Biomedical subjects

K D Wilner

Publications and source records attributed to K D Wilner.

33 records · Page 2Linked to original sources

PubMed1995

Cimetidine does not alter the clearance or plasma binding of tenidap in healthy male volunteers.

1. An open-label, placebo-controlled study was conducted to examine the effect of cimetidine on the steady-state pharmacokinetics of tenidap. 2. Twenty-four healthy volunteers received tenidap sodium (120 mg) each morning throughout the study. On day 14 plasma levels of tenidap had reached steady state; half of the subjects were treated concomitantly with cimetidine 800 mg at night, while the other half received placebo. Allocation of cimetidine or placebo was randomised. Plasma profiles of tenidap were measured on days 14 and 16. 3. The addition of cimetidine did not significantly affect the Cmax, tmax, or lambda z of tenidap. The AUC(0,24h) increased by 4% between days 14 and 16 in the cimetidine treatment group, compared with a decrease of 2% in the placebo group. This small difference is statistically significant (P = 0.047), but it is not considered to be clinically relevant. 4. It is concluded that concomitant administration of cimetidine does not significantly affect the pharmacokinetics of tenidap at steady state.

Adolescent↗

PubMed1995

Tenidap sodium decreases renal clearance and increases steady-state concentrations of lithium in healthy volunteers.

1. An open-label, randomised placebo-controlled study was conducted to determine the effects of tenidap sodium, a novel, cytokine-modulating anti-rheumatic drug, on the steady-state concentrations and renal clearance of lithium carbonate. 2. Eighteen healthy male volunteers received 450 mg lithium carbonate twice daily for 15 days and once on day 16. On days 9-16 subjects also received either placebo or 120 mg day-1 tenidap 2 h prior to the morning dose of lithium. 3. Following a single dose of tenidap, the renal clearance of lithium decreased significantly by 0.36 l h-1 (-23%) compared with the clearance in the placebo group, which increased by 0.18 l h-1 (+14%). Steady-state serum lithium levels increased after a single dose of tenidap by 0.069 mEq l-1 (+13%), and in the placebo group levels increased by 0.003 mEq l-1 (+0.5%); this difference was not significant. 4. After 7 days' continuous administration of tenidap, the renal clearance of lithium had decreased by 0.38 l h-1 (-25%), compared with the placebo group in which clearance had increased by 0.16 l h-1 (+12%). The steady-state serum concentration of lithium increased by 0.208 mEq l-1 (+39%) in the tenidap group and by 0.063 mEq l-1 (+10%) in the placebo group. Both of these differences were significant. 5. Two subjects who received lithium plus tenidap experienced gastrointestinal side effects, compared with none of those who were administered lithium plus placebo. 6. It is recommended that serum lithium levels be monitored when tenidap and lithium are administered concomitantly.

Adult↗

PubMed1995

Effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin in healthy volunteers.

1. An open-label, randomised study was performed to assess the effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin. 2. Fourteen healthy male volunteers received either a single oral dose of 120 mg tenidap sodium or matching placebo capsules from days 11 to 36. A single oral dose of 0.75 mg kg-1 warfarin was administered on days 1 and 32. 3. The mean prothrombin AUC(1,120h) value between baseline and day 32 increased from 1692.4 +/- 234.5 s h to 1769.3 +/- 218.0 s h in the group given tenidap, and decreased from 1747.6 +/- 289.4 s h to 1708.1 +/- 236.8 s h in the placebo group. 4. Tenidap caused a slight delay in the normalisation of prothrombin times following the second dose of warfarin on day 32 compared with the first dose on day 1. This was significant at 36, 48, 72 and 96 h but not at 120 h after administration of warfarin. 5. The mean percentage of unbound warfarin in the tenidap group (0.08% +/- 0.09) was significantly different (P = 0.047) from that in the placebo group (-0.03% +/- 0.10) but this was not considered to be clinically meaningful. 6. These data indicate that prothrombin times should be monitored during concomitant administration of tenidap and warfarin.

Adult↗

PubMed1995

The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers.

