Volume 45, No. 3/2007(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration
Abstract
J.M. Conil, B. Georges, O. Fourcade, T. Seguin, G. Houin and S. Saivin
1Service d’Anesthésie-Réanimation, 2Laboratoire de Pharmacocinétique et Toxicologie Clinique, Hôpital de Rangueil, 3Laboratoire de Cinétique des Xénobiotiques, Physiopathologie et Toxicologie Expérimentale, Faculté des Sciences Pharmaceutiques, Toulouse, France
Objective: The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in burns patients. Methods: 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 × 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g × 8 administrations or it was decreased to 1 g × 4 or 1 g × 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). Results: From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft’s formula. Conclusion: This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft’s formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g × 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 × the MIC.Correspondence to:
Dr. S. Saivin; L aboratoire de Pharmacocinétique et Toxicologie Clinique, 1, avenue Jean-Poulhès, TSA 50032, 31403 Toulouse Cedex, France
Email: saivin.s@chu-toulouse.fr
Therapeutics
Isopropanolic black cohosh extract and recurrence-free survival after breast cancer
Abstract
H.H. Henneicke-von Zepelin, H. Meden, K. Kostev, D. Schröder-Bernhardi, U. Stammwitz and H. Becher
1Schaper & Brümmer GmbH & Co. KG, Salzgitter, 2Diakoniekrankenhaus Rotenburg/Wümme gGmbH, 3IMS Health GmbH & Co. OHG, Frankfurt am Main, and 4Ruprecht-Karls-Universität, Abteilung Tropenhygiene und öffentliches Gesundheitswesen, Heidelberg, Germany
Objective: To investigate the influence of an isopropanolic Cimicifuga racemosa extract (iCR) on recurrence-free survival after breast cancer, including estrogen-dependent tumors. Methods: This pharmacoepidemiologic observational retrospective cohort study examined breast cancer patients treated at general, gynecological and internal facilities linked to a medical database in Germany. The main endpoint was disease-free survival following a diagnosis of breast cancer. The impact of treatment with iCR following diagnosis was analyzed by Cox-proportional hazards models, controlling for age and other confounders. Results: Of 18,861 patients, a total of 1,102 had received an iCR therapy. The mean overall observation time was 3.6 years. Results showed that iCR was not associated with an increase in the risk of recurrence but associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a recurrence, while the iCR group reached this proportion after 6.5 years. The primary Cox regression model controlling for age, tamoxifen use and other confounders demonstrated a protractive effect of iCR on the rate of recurrence (hazard ratio 0.83, 95% confidence interval 0.69 – 0.99). This effect remained consistent throughout all variations of the statistical model, including subgroup analyses. TNM status was unknown but did not bias the iCR treatment decision as investigated separately. Hence, it was assumed to be equally distributed between treatment groups. Correlation analyses showed good internal and external validity of the database. Conclusion: An increase in the risk of breast cancer recurrence for women having had iCR treatment, compared to women not treated with iCR is unlikely.Correspondence to:
Prof. H. Becher; Ruprecht-Karls-Universität, Abteilung Tropenhygiene und öffentliches Gesundheitswesen, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
Email: heiko.becher@ urz.uni-heidelberg.de
Therapeutics
Intraoperative small-dose ketamine does not reduce pain or analgesic consumption during perioperative opioid analgesia in children after tonsillectomy
Abstract
Y.K. Batra, M. Shamsah, M.J. Al-Khasti, H.J.F. Rawdhan, A.R. Al-Qattan and K.G. Belani
1Department of Anesthesia and Intensive Care, Al-Sabah Hospital, Kuwait, and 2Departments of Anesthesiology, Medicine and Pediatrics, University of Minnesota, MN, USA
