Comparative bioavailability of two atenolol tablet formulations in healthy male volunteers after a single dose administration

The bioavailability of 2 atenolol tablet formulations (Angipress from Laboratórios Biosintética, and Atenol from Wellcome ICI Laboratory, Brazil) were compared in 18 healthy male volunteers who received a single 50 mg dose of each atenolol formulation. The study was conducted following an open randomized 2-period crossover design with a 14-day washout interval between doses. Plasma samples were obtained over a 24-hour interval and atenolol concentrations were determined by HPLC with fluorimetric detection. From the plasma atenolol concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(zero-24) (area under the concentration vs time curves from 0-24 h), ke (terminal elimination constant), t1/2 (terminal first order elimination half-life), AUC (area under the concentration vs time curves extrapolated to infinity), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax) and Cmax/AUC. All these variables were analyzed using both parametric and nonparametric statistics. Geometric mean Angipress/Atenol individual percent ratios were 99.6% for AUC(zero-24), 99.7% for AUC, 98.0% for Cmax, 102.8% for t1/2, 97.2% for ke and 97.8% for Cmax/AUC, with all their 90% confidence intervals within the bioequivalence range 80-125%, thus showing similar patterns of absorption and disposition. Arithmetic mean for individual Tmax differences was 0.8 h, and the 90% confidence interval did not include the zero value. Based on these results and in accordance with the European Union and the US Food and Drug Administration bioequivalence requirements we conclude that both atenolol formulations are bioequivalent for both the extent and the rate of absorption.     

Relative bioavailability of different butamirate citrate preparations after single dose oral administration to 18 healthy volunteers

The action of purified cathepsin D on hemoglobin was examined using micellar electrokinetic chromatographic separation of peptide products. Purified cathepsin D was incubated with hemoglobin in 40 mM Na-formate pH 3.1 at 37 degrees C for varying lengths of time. The reaction was stopped by the addition of the inhibitor pepstatin, and the peptide products were isolated from the reaction mixture by ultrafiltration with a 10,000 molecular weight cut-off (MWCO) microfuge type filter. Filtered samples were then separated in 100 mM Tris-Cl pH 8.5 containing sodium dodecyl sulfate (SDS) or Na-deoxycholate at micellar concentrations using a 50-microns (i.d.) fused-silica capillary. Detection was performed at 214 nm. It was found that Na-deoxycholate containing separations were superior in resolution and required less time. This technique was used to determine initial velocity (expressed as peak area per unit time) for nine peptides. Several peptides resulted after very short incubation times (< 10 min). This suggests that this approach may be useful for the determination of cathepsin D activity.     

Zopiclone versus diazepam effects on EEG power maps in healthy volunteers

AIMS: The aim of this study was to compare the effects of aspirin on platelet function as measured by the 'classical' template bleeding time with a new ex vivo method measuring closure times using the PFA-100 machine. Platelet aggregation in response to arachidonic acid was also measured ex vivo. METHODS: The trial was a randomized, double-blind, placebo-controlled crossover design, with each volunteer taking 750 mg aspirin (BP) or placebo, three times a day for 5 days, with an 18 day wash-out period between treatments. Bleeding times and closure times were measured before the first dose on the first day and 0.5 h after the last dose on the fifth day of each treatment period. They were also measured 2 weeks after the last day of the trial. RESULTS: Baseline bleeding times (pre-placebo) were 415 s using the Simplate, whilst baseline closure times were 115 s using the PFA-100. Aspirin treatment caused an increase of both the template bleeding time (61%) and the closure time of the PFA-100 (79%) when compared with the effects of placebo. The platelet aggregatory response to arachidonic acid was completely inhibited following aspirin treatment and was unaffected following placebo. Two weeks after the end of the trial, all values had returned to pre-treatment levels. The template bleeding time was unaltered in 1 of the 12 volunteers during aspirin treatment and was significantly prolonged in 3 of the 12 volunteers during placebo treatment. The PFA-100 closure time was unaltered in 1 of the 12 volunteers during aspirin treatment and was prolonged in 1 subject during placebo treatment. CONCLUSIONS: The change in closure time using the PFA-100 is as sensitive and reproducible to the effects of aspirin on platelet function as is the template bleeding time test. However, the PFA-100 produced less variable effects with fewer false positive results.     

