Part 1 (n = 12) assessed the onset and duration of the effect of eprosartan 350 mg or placebo; part 2 (n = 14) assessed the dose-response profile of placebo or 10, 30, 50, 70, 100 or 200 mg eprosartan; and part 3 (n = 5) assessed the duration of the effect of 50, 100, or 350 mg eprosartan. RESULTS: In part 1 of the study; 350 mg eprosartan caused complete inhibition of angiotensin II-induced pressor and renal blood flow hemodynamic effects (effects on effective renal plasma flow [ERPF]) and inhibited angiotensin II-induced stimulation of aldosterone secretion from 1 to 3 hours after administration. Eprosartan, 350 mg, inhibited the effects of exogenous angiotensin II by approximately 50% to 70% from 12 to 15 hours after dosing. Eprosartan had no angiotensin II agonistic activity and produced an increase in ERPF starting at 1 to 4 hours after dosing. In study part 2, at 3 hours after single doses of 10, 30, 50, 70, 100, and 200 mg, eprosartan inhibited angiotensin 11-induced decreases in ERPF by 39.1%, 49.9%, 33.0%, 56.0%, 71.0%, and 85.7%, respectively, compared with placebo. In study part 3, 50, 100, and 350 mg eprosartan produced measurable Inhibition of angiotensin II-induced decreases in ERPF from 12 to 15 hours after administration. In parts 2 and 3, the eprosartan angiotensin II antagonism on blood pressure response and aldosterone secretion mirrored the angiotensin II antagonism on ERPF.

Pharmacokinetics and protein binding of eprosartan in healthy volunteers and in patients with varying degrees of renal impairment.

This was an open-label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr > 80 mL/min; n = 8) and patients with mild (Clcr 60-80 mL/min; n = 8), moderate (Clcr 30-59 mL/min; n = 15), or severe (Clcr < 30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration-time curve from 0 to 12 hours (AUC0-12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two-fold in the group with severe renal impairment. Mean unbound Cmax and AUC0-12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.

Effect of ranitidine on the pharmacokinetics of orally administered eprosartan, an angiotensin II antagonist, in healthy male volunteers.

OBJECTIVE: To assess the effect of ranitidine on the pharmacokinetics of eprosartan in healthy male volunteers. DESIGN: Single-center, randomized, open-label, two-period, period-balanced, crossover study. PATIENTS: Seventeen healthy men aged 19 to 43 years. INTERVENTION: In each period (separated by a > or = 7 d washout), subjects received a single 400-mg oral dose of eprosartan alone, or a single oral dose of eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following eprosartan dosing. MAIN OUTCOME MEASURES: Plasma and urine eprosartan concentrations during each treatment session. RESULTS: Eprosartan maximum concentration (Cmax), the AUC from time-zero to the last quantifiable concentration (AUC0-t), and renal clearance (Cl(r)) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with eprosartan alone. The 95% CIs for the ratio of eprosartan plus ranitidine compared with eprosartan alone were 0.81 to 1.07, 0.77 to 1.03, and 0.64 to 1.43, for Cmax, AUC0-t, and Cl(r), respectively, indicating no statistically significant difference between regimens. CONCLUSIONS: Repeated doses of ranitidine did not have a marked effect on the single-dose pharmacokinetics of eprosartan.

Effect of hepatic disease on the pharmacokinetics and plasma protein binding of eprosartan.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and plasma protein binding of eprosartan in hepatic disease. DESIGN: Single-dose, parallel-group study. SETTING: Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. PATIENTS: Eight healthy subjects with normal hepatic function and eight patients with hepatic disease. INTERVENTION: All subjects received a single oral dose of eprosartan 100 mg. MEASUREMENTS AND MAIN RESULTS: Eprosartan plasma concentrations were quantified by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Using analysis of variance, point estimates (PE) and 90% CIs were calculated. Total and unbound maximum concentrations and degree of plasma protein binding were similar for both groups. Total area under the plasma concentration-time curve (AUC0-t) was approximately 40% higher for the group with hepatic disease (PE 1.42, 90% CI 0.94-2.14). Similarly, unbound AUC0-t was approximately 50% higher (PE 1.53, 90% CI 0.98-2.39). CONCLUSION: Eprosartan was safe and well tolerated by both groups. Based on the increase in AUC in patients with hepatic disease compared with those with normal hepatic function, the dosage of eprosartan in patients with hepatic disease should be individualized based on tolerability and response.

Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers.

