The anti-secretory effect and pharmacokinetics of omeprazole in chronic liver disease

The anti-secretory effects and pharmacokinetics of omeprazole were investigated in ten patients with chronic liver disease. Plasma omeprazole concentrations were measured after a 10-mg intravenous dose of omeprazole and on the first and seventh days of a 7-day course of 10 mg oral omeprazole daily. Pentagastrin tests were performed on the day before oral omeprazole was commenced and 24 h after the last oral dose. The pre-treatment basal and peak gastric acid outputs were low (mean rates of 1.44 mmol/h and 9.26 mmol/h, respectively) and following 7 days of oral 10 mg omeprazole daily, were lowered by 95% and 90% respectively. Following 10 mg intravenous omeprazole, plasma clearance was reduced, and plasma half-life and area under the concentration curve were increased, in comparison with previous studies in healthy subjects. The plasma concentration curves for oral and intravenous doses were very similar. After both the first and seventh oral doses, maximum plasma concentration and area under the curve were higher than in healthy subjects. No accumulation of omeprazole was demonstrated. The pharmacokinetics of omeprazole in chronic liver disease could be influenced by low gastric acidity, poor liver function and/or portasystemic shunting. A dose of 10 mg omeprazole daily has been shown to be an effective anti-secretory agent in chronic liver disease.     

Elimination kinetics of amsacrine in the rabbit: evidence of nonlinearity

Plasma amsacrine kinetics have been studied in rabbits after different doses (2.5-10 mg/kg) infused over 35 min. Amsacrine concentrations were measured by HPLC and plasma protein binding by equilibrium dialysis. All elimination curves were best fitted by a bi-exponential expression with a mean t 1/2 alpha of 0.56 h and t 1/2 beta of 2.47 h. At doses greater than 5 mg/kg, there appeared to be an overproportional increase in the area under the curve, suggesting non-linear kinetics. Comparison of pharmacokinetic parameters indicated a significant decrease in plasma Cl after the 10-mg/kg dose compared to the 5- and 2.5-mg/kg dose. Amsacrine was highly bound by plasma (96.8%) over the concentration range 1-100 mumol/l. It is concluded that the rabbit is an acceptable model for further studies of the pharmacokinetics of amsacrine and its analogues at doses less than or equal to 5 mg/kg.     

Lack of Effect of Olanzapine on the Pharmacokinetics of a Single Aminophylline Dose in Healthy Men

Study Objective . To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Design . Two-way, randomized, crossover study. Setting . Clinical research laboratory. Subjects . Nineteen healthy males (16 smokers, 3 nonsmokers). Interventions . Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Measurements and Main Results . Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4′-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. Conclusion . As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.     

Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation

The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained-release (SR) tablet administration were evaluated in 42 healthy, normal, male volunteers. All 42 subjects received a single 1-mg intravenous (IV) alprazolam dose. After a 1-week washout period, the subjects received one of three SR treatments as a single dose: one 1-mg SR tablet, three 1-mg SR tablets, or six 1-mg SR tablets. Beginning 2 days after single-dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple-dose study was the same as the subject received in the single-dose study. Serial blood samples were collected after each treatment (single-dose IV, single-dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were greater than 0.84 after single SR doses. Maximal sedation was related to dose after single-dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple-dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe

This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.     

The effects of concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.     