1. The effects of tenidap sodium 120 mg day-1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this randomised, double-blind, placebo-controlled, parallel-group study, involving 12 healthy young men, conducted over 34 days. 2. Single oral doses of phenytoin 200 mg were given on days 1-3 and 29-31, and intravenous phenytoin, 250 mg infused over 20 min, was given on days 4 and 32. Tenidap (120 mg day-1), or matching placebo, was administered as single oral daily doses from days 8 to 34 inclusive. 3. The plasma protein binding of phenytoin was determined immediately before oral phenytoin administration on days 1 and 29. Pharmacokinetic parameters were estimated from the serum phenytoin concentration-time curves derived on days 4 and 32 following the phenytoin infusions. The differences between the pre- and post-treatment mean percentage of unbound plasma phenytoin and mean pharmacokinetic parameters were compared between treatment groups. 4. Tenidap sodium 120 mg day-1, at steady state, increased the percentage of unbound phenytoin in plasma by approximately 25%, but did not significantly affect AUC(0,48h) or Cmax. 5. Since tenidap increases the percentage of unbound phenytoin in plasma, when monitoring phenytoin plasma concentrations free concentrations of phenytoin should be considered. 6. Tenidap was well tolerated throughout the study.

Adult↗

PubMed1995

Tenidap sodium does not alter the clearance or plasma protein binding of tolbutamide in healthy male volunteers.

1. This randomised, double-blind, parallel group study in 12 healthy young men compared the effects of tenidap sodium 120 mg day-1, at steady state, with placebo on the plasma protein binding and clearance of tolbutamide. 2. Each subject received a 1000 mg intravenous infusion of tolbutamide given over 5 min on day 1 of the study, and again on day 30 following 22 days of successive tenidap or placebo administration. 3. The percentage of unbound tolbutamide in plasma was determined immediately before each infusion. Mean pharmacokinetic parameters (system plasma clearance, terminal phase rate constant, apparent volume of distribution at steady state) of tolbutamide were derived from individual tolbutamide plasma concentration-time curves generated after infusion. The within group day 30 minus day 1 differences were compared between treatment groups. 4. Tenidap was shown to have no statistically or clinically significant effects on any of the parameters assessed. These results indicate that tenidap does not induce or inhibit the P450IIC9 isozyme which metabolises tolbutamide and that tenidap does not displace tolbutamide from plasma protein binding sites. 5. Both tenidap and tolbutamide were well tolerated. No severe treatment-related adverse events were reported, no subject withdrew from the study, and there were no reports of treatment-related laboratory abnormalities, or significant variations in vital signs.

Adult↗

PubMed1995

Pharmacokinetics of fluconazole in renal failure.

Fluconazole (FLU) is a widely used antifungal agent. The multiple-dose pharmacokinetics of FLU in renal impairment have not been previously investigated. The following groups were studied: volunteers with creatinine clearances (CLcr, > 50 mL/min) of 107 mL/min, given a loading dose of 400 mg and a daily dose of 200 mg/day for 9 days (Group 1); subjects with CLcr between 21 and 50 mL/min with a mean of 38 mL/min, given a loading dose of 200 mg and a maintenance dose of 100 mg/day for 9 days (Group 2); subjects with CLcr between 11 and 20 mL/min with a mean of 14.8 ml/min, given a loading dose of 100 mg and a maintenance dose of 50 mg/day for 9 days (Group 3); and subjects on hemodialysis (three times per week) receiving a loading dose of 200 mg and then 100 mg after each of four dialysis sessions (Group 4) (N = 10 per group). After the administration of the loading dose on Day 1, the mean area under the curve (AUC) (0-24) measurements were approximately proportional to the dose of FLU and independent of renal function. After 10 days of FLU dosing, the mean renal clearance of FLU decreased as CLcr decreased for Groups 1 to 3, and the Day 10 mean half-lives were inversely related to mean CLcr (36.7 h in Group 1, 84.5 h in Group 2, and 101.9 h in Group 3). The mean AUC (0-24) on Day 10 was similar for Group 1 compared with Group 2, despite a reduction in the maintenance dose by 50%. (ABSTRACT TRUNCATED AT 250 WORDS)

Creatinine↗

PubMed1992

Effect of the anti-inflammatory agent tenidap on the pharmacokinetics and pharmacodynamics of prednisolone.