Objective: Ketamine inhibits the NMDA receptors via non-competitive antagonism, resulting in an antihyperalgesic effect achieved by doses of ketamine much smaller than are required for analgesia. The aim of this study was to determine the extent to which small-dose ketamine, when used in conjunction with remifentanil, has a morphine-sparing effect in the perioperative period. Materials and methods: In this randomized, double-blind, placebo-controlled prospective study, we enrolled 40 children undergoing tonsillectomy. Anesthetic care was standardized. Intraoperative analgesia was provided with remifentanil 0.5 mg ´ kg–1 followed by an infusion of 0.25 mg ´ kg–1 ´ min–1. Group I (ketamine, n = 20) received a bolus dose of ketamine 0.5 mg ´ kg–1 followed by a continuous infusion of 2 mg ´ kg–1 ´ min–1 before start of surgery. The infusion was stopped when surgery ended. Group II (placebo, n = 20) received normal saline in the same manner. Pain was assessed postoperatively using the Children’s Hospital Eastern Ontario Pain Scale (CHEOPS; range of scores 4 – 13), and total morphine consumption was recorded in the postanesthesia care unit (PACU). Patients were transferred to the ward and morphine was administered via a patient-controlled analgesia (PCA) device and analgesia was recorded using a visual analogue scale (VAS) (0 – 10). Results: Intraoperative remifentanil consumption was not different between the ketamine group (0.29 ± 0.09 mg ´ kg ´ min–1) and the control group (0.24 ± 0.07 mg ´ kg ´ min–1). There were no significant differences between CHEOPS scores and VAS score between the two groups. The total mean morphine consumption in the ward was not significantly different between the two groups: 376.5 ± 91.6 mg ´ kg–1 with ketamine and 384.4 ± 97.3 mg ´ kg–1 with placebo. The time-to-first analgesic requirement was also similar in both groups. Conclusions: Small-dose ketamine did not decrease postoperative pain after tonsillectomy in children when added to a continuous intraoperative remifentanil infusion.Correspondence to:
Dr. Y.K. Batra; Professor of Anesthesia, Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
Email: ykbatra@glide.net.in
Molecular Target Therapy
Transgenic avian-derived recombinant human interferon-a2b (AVI-005) in healthy subjects: an open-label, single-dose, controlled study
Abstract
T.B. Patel, E. Pequignot, S.H. Parker, M.C. Leavitt, H.E. Greenberg and W.K. Kraft
1Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, and 2AviGenics, Athens, GA, USA
Background/Aims: This study characterized the safety and pharmacological properties of AVI-005, a novel glycosylated recombinant human interferon-a2b produced from the egg whites of chickens transfected with human cDNA. Methods: 18 healthy volunteers received single subcutaneous rising doses (0.5, 1.66 or 5 million international units, MIU) of AVI-005. A randomized parallel comparator group of 10 subjects received 5 MIU of unglycosylated IFN-a2b (Intron A). The pharmacokinetic parameters t1/2, tmax, Cmax, AUC0-24h, Vd, and clearance were compared between AVI-005 and unglycosylated IFN-a2b. Results: At equipotent doses, AVI-005 had a larger AUC0-24h than the control interferon. Pharmacodynamic markers of neopterin and b2-microglobulin for the two treatments were similar. These markers were increased by AVI-005 in a dose-dependent manner. Pharmacodynamic responses to treatment with AVI-005 were shown by the change in mRNA expression for interferon inducible protein kinase and 2’5’-oligoadenylate synthetase. Adverse events in the two groups were qualitatively and quantitatively similar. Conclusion: AVI-005 demonstrates biological activity and pharmacokinetic properties in humans that support further development.Correspondence to:
W. Kraft, MD, MS, FACP; Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South 10th Street, 1170 Main Building, Philadelphia, PA 19107, USA
Email: walter.kraft@jefferson.edu
Drug Utilization
Antimicrobial use at a university hospital: appropriate or misused? A qualitative study
Abstract
V. Vlahovic-Palcevski, I. Francetic, G. Palcevski, S. Novak, M. Abram and U. Bergman
1Department for Clinical Pharmacology, University Hospital Center Rijeka, University of Rijeka Medical School, Rijeka, Croatia, 2Unit for Clinical Pharmacology, Department of Medicine, University Hospital Center Rebro, University of Zagreb Medical School, Zagreb, Croatia, 3Pediatric Clinic, University Hospital Center Rijeka, Rijeka, Croatia, 4Department of Medicine, and 5Department for Clinical Microbiology, University Hospital Center Rijeka, University of Rijeka Medical School, Rijeka, Croatia, 6Division of Clinical Pharmacology, Department of Laboratory Medicine, WHO Collaboration Center for Drug Utilization Research and Clinical Pharmacological Services, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Objective: To evaluate the quality of antimicrobial drug use in a university hospital medical department (Department of Medicine, University Hospital Rijeka, Croatia) with 279 hospital-beds in wards containing patients from endocrinology, gastroenterology, hematology, clinical immunology, cardiology