Intravenous omeprazole: effect of a loading dose on 24-h intragastric pH

To determine the effect of three times daily dosing with intravenous omeprazole on intragastric acidity, 24 h intragastric pH was measured continuously with a monocrystalline antimony electrode system in II patients with inactive duodenal ulceration during fasting conditions. After a baseline investigation, two different dosage regimens of intravenous omeprazole were compared in a double-blind crossover study, with regard to their ability to keep the pH greater than or equal to 4 for as long as possible. Success in the individual patient was defined as pH greater than or equal to 4 for at least 90% over the 24-h period. Two doses of omeprazole [40 mg t.d.s. (120 mg) and 80 mg + 40 mg + 40 mg (160 mg)] were compared. Omeprazole (120 mg) increased the median of individual median intragastric 24-h pH from 1.49 to 6.67. The pH was greater than or equal to 4 for greater than or equal to 90% of the 24 h in three of the 11 patients. With omeprazole, 160 mg (a loading dose of 80 mg), the median of individual median intragastric 24-h pH increased to 7.33. The pH was greater than or equal to 4 for greater than or equal to 90% of the 24 h in seven of the 11 patients. Median time to reach pH 4 was 39 min after 40 mg and 20 min after 80 mg omeprazole. An initial loading dose of 80 mg omeprazole seems preferable to 40 mg to achieve a fast and sustained increase in intragastric pH to above 4 in the fasting patient.     

Pharmacokinetics of high-dose abetimus sodium in normal subjects with specific assessment of effect on coagulation

Abetimus sodium is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-double-stranded DNA antibody levels. The safety and pharmacokinetics of abetimus were evaluated in 24 healthy volunteers at intravenous doses of 600 mg, 1200 mg, and 2400 mg. The mean half-life ranged from 0.8 to 1.5 hours. Maximum exposure assessed by maximum observed plasma concentration was dose proportional. Total exposure assessed by area under the plasma concentration-time curve was dose proportional between 1200-mg and 2400-mg doses and greater than proportionate between the 600-mg and 1200-mg doses. Abetimus was well tolerated in all dose groups, with adverse events observed in 33.3% (2/6) of placebo subjects and 16.7% (3/18) subjects receiving abetimus. No clinically significant effects were observed on laboratory values, vital signs, or electrocardiogram, with the exception of a transient, dose-dependent, prolongation in activated partial thromboplastin time. In vitro coagulation studies suggested that the effect on activated partial thromboplastin time was attributable to a nonspecific interaction rather than specific factor depletion. Exposure to abetimus at intravenous doses of 600 mg, 1200 mg, and 2400 mg was well tolerated. Total exposure assessed by area under the plasma concentration-time curve was greater than dose proportional across the dose range of 600 mg to 2400 mg.     

Safety,tolerability, pharmacokinetics,and time course of pharmacologic response of the active metabolite of roxifiban,XV459, a glycoprotein IIb/IIIa antagonist,following oral administration in healthy volunteers

Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.75-1.5 mg; n = 20) and 10 (0.75-1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47-75 years) received roxifiban qd doses (0.5-0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18-46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1-mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 microM adenosine 5'-diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP-induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greater than 1.0 mg, a dose-proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] < 15%) and higher interindividual variability (CV < 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose-related increase in template bleeding time was observed at 1.25- and 1.5-mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25- and 1.5-mg dose groups were not significantly different from those at the lower dose groups. Overall, once-daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.     

Effect of nizatidine on paracetamol and its metabolites in human plasma

The effect of the histamine H2-receptor antagonist, nizatidine, on plasma concentrations of paracetamol has been investigated with respectto hepatic metabolism. Paracetamol (1000 mg) together with 300 or 150 mg nizatidine or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and paracetamol conjugates (glucuronide and sulfate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma paracetamol concentration-time curves of each volunteer. The plasma nizatidine concentration was highest (2420.0+/-192.4 and 996.0+/-54.6 ng mL(-1)) in the sample taken 1 h after administration of 300 mg nizatidine (high dose) and 150mg nizatidine (low dose), respectively. Plasma paracetamol concentrations with nizatidine (high and low doses) were increased significantly at 45-120 min and 45-60 min, respectively, compared with placebo. The total area under the plasma paracetamol concentration-time curve from 0 to 180 min (2361.5+/-146.4 and 2085.75+/-73.5 microg min mL(-1)) significantly increased after coadministration of nizatidine (high and low doses), respectively (P < 0.01 vs placebo). Paracetamol glucuronide concentrations with nizatidine (high and low doses) were decreased significantly at 30-45 min and 30 min, respectively, compared with placebo. However, plasma paracetamol sulfate concentrations with nizatidine (high and low doses) were not significantly altered. The coadministration of nizatidine (150 and 300 mg) dose-dependently reduces plasma paracetamol glucuronide concentrations and increases plasma paracetamol concentrations. The effects of nizatidine could result from the inhibition of glucuronyltransferase. Thus, care is necessary when paracetamol and nizatidine are coadministered.     

Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic EM genotype for CYP2C19

AIMS: The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity. METHODS: Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5-hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide. RESULTS: The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml(-1) h) and C(max) (from 987 to 1649 ng ml(-1)) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5-hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5-hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs. CONCLUSIONS: A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates.     

The rise and fall of serum theophylline concentration: a comparison of sustained-release formulations in volunteers with rapid theophylline clearance.

The pharmacokinetics of four sustained-release formulations of theophylline have been examined after single doses (Nuelin SA, Phyllocontin, Slo-phyllin and Theo-Dur) and at steady-state (Phyllocontin, Theo-Dur) in six healthy adult volunteers, selected because they all eliminated theophylline rapidly after an intravenous dose of aminophylline. After a single dose of Theo-Dur, the peak concentration of theophylline was smaller and occurred later than after single doses of Nuelin SA, Phyllocontin and Slo-phyllin, suggesting that absorption occurs over a longer period. The systemic availability of theophylline was virtually complete after all four formulations. After repeated 12-hourly dosing to steady-state, and adjustment of dose to achieve trough concentrations of between 5 and 10 mg l-1 (28-55 mumol l-1), theophylline concentration fluctuated to a significantly greater extent within a dose interval when the subjects were taking Phyllocontin than when they were taking Theo-Dur.     

Pharmacokinetics of PC-SOD, a lecithinized recombinant superoxide dismutase, after single- and multiple-dose administration to healthy Japanese and Caucasian volunteers

To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized C(max) and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.     

Correlation between pharmacological effects and plasma cocaine concentrations after smoked administration

The relationship between blood cocaine concentrations and pharmacological effects is of both theoretical and practical interest. This study utilized a computer-assisted smoking device for the delivery of three active doses (10, 20, and 40 mg) of cocaine base to seven human volunteers. Doses were administered in an ascending dose design with random placement of placebo. Physiological, subjective, and performance measures were collected concurrently with blood samples. Mean peak plasma cocaine concentrations were achieved at 2 min after the 20-mg and 40-mg doses and at 5 min after the 10-mg dose. Maximal responses in systolic and diastolic blood pressure, "feel", "good" drug, and drug "liking" subjective effects were also achieved immediately after drug administration. Pupil diameter and heart rate increases demonstrated a modest counter-clockwise hysteresis in relation to plasma cocaine concentrations shortly after dosing. Systolic and diastolic blood pressure, heart rate, and some subjective and performance measures of drug effect demonstrated a biphasic response after smoked cocaine. Initial increases above baseline levels were followed by an apparent compensatory decrease below baseline levels at a later time after smoked cocaine. Despite evidence of hysteresis and biphasic responses for some measures, linear correlation was obtained between mean plasma cocaine concentrations and several pharmacological effects over a period of 4 h after dosing. Several subjective and cardiovascular measures returned to baseline levels in the presence of detectable concentrations of cocaine.     

