Volume 46, No. 12/2008(December)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Introduction to Pharmacotherapy Guidelines for the aged by family doctors for the use of family doctors
L. von Ferber
Drug Utilization
Pharmacotherapy Guidelines for the aged by family doctors for the use of family doctors
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Abstract
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Population Pharmacokinetics
Estimation of lithium clearance from routine clinical data in Egyptian bipolar patients. A population pharmacokinetic approach
E.S. ELDesoky, V. Kumar, M.S. Alorainy, M.M. Hamdi and H. Derendorf
Abstract
E.S. ELDesoky1, V. Kumar2, M.S. Alorainy3, M.M. Hamdi1 and H. Derendorf2
1Pharmacology Department, Faculty of Medicine, Assiut University, Assiut, Egypt, 2Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, and 3Pharmacology Department, College of Pharmacy, Qasseem University, Saudi Arabia
Population pharmacokinetics (PK) of lithium as a mood stabilizer was investigated in Egyptian patients with bipolar affective disorders (n = 50) of whom 31 were suffering from lithium toxicity. The mean (± SD) age and body weight of patients were 33 ± 10 years and 67 ± 3.6 kg, respectively. Patients selected were maintained on lithium carbonate controlled release tablets at doses of 400 mg/12 hours (n = 43) or 200 mg/12 hours (n = 7) respectively. In 19 patients who continued lithium therapy, 1 blood sample/patient was withdrawn for lithium level determination before the morning dose of the drug was given while for 31 patients who suffered from lithium-related toxicity and cessation of drug intake was therapeutically decided, a single blood was drawn at variable time (36, 48 or 72 h) following the last administered dose of the drug. The data was subjected to population PK analysis using NONMEM and a two-compartment model was used. Due to single point sparse data, not all parameters and their between subject variability (BSV) could be determined. Therefore, lithium clearance (CL) and BSV were estimated while other PK parameters were fixed using available literature information. First order (FO) estimation method was used in the analysis. Covariates were evaluated by univariate analysis using likelihood ratio test. The most significant covariate on lithium CL was found to be creatinine clearance (CrCL). The population CL of lithium in the final model was expressed as CLpop = 0.51 × (CrCL/105.3)0.44. The final population PK parameters estimates of lithium were: CL = 0.51 l/h with 12.7% BSV, V1 (Fixed) = 15.2 l, Q (Fixed) = 7.44 l/h, and V2 (Fixed) = 6.7 l. The mean value of lithium concentration at 12 hours as predicted by the final model in the patients with drug toxicity was 1.3 ± 0.1 mmol/l versus 0.8 ± 0.14 mmol/l in patients without toxic signs. External validation of the final model on another group of adult bipolar patients (n = 12) maintained on lithium therapy showed a predictive ability of –35 to 65% as represented by% error for the predictions.Correspondence to:
Prof. Dr. E.S. ELDeskoy; Pharmacology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Email: ehegypt@yahoo.com
Pharmacokinetics
Pharmacokinetics of emtricitabine/tenofovir disoproxil fumarate and tacrolimus at steady state when administered alone or in combination
G.E. Chittick, J. Zong, J.A. Begley, J.R. Alianti, J.J. Sorbel and M.R. Blum
Abstract
G.E. Chittick, J. Zong, J.A. Begley, J.R. Alianti, J.J. Sorbel and M.R. Blum
Gilead Sciences, Inc., Durham, NC, USA
Objective: An open-label, randomized, 3-way crossover, drug-drug interaction study of the investigational anti-HBV combination agent, emtricitabine/tenofovir DF and the antirejection agent, tacrolimus was conducted in healthy volunteers to evaluate the potential for a pharmacokinetic interaction between these drugs. Methods: Subjects received emtricitabine/tenofovir DF (200/300 mg q.d.) and tacrolimus (0.1 mg/kg/day) alone or in combination for 7 days, with a 2-week washout between successive treatments. Drug concentrations were measured by LC/MS/MS and steady state pharmacokinetic parameters were calculated for each drug using noncompartmental methods. Results: The 90% confidence intervals (CIs) of the geometric least-squares mean ratio for AUCtau, Cmax and Ctau for each drug together vs. alone were within the predetermined no-effect boundaries of 80 – 125% (representing a maximum 20% effect), other than the upper limit of the 90% CI for tenofovir Cmax, which was just outside the 125% threshold. Conclusions: It was concluded that there was no clinically relevant pharmacokinetic interaction between emtricitabine/tenofovir DF and tacrolimus when administered together.Correspondence to:
J. Zong, PhD; Gilead Sciences, Inc., Department of Clinical Pharmacology, 4 University Place,
4611 University Drive, Durham, NC 27707, USA
Email: jian.zong@gilead.com
Therapeutics
Predictors of in-hospital mortality after acute stroke: impact of renal dysfunction
W.M. Sweileh
Abstract
W.M. Sweileh
Clinical Pharmacology, College of Pharmacy, Clinical Pharmacy Graduate Program, An-Najah National University Nablus, Palestine
Objective: The objective of this 1-year, hospital-based study was to identify the impact of renal dysfunction on in-hospital mortality after acute stroke. Methodology: All patients admitted to Al-Watani governmental hospital and diagnosed with acute stroke from September 2006 to August 2007 were included in the study. Data were obtained from patients’ medical files. Creatinine clearance (CrCl) was calculated using Cockcroft-Gault equation. Patients with CrCl < 60 ml/min were designated as Group 1 while those with CrCl >= 60 ml/min were designated as Group 2. The main outcome measure in this study was vital status at discharge. Pearson chi2 and independent Student’s t test were used in the univariate analysis while multiple logistic regression analysis was used to identify independent predictors of in-hospital mortality. Statistical testing and graphics were carried out using SPSS 15. Results: A total of 186 acute stroke cases were included. Hypertension (HTN) (69.9%) and diabetes mellitus (DM) (45.2%) were the most prevalent risk factors. Patients in Group 1 were significantly older than those in Group 2 (74.11 ± 9.46 versus 66.53 ± 10.74 years). Thirty nine (21%) of the stroke patients died during their hospital stay. In the total stroke patients, three predictors of in-hospital mortality were identified: CrCl (p = 0.004), number of post-stroke complications (p = 0.001), and type of stroke (p = 0.034). In Group 1, CrCl (p = 0.012) was the only independent predictor of mortality, with patients who died having significantly lower CrCl than those who survived. However, in Group 2, CrCl level was not a predictor of mortality and was not significantly different (p = 0.26) between those who died and those who survived. In Group 2, no predictors of mortality were identified. Conclusion: Screening and better control of renal dysfunction is required to decrease the risk of in-hospital mortality among patients after acute stroke. Our study also shows that the lower the CrCl, the greater is the risk of in-hospital mortality after acute attack. This finding needs to be considered in preventive and therapeutic strategies of acute stroke.Correspondence to:
W.M. Sweileh, PhD; Associate Professor
Clinical Pharmacology, Dean, College of Pharmacy, An-Najah National University, Nablus, Palestine
Email: waleedsweileh@najah.edu
Therapeutics
Sildenafil for pulmonary hypertension: need for evidence generation
N. Shafiq, S. Reddy, P. Pandhi, R. Manoj, K.K. Talwar and S. Malhotra
Abstract
N. Shafiq1, S. Reddy2, P. Pandhi1, R. Manoj2, K.K. Talwar2 and S. Malhotra1
1Department of Pharmacology, 2Department of Cardiology, PGIMER, Chandigarh, India
Background: The present meta-analysis was conducted with the aim of comparing the usefulness of sildenafil for the management of pulmonary hypertension (PH). Methods: A systematic electronic and manual search was conducted to retrieve all published and unpublished randomized clinical trials of sildenafil in PH. Pertinent data related to various outcomes were extracted. Sildenafil was planned for comparison with placebo, prostacyclin analogs and endothelin receptor antagonists. For continuous data weighted mean difference was used while fixed or random effects models were used for dichotomous data. Revman (Version 4.2) was used for all