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Dosing Interval (dosing + interval)
Selected AbstractsCLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source] The efficacy of telmisartan compared with perindopril in patients with mild-to-moderate hypertensionINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2004I. Nalbantgi Summary In this study, efficacy of the angiotensin II type 1 receptor blocker telmisartan given as monotherapy was compared with that of perindopril monotherapy in patients with mild-to-moderate hypertension. After a 2-week, single-blind, placebo run-in period, 60 patients were randomised to double-blind, once-daily treatment with telmisartan 80 mg or perindopril 4 mg for 6 weeks. Clinic and ambulatory blood pressure measurements and clinical laboratory evaluation were performed at the end of the placebo run-in and active treatment phases. Both telmisartan and perindopril significantly (p < 0.0001) reduced clinic systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared with baseline values. Also, both drugs significantly (p < 0.0001) reduced 24-h mean ambulatory SBP and DBP compared with baseline. Comparison of the mean hourly antihypertensive activities showed that the reduction in mean ambulatory DBP for the last 8 h of the dosing interval was significantly greater (p < 0.05) in telmisartan-treated patients. A 24-h mean DBP of <85 mmHg was observed in 66.6% of the telmisartan-treated patients but in only 46.6% of the perindopril-treated patients (p < 0.05). It is concluded that telmisartan and perindopril both produce significant reductions in clinic SBP and DBP, but the mean reduction in ambulatory DBP during the last 8 h of the dosing interval is greater in patients treated with telmisartan. [source] Population pharmacokinetics of cefepime in neonates with severe nosocomial infectionsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008V. Lima-Rogel MD Summary Objective:, To define the pharmacokinetic behaviour of cefepime in neonates with severe nosocomial infections using a mixed effects model. Patients and methods:, Thirty-one newborn infants were included in the study; 10 additional infants participated in the validation of the pharmacokinetic model. Cefepime CL and V were determined using an open monocompartmental model with first-order elimination. The influence of demographic and clinical characteristics on the model was evaluated. The non-linear mixed effect model (nonmem) program was used to determine the pharmacokinetic population model. Results:, The mean corrected gestational age for infants participating in the construction and validation of the model were 35 and 33 weeks, respectively. Factors included in the final pharmacokinetic model were body surface area (BSA) and calculated CLCR. The final population model was CL (L/h) = 0·457 BSA (m2) + 0·243 CLCR (L/h) and V(L) = 4·12 BSA (m2). This model explains 33·3% of the interindividual variability for CL and 12·8% for V. This model was validated in ten neonates with nosocomial infections by assessing the predictive capacity of plasma cefepime concentrations using a priori and Bayesian strategies. Conclusions:, The predictive performance of this population model for cefepime plasma concentrations was adequate for clinical purposes and can be used for individualizing cefepime therapy in newborn infants with severe infections. Cefepime plasma concentrations can be predicted based on BSA and calculated CLCR. Cefepime therapy using a 250 mg/m2 dose administered every 12 h is adequate to achieve plasma concentrations greater than 8 ,g/mL during more than 60% of the dosing interval and is expected to be effective in the treatment of bloodstream infections caused by most gram negative organisms in newborn infants. A dose of 550 mg/m2 would be required for the treatment of infections caused by Pseudomonas sp. [source] Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2006Jonathan F. Bach DACVIM (SA-IM) Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide-mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPS) 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPS, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPS was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPS was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPS and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension. [source] Pharmacodynamics of Carvedilol in Conscious, Healthy DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Sonya G. Gordon The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for >5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54,76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80,100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful. [source] Selected pharmacokinetic parameters for Cefovecin in hens and green iguanasJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009L. R. THUESEN The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile hens and green iguanas, following subcutaneous injections with 10 mg cefovecin/kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid absorption with peak plasma concentration of 6 ± 2 ,g/mL in hens and 35 ± 12 ,g/mL in green iguanas. The mean plasma half-life for cefovecin was 0.9 ± 0.3 h for hens