OBJECTIVE: To investigate the effect of steady-state fluconazole administration on the disposition of eprosartan, losartan, and E-3174. METHODS: Sixteen healthy male subjects received 300 mg eprosartan every 12 hours, and 16 received 100 mg losartan every 24 hours on study days 1 to 20. All 32 subjects received 200 mg fluconazole every 24 hours beginning on day 11 and continuing through day 20. Serial blood samples were collected over one dosing interval on study days 10 and 20 for measurement of plasma concentrations of eprosartan, losartan, and E-3174 (the active metabolite of losartan). RESULTS: There was no significant difference in eprosartan area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC(0-t)] or maximum concentration (Cmax) when administered alone and with fluconazole. After concomitant administration with fluconazole, losartan AUC(0-t) and Cmax were significantly increased 66% and 30%, respectively, compared with those values for losartan alone. The AUC(0-t) and Cmax for E-3174 were significantly decreased 43% and 56%, respectively, after administration of losartan with fluconazole. CONCLUSIONS: Fluconazole significantly increases the steady-state AUC of losartan and inhibits the formation of the active metabolite of losartan, E-3174. In contrast, fluconazole administration has no effect on the steady-state pharmacokinetics of eprosartan.

Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers.

AIMS: To study the effect of eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, on digoxin pharmacokinetics in a randomized, open-label, two period, period balanced crossover study in 12 healthy men. METHODS: Each subject received a single 0.6 mg oral dose of digoxin (Lanoxicaps 0.2 mg/capsule, Glaxo Wellcome) alone or following 4 days of dosing with eprosartan 200 mg orally every 12 h. Each study period was separated by a 14 day washout interval. Serial blood samples were obtained for up to 96 h after each digoxin dose for determination of digoxin pharmacokinetics. The effect of eprosartan on digoxin pharmacokinetics was assessed through an equivalence-type approach using AUC(0, t') as the primary endpoint. RESULTS: For AUC(0, t'), the ratio of digoxin+eprosartan: digoxin alone was 0.99 with a 90% confidence interval (CI) of [0.90, 1.09]. For Cmax, the ratio was 1.00 with a 90% CI of [0.86, 1.17]. tmax was similar for both regimens. Both regimens were safe and well tolerated. CONCLUSIONS: Based on AUC and Cmax data, it can be concluded that eprosartan has no effect on the pharmacokinetics of a single oral dose of digoxin.

Cardiovascular effects of i.v. granisetron at two administration rates and of ondansetron in healthy adults.

The cardiovascular effects of granisetron given as a 30-second i.v. bolus dose and of granisetron and ondansetron given by currently recommended methods were studied. Healthy adults 18 to 50 years of age were randomly assigned to one of four treatments during each of four study periods: granisetron 10 micrograms/kg (as the hydrochloride salt) i.v. over 5 minutes, granisetron 10 micrograms/kg i.v. over 30 seconds, ondansetron 32 mg (as the hydrochloride salt) i.v. over 15 minutes, and placebo. During each study period, the researchers gave each subject three sequential injections using a double-blind, double-dummy technique. Each subject was to receive all four regimens. Two resting 12-lead electrocardiograms (ECGs) were obtained before the regimen, and one was obtained at the end of each injection and at intervals up to 24 hours after the third injection. Sitting blood pressure and pulse were measured before treatments, immediately after the end of each injection, and at intervals up to 24 hours after injection 3. Safety data were analyzed for 13 subjects, and ECG interval data for 12 of them. The mean postdose QTc interval differed significantly among regimens. There were no other significant regimen-associated differences among the four mean results for any ECG interval. The mean post-dose QTc interval for ondansetron was significantly greater than that for each of the other regimens. The drug regimens were comparable in safety and tolerability. A total of 20 adverse effects, all mild to moderate, were reported in 10 subjects. Changes in vital signs were minimal. There were no clinically important cardiovascular changes associated with the i.v. administration of granisetron 10 micrograms/kg over 30 seconds, granisetron 10 micrograms/kg over 5 minutes, or ondansetron 32 mg over 15 minutes in healthy adults.

Effect of intravenous fenoldopam on intraocular pressure in ocular hypertension.

Intravenous fenoldopam, a selective dopamine-1 receptor agonist, was compared with placebo in this randomized, double-blind, two-period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open-angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 microgram/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P < 0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam-associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine-1 receptors play a role in the regulation of intraocular pressure.

Eprosartan, an angiotensin II receptor antagonist, does not affect the pharmacodynamics of glyburide in patients with type II diabetes mellitus.

The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24-hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo-controlled, double-blind (eprosartan-placebo phase only), two-period, period-balanced, crossover study. All patients received a stable oral dose (3.75-10 mg/day) of glyburide for at least 30 days before the first dose of double-blind study medication was administered. Patients were randomized to receive either 200-mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24-hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24-hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24-hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide.

Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose.

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 +/- 10.5 years) were enrolled in an open-label, randomized, crossover study. Each application period comprised 4 days: a 2-day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patient's back. On day 4 of each period, serial blood samples were collected for determination of total and non-sex hormone binding globulin (non-SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration-time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non-SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.