Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women

The protease thrombin seems to play a central role in events following neural injury, whereby the enzyme can act, in concert with other molecules as a hormone or as a growth factor. In cells derived from the nervous system, thrombin induces changes in morphology and proliferation. The signalling mechanisms involved in these thrombin-activated processes are still unclear. In the present study we investigated Ca2+ signals in fura-2 loaded rat astrocytes in primary culture. Brief stimulation of astrocytes with thrombin induced a dose-dependent transient elevation of [Ca2+]i, best fitted by a double-sigmoidal curve giving two EC50 values of 3 pM and 150 pM. Continuous superfusion of cells with thrombin induced Ca2+ responses with three different types of kinetics. In 48% of the cells tested a single transient rise superimposed with fast fluctuations of [Ca2+]i was seen. The following complex long-term changes of [Ca2+]i, dependent on the presence of the agonist thrombin, were observed: i) a biphasic [Ca2+]i elevation, characterized by an initial peak followed by a sustained plateau phase (in 43% of the cells) and ii) oscillations of [Ca2+]i (in 9% of the cells). The observed Ca2+ responses were inhibited by the phospholipase C (PLC) inhibitor U-73122 and the thrombin inhibitor protease nexin-1/glia-derived nexin. The synthetic thrombin receptor activating peptide could mimic the thrombin-induced changes of [Ca2+]i. In astrocytes in Ca2+-free medium, thrombin induced a sharp single transient Ca2+ rise, without superimposed fluctuations. After depletion of intracellular Ca2+ stores with thapsigargin the Ca2+ response to thrombin was diminished or completely suppressed indicating that thrombin induces the release of Ca2+ from intracellular stores. During long-term Ca2+ responses, omission of extracellular Ca2+ resulted in a reversible interruption of the signal. In conclusion our results demonstrate that thrombin by activation of its plasma membrane receptor induces through activation of PLC different types of Ca2+ responses. The complex Ca2+ signals are generated by an interplay of InsP3-mediated Ca2+ release from intracellular stores and Ca2+ entry across the plasma membrane.     

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.     

Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment

In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.     

Pharmacokinetics and tolerance of pantoprazole, a proton pump inhibitor after single and multiple oral doses in healthy Japanese volunteers

The pharmacokinetics and tolerance of pantoprazole were investigated after single (20, 40, 80, and 120 mg) and multiple (80 mg once a day for 7 days) oral administration as enteric-coated tablet formulation to healthy male Japanese volunteers. Pantoprazole was well tolerated with no serious adverse events at all doses. Pantoprazole was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 1.77-9.25 micrograms/ml for the 20-120 mg dose and the mean time to reach Cmax (tmax) ranged from 1.92-2.42 h. The half-life (t1/2) ranged from 0.74-1.16 h. A good linear correlation was found between the administered doses (20-120 mg) and the resulting area under the concentration-time curve (AUC) and Cmax with the correlation coefficients of 0.9088 and 0.9263, respectively. Within 24 h, pantoprazole was excreted into urine as the unchanged drug to a negligible extent. In the multiple dose study, 2 apparent poor metabolizers (PMs) of pantoprazole were observed. The means of Cmax, AUC and t1/2 for these 2 PMs were 1.6, 6.7, and 6.8 times higher than those of the extensive metabolizers (EMs). The pharmacokinetic parameters such as Cmax, AUC, and t1/2 after the 7th oral dose were not significantly different from those after the 1st dose both in the PMs and the EMs, which indicated that there was virtually no drug accumulation.     

Pharmacokinetics of lubeluzole (Prosynap) after single intravenous doses in healthy subjects

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.     

Pharmacokinetic analysis of mizolastine in healthy young volunteers after single oral and intravenous doses: noncompartmental approach and compartmental modeling

This paper presents the analysis of the kinetics of a new antihistamine, mizolastine, in 18 healthy volunteers, from concentrations measured after an intravenous infusion and two different oral administrations: tablet and capsule. Two approaches were used to analyze these data: (i) a noncompartmental approach implemented in PHARM-NCA; (ii) a compartmental modeling approach implemented in a new S-PLUS library, NLS2, which allows the estimation of variance parameters simultaneously with the kinetic parameters. For the compartmental modeling approach, two-compartment open models were used. According to the Akaike criterion, the best model describing the kinetics of mizolastine after oral administration was the zero-order absorption model. The kinetic parameters obtained with PHARM-NCA and NLS2 were similar. The estimated duration of absorption was greater for the tablets than for the capsules (with means equal to 1.13 hr and 0.84 hr respectively). After an intravenous infusion, the mean estimated clearance was 4.9 L/hr, the mean lambda 2-phase apparent volume of distribution was 89.6 L and the mean terminal half-life was 12.9 hr.     

Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers

The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.     

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.     

A double-blind, placebo-controlled, dose-ranging safety evaluation of single-dose intravenous dolasetron in healthy male volunteers

The safety and tolerability of dolasetron mesylate, a potent and selective 5-HT3 receptor antagonist, were evaluated after single intravenous doses in healthy male volunteers. In this double-blind, placebo-controlled, randomized, phase I study, 80 subjects received either placebo or dolasetron in escalating doses (0.6 to 5.0 mg/k). Subjects were monitored for adverse events, vital sign and laboratory alterations, and changes in electrocardiographic (ECG) intervals and electroencephalographic (EEG) patterns. Overall, the percentage of subjects reporting adverse events was similar in those receiving dolasetron (44/64; 68.8%) or placebo (10/16; 62.5%); most adverse events were mild in severity. Subjects receiving dolasetron reported a higher incidence of central nervous system (headache and dizziness/lightheadedness), gastrointestinal (increased appetite and nausea), and visual adverse events and taste alterations. No clinically significant changes in laboratory variables were observed. Transient and asymptomatic ECG changes (small mean increases in PR interval and QRS complex duration versus baseline) were noted in several subjects at 1 to 2 hours after infusion at doses > or = 3.0 mg/kg. Transient, mild blood pressure decreases were observed in five subjects, including one on placebo. Dolastron mesylate was well tolerated in single intravenous doses up to 5.0 mg/kg in healthy male volunteers. Clinical studies of the drug are ongoing for antiemetic indications.     

Treatment of postoperative nausea and vomiting with single intravenous doses of dolasetron mesylate: a multicenter trial. Dolasetron Mesylate PONV Treatment Study Group

This study was conducted to determine the efficacy and safety of four intravenous (I.V.) doses of dolasetron, an investigational 5-HT3 receptor antagonist, for the treatment of postoperative nausea and/or vomiting (PONV) after outpatient surgery under general anesthesia. This multicenter, randomized, double-blind trial compared the antiemetic efficacy of 12.5, 25, 50, or 100 mg I.V. dolasetron with placebo over 24 h using complete response (no emetic episodes and no rescue medication), time to first emetic episode or rescue medication, and patient nausea and satisfaction with antiemetic therapy as rated by visual analog scale (VAS). Of 1557 patients enrolled, 620 patients were eligible for treatment. Complete response rates for all dolasetron doses--12.5 mg (35%), 25 mg (28%), 50 mg (29%), and 100 mg (29%)--were significantly more effective than placebo (11%, P < 0.05). There was a significant gender interaction for complete response (P < 0.01). Of the patients in the 25-mg and 100-mg dose groups, 12% and 13%, respectively, experienced no nausea (VAS score < 5 mm) versus 5% in the placebo group (P < 0.05). There were no clinically relevant changes in vital signs or laboratory values and no trends with dose for adverse events. Dolasetron is effective for treating PONV and has an adverse event profile similar to that of placebo. The 12.5-mg dose was as effective as larger doses for complete response. IMPLICATIONS: Nausea and vomiting are common problems for postsurgical patients. In this study of 620 patients undergoing surgery, a 12.5-mg dose of intravenous dolasetron, a new serotonin-receptor blocker, was significantly more effective than placebo in treating established postoperative nausea and vomiting. Dolasetron 12.5 mg was as safe as placebo.     

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.     

Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.     

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.     

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 dolasetron with coadministration of cimetidine or rifampin in healthy subjects