and 3.9 h in green iguanas. Volume of distribution was 1.6 ± 0.5 L/kg for hens and 0.3 L/kg for green iguanas and clearance was 1252 ± 185 mL·h/kg for hens and 53 mL·h/kg for green iguanas. Results from preliminary studies did not differ notably from those seen in hens and green iguanas. Cefovecin is not suitable for the treatment of bacterial infections with a 14-day dosing interval in hens or green iguanas and seems not to be in a number of other bird and retile species either. [source] Pharmacokinetics of oral doxycycline and concentrations in body fluids and bronchoalveolar cells of foalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2007A. WOMBLE The objective of this study was to determine the disposition of orally administered doxycycline in foals. Six healthy 4- to 8-week-old foals were used. Doxycycline was administered to each foal via the intragastric (IG) route at dosages of 10 and 20 mg/kg, in a cross-over design. After the first 10 mg/kg dose, five additional doses were administered at 12-h intervals. A microbiological assay was used to measure doxycycline activity in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal (CSF), pulmonary epithelial lining fluid (PELF), and bronchoalveolar (BAL) cells. Following administration at 10 mg/kg, mean ± SD time to peak serum doxycycline activity (tmax) was 3.0 ± 1.2 h, maximum serum activity (Cmax) was 2.54 ± 0.27 ,g/mL, and terminal half-life (t1/2) was 8.5 ± 2.8 h. Administration at a dose of 20 mg/kg resulted in a significantly longer tmax (5.5 ± 1.8 h) as well as a tendency toward higher Cmax (2.89 ± 0.33 ,g/mL) and longer t1/2 (11.9 ± 2.6 h). After multiple IG doses, doxycycline activity in CSF was significantly lower than concurrent serum activity, whereas peritoneal fluid, synovial fluid, and BAL cell doxycycline activity was similar to concurrent serum activity. Doxycycline activity in urine and PELF was significantly higher than that found at other sites. Oral administration at a dosage of 10 mg/kg every 12 h would maintain serum, PELF, and BAL cell activity above the minimum inhibitory concentrations of Rhodococcus equi, , -hemolytic streptococci, and other susceptible bacterial pathogens for the entire dosing interval. [source] Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002E. HEINEN The pharmacokinetics after oral application of the fluoroquinolones (FQs), enrofloxacin, difloxacin, marbofloxacin and orbifloxacin were compared in independent crossover studies in Beagle dogs. Commercially available tablet formulations were given at common dosage recommended by the manufacturers which were 2.0 mg/kg body weight (bw) for marbofloxacin, 2.5 mg/kg bw for orbifloxacin and 5.0 mg/kg bw for enrofloxacin and difloxacin. Analysis was performed by an agar diffusion assay. Pharmacokinetic parameters were calculated by noncompartmental methods. All FQs were rapidly absorbed and achieved average peak serum concentrations of 1.41, 1.11, 1.47 and 1.37 ,g/mL for enrofloxacin, difloxacin, marbofloxacin and orbifloxacin, respectively. Enrofloxacin was eliminated at a terminal half-life (t˝) of 4.1 h, difloxacin at 6.9 h, orbifloxacin at 7.1 h and marbofloxacin at 9.1 h. While the area under the serum concentration,time curve of the 24-h dosing interval (AUC0,24) for marbofloxacin and orbifloxacin were similar (approximately 13 ,g · h/mL), enrofloxacin attained an AUC0,24 of 8.7 and difloxacin of 9.3 ,g · h/mL. Because of its favourable pharmacokinetics combined with excellent in vitro activity, enrofloxacin exhibited superior pharmacodynamic predictors of in vivo antimicrobial activity as Cmax/MIC (maximum serum concentration/minimum inhibitory concentration) and AUC0,24/MIC (area under the 24-h serum concentration,time curve/minimum inhibitory concentration) compared with other FQs. [source] Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patientsLIVER TRANSPLANTATION, Issue 7 2004Martin Vogel Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV-infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug-to-drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12-hour pharmacokinetic profiles in 3 HIV-positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir-boosted indinavir or lopinavir-based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1-mg increments. Under ritonavir-boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood-levels throughout the dosing interval and prolonged elimination half-lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5,20% of the individual standard doses given before initiation of ritonavir-boosted HAART. Because of the flat absorption/elimination profiles under ritonavir-boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough-levels. (Liver Transpl 2004;10:939,944.) [source] Ebastine in allergic rhinitis and chronic idiopathic urticariaALLERGY, Issue 2008J. Sastre Histamine is a key mediator in the development of allergy symptoms, and oral H1 -antihistamines are among the most widely used treatments for symptomatic relief in conditions such as allergic rhinitis and chronic urticaria. Ebastine is a second-generation antihistamine which has been shown to be an effective treatment for both seasonal and perennial allergic rhinitis. In controlled clinical trials