Volume 47, No. 11/2009(November)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Commentary on the contents of this issue
B.G. Woodcock
Original Research
The effect of exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension
H. Linnebjerg, P. Kothare, S. Park, K. Mace and M. Mitchell
Abstract
H. Linnebjerg1, P. Kothare2, S. Park2, K. Mace2 and M. Mitchell2
1Eli Lilly and Company Limited, Lilly Research Center, Windlesham, Surrey, UK, and 2Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
Objectives: This study evaluated the potential effect of exenatide on the pharmacokinetics and pharmacodynamics of lisinopril in patients with mild-to-moderate hypertension. Methods: 22 patients with mildto-moderate primary hypertension participated in a double-blind, randomized, placebo-controlled, 2-period, 2-sequence crossover study. Patients on stable lisinopril therapy were randomly assigned to receive subcutaneous exenatide (10 µg b.i.d.) and placebo b.i.d. separated by at least 2 days washout period. The primary pharmacodynamic parameters were baseline-adjusted 24-hour mean systolic and diastolic blood pressure. Steady state plasma lisinopril concentration-time profiles were also assessed. Results: Mean blood pressure changes were not significantly different between exenatide and placebo coadministered with lisinopril. The least squares mean differences (95% CI) between treatments were +1.38 mmHg (–1.41, 4.17) for diastolic and +1.38 mmHg (–1.95, 4.71) for systolic blood pressure. Exenatide delayed the time to attain maximum lisinopril concentration (tmax,ss) by 2 hours but did not significantly alter maximum lisinopril concentration (Cmax,ss) or area under the concentration-time profile (AUCtau,ss) over the 24-hour steady-state dosing interval. Conclusions: This study demonstrated that concurrent administration of exenatide did not produce clinically relevant changes in blood pressure and did not significantly alter lisinopril pharmacokinetics in patients with mild-to-moderate hypertension.Correspondence to:
Dr. H. Linnebjerg
Lilly Research Center, Erl Wood Manor
Sunninghill Road, Windlesham
Surrey GU20 6PH, United Kingdom
Email: linnebjerg_helle@lilly.com
Original Research
A randomized study of the serum pharmacokinetics of lower thoracic extended-release epidural morphine (DepoDur®) after lidocaine-epinephrine test dose administration in patients undergoing upper abdominal surgery
E.R. Viscusi and G.Z. Manvelian,
Abstract
E.R. Viscusi1 and G.Z. Manvelian2, 3
1Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 2SkyePharma Inc., San Diego, CA and 3present address: ImaRx Therapeutics, Inc., Tucson, AZ, USA
Objective: The primary objective was to evaluate the serum pharmacokinetic profile of a single 15-mg dose of extended-release epidural morphine (EREM) administered at the lower thoracic epidural space alone or following a lidocaine-epinephrine test dose in patients undergoing major upper abdominal surgery. Materials and methods: This randomized, open-label study recruited men and women >= 18 years of age scheduled for major upper abdominal surgery. Patients were randomly assigned to 1 of 5 treatment groups and were administered a single 15-mg dose of EREM or EREM preceded by a 3 ml lidocaine (1.5%)/epinephrine (1 : 200,000) test dose with or without a saline flush: EREM alone; test dose + flush + 3-minute wait + EREM; test dose + flush + 10-minute wait + EREM; test dose + flush + 15-minute wait + EREM; or test dose + 3-minute wait + EREM. EREM was administered at the lower thoracic epidural intervertebral space (T8 – T12) approximately 30 minutes before the surgical incision. Noncompartmental pharmacokinetic parameters were determined based on the serum concentration-time profiles of morphine and morphine metabolites. Effectiveness and safety were also assessed. Results: The intent-to-treat and safety populations included 39 patients; the pharmacokinetic population included 37 patients. Administration of EREM 3 minutes after a lidocaine-epinephrine test dose, with or without a flush, resulted in an increased mean maximum serum concentration of morphine (Cmax; flush, 30.2 ± 8.5 ng/ml; no flush, 25.6 ± 10.1 ng/ml; EREM alone, 11.5 ± 7.3 