Biomedical subjects

F A Sollie

Publications and source records attributed to F A Sollie.

10 recordsLinked to original sources

PubMed2000

Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers.

The study was conducted in healthy male volunteers to evaluate the absorption, metabolic pattern, and mode of elimination of telmisartan, a nonpeptide angiotensin II receptor antagonist. [14C]telmisartan was administered orally in solution as a single 40 mg dose to 5 subjects. A further 5 subjects received short-term intravenous infusion of [14C]telmisartan 40 mg. Measurement of total 14C radioactivity in plasma showed that about 50% was absorbed following oral administration, with maximum plasma concentration observed after 0.5 to 1 hour. Absolute bioavailability was 43%. On average, 84% of total radioactivity in plasma reflected the parent compound. The remainder of total radioactivity could be ascribed to the glucuronide conjugate of telmisartan, which represented the only metabolite in man. About 99.5% of telmisartan was bound to plasma protein, mainly to albumin and alpha-1-acid glycoprotein. Telmisartan was reversibly distributed into erythrocytes. More than 90% of administered dose was excreted within 120 hours, and the excretion balance was complete 144 hours after dosing. Radioactivity was almost exclusively (> 98%) excreted via the feces; urinary excretion accounted for < 1% of the dose, irrespective of the route of administration. In the small fraction excreted into urine, the glucuronide conjugate of telmisartan was predominant. Although some telmisartan glucuronide was detected in plasma, only unchanged drug was identified in the feces. No changes in vital signs, electrocardiogram, or clinical laboratory tests were detected following telmisartan administration, and adverse events, predominantly unrelated to treatment and of mild intensity, were infrequent. One subject fainted and, on another occasion, reported faintness; these events were probably due to the antihypertensive action of the intravenous study medication.

Absorption↗

PubMed2000

Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy male volunteers.

The effects of multiple-dose telmisartan on the steady-state pharmacodynamics and pharmacokinetics of warfarin were assessed in 12 healthy young males in an open-label, single-period study conducted over 30 days. Subjects received loading doses of oral once-daily warfarin on days 1 to 5, which were individually adjusted at days 6 and/or 9 to attain stable predose prothrombin time values (INRpre) of between 1.2 and 1.8 by the end of medication phase 1 (day 14). From days 15 to 24 (medication phase 2), subjects received oral once-daily telmisartan 120 mg in addition to individualized oral doses of once-daily warfarin. On days 25 to 31 (medication phase 3), oral once-daily warfarin was again administered alone at individualized doses. Under steady-state conditions, INRpre remained unchanged during medication phases 1, 2, and 3. The difference between phases 1 and 3 was -0.04 (95% confidence interval [CI]: -0.7 to 0.10) and between phases 2 and 1 was 0.03 (95% CI: -0.11 to 0.10). Mean trough plasma warfarin concentrations (Cpre) were stable during medication with warfarin alone but showed a small, although statistically significant, decrease during the combined-medication phase. The point estimate of the ratio of phase 2/phase 1 was 0.89 (95% CI: 0.84 to 0.95). The decrease in Cpre did not result in decreased anticoagulation. This suggests that the extent of pharmacokinetic interaction between telmisartan and warfarin is limited, and since telmisartan had no effect on INRpre and the concomitant medication was well tolerated, there is no evidence for a clinically relevant interaction between telmisartan and warfarin.

Adolescent↗

PubMed2000

The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers.

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Adolescent↗

PubMed1998

The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers.

AIMS: Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS-MS assay has been developed which allows quantification of plasma concentrations of zolmitriptan and its active metabolite, 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose-proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose. METHODS: Two randomized, balanced, open-label, 4-period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined the dose-proportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored. RESULTS: The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48+/-0.14 and 0.36+/-0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (+/-s.d.) AUC was 32.7+/-10.1 and 60.2+/-26.8 ng ml(-1) h after 5 mg in men and women, respectively (95% CI for ratio 0.43-0.77). After 2.5 mg mean (+/-s.d.) AUC was 18.4+/-5.4 and 23.1+/-9.9 ng ml(-1) h in men and women, respectively (95% CI for ratio 0.61-1.09). However, these differences were of no clinical significance. Cmax and AUC of oral zolmitriptan were dose-proportional and there was a 13 and 16% fall in mean zolmitriptan Cmax and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and there were no clinically significant effects on ECG, blood pressure, or laboratory parameters. CONCLUSIONS: At therapeutic doses zolmitriptan has good oral bioavailability in healthy volunteers and has dose-proportional pharmacokinetics that are not affected by food to any clinically relevant extent.

