Home About us Contact
|
Home About us Contact | ||
|
|
||
Mean Cmax (mean + cmax)
Selected AbstractsIntravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy VolunteersALCOHOLISM, Issue 5 2009Vijay A. Ramchandani Background:, Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. Methods:, This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (Cmax), times of peak BrAC (Tmax), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. Results:, The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean Cmax, Tmax, and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in Cmax and AUC were both 11%, while the mean %difference for Tmax was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. Conclusions:, Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response. [source] Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2000J. J. Miceli Aims, To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels. Methods, Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day,,1, and using titrated regimens of 40,80 and 40,120 mg day,,1, for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated. Results, Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day,,1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered first-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. Conclusions, Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action. [source] Pharmacokinetics of pradofloxacin and doxycycline in serum, saliva, and tear fluid of cats after oral administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008A. HARTMANN The pharmacokinetic properties of pradofloxacin and doxycycline were investigated in serum, saliva, and tear fluid of cats. In a crossover study design, six cats were treated orally with a single dose of pradofloxacin (Veraflox® Oral Suspension 2.5%) and doxycycline (Ronaxan® 100 mg) at 5 mg/kg body weight. Following administration, samples of serum, saliva, and tear fluid were taken in regular intervals over a period of 24 h and analysed by turbulent flow chromatography/tandem mass spectrometry. All values are given as mean ± SD. Pradofloxacin reached a mean maximum serum concentration (Cmax) of 1.1 ± 0.5 ,g/mL after 1.8 ± 1.3 h (tmax). In saliva and tear fluid, mean Cmax was 6.3 ± 7.0 and 13.4 ± 20.9 ,g/mL, respectively, and mean tmax was 0.5 ± 0 and 0.8 ± 0.3 h, respectively. Doxycycline reached a mean Cmax in serum of 4.0 ± 0.8 ,g/mL after 4.3 ± 3.2 h. Whilst only at two time-points doxycycline concentrations close to the limit of quantification were determined in tear fluid, no detectable levels were found in saliva. The high concentrations of pradofloxacin in saliva and tear fluid are promising to apply pradofloxacin for the treatment of conjunctivitis and upper respiratory tract infections in cats. As doxycycline is barely secreted into these fluids after oral application the mechanisms of its clinical efficacy remain unclear. [source] Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000A. L. CRAIGMILL The pharmacokinetics of a long-acting oxytetracycline (OTC) formulation (Liquamycin® LA-200®) injected intramuscularly (i.m.) at a dose of 20,mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168±14.6 (,g ? h/mL) and was significantly less than the AUC for sheep (209±43,,g ? h/mL). Using the standard two-stage approach and a one-compartment model, the mean Cmax for the calves was 5.2±0.8,,g/mL, and for the sheep was 6.1±1.3,,g/mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08,L/kg for the calves and sheep respectively. Analysis of the data using the standard two-stage approach, the naive pooled-data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20,mg/kg OTC. Half-lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9,h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6,p.p.m.), muscle (2,p.p.m.) and kidney (12,p.p.m.) by 48,h, and in injection site muscle by 14,days after the single i.m. injection of 20,mg/kg. [source] A double-blind, randomized controlled trial of cystometry using saline versus 0.3 M potassium chloride infusion in women with overactive bladder syndrome,,NEUROUROLOGY AND URODYNAMICS, Issue 1 2007Joe Philip Abstract Aim To evaluate the effect of 0.3 M potassium chloride on cystometric parameters by comparing it with normal saline as a filling solution in women with overactive bladder (OAB). Patients and Methods Twenty-three women with significant OAB symptoms underwent consecutive cystometrograms (CMGs) using 0.9% normal saline (NS) and 0.3 M potassium chloride (KCl), the order of which was randomized for each patient. Individual CMGs were performed by separate investigators and both patients and investigators were blinded to the order in