ng/ml) and a decreased median time to Cmax (tmax; flush, 0.2 h; no flush, 0.2 h; EREM alone, 2.0 h) compared with administration of EREM alone, without affecting relative morphine bioavailability. Flushing the catheter and waiting 15 minutes normalized the Cmax (11.4 ± 6.4 ng/ml) but not the median tmax (0.5 h). There were no significant group differences in safety, tolerability, or analgesic effectiveness. Conclusions: The interaction between EREM and a lidocaine-epinephrine test dose administered at T8 – T12 can be minimized by waiting 15 minutes after test dose administration. The overall safety and effectiveness of 15 mg EREM administered at the lower thoracic epidural intervertebral space in patients undergoing major upper abdominal surgery appears similar to that observed in previous studies assessing lumbar administration. ClinicalTrials.gov Identifier: NCT00728832Correspondence to:
E.R. Viscusi, MD
Director, Acute Pain Management
Department of Anesthesiology
Thomas Jefferson University
111 S 11th Street, Suite G-8490
Philadelphia, PA 19107, USA
Email: eugene.viscusi@jefferson.edu
Original Research
The impact of rational pharmacotherapy training reinforced via prescription audit on the prescribing skills of fifth-year medical students
Z. Guney, C. Uluoglu, B. Yucel and O. Coskun
Abstract
Z. Guney1, C. Uluoglu1, B. Yucel1 and O. Coskun2
Gazi University Medical School Departments of 1Pharmacology and 2Medical Education, Ankara, Turkey
Objective: The aim of the study was to demonstrate the impact of a rational pharmacotherapy (RPT) clerkship reinforced via prescription audit (PA) on the prescribing skills of fifth-year medical students trained by both pharmacologists and clinicians at Gazi University Medical School. Methods: The RPT training lasted for five days. A total of 101 medical students were included in the study. The students were asked to prescribe for standardized patients with uncomplicated essential hypertension. PA was performed on the prescriptions on the first (PA1) and last (PA2) days of the clerkship to determine the influence of the clerkship on the prescribing habits. The students were also asked to comment on PA with a short questionnaire at the end of the clerkship. The difference between PA scores was analyzed using the Mann-Whitney-Rank-Sum-test. Results: Scores for PA1 and PA2 and the feedback of the medical students were compared. A significant improvement in PA scores was observed by the end of the clerkship. The commonest drugs in the prescriptions in both PA1 and PA2 were angiotensin-converting enzyme (ACE) inhibitors. The feedback from the medical students revealed that PA improved their prescription skills and that the trainers helped them to reach the targets, helped them to gain self-confidence and they agreed that PA should be applied in clinical pharmacology courses. Conclusions: RPT training reinforced via PA guided by clinicians and pharmacologists is helpful in improving the prescribing skills of medical students. ACE inhibitors were the commonest group of drugs chosen by the medical students both before and after the clerkship. Prescription audit together with the clerkship caused a significant improvement in all parts of the prescription determined by prescription audit. The cooperation of pharmacologists and clinicians helped the clerkship to reach the targets.Correspondence to:
Z. Guney, MD, PhD
Gazi University, Faculty of Medicine
Department of Pharmacology
Besevler, 06500, Ankara, Turkey
Email: zguney@gazi.edu.tr
Original Research
Population pharmacokinetics of albendazole in patients with neurocysticercosis
N. Castro, C. Márquez-Caraveo, R.C. Brundage, D. González-Esquivel, A.M. Suárez, F. Góngora , A. Jara, J. Urizar, J.M. Lanao and H. Jung
Abstract
N. Castro1,2, C. Márquez-Caraveo1, R.C. Brundage3, D. González-Esquivel1, A.M. Suárez4, F. Góngora 1, A. Jara1, J. Urizar5, J.M. Lanao4 and H. Jung1,2
1Instituto Nacional de Neurologia y Neurocirugía, 2Universidad Nacional Autónoma de México, México City, Mexico, 3Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis MN, USA, 4Facultad de Farmacia, Universidad de Salamanca, Spain, and 5Universidad de San Luis Potosi, Mexico