in adult and adolescent patients with allergic rhinitis, ebastine 10 mg once-daily improved symptoms to a significantly greater extent than placebo and to a similar extent as loratadine 10 mg and cetirizine 10 mg (both once-daily), while ebastine 20 mg proved to be more effective than these two comparator antihistamines. In addition, ebastine was significantly more effective than placebo at relieving the symptoms of chronic idiopathic urticaria. Ebastine provides efficacy throughout the 24-h dosing interval with once-daily administration and clinical benefit is seen from the first day of treatment. Small studies have found beneficial effects for ebastine in patients with other disorders, including cold urticaria, dermographic urticaria, atopic asthma, mosquito bites and (in combination with pseudoephedrine) the common cold. In addition to the regular ebastine tablet, a fast-dissolving tablet (FDT) formulation, which disintegrates in the mouth without the aid of a drink, is also available. It has been shown to be bioequivalent to the regular tablet, and to be significantly more effective than desloratadine at reducing histamine-induced cutaneous wheals. A number of patient surveys demonstrated that the majority of individuals who tried the fast-dissolving formulation reported it to be convenient for use, fast-acting and preferred it to their previous antihistamine medication. Perhaps most importantly, a large proportion of patients indicated that they would prefer to use this new formulation in the future. Ebastine has a rapid onset of action and it can be administered once-daily, with or without food. Dose modifications are not needed in elderly patients, or in those with renal or mild to moderate hepatic impairment. Ebastine is generally well-tolerated, and clinical studies showed that at usual therapeutic doses of 10 and 20 mg once-daily, it had no clinically relevant adverse effects on cognitive function and psychomotor performance or on cardiovascular function. In conclusion, ebastine is an effective and generally well-tolerated treatment for allergic rhinitis and chronic idiopathic urticaria. In addition to the regular tablet formulation, ebastine is available as a FDT, providing a treatment option that is particularly convenient for patients. [source] A pharmacodynamic assessment of the impact of antihypertensive non-adherence on blood pressure controlPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2000DrPh, Peter W. Choo MD Abstract Objectives To evaluate if antihypertensive regimens that conform to present FDA guidelines by maintaining ,,50% of their peak effect at the end of the dosing interval protect patients during sporadic lapses in adherence. Methods 169 patients on monotherapy for high blood pressure underwent electronic adherence monitoring for 3 months. Blood pressures were measured during non-study office visits and were retrieved from automated medical records. Questionnaires were used to obtain other covariate information. The ratio of the dosing interval to the half-life of drug activity (I,) was used to capture conformity with FDA guidelines. Data analysis focused on the interaction between I, and the impact on blood pressure of delayed dosing. Results The average (,±,standard deviation) blood pressure during the study was 139.0 (,±,12.0)/85.0 (,±,6.9) mm Hg. Lisinopril followed by sustained-release verapamil, atenolol, and hydrochlorothiazide were the most frequently prescribed agents. The majority of regimens (99%) conformed to FDA dosing guidelines. Of the patients 23% missed a dose before their blood pressure check. Non-adherence, however, did not have a direct impact on blood pressure, and no interaction with I, of was detected. Conclusions Among patients with relatively mild hypertension on single-drug therapy, regimens that conform to current FDA dosing guidelines may prevent losses of blood pressure control during episodic lapses of adherence. These findings should be replicated in other patient populations with standardized blood pressure measurement to confirm their validity. Copyright © 2000 John Wiley & Sons, Ltd. [source] Safety, Efficacy, and Pharmacokinetic Overview of Low-Dose Daily Administration of TadalafilTHE JOURNAL OF SEXUAL MEDICINE, Issue 7 2009Rebecca Wrishko PhD ABSTRACT Introduction., Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. Aim., To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. Methods., Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. Main Outcome Measures., Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. Results., Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. Conclusions., Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED. Wrishko R, Sorsaburu S, Wong D, Strawbridge A, and McGill J. Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil. J Sex Med 2009;6:2039,2048. [source] Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrugTHE PROSTATE, Issue 4 2006Samuel Janssen Abstract BACKGROUND Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 µmole/kg) which produced peak serum concentration of ,36 µM and had a half-life of ,40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development. © 2005 Wiley-Liss, Inc. [source] Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008Christa E. Nath WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The pharmacokinetics of oral busulphan given four times daily has been extensively studied. , Large inter- and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring. , However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6-h dosing interval, due to late absorption in some patients. , Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose. WHAT THIS STUDY ADDS , Inter- and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable. , Children with immune deficiencies, in particular, have widely variable exposure. AIM To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. METHODS Busulphan (120 mg m,2, 130 mg m,2 or 3.2 mg kg,1) was administered over median 2.1 h. Blood samples (4,10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration,time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m,2 dose in 13 children who had busulphan pharmacokinetic monitoring. RESULTS Clearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h,1 (% CV 61%), 0.23 ± 0.08 l h,1 kg,1 (% CV 35%) and 5.79 ± 1.59 l h,1 m,2 (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h,1) and CL (l h,1 kg,1), but not with CL (l h,1 m,2). AUC normalized to the 130 mg m,2 dose ranged from 14.1 to 56.3 mg l,1.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h,1 m,2) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. CONCLUSIONS There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h,1 m,2) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required. [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] Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjectsACTA NEUROLOGICA SCANDINAVICA, Issue 4 2010L. Almeida Almeida L, Nunes T, Sicard E, Rocha J-F, Falcăo A, Brunet J-S, Lefebvre M, Soares-da-Silva P. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. Acta Neurol Scand: 2010: 121: 257,264. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective,,, Anti-epileptic drugs are often used in combination. Both eslicarbazepine (main metabolite of eslicarbazepine acetate, ESL) and lamotrigine undergo conjugation with glucuronic acid, and both eslicarbazepine and its glucuronide and lamotrigine glucuronide undergo extensive renal elimination; therefore, there is a potential for interaction. This study investigated the interaction between ESL and lamotrigine in healthy subjects. Methods,,, Open-label study in two parallel groups of 16 healthy volunteers each. After an 8-day treatment with ESL or lamotrigine, ESL (1200 mg once-daily) and lamotrigine (150 mg once-daily) were co-administered for 19 days. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for maximum plasma concentration (Cmax) and area under the plasma concentration,time curve in the dosing interval (AUC0,24) were calculated for eslicarbazepine (ESL active metabolite) and lamotrigine. Results,,, The Cmax and AUC0,24 GMR (90% CI) were, respectively, 95% (87,102%) and 96% (91,102%) for eslicarbazepine, and 88% (82,94%) and 86% (81,92%) for lamotrigine. The 90% CI of the Cmax and AUC0,24 GMR fell within the prespecified acceptance interval (80,125%) both for eslicarbazepine and lamotrigine. Conclusion,,, There was no significant pharmacokinetic interaction between ESL and lamotrigine in healthy subjects. Therefore, no dosage adjustment appears to be usually required in either lamotrigine or ESL when the drugs are co-administered. [source] Educational strategy to reduce medication errors in a neonatal intensive care unitACTA PAEDIATRICA, Issue 5 2009Ainara Campino Abstract Objective: We aimed to evaluate the effect of a comprehensive preventive educational strategy on the number and type of drug errors in the prescription process in a regional neonatal intensive care unit (NICU). Design: Medication errors during prescription were recorded in a 41 bed, level III regional neonatal unit by a pharmacist. Data were retrieved from handwritten doctor's orders and introduced at bedsite into an e-database. Each prescription, not related to enteral and parenteral nutrition and blood products, was evaluated for dosage, units, route and dosing interval. The study was developed in three phases: pilot phase to know the baseline drug error rate and estimate sample size; pre-intervention (4182 drug orders reviewed); and post-intervention seven months after a comprehensive preventive educational intervention consisting sessions about drug errors and study's aims was implemented. Results: After the preventive educational intervention was implemented, the prescription error rate and the percentage of registers with one or more incident decreased significantly from 20.7 to 3% (p < 0.001) and from 19.2 to 2.9% (p < 0.001), respectively. Simultaneously, an improvement in correct identification of the prescribing physician was registered (from 1.3 to 78.2%). The rest of items analysed were similar in both periods. Conclusion: The implementation of a structured preventive educational intervention for health professionals in a regional NICU reduced the medication error rate, possibly by the dissemination of a patient safety culture. [source] Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIIIHAEMOPHILIA, Issue 2006M.