The effect of tenidap, a new nonsteroidal anti-inflammatory agent, on the pharmacokinetics and pharmacodynamics of prednisolone was studied in healthy male subjects. In a randomized crossover study, 12 subjects received either tenidap sodium 120 mg daily or placebo orally for 28 days. On day 21, each subject received a single dose of either 0.8 mg/kg oral prednisone or 0.66 mg/kg intravenous prednisolone followed by the other steroid on day 28. Blood and urine samples were collected, and the pharmacokinetic parameters of prednisone and prednisolone were determined in each treatment period. Pretreatment with tenidap did not cause any significant changes in the overall disposition of prednisone or prednisolone. For example, for free prednisolone, the intravenous area under concentration was 1,144 +/- 195 ng.h/mL and 1,244 +/- 140 ng.h/mL, and the systemic availability after oral prednisone was 53 +/- 10% and 51 +/- 12% with placebo and tenidap, respectively. The renal clearance of prednisolone was significantly reduced after tenidap pretreatment, however (from 143 to 77 mL/min/1.73 m2). The suppression of plasma cortisol and whole blood histamine levels were analyzed to evaluate the potential pharmacodynamic interactions between tenidap and prednisolone. There were no significant changes in the pharmacodynamic parameters between placebo and tenidap groups. The excretion of less than 20% of the dose of prednisolone in urine makes the overall effects of tenidap on prednisolone kinetics and dynamics of inconsequential clinical importance.

Adolescent↗

PubMed1992

Sertraline does not alter steady-state concentrations or renal clearance of lithium in healthy volunteers.

An open-label, placebo-controlled study was conducted to determine the effects of sertraline on the steady-state levels and renal clearance of lithium in 20 healthy volunteers. Subjects received 600 mg of lithium twice daily for 9 days. On the evening of day 8, subjects received orally either placebo or 100 mg of sertraline; these were administered twice, 8 hours apart, beginning 2 hours after the evening dose of lithium. In a comparison of day 8 with day 9 (before administration of the morning doses of lithium), sertraline was associated with only a 0.01 mEq/L (1.4%) decrease in steady-state levels and a 0.11 L/hour (6.9%) increase in the renal clearance of lithium. Neither change was statistically significant relative to placebo. Four subjects were excluded from analysis because of protocol violations or laboratory abnormalities unrelated to sertraline. Seven subjects who received lithium plus sertraline experienced side effects, mainly tremors, possibly related to treatment, whereas none of those administered lithium plus placebo experienced side effects. No sertraline-related laboratory abnormalities were observed.

1-Naphthylamine↗

PubMed1988

Atrial natriuretic factor in renal failure and posthemodialytic postural hypotension.

Atrial natriuretic factor (ANF) levels were ten times normal in hemodialysis patients before dialysis. ANF was not cleared by the dialyzer membrane but plasma levels decreased 47% by the end of dialysis. Patients undergoing peritoneal dialysis had plasma ANF levels four times normal and had detectable ANF in their dialysate. Hemodialysis patients with a marked fall in BP after dialysis had higher ANF levels (P less than 0.05) and lower norepinephrine (NE) levels (P less than 0.05) associated with a failure to increase NE in response to dialysis. Elevated ANF levels are associated with postdialysis hypotension in hemodialysis patients.

Adult↗

PubMed1988

The effect of hemorrhage and resuscitation on serum levels of immunoreactive atrial natriuretic factor.

To determine if atrial natriuretic factor (ANF) might have a role in blood volume regulation during hypovolemia, the serum level was measured before and after hemorrhage and resuscitation (RESUS) in a porcine shock model. Hemorrhage of 40% of the blood volume produced significant (p less than 0.01) decreases in mean arterial pressure, central venous pressure, and cardiac output and a significant increase in heart rate (HR), plasma renin activity, and catecholamines (p less than 0.01). Hemorrhage was also associated with a significant increase in ANF (p less than 0.05). All parameters except HR returned to baseline values with RESUS. The rise in ANF associated with moderate hemorrhage was unexpected, but may have been due to the profound tachycardia or decreased degradation during shock. Sodium excretion and urine flow increased significantly with RESUS without an associated increase in ANF, suggesting that ANF may not be involved in the early phase of postresuscitation diuresis.

Animals↗

PubMed1987

Atrial natriuretic factor in hypovolemic tachycardia.

Atrial natriuretic factor (ANF) is released in response to many stimuli which increase right atrial pressure. Following hemorrhage pigs lowered their atrial pressures, developed a tachycardia and increased ANF levels. Electrical pacing increased heart rate and ANF levels. There is a stimulus to ANF release other than atrial stretch, probably heart rate.

