Volume 47, No. 8/2009(August)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
A short note on the discipline of Clinical Pharmacology
M. Müller and S.R. Maxwell
Abstract
M. Müller and S.R. Maxwell
Original Research
Exenatide versus insulin glargine: a cost-effectiveness evaluation in patients with Type 2 diabetes in Switzerland
M. Brändle, K.M. Erny-Albrecht, G. Goodall, G.A. Spinas, P. Streit and W.J. Valentine
Abstract
M. Brändle1, K.M. Erny-Albrecht2, G. Goodall2, G.A. Spinas3, P. Streit4 and W.J. Valentine2
1Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, Switzerland, 2IMS Health Basel, 3Department of Endocrinology and Diabetes, University Hospital Zürich, and 4Eli Lilly S.A. Switzerland
Objectives: To investigate the long-term clinical and economic outcomes associated with exenatide versus insulin glargine as “add-on” treatments to oral therapy in individuals with Type 2 diabetes inadequately controlled with combination oral agents in the Swiss setting. Methods: A computer simulation model of diabetes was used to project complications, life expectancy, quality-adjusted life expectancy and direct medical costs over a 35-year time horizon. Cohort characteristics and treatment effect data were derived from a 26-week randomized clinical trial comparing exenatide and insulin glargine. Modeled treatment effects included reductions in glycosylated hemoglobin (HbA1c) by –0.99% and –1.07% and in body mass index (BMI) by –0.80 and +0.55 kg/m2 with exenatide and insulin glargine respectively. Changes in systolic blood pressure and serum lipid levels were also captured. Simulations incorporated published quality of life utilities and Swiss costs from 2006. Extensive sensitivity analyses were conducted to assess the robustness of projected outcomes. Future clinical and economic outcomes were discounted at 2.5% per annum. Results: In the base-case analysis exenatide was associated with comparable life expectancy (11,549 years versus 11,468 years) and an improvement in quality-adjusted life expectancy of 0.43 quality-adjusted life years (QALYs) versus insulin glargine over a 35-year time horizon. Exenatide was associated with a reduced cumulative incidence of most diabetes-related complications including an absolute reduction in myocardial infarction by 0.28%. Assuming an annual treatment cost of CHF 2,797.74 for exenatide, direct costs increased by CHF 8,378 per patient over the 35-year time horizon compared to insulin glargine. The resultant incremental cost-effectiveness ratio was CHF 19,450 per QALY gained for exenatide versus insulin glargine. Conclusions: Exenatide was associated with comparable life expectancy and an improvement in quality-adjusted life expectancy versus insulin glargine over a 35-year time horizon. Based on current standards exenatide would be a cost-effective treatment alternative to insulin glargine in Switzerland for Type 2 diabetes patients inadequately controlled on oral therapy.Correspondence to:
Dr. M. Brändle, MD, MS
Division of Endocrinology and Diabetes
Department of Internal Medicine
Kantonsspital St Gallen, Switzerland
Email: Michael.Braendle@kssg.ch
Original Research
Open labeled, uncontrolled pharmacokinetic study of a single intramuscular hCG dose in healthy male volunteers
A.W