Pantoprazole has no influence on steady state pharmacokinetics and pharmacodynamics of metoprolol in healthy volunteers

The new H+/K+ ATPase inhibitor pantoprazole, a substituted benzimidazole, is metabolized by the hepatic cytochrome P450 enzymes 2C19 or 3A4 and subsequently undergoes phase II metabolism. The widely used beta 1-adrenoreceptor-blocking agent metoprolol is metabolized via CYP2D6. The influence of pantoprazole on the pharmacokinetics of an orally administered zero order kinetics formulation (ZOK) of metoprolol was the objective of this study. Eighteen volunteers (9 female, 9 male, age 20-44 years) completed the randomized, double-blind crossover study. Each subject received either 95 mg metoprolol and placebo (reference (R)) or 95 mg metoprolol and 40 mg pantoprazole (test (T)) as oral doses (sid) for 5 consecutive days. On day 5 of each period serum concentrations of R- and S-metoprolol were determined and a treadmill ergometry was performed. The primary pharmacokinetic characteristics for extent and rate of absorption were AUC(0-24h) and % PTF, respectively. To assess the pharmacodynamic effect of metoprolol the excess area under the effect vs. time curve was calculated for heart rate during ergometry (AUCexHR). Point estimate and 90% confidence limits (CI) for the ratios of population medians of T and R were given. The respective point estimates (90% CI) of the ratios of both primary and secondary characteristics were entirely within the equivalence range of 0.80 and 1.25 for both enantiomers of metoprolol. Moreover, equivalence could be shown for the pharmacodynamic characteristic AUCexHR. Hence, it was concluded that pantoprazole does not interact with metoprolol pharmacokinetics or pharmacodynamics. Therefore, no dose adjustment of metoprolol during therapy with pantoprazole is necessary.     

Neuroactive steroid concentrations following metyrapone administration in depressed patients and healthy volunteers

BACKGROUND: There is evidence that treatment with the 11 beta-hydroxylase inhibitor metyrapone may represent an alternative treatment strategy in major depression. As a consequence of inhibition of cortisol synthesis the overdrive of corticotropin leads to an accumulation of precursor steroids. However, the effects of metyrapone on the concentrations of endogenous neuroactive steroids that modulate ion channels, e.g., the GABAA receptor, have not yet been studied systematically. METHODS: Therefore, we quantified the concentrations of an array of neuroactive steroids following administration of 1.5 g metyrapone before and after pretreatment with 1 mg dexamethasone in 19 patients suffering from severe depression in comparison to 13 healthy controls by means of a highly sensitive gas chromatography/mass spectrometry analysis. RESULTS: The administration of metyrapone induced a pronounced increase in all neuroactive steroids studied both in patients and controls that was prevented by dexamethasone pretreatment. CONCLUSIONS: Thus, the psychotropic properties of endogenous neuroactive steroids may contribute to the antidepressant properties of metyrapone in the treatment of major depression.     

Topographical analysis of the EEG effects of a subconvulsive dose of lidocaine in healthy volunteers

BACKGROUND: The purpose of the present study was to assess the effects of intravenous lidocaine on spatial changes of electroencephalographic power and on psychomotoric status in conscious volunteers. METHODS: In 11 healthy volunteers lidocaine (2-min bolus, 100 mg; 15 min infusion, 40 micrograms.kg-1.min-1) or placebo were given intravenously in a randomized, single-blinded, two-way crossover study. Haemodynamics and lidocaine plasma concentrations were measured at baseline and within a period of 30 min following bolus injection. Vigilance and emotional status were tested using visual analogue scales (VAS). Toxic CNS effects were evaluated by a questionnaire. The raw EEG (17 leads, reference Cz) and computed power spectra were continuously recorded. RESULTS: The chosen lidocaine dosage led to nearly constant plasma concentrations (unbound lidocaine 2.5 min and 15 min after bolus 0.36 +/- 0.14 microgram/ml and 0.30 +/- 0.06 microgram/ml, respectively [mean +/- SD]). The placebo caused no symptoms, changes in VAS-scores or EEG-parameters. Lidocaine induced pronounced subjective symptoms and significant increases in delta activity for 15 min, most dominant at the frontotemporal and occipital leads (max. +219% O1). Frontal and occipital beta 1 and beta 2 power (max. +131% and +124% at O1, respectively) was immediately increased after the bolus injection. No EEG changes occurred at central region Cz, and no interhemispheric EEG differences were noted. Theta, alpha 1, and alpha 2 power remained unchanged. CONCLUSION: The current data demonstrate simultaneous changes in psychomotoric status as well as delta and beta spectral power during lidocaine infusion. These data could be an indication that the pronounced frontotemporal and occipital EEG changes are the electroencephalographic expression of subjective sensations.     