which each solution was given and to the results of the other CMG. Results Regardless of the nature of the filling solution, the order in which the CMGs were performed had little influence on either first desire to void (FDV, mean 83.5 ml vs. 117.8 ml for first and second CMGs respectively, P,=,0.10) or on maximum cystometric capacity (Cmax, mean 265.0 ml vs. 264.4 ml, P,=,0.98). KCl produced a significant (24%) reduction in mean Cmax compared to NS (mean 228.6 ml vs. 300.8 ml, P,=,0.001), irrespective of the order of infusion. Conclusion This comparative study using 0.3 M KCl versus NS as filling solutions suggests that intravesical potassium may not simply act on urothelial sensory nerve endings; it may also stimulate detrusor muscle contraction. These findings may influence the interpretation of the potassium sensitivity test in patients with OAB symptoms, particularly in those suspected of having interstitial cystitis. Neurourol. Urodynam. © 2006 Wiley-Liss, Inc. [source] A Randomized, Double-Blind, Pharmacokinetic Study of Oral Maribavir with Tacrolimus in Stable Renal Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009M. D. Pescovitz Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean Cmax increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC(0-,) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and Tmax was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment. [source] Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailabilityBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2008N. Ceren Alemdaroglu Abstract Previous in vitro studies using Caco-2 cell monolayers suggested a possible interaction between green and black tea and folic acid at the level of intestinal absorption. The main purpose of the present study was to investigate a possible pharmacokinetic interaction between tea and folic acid in healthy volunteers. In an open-labeled randomized cross-over study, the pharmacokinetic interaction between tea and folic acid (0.4,mg and 5,mg) was investigated in healthy volunteers. Water was used as the reference drink. Subjects ingested 0.4,mg folic acid tablets with water, green or black tea (0.3,g extract/250,ml) or 5,mg folic acid tablets with water or green tea (0.3,g extract/250,ml). Blood samples were collected over a period of 8,h. Serum folate analysis was carried out by a competitive immunoassay which uses direct chemiluminescent technology. At the 0.4,mg folic acid dose, green and black tea reduced the mean Cmax of serum folate by 39.2% and 38.6%, and the mean AUC0 , , by 26.6% and 17.9%, respectively. At the 5,mg folic acid dose, the mean Cmax of serum folate was reduced by 27.4% and the mean AUC0 , , was decreased significantly by 39.9% by the co-application of green tea. The present results suggest an in vivo interaction between tea and folic acid with even low concentrations of green and black tea extracts yielding decreased bioavailabilities of folic acid. Copyright © 2008 John Wiley & Sons, Ltd. [source] ,-blockers improve chronic ischaemia of the lower urinary tract in patients with lower urinary tract symptomsBJU INTERNATIONAL, Issue 3 2008Germar-M. OBJECTIVE To investigate whether a mechanism of action of ,-blockers on lower urinary tract symptoms (LUTS) involves improved perfusion of the LUT. PATIENTS, SUBJECTS AND METHODS The accuracy of perfusion measurements using transrectal colour Doppler ultrasound (TRCDUS) and colour pixel density (CPD) was initially confirmed in a porcine model. Following this confirmation, measurements were taken from four healthy male volunteers and 19 patients with LUTS. The urinary bladder was filled slowly (50 mL/min) with 0.2 m KCl, which resembles the osmolarity of concentrated urine, and evaluated by cystometry. In parallel, TRCDUS and measurement of the CPD of the LUT were performed. The patients with LUTS were then treated with daily ,-blocker (0.4 mg tamsulosin) for 5 weeks and urodynamic variables as well as perfusion were evaluated again. RESULTS In the healthy men, perfusion of the LUT increased considerably (157%) during filling of the bladder to a mean (sd) maximum cystometric capacity (Cmax) of 481 (28.9) mL. All the patients with LUTS had a reduced mean Cmax during filling with KCl at 322.4 (58.5) mL. The mean CPD in the urinary bladder and the prostate were only increased by 58.4% during filling with KCl. After ,-blocker therapy the mean Cmax during filling with KCl rose to 382.5 (42.9) mL; furthermore, perfusion of the LUT measured by CPD was significantly increased (132.8%). CONCLUSIONS The present data strongly suggest that LUTS are associated with chronic ischaemia of the prostate and urinary bladder. ,-blockers