Animals↗

PubMed1987

Effects of alpha 1 inhibition on renal blood flow and sympathetic nervous activity in systemic hypertension.

Doxazosin is a competitive inhibitor of norepinephrine at alpha 1 adrenoceptors on vascular smooth muscle, where it blocks vasoconstriction. Twenty-four patients with mild hypertension were treated with either doxazosin or placebo for 6 weeks. Supine and upright mean arterial pressures decreased by 9 and 12 mm Hg, respectively, in patients receiving doxazosin. This decrease was significantly more than the blood pressure change with placebo (p less than 0.05). Doxazosin therapy led to a small increase in weight (p less than 0.05). It was also associated with a statistically insignificant decrease in renal vascular resistance (568 dynes s/cm5) so that renal blood flow and creatinine clearance did not change. Doxazosin increased renin levels acutely and norepinephrine levels with 6-week treatment, but these changes were not significantly different from placebo. Norepinephrine clearance, measured after a 120-minute infusion of 3H norepinephrine, did not change. Heart rate increased acutely after doxazosin administration, but returned to baseline during 6-week therapy. Blood pressure, measured hourly for 14 hours after treatment, was consistently decreased in all patients. Doxazosin taken once daily lowers blood pressure without affecting renal blood flow or heart rate.

Adrenergic alpha-Antagonists↗

PubMed1986

Sympathetic nervous withdrawal in the vasodepressor (vasovagal) reaction.

When 40 subjects had 134 ml of blood drawn, 8 of them developed hypotension. These 8 subjects were younger, and when they stood they decreased their systemic arterial pressure, pulse rate and plasma norepinephrine. In contrast, normal subjects increased all these parameters after standing. The fall in plasma norepinephrine suggests a generalized withdrawal of sympathetic nervous tone during vasodepressor reactions. Three subjects maintained a heart rate above 60, but still developed hypotension. Withdrawal of sympathetic tone to the vasculature appears more important than increased vagal tone to the heart in causing hypotension in this reaction.

Adrenergic Fibers↗

PubMedDate not supplied

Drug interactions with fluconazole.

Fluconazole, a water-soluble bis-triazole antifungal agent that effectively penetrates the cerebrospinal fluid, is a highly selective inhibitor of the fungal cytochrome P450 system. In single-dose studies, coadministration of cimetidine and fluconazole (100 mg) resulted in an insignificant decrease in the absorption of fluconazole. The coadministration of rifampin and fluconazole (200 mg) decreased both the half-life and the area under the plasma concentration-time curve (AUC) of fluconazole. In multiple-dose studies, fluconazole (50 mg) did not significantly alter the pharmacokinetics of the two steroid components of an oral contraceptive. Coadministration of tolbutamide with fluconazole (100 mg) increased both the maximal plasma concentration and the AUC of tolbutamide without changing levels of blood glucose. The coadministration of cyclosporin A with a low dose of fluconazole (100 mg) was not associated with significant changes in the minimal and the maximal plasma concentrations of cyclosporin A. While higher doses of fluconazole (200 mg) did not affect endogenous steroids, coadministration resulted in changes in the pharmacodynamics of warfarin and the pharmacokinetics of phenytoin and cyclosporin A.

Adrenal Glands↗

PubMedDate not supplied

The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone.

STUDY OBJECTIVE: To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic drug ziprasidone. DESIGN: Open, randomized, three-way crossover study. SETTING: University-based research facility. SUBJECTS: Eight healthy male volunteers. INTERVENTIONS: Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-infinity), maximum serum concentration, and half-life (analysis of variance all p<0.05), with the mean AUC0-infinity being significantly greater (627.2 +/- 206.4 vs 371.0 +/- 126.5 ng x hr/ml, ANOVA with Bonferroni's criteria p<0.016) and half-life significantly shorter (4.7 +/- 0.8 vs 6.6 +/- 1.3 hrs, ANOVA with Bonferroni's criteria p<0.016) after treatment B compared with treatment A. Although similar trends were observed after treatment C compared with treatment A, the differences did not reach statistical significance when Bonferroni's correction criteria were applied (p>0.016). CONCLUSION: These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug's longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-infinity and maximum concentration, daytime vigilance was not affected.

Adolescent↗