Usefulness and safety of theophylline injection form (Theodrip) for the treatment of acute asthma

The effects of the speed of intravenous infusion on the pharmacokinetics of theophylline were studied in 9 healthy volunteers (Ex I). Subjects were intravenously administered either six 4.8 mg/kg theophylline (Theodrip, Nikken Chemicals Co., Ltd., Japan) or three matching placebo injections (4.8 ml/kg physiological saline) for 30 min (Step I) or for 15 min (Step II). In Steps I and II, Cmax was 10.8 +/- 1.1 and 10.8 +/- 0.8 micrograms/ml, respectively. These Cmaxs were concentrations yielding therapeutic effects in patients with acute asthma. Next, comparative pharmacokinetics between theophylline (Theodrip) and aminophylline were examined by a crossover method in 16 healthy volunteers (Ex II). The 90% confidence limits of the differences of mean values were within 80-120% and were 92.8-100.1% for Cmax, 99.7-105.3% for t1/2 and 100.2-104.4% for AUC. Thus, we concluded that the pharmacokinetics of the plasma theophylline after intravenous administration of Theodrip (theophylline at 4.8 mg/kg) were bioequivalent to those of aminophylline (6.0 mg/kg) for 30 min. In Ex I and II, no subjects had adverse effects and in Ex I no influence on ECG was seen. In addition, the convenience of Theodrip was compared with that of ampules of aminophylline among nurse volunteers (Ex III). The times required for set-up of Theodrip were significantly shorter than those of aminophylline ampules. On the other hand, the adverse reactions to aminophylline resulting from hypersensitivity reactions to its ethylenediamine component have been reported. Theodrip consists of 200 mg theophylline and 200 ml physiological saline in a plastic bag. Therefore, Theodrip, which does not contain ethylenediamine, is expected to have less adverse effects and be easier to handle than aminophylline.     

Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia

Fluvastatin sodium (Lescol, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor that limits cholesterol biosynthesis, is available as a 40-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. This phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-640 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabilization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, were randomly assigned to four groups to receive oral fluvastatin extended-release (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was observed after single and multiple dosing. At 640 mg, fluvastatin extended-release was not well tolerated. Six of the seven actively treated patients at this dose experienced adverse events, including diarrhea, headache, and clinically relevant elevations in serum transaminase concentrations. In addition, nonlinear pharmacokinetics, possibly due to saturation of first-pass metabolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.     

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.     

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.     

Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users

Rationale A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans. Objectives The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose. Materials and methods Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory. Results Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Δ⁹-tetrahydrocannabinnol pharmacokinetics. Conclusions Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.     

Individual and group dose-responses to intravenous omeprazole in the first 24 h: pH-feedback-controlled and fixed-dose infusions.

1. Individual responses to intravenous boli of omeprazole have shown considerable variability. Data on the individual responses to the new omeprazole infusion formulation are lacking. 2. Individual dose-responses in the first 24 h of fixed-dose and pH-feedback-controlled infusions of omeprazole were assessed in two randomised, third-party blinded, cross-over studies, using two separate groups of eight healthy subjects. In study A, feedback-controlled infusions of omeprazole (target pH 5, dose range 0-12 mg h-1) and fixed-dose infusions (8 mg h-1) were compared, both with an initial bolus of 80 mg. Omeprazole plasma concentrations were measured. Study B assessed the effect on individual pH-control of a loading bolus of either 40 mg or 80 mg omeprazole, followed by feedback-controlled infusions. 3. Study A: the median % time of pH > 5 was 71.2 (total range: 48.9-83.2) with feedback infusions and 57.9 (28.0-95.3) with fixed-dose infusions (P = 0.06). The mean 24 h infusion doses were 173.1 mg (44.5-253.1) in the feedback group and 192 mg in the fixed-dose group. The AUC of omeprazole plasma concentrations ranged widely, but correlated with the % time of pH > 5 during fixed-dose infusions. Study B: initial boli of 40 mg and 80 mg of omeprazole resulted in similar 24 h median % of time with pH > 5, 69.2 (49.9-78.8) and 69.6 (44.4-87.7), respectively. Mean omeprazole doses infused by feedback pump were 187.6 mg (83.1-253.6) after 40 mg boli and 159.9 mg (61.8-227.0) after 80 mg boli.(ABSTRACT TRUNCATED AT 250 WORDS)