increase perfusion in the LUT and Cmax. These results might explain the therapeutic effects of ,-blockers on LUTS. [source] Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metaboliteBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Bharat D. Damle WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The true influence of CYP2C19*2 mutation on the pharmacokinetics of nelfinavir and its active metabolite, M8, is not clear. , Often, published studies have combined *2 hetero- and homozygous poor metabolizers (PMs) and/or have very limited data from *2 homozygotes, which contributes to the lack of clarity. WHAT THIS STUDY ADDS , The pharmacokinetics of nelfinavir was delineated using pharmacogenomic data from 66 healthy subjects. , The exposure of nelfinavir was elevated, whereas that of M8 was reduced, in heterozygous and homozygous PMs in an incremental manner consistent with the loss of functional alleles. , However, the exposure of active moiety was only modestly elevated in hetero- and homozygous PMs. AIMS This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS At steady state, the mean Cmax was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean Cmax and AUC were 35% (95% CI 6, 55) and 33% (95% CI ,3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean Cmax and AUC values for the active moiety were higher by 30,35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype. [source] Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitusBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2009Patricia N. Sidharta WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Urotensin-II (U-II) is one of the most potent vasoconstrictors identified thus far. , Although differences in both U-II blood levels and U-II receptor (UT-receptor) expression have been observed in patients with cardiovascular and cardiorenal disease, the precise function in humans has not been elucidated. , U-II and its receptor have been reported to be involved in glucose metabolism and insulin resistance, which can lead to the development of Type 2 diabetes mellitus. , In rat models of diabetes, palosuran, a selective, potent antagonist of the human UT-receptor, improved several disease markers. WHAT THIS STUDY ADDS , In this study in diabetic patients, the effects of palosuran on insulin secretion and sensitivity were investigated using a hyperglycaemic glucose clamp and a meal tolerance test and daily glucose levels were also studied. , Although no obvious beneficial effect of palosuran in this patient population was observed, the study contributes to providing more insight inro the human U-II/UT-receptor system. AIMS To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. METHODS After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d., effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. RESULTS Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of ,1.8 µU ml,1, 95% confidence interval (CI) ,7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean Cmax and AUC, (95% CI) and median tmax (range) in this patient population were 180 ng ml,1 (125, 260), 581 ng·h ml,1 (422, 800) and 3.0 h (0.67, 4.3), respectively. CONCLUSIONS The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes. [source] Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Zeruesenay Desta Aims, To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. Methods, The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac -cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. Results, This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 ± 13.6 ng ml,1; P = 0.0008) and AUC(0, ,) (201 ± 161 ng ml,1 h; P = 0.029) of (,)-cisapride were significantly higher than the Cmax (10.5 ± 3.4 ng ml,1) and AUC(0, ,) (70 ± 51.5 ng ml,1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (,)-cisapride (4.7 ± 2.7 h) and (+)-cisapride (4.8 ± 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (,)-cisapride from 30 ± 13.6,55.5 ± 18 ng ml,1 (95% CI on mean difference, ,33, ,17; P = 0.00005) and of (+)-cisapride from 10.5 ± 3.4 to 18.4 ± 6.2 ng ml,1 (95% CI on mean difference, ,11.8, ,3.9, P = 0.00015). The mean AUC(0, ,) of (,)-cisapride was increased from 201 ± 161 to 521.6 ± 303 ng ml,1 h (95% CI on mean difference, ,439, ,202; P = 0.0002) and that of (+)-cisapride from 70 ± 51.5 to 170 ± 91 ng ml,1 h (95% CI on mean difference, ,143, ,53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (,)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t½ of (,)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. Conclusions, The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (,)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride. [source] | ||||||||||