Adolescent↗

PubMed1997

Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1-84)] in healthy postmenopausal volunteers.

BACKGROUND: Parathyroid hormone [PTH(1-84)] is intended for treatment of osteoporosis because it stimulates new bone formation of normal structure and composition. Recently, recombinant human PTH(1-84) [rhPTH(1-84)] has become available for therapeutic evaluation. OBJECTIVES: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single-dose subcutaneous administration of rhPTH(1-84) or placebo to 32 healthy postmenopausal volunteers (dose range, 0.02 to 5.0 micrograms.kg-1). RESULTS: In the lower dose range (0.02 to 2.0 micrograms.kg-1), serum ionized and total calcium concentrations increased dose dependently, with approximately 0.15 mmol/L for dose levels > 0.2 microgram.kg-1 and > 1.5 micrograms.kg-1, respectively, unlike the higher dose range (2.0 to 5.0 micrograms.kg-1), for which concentration-time profiles clearly exhibited a biphasic pattern. Urine evaluation revealed an increase in both calcium/ creatinine and phosphate/creatinine ratios, the former appearing in the 12- to 24-hour and 24- to 36-hour collections for doses > 2.5 micrograms.kg-1 and the latter in the 0- to 12-hour collection for doses > or = 1.5 micrograms.kg-1. Urinary deoxypyridinoline excretion was used as a biochemical marker of bone resorption, but no consistent changes were found. Urinary cyclic adenosine monophosphate excretion, which is an indirect measure of PTH(1-84) action on the kidney, showed a clear increase in the 0- to 12-hour urine collection for doses > or = 1.5 micrograms.kg-1. As for ionized and total calcium, serum concentration-time curves of PTH(1-84) exhibited a double-peak profile, the first peak appearing about 5 to 10 minutes after administration and the second peak occurring about 1 1/2 to 2 hours after administration. Serum terminal half-life of PTH(1-84) was approximately 2 1/2 hours. CONCLUSION: Up to a dose of 5.0 micrograms.kg-1, rhPTH(1-84) was safe and well tolerated by healthy postmenopausal volunteers.

Adult↗

PubMed1996

No pharmacokinetic or pharmacodynamic interaction between theophylline and the leukotriene biosynthesis inhibitor BAY x 1005.

An open, randomized, three-period crossover study was conducted to compare the steady-state pharmacokinetics, pharmacodynamics, and tolerability of concomitant administration of BAY x 1005 and theophylline in 12 healthy volunteers. BAY x 1005 (250 mg twice daily; treatment A) and theophylline (400 mg twice daily; treatment B), were administered alone and concomitantly (treatment C) for 6 days with a final morning dose on day 7. The treatments were separated by washout periods of at least 5 days. Pharmacokinetic parameters were derived from concentrations of BAY x 1005 and theophylline as measured by high-performance liquid chromatography in plasma collected before the morning dose on days 5 and 6 and at various times on day 7 of each period until 24 hours after drug administration. Adverse events, vital signs, electrocardiograms, and clinical laboratory studies were monitored as safety parameters. Levels of leukotriene B4 (LTB4) were assessed in plasma collected on days 1 and 7. The treatments were well tolerated by all participants. The ratios of maximum concentration (Cmax) and area under the concentration-time curve for one 12-hour dosing interval (AUC tau) for treatment C versus B for theophylline on day 7 was 98% for both parameters. For BAY x 1005, the ratios of treatment C versus treatment A were 94% for Cmax and 101% for AUC tau. Plasma LTB4 remained virtually unchanged during either treatment. Steady-state concentrations of theophylline were not affected by concomitant BAY x 1005 intake, and addition of theophylline had no clinically relevant effect on steady-state plasma concentrations of BAY x 1005. The combination of theophylline and BAY x 1005 did not lead to a change in nature, intensity, or frequency of adverse events.

Adult↗

PubMed1994

Lack of pharmacokinetic interaction between vinpocetine and oxazepam.

The influence of multiple doses of vinpocetine (10 mg three times daily) on the steady state plasma concentrations of oxazepam (10 mg three times daily) was studied in 16 healthy subjects. The mean (+/- s.d.) AUC (ng ml-1h-1) of oxazepam over 24 h during combined treatment was 4716 +/- 2296 and for oxazepam treatment alone it was 4737 +/- 2448 (95% confidence intervals for ratio of means = 95.4-103.7%). The degree of plasma protein binding of oxazepam was 98.11 +/- 0.32% and was not affected by vinpocetine. Independent of vinpocentine treatment a significant diurnal change in the plasma binding of oxazepam was observed; the free drug fraction was 20% higher during the night than during the day. Cmax and AUC values based on total oxazepam in plasma were 10% lower during the night. The results indicate a lack of influence of vinpocetine on oxazepam kinetics. Diurnal changes in the plasma binding of oxazepam probably have no clinical consequences.