Objectives: To determine a population pharmacokinetic model of the antihelmintic drug, albendazole, and identify the factors influencing the pharmacokinetic parameters in patients with neurocysticercosis. Methods: A prospective study was performed in 90 patients receiving 30 mg/kg/day of albendazole for 8 days. Blood samples were collected at steady state. Plasma concentrations of albendazole sulfoxide, the main active metabolite of albendazole, were determined by HPLC. The population pharmacokinetics analysis was performed using non-linear mixed-effect modeling (NONMEM). A one-compartment model with first order absorption and elimination was used. Results: Body weight was included empirically on CL/F and V/F using an allometric relationship. Although none of the investigated covariates had a significant influence on the pharmacokinetic parameters of albendazole, the final model identified two subpopulations on the bioavailability parameter. One subpopulation comprising of 27% of the total population had a bioavailability of 28%, with the remaining subpopulation defined to have complete bioavailability. The CL/F and V/F for a standard 70 kg individual was determined to be 51.6 l/h and 4560 l, respectively. Interindividual variability in CL/F was 32%; the residual unexplained variability was 32%. Conclusions: The considerable variability reported in albendazole pharmacokinetics and plasma concentrations is likely due to issues related to bioavailability. With one-fourth of the population absorbing as little as 30% of the drug relative to others, low drug exposures might be responsible for treatment failures. Therapeutic drug monitoring may be warranted to optimize the eradication of the infecting parasite.Correspondence to:
H. Jung, PhD
Instituto Nacional de Neurología y Neurocirugía,
Insurgentes Sur 3877
14269, Mexico City, Mexico
Email: helgijung@yahoo.com.mx
Original Research
The effects of 1 month antihypertensive treatment with perindopril, bisoprolol or both on the ex vivo ability of monocytes to secrete inflammatory cytokines
A. Madej, L. Buldak, M. Basiak, W. Szkrobka, A. Dulawa and B. Okopien
Abstract
A. Madej1, L. Buldak1, M. Basiak1, W. Szkrobka1, A. Dulawa2 and B. Okopien1
1Department of Internal Medicine and Clinical Pharmacology, 2Chair and Department of Anaesthesiology and Intensive Care, Medical University of Silesia, Poland
Introduction: Monocytes are key elements in pathogenesis of atherosclerosis and inflammation. The data regarding associations between antihypertensive treatment and monocytes’ function are still lacking. The aim of this study was to evaluate the influence of antihypertensive drugs (bisoprolol, perindopril or both) in patients suffering from mild to moderate hypertension. Patients and methods: The study population consisted of 67 patients divided into 3 groups (2 consisted of patients with Grade I essential hypertension and one consisted of patients with Grade II essential hypertension). At baseline and 1 month after treatment we performed 24-h ambulatory noninvasive blood pressure monitoring and measured IL-1beta, IL-6, IL-10, MCP-1 and TNF-alpha in a medium derived from LPS-stimulated monocytes’ culture. Results: Both monotherapies with bisoprolol or perindopril were equally effective in lowering blood pressure (reduction in mean 24-h systolic blood pressure 12.07 vs. 15.91 mmHg, p = 0.678). Antihypertensive treatment led to significant decrease in IL-1b, IL-6, MCP-1 and TNF-alpha concentration and significant rise in IL-10 level compared to the baseline levels and the decrease was associated with reduction in blood pressure. Conclusions: Bisoprolol and perindopril effectively reduced elevated blood pressure. As a result, an alteration in cytokine net was observed at the end of the study. These results support the concept of possible anti-inflammatory effects of antihypertensive drugs (e.g., perindopril and bisoprolol).Correspondence to:
Department of Internal Medicine and Clinical Pharmacology
Medical University of Silesia
Medyków 14
43-752 Katowice, Poland
Email: boolean@poczta.onet.pl
Case Reports
Different time courses of nephrogenic systemic fibrosis: Is there a role for pharmacokinetic aspects in explaining a new clinical entity?
S. Schmiedl, U. Wesselmann, P. Lehmann, P. Haage and S.O. Grebe
Abstract
S. Schmiedl1, U. Wesselmann2, P. Lehmann2, P. Haage3 and S.O. Grebe4
1Philipp Klee-Institute of Clinical Pharmacology, 2Clinic of Dermatology, 3Department of Diagnostic and Interventional Radiology, and 4Clinic of Internal Medicine, Section of Nephrology, HELIOS Klinikum Wuppertal, University Witten/Herdecke, Wuppertal, Germany
Objective: To report 3 cases of nephrogenic systemic fibrosis (NSF) focussing on the time course of clinical symptoms after exposure to gadolinium based contrast agents (GBCA) and to discuss pharmacokinetic aspects of commercially available GBCA. Patients’ details: All 3 patients (2 men, 1 woman, aged 51 – 54 years) suffered from end-stage renal disease (ESRD) and were on long-term dialysis. Linear GBCA compounds were given to all patients and NSF symptoms started 6 months, 1 and 4 years after the last GBCA exposure. In 2 patients, GBCA was administered after the occurrence of (unrecognized) NSF symptoms leading to worsening of clinical courses. 1 of the patients received multiple therapies (e.g. UV-A1 treatment, physical therapy) without significant improvement, 2 patients died from cardiac complications shortly after the diagnosis of NSF. Conclusion: NSF may develop after a longer period of time than generally reported and GBCA administration may aggravate or accelerate chronic, subclinical NSF symptoms.Correspondence to:
Dr. S. Schmiedl
Philipp Klee-Institute of Clinical Pharmacology
University Witten/ Herdecke
HELIOS Clinic Wuppertal
Heusnerstraße 40
42283 Wuppertal, Germany
Email: sven.schmiedl@helios-kliniken.de
Case Reports
Unexpected serum level of vancomycin after oral administration in a patient with severe colitis and renal insufficiency
S. Yamazaki, H. Nakamura, S. Yamagata, G. Miura, N. Hattori, K. Shinozaki, T. Sadahiro, A.Toyoda, H. Nakasa, N. Ariyoshi, S. Oda, K. Harigaya and M. Kitada
Abstract
S. Yamazaki1, H. Nakamura1, S. Yamagata1, G. Miura1, N. Hattori2, K. Shinozaki2, T. Sadahiro2, A.Toyoda3, H. Nakasa1, N. Ariyoshi1, S. Oda2, K. Harigaya3 and M. Kitada1
1Division of Pharmacy, Chiba University Hospital, 2Department of Emergency and Critical Care Medicine, University Hospital, Chiba University School of Medicine, Chiba, 3Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
Objective: To report a case in which the serum concentration of vancomycin (VCM) reached the supratherapeutic range following oral administration in a patient with severe pseudomembranous colitis and renal insufficiency. Case summary: A 65-year-old, 70 kg weighing man with severe acute pancreatitis and acute renal failure was subjected to continuous hemodiafiltration (CHDF). CHDF could only be performed intermittently because of the unstable circulation dynamic of this patient. After admission, intravenous VCM therapy was initiated. Thereafter, oral VCM administration was begun (0.5 g every 6 h). Despite the discontinuation of intravenous VCM after the first 2 days of oral VCM, the serum VCM concentration increased gradually to 49.8 mg/l over a period of 2 weeks from the initiation of oral administration (34.4 mg/l). Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to over 33%. Autopsy findings indicated broadly distributed necrosis on the lamina propria of the mucosa throughout all parts of the intestine below the duodenum. Discussion: This case indicates necessity of the careful monitoring after oral high-dose VCM administration in a patient with a broadly distributed necrosis and renal insufficiency. Conclusions: TDM should be considered according to renal function, the severity of enteritis and the total dosage of oral VCM administration.Correspondence to:
S. Yamazaki, MSc
Division of Pharmacy
Chiba University Hospital
1-8-1 Inohana, Chiba 260-8677, Japan
Email: s-yamazaki@ho.chiba-u.ac.jp