-C. POON Summary., There is now a volume of literature on the pharmacokinetics (PK) of coagulation factor concentrates, although the majority is on factor VIII (FVIII) and factor IX (FIX). PK of FIX and FVIII are different with FIX having a larger volume of distribution (Vdss), higher elimination clearance (CL), longer mean resident time (MRT) and longer terminal half-life (T1/2,,). Factor IX in vivo recovery (IVR) is also much shorter possibly due to reversible binding of FIX to the endothelium and possibly to platelets. There is considerable FIX PK variability between products (particularly between plasma-derived FIX and recombinant FIX), and between individuals. Important inter-individual factors leading to PK variability include age and body weight because plasma volume as a fraction of body weight decreases with increasing weight and hence age. Thus, IVR increases with body weight and hence age and is consequently lower in children than in adults. Absolute Vdss and CL increase linearly with body weight and age in children and adolescents, becoming stable in adults with more stable weight. Inter-individual variability also likely applies to other clotting factors, particularly to recombinant activated FVII (rFVIIa) but likely also to the less well studied factor XIII (FXIII). The former is known to have an extremely short T1/2,,, large Vdss, high CL, short MRT, whereas the latter has an extremely long T1/2,,, large Vdss, short CL and long MRT. Both are discussed in this article. Understanding of PK of specific clotting factors in individual patients is important in order to make decisions regarding appropriate dosage and dosage intervals to treat patients, and to allow by means of computer modelling the determination of dosage to achieve target trough level at various dosing intervals for patients undergoing prophylaxis. [source] Children's prescription medicines: parents' perceptions on dosing intervals, dosing devices and prescription adviceINTERNATIONAL JOURNAL OF PHARMACY PRACTICE, Issue 1 2007Dr. Therése Kairuz senior lecturer, pharmacy practice Objective To gather information on devices used to administer liquid medicines, dosing intervals for antibiotic administration, and parents' perceptions of the advice received from pharmacists about prescription medicines, for children up to the age of six years. Setting Six schools from different socio-economic areas were selected within the Auckland area of New Zealand. To facilitate distribution and collection of questionnaires, the headmaster or a teacher was known to the researchers. Method An anonymous questionnaire was distributed to year 1 and 2 students (aged five and six years) to take home for completion by a parent or primary caregiver. Respondents were asked to refer to their youngest child and/or to the last time they had given medicines or received a prescription for a child. Key findings A total of 299 completed questionnaires were received (48.2%); 60 questionnaires had not been distributed by school teachers in error, and the overall return rate was thus adjusted to 53.4%. The device used most frequently to administer medicines to younger children up to the age of three years was an oral medicine syringe, while nearly one-third of children aged three to six years received medicine in a ,teaspoon'. Almost half the respondents (48.8%) indicated they would be most likely to forget the midday dose of antibiotics, and dosing deviated from recommended intervals. Most respondents had received advice from a pharmacist on how to take the medicine, and had understood instructions and had the opportunity to ask questions. Conclusion This study highlights areas that pharmacists can include when advising parents and guardians about children's medicines, such as ideal dosing intervals of antibiotics and the use of accurate dosing devices. [source] Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosingLIVER TRANSPLANTATION, Issue 2 2006Masahide Fukudo We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC0,4), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA0,12) and 24 hours (AUA0,24) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC0,4 (r2 = 0.95), which was negatively related to the AUA0,12 with a large interindividual variability (r2 = 0.59). However, a significant correlation was found between the AUA0,12 or AUA0,24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (Emax) model, the mean estimates of Emax and the Cb value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration. Liver Transpl 12:292,300, 2006. © 2006 AASLD. [source] Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricinARTHRITIS & RHEUMATISM, Issue 3 2009Carl R. Flannery Objective Lubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction-resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis-associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA). Methods Binding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage-lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell-binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis. Results LUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease-modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage. Conclusion Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities. [source] | |||||||||||||||||||||||||