and coronary care unit, nephrology and pulmonology sections of the hospital. Methods: The appropriateness of antimicrobial treatment for all in-patients in the Department of Medicine was assessed in a prospective, longitudinal survey carried out during a 21-week period using Kunin’s criteria where Categories I and II indicate “appropriate therapy”, Categories III and IV indicate major deficiency in the choice or use of antimicrobials. Category V indicates unjustified antimicrobial administration. Results: During the study period, a total of 438 patients were treated with antimicrobials in the Department of Medicine. Of these, 159 (36%) received antimicrobials appropriately (Category I and II), 180 (41%) needed antimicrobials (Category III and IV) but they should have been prescribed differently. The main reason for inappropriate antimicrobial treatment was the wrong choice of antimicrobials (broad-spectrum where a narrow spectrum antibiotic would have been sufficient). In the case of 99 patients (23%) an indication for antimicrobial therapy did not exist (Category V). Conclusion: The main reason for suboptimal use of antimicrobials was the over-prescribing of broad-spectrum antimicrobials. This situation should be corrected e.g. by changes in the post-graduate medical teaching program.Correspondence to:
V. Vlahovic-Palcevski, MD, PhD; Department of Clinical Pharmacology, University Hospital Center Rijeka, Kresimirova 42, 51000 Rijeka, Croatia
Email: vvlahovic@inet.hr
Bioavailability Section
A bioequivalence study of gliclazide based on quantification by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry
Abstract
G.D. Mendes, L.D. Moreira, A. dos S. Pereira, A. Borges, F. Yui, F.D. Mendes and G. de Nucci
1Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), SP, Brazil, 2Galeno Development Research, Campinas, SP, Brazil, and 3Cartesius Analytical Unit, Department of Pharmacology ICB-USP, Sao Paulo, SP, Brazil
Objective: The aim of this study was to evaluate, in human volunteers, the performance of one gliclazide tablet formulation (gliclazide 80 mg tablet from EMS Indústria Farmacêutica Ltda.) against two reference gliclazide tablet formulations (Diamicron 80 mg tablet from Servier do Brazil Ltda. and Diamicron 80 mg tablet from Servier (Ireland) Industries Limited). Methods: The study had an open, randomized, three-period crossover design with a one-week washout interval between doses. The samples were obtained over a 48-h interval after each oral administration of gliclazide. The samples were extracted from plasma using diethylether : hexane (80 : 20, v/v) and the extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/ MS). Chromatography was performed isocratically using a Jones Chromatography Genesis C8 120A 4u. The method had a chromatographic run-time of 2.5 min and a calibration curve of the range of 0.02 – 10 mg ´ ml–1 (r2 > 0.9993). The limit of quantification was 0.02 mg ´ ml–1. Results: The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Ireland) ratio were 588.68% (90% CI = 491.16, 705.58%) for AUClast, 423.50% (90% CI = 338.25, 530.23%) for AUCinf, and 1395.77% (90% CI = 1116.62, 1744.72%) for Cmax. The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Brazil) ratio were 249.16% (90% CI = 207.96, 298.54%) for AUClast, 249.16% (90% CI = 207.96 – 298.54%) for AUCinf, and 188.04% (90% CI = 151.72, 233.05%) for Cmax. Conclusion: Since the 90% CI for Cmax, AUClast and AUC(0–¥) ratios were all outside the 80 – 125% interval proposed by the US Food and Drug Administration, we concluded that the gliclazide test formulation were not bioequivalent to either reference formulation. Interestingly, the pharmacokinetic parameters such as Cmax, AUClast of both reference formulations are compatible with neither the literature nor the profile of an immediate release formulation. In addition, both reference formulations were not bioequivalent in themselves, indicating significant differences in reference product formulation.Correspondence to:
G. de Nucci, MD, PhD; 415 Av. Jesuino Marcondes Machado, Campinas, SP 13092-320, Brazil
Email: denucci@dglnet.com.br
Letters to the Editor
Interaction between activated VD3 and Ca channel blockers in patients undergoing hemodialysis
Abstract
S. Negoro, S. Izumi, T. Furukubo, M. Satoh, C. Matsunaga, T. Yamakawa, S. Ikegawa, H. Nakanishi, D. Kadowaki and S. Hirata
Letters to the Editor
Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem
Abstract
S. Padol, Y. Yuan, M. Thabane, I.T. Padol and R.H. Hunt
Letters to the Editor
Reply to S. Padol et al.