Adult↗

PubMed1993

Dose-dependent uricosuric effect of ambroxol.

Ambroxol is known to promote bronchial secretion and is used as an expectorant. Previous studies had suggested that high doses of ambroxol could reduce the plasma uric acid concentration. The present study was undertaken to confirm this finding, to determine its dose-response relationship and to identify the underlying mechanism of action. Using a placebo-controlled, double-blind parallel group design, 48 healthy male volunteers were randomly allocated to receive placebo b.d. and ambroxol 125 mg b.d., 250 mg b.d. or 500 mg b.d. (12 subjects per group). The subjects were hospitalised during a dietary run-in period of 3 days (Days -3 to -1) and a treatment period of 5 days (Days 1 to 5). On Day -1 (baseline) and Days 1 to 5, all urine was collected and blood samples were taken for the analysis of uric acid, creatinine, xanthine and ambroxol. The measurements were repeated four days after treatment had closed. Steady state plasma concentrations of ambroxol (trough levels) were reached after 2 or 3 days and were linearly related to dose. Ambroxol induced a significant, dose-dependent, reduction in plasma uric acid (250 mg b.d. about 20%; and at 500 mg b.d. about 30%). The diurnally fluctuating uric acid clearance was dose dependently increased and there was no notable effect on creatinine clearance. Plasma hypoxanthine levels were not affected by ambroxol. No severe adverse events were reported and no drug induced changes in the clinical laboratory values were observed. It is concluded that ambroxol has an uricosuric action following oral administration of higher doses (250 mg-500 mg b.d.) and it is well tolerated.

Adult↗

PubMed1991

The influence of caffeine on the steady-state pharmacokinetics of theophylline.

During this open, two-period crossover study in eight healthy volunteers, 1200 mg anhydrous theophylline was administered as a two-stage infusion during 24 hours on day 6. During one of the 8-day periods, 300 mg caffeine, t.i.d., was administered orally. After the start of the theophylline infusion, plasma concentrations of theophylline and caffeine and urinary excretion of theophylline and four metabolites were determined frequently during 60 hours. With caffeine administration theophylline steady-state concentration and area under the curve increased by 23% and 40%, respectively, whereas the volume of distribution at steady state seemed unchanged. The cumulative urinary excretion of 1-methyluric acid and 1-methylxanthine did not reach a plateau, suggesting a capacity-limiting factor in their formation. Notwithstanding the mutual interference of theophylline and caffeine metabolism, the reduction in apparent total body clearance and elimination rate constant of theophylline by 29% and 31%, respectively, indicated a pronounced influence of concomitant administration of realistic amounts of caffeine.

Administration, Oral↗

PubMed1988

Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure.

This investigation developed strategies along which the anticonvulsant effect of oxazepam in the rat could be pharmacokinetically modeled. After determination of the pharmacokinetics of oxazepam, which could be described with a two-compartment model (half-lives of distribution and elimination 6 and 52 min, respectively), the drug was administered iv to groups of animals to achieve a serum concentration range of 0.1-2.5 mg/L at 10, 45, and 120 min after administration. At these time points pentylenetetrazol (PTZ) was infused slowly until the first myoclonic jerk occurred. The anticonvulsant response, expressed as the elevation of the serum or brain threshold concentration of PTZ, was modeled versus the serum (both total and free) and brain oxazepam concentration, according to the sigmoid Emax model. The total serum and brain oxazepam EC50 values are about 0.5 mg/L and 1.1 mg/kg, respectively, and Emax 120 mg/L PTZ. No marked differences in pharmacodynamic parameters between the three time groups were found, which indicates that serum and brain are pharmacokinetically indistinguishable from the effect compartment, that there is no (inter)activity of oxazepam metabolites and absence of development of acute tolerance during the investigated time frame. An interfering role of metabolites was also excluded by a direct radioreceptor assay of oxazepam, yielding very similar results as the specific chromatographic assay. It is concluded that the conception-anticonvulsant effect relationship of oxazepam can satisfactorily be described by the sigmoid Emax model, when utilizing the employed experimental strategies.

Animals↗