This study examines normative bone mineral density (BMD) data, as measured by peripheral quantitative computed tomography of the ultradistal radius, in 332 Scottish women aged 18-90 years, comparing it to a recently reported normal German population. The normative Scottish data were higher in almost all decades compared with German counterpart, percentage differences being +0.002%-+21.6% for total (Qtot), and -0.06%-+31.9% for trabecular (Qtrab) BMD. Differences in calibration of the Stratec XCT-960 and XCT-900 systems are thought to be largely responsible for these differences. Estimated age-related changes were determined in the Scottish population. A cubic regression model best fitted age-related changes in the whole population, and changes as a function of years postmenopause in the postmenopausal subgroup, for Qtot, subcortical (Qscort), and cortical (Qcort) BMD, whereas a parabolic regression model best fitted corresponding changes in Qtrab BMD. Percentage age-related changes (5 years: 10 years postmenopause) in Qtot (-0. 79%-1.12%/year) and Qscort (-0.72%-1.12%/year) were greater than Qtrab (-0.53%-0.56%/year) in the early postmenopausal years. Maximum age-related changes were found at 20 years postmenopause for Qtot (-1.36%/year), Qscort (-1.39%/year), and Qcort (-1.39%/year). This study has highlighted variation in normative data derived by different Stratec pQCT systems. The estimated age-related changes suggest that early postmenopausal bone loss preferentially affects subcortical rather than trabecular bone at the radius.     

Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers

Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers. With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg.kg-1.hr-1 for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg.kg-1.hr-1 for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G. In addition, metabolite kinetics of M-6-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.     

Pharmacokinetics of minoxidil in patients with cirrhosis and healthy volunteers

OBJECTIVES: To determine the effect of reduced hepatic function on the pharmacokinetics of minoxidil. The pharmacokinetics of antipyrine, lorazepam, and indocyanine green were included as indicators of hepatic function. METHODS: Eight mild cirrhotics and eight healthy subjects received antipyrine (po), lorazepam (IV), indocyanine green (IV) and minoxidil 5 mg (po). Blood and urine were sampled for up to 72 h after each drug, and drug concentrations were measured by validated HPLC methods. Blood pressure and heart rate were measured for safety. RESULTS: For unchanged minoxidil, the serum elimination rate constant was significantly smaller and mean residence time was significantly longer in cirrhotic patients. Urinary elimination rate constant for minoxidil glucuronide was significantly smaller and fraction of dose excreted in urine was significantly higher in cirrhotic patients. Antipyrine elimination was significantly slower for cirrhotic patients. No differences were observed in lorazepam pharmacokinetic parameters. CONCLUSION: Pharmacokinetic analysis suggests a longer dosage interval may be appropriate in patients with hepatic impairment. In the absence of multiple-dose minoxidil pharmacodynamic studies in this population, minoxidil should be used as in other populations: begin with a modest dose, and adjust the dose based on clinical response.     

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.     

Prophylactic oral dolasetron mesylate reduces nausea and vomiting after abdominal hysterectomy. The Canadian Dolasetron Study Group

PURPOSE: The incidence of postoperative nausea and vomiting (PONV) varies from 50% to 75% after gynaecological surgery under general anaesthesia. This study evaluates the dose-response relationships, safety, and efficacy of the new 5-HT3 antagonist, dolasetron mesylate, in the prevention of PONV in women undergoing total abdominal hysterectomy (TAH). METHODS: Three hundred and seventy four women scheduled for TAH under general anaesthesia were studied at 13 Canadian centres. Patients received in a randomized, double-blind manner 25, 50, 100, or 200 mg dolasetron or placebo po one to two hours before induction of anaesthesia. The anesthetic protocol was standardized. Efficacy was evaluated for 24 hr after surgery by comparing the number of emetic episodes, administration of rescue medication, severity of nausea, and patient satisfaction. RESULTS: Analysis of complete response (no emetic episodes and no rescue for 24 hr) revealed a linear dose-response relationship across dolasetron groups (P < 0.002). Dolasetron 100 mg (P < 0.003) and 200 mg (P < 0.01) were superior to placebo. The percentage of patients with no emetic episodes increased from 29.3% (placebo) to 54.1 % (100 mg). Subgroup analysis revealed ASA status (I > II), previous history of PONV, previous history of motion sickness, and total morphine dose (> 55 mg associated with less PONV than < 55 mg) influenced the incidence of emetic symptoms, but did not alter the results of the primary analysis. CONCLUSION: Prophylactic dolasetron (100 mg and 200 mg) reduces the incidence of PONV in patients having total abdominal hysterectomy.     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Psychotherapy research with children is based mainly on adult methodologies. Common issues include bias in recruitment of subjects, demographics, developmental concerns, and control group considerations. The advantages and drawbacks of various types of control groups, such as wait-list controls, and placebo conditions are discussed along with ethical issues. Instrument choice, validity and reliability, and standardization of procedures in conducting research are addressed. Finally, the therapist as a variable is reviewed, including selection and assignment of therapists, and therapist bias.