calculations. Results: Five studies with a total of 190 patients were included in the final analysis. As compared to placebo sildenafil showed a significant improvement in 6-min walk test (68.90 (95% CI 31.14 – 106.65), p = 0.0003), mean pulmonary artery pressure (–13.04 (95% CI – 25.94 to –0.15), p = 0.05), mean cardiac index (0.39 (95% CI 0.24 – 0.54), p < 0.00001), mean Borg dyspnea score (–1.23 (95% CI –1.36 to –1.10), p < 0.00001), mean pulmonary vascular resistance (–171 (95% CI –300 to –30.90), p = 0.02), improvement in functional class (6.48 (95% CI 2.74 – 15.33), p < 0.001) and a nonsignificant change in mean right atrial pressure and clinical worsening. No study satisfied inclusion criteria for comparison with prostacyclin analogs. In comparison with bosentan, sildenafil did not show a significant difference for any of the clinical outcomes of concern. Conclusion: In conclusion, sildenafil was shown to produce a significant improvement in functional and clinical outcomes as compared to placebo. There was no significant difference between sildenafil and bosentan for the study outcomes. There is a definite need for conducting adequately powered randomized controlled trials of sildenafil comparing it to placebo and also to other treatments approved for use in PH.Correspondence to:
Dr. S. Malhotra; Associate Professor, Department of Pharmacology, PGIMER, Chandigarh, India 160012
Email: samirmalhotra345@yahoo.com
Letter to the Editor
Preventing exposure of hospital staff to incorrect drug information
S.M. Jankovic, V. Radonjic, S. Cupara and S. Stefanovic
Abstract
S.M. Jankovic, V. Radonjic, S. Cupara and S. Stefanovic
Bioavailability Section
A randomized, open-label, 2-period, crossover bioequivalence study of two oral formulations of 75 mg oseltamivir in healthy Thai volunteers
S. Kongpatanakul, S. Chatsiricharoenkul, U. Panich, K. Sathirakul, P. Pongnarin and P. Sangvanich
Abstract
S. Kongpatanakul1, S. Chatsiricharoenkul1, U. Panich1, K. Sathirakul2, P. Pongnarin1 and P. Sangvanich3
1Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand, 3Research Centre for Bioorganic Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
Aim: Oseltamivir, an ester prodrug of its active carboxylate metabolite, is an effective neuraminidase inhibitor used to treat influenza A and B virus infections. The purpose of this study was to compare the bioavailability of two 75 mg oral formulations of oseltamivir: a generic drug, GOP-A-FluTM (test, Government Pharmaceutical Organization, Thailand) and Tamiflu® (reference, Hoffmann-La Roche Ltd., Nutley, NJ, USA) in healthy volunteers. Subjects and methods: A single-dose, randomized, 2-sequence, crossover study was conducted in 24 healthy Thai volunteers. Each volunteer received a 75 mg capsule of the reference or test drugs under fasting conditions. Blood samples were collected before dosing and at various time points up to 48 hours after dosing and analyzed for plasma oseltamivir and oseltamivir carboxylate concentrations. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-¥, tmax and t1/2 were analyzed using the non-compartmental method. Drug safety was assessed. Results: 23 volunteers completed both treatment periods. The geometric mean ratios (test/reference) between the two formulations of oseltamivir were 96.83% (90% CI, 76.85 – 123.15%) for Cmax 103.66% (86.44 – 113.56%) for AUC0-t, and 103.98% (86.44 – 113.56%) for AUC0-¥. Those of oseltamivir carboxylate were 102.17% (90% CI, 90.90 – 109.10%) for Cmax, 103.95% (90.90 – 109.10%) for AUC0-t, and 103.95% (90.92 – 109.08%) for AUC0-¥. No significant difference of the tmax of oseltamivir and oseltamivir carboxylate between the two formulations was detected (p > 0.05). Both formulations were well-tolerated. Conclusion: Although the Cmax of oseltamivir was the only parameter not entirely within the equivalence criteria, the two capsule formulations were considered bioequivalent in terms of rate and extent of absorption regarding its active carboxylate metabolite.Correspondence to:
Associate Prof. S. Kongpatanakul; Department of Pharmacology, Faculty of Medicine Siriraj Hospital
Mahidol University, Bangkok 10700, Thailand; supornchai@biotec.or.th
Email: siskt@mahidol.ac.th