Pharmacokinetics and pharmacodynamics of FK143, a nonsteroidal inhibitor of steroid 5 alpha-reductase, in healthy volunteers

Results from a comparative analysis of the efficiency of countermeasures in agriculture in a long term after the ChNPP accident are presented. Based on criteria such as reduction factor for 137Cs transfer to plants, averted dose and cost of 1 manSv relative ratings of countermeasures are given. Using one of the farms, located in the contaminated area as an example radiological justification of the optimal systems of countermeasures application is provided.     

Pharmacokinetics of mivacurium isomers and their metabolites in healthy volunteers after intravenous bolus administration

BACKGROUND: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma. METHODS: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters. RESULTS: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml.min 1.kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed. CONCLUSIONS: Substantial hydrolysis of mivacurium isomers by cholinesterases was confirmed by the rapid appearance of mivacurium metabolites in plasma. The intensive arterial sampling proved to be critical for the trans-trans and cis-trans isomers because the area under the curve between 0 and 2 min accounted for 75% and 86% of the total, respectively.     

Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects

OBJECTIVES: To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration. METHODS: Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open-label, randomized placebo-controlled studies in healthy volunteers. RESULTS: The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose-dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage of reticulocytes after single-dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa. CONCLUSIONS: These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.     

The safety and tolerability of single intravenous doses of lubeluzole (Prosynap) in healthy volunteers

The safety and tolerability of single escalating doses of lubeluzole were evaluated in healthy male volunteers in 2 studies. In the first of 2 randomized, single-blind, placebo-controlled, dose-escalation studies, 6 subjects received single 30-minute infusions of 2.5, 5, and 10 mg of lubeluzole, and 2 additional subjects received placebo. In the second study 6 different subjects received a 1-hour infusion of 15 mg of lubeluzole, 5 of whom received the 20-mg dose, and 2 received 25 mg of lubeluzole. Two additional subjects received placebo. Small increases and decreases in PQ, QRS, QT, QTc, and QTm intervals were noted after infusion of all lubeluzole doses and placebo, however, these changes were within the normal ranges for these values except for the QTc for the 25-mg dose of lubeluzole. Significant prolongation of the QTc interval was observed at the end of the 1-hour infusion in both subjects receiving the 25-mg dose of lubeluzole. No clinically relevant changes in systolic time intervals, heart rate, blood pressure, and clinical laboratory values were noted in subjects receiving 2.5-25 mg of lubeluzole or placebo. Adverse experiences, predominantly lightheadedness and dizziness, were reported by subjects receiving doses of lubeluzole greater than or equal to 10 mg. Lubeluzole, administered as single intravenous doses of 2.5-15 mg, is safe and well tolerated in healthy male volunteers.     

Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers

The pharmacokinetics of iron were investigated after intravenous administration to 12 healthy volunteers of iron(III)-hydroxide sucrose complex (Venofer) as a single i.v. dose containing 100 mg Fe. The average predose concentration was 35.7 +/- 12.5 mumol/l. There was no statistically significant difference between the serum iron level before injection (0 h) and the level at 24 h after the injection. The compartment model used includes a Michaelis-Menten term and is in excellent agreement with the observed exchange of iron to transferrin and with the daily iron turnover by transferrin. The intravenously injected iron(III)-hydroxide sucrose complex led rapidly to high serum iron levels. Maximum measured levels averaged 538 mumol/l (30.0 mg/l) at 10 min after the injection. The terminal half-life of the injected iron was calculated to be 5.3 h. Mean total area under the curve (AUC) was 1491 mumol/l h, the mean residence time (MRT) was 5.5 h. The total body clearance was 20.5 ml/min. The volume of distribution of the central compartment (Vc) was 3.21, hence close to the volume of the serum; the volume of distribution at steady state (Vdss) was 7.31; and the volume of distribution during elimination (Vdarea) was 9.21. The calculated amount of iron transported by transferrin was 31.0 +/- 6.6 mg Fe/ 24h. In summary, the data show that the injected iron(III)-hydroxide sucrose complex is quickly cleared from the serum with a terminal half-life of approximately 5-6 h. Renal elimination of iron contributed very little to the overall elimination (in average < 5%). Renal elimination of sucrose averaged about 68 +/- 10% and 75 +/- 11% of the administered dose after 4 h and 24 h, respectively.     

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.     

Steady-state pharmacokinetic properties of pramipexole in healthy volunteers

Pramipexole is a dopamine receptor agonist that has proved effective in the treatment of Parkinson's disease. The pharmacokinetic properties of pramipexole at steady-state concentrations were studied in 16 healthy men and women at four dose levels throughout the range recommended for Parkinson's patients. Plasma and urine samples collected within the four dose intervals were assayed for concentrations of pramipexole, using high-performance liquid chromatography. The total oral clearance for all participants was 419 mL/min. The mean volume of distribution and elimination half-life for all participants was 486 +/- 93.2 L and 12.9 +/- 3.27 hours. Concentrations of pramipexole were proportional to dose, although the drug's pharmacokinetic properties differed between men and women. The area under the concentration-time curve for each dose level was 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The mean creatinine clearance in men and women was 112 +/- 12.8 mL/ min/1.73 m2 and 80.9 +/- 15.6 mL/min/1.73 m2, respectively. The renal clearance of pramipexole accounts for approximately 80% of oral clearance, and there was a significant correlation between renal and creatinine clearances. The influence of gender could not be distinguished from the influence of age and the resulting reduced creatinine clearance, but the measurement of pharmacokinetic properties produced linear results in both men and women.     

Effects of anesthetics on somatosensory evoked potentials by median nerve stimulation in human--analyses after single administration in volunteers

In the present study, effects of midazolam, thiopental sodium, propofol, and nitrous oxide upon SEP in a clinically used dose were investigated on 24 male volunteers. In addition, antagonistic actions of flumazenil and naloxone against effects of midazolam and nitrous oxide, respectively, on SEP were studied. Midazolam had no effect on latencies of N 20 and P 25, but increased latency of P 45 and attenuated P 100 amplitude. Flumazenil reversed these effects of midazolam of P 45 latency and P 100 amplitude to their control values. While thiopental sodium and propofol suppressed P 100 amplitude, they had no effect on N 20, P 25, P 45 latencies. Nitrous oxide elongated latencies of N 20, P 25, P 45 and decreased P 100 amplitude. Naloxone reversed the effects of nitrous oxide on N 20 and P 25 latencies without affecting increased P 45 latency and attenuated P 100 amplitude. These results suggest that midazolam might have an analgesic action of suppressing cortical sensory neurons, whereas thiopental sodium and propofol have no effect on neurons in the primary sensory cortex. The finding that naloxone antagonized the increased latencies of N 20 and P 25 by nitrous oxide could be explained by the analgesic action of nitrous oxide that could be mediated by opioid receptors. The results also indicate that electrical activities of the cortical neurons in the associated area are more susceptible to psychotropic agents than those in the primary sensory cortex. The effects of anesthetics on SEP appear to reflect their characteristics of functioning mechanisms on cortical neurons. Analysis of SEP is, therefore, useful for the assessment of the mechanism and the acting site of anesthetics in the sensory cortex.     

Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils

In four healthy volunteers, we analyzed in detail the immediate in vivo effects on circulating neutrophils of subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF). Neutrophil activation was assessed by measurement of degranulation. Mobilization of secretory vesicles was shown by a decrease in leukocyte alkaline phosphatase content of the circulating neutrophils. Furthermore, shortly postinjection, Fc gamma RIII was found to be upregulated from an intracellular pool that we identified by immunoelectron microscopy as secretory vesicles. Intravascular release of specific granules was shown by increased plasma levels of lactoferrin and by upregulation of the expression of CD66b and CD11b on circulating neutrophils. Moreover, measurement of fourfold elevated plasma levels of elastase, bound to its physiologic inhibitor alpha 1-antitrypsin, indicated mobilization of azurophil granules. However, no expression of CD63, a marker of azurophil granules, was observed on circulating neutrophils. G-CSF--induced mobilization of secretory vesicles and specific granules could be mimicked in whole blood cultures in vitro, in contrast to release of azurophil granules. Therefore, we postulate that the most activated neutrophils leave the circulation, as observed shortly postinjection, and undergo subsequent stimulation in the endothelial microenvironment, resulting in mobilization of azurophil granules. Our data demonstrate that G-CSF should be regarded as a potent immediate activator of neutrophils in vivo.     

Pharmacokinetics of dolasetron after oral and intravenous administration of dolasetron mesylate in healthy volunteers and patients with hepatic dysfunction

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.     

Fecal recovery following oral administration of Lactobacillus strain GG (ATCC 53103) in gelatine capsules to healthy volunteers

Recovery of the suggested probiotic strain Lactobacillus GG in feces was studied after oral administration. Lactobacillus GG was given to 20 healthy human volunteers for 7 days in gelatine capsules with daily doses of 1.6 x 10(8) cfu and 1.2 x 10(10) cfu. All the volunteers in the higher dose group had detectable numbers of Lactobacillus GG in their feces during the test period. The strain was detected in feces of all the volunteers after 3 days of administration. No effect was observed on the total number of fecal lactobacilli. Fecal detection of the strain may facilitate dose-response studies and provide a useful tool in dietary studies utilizing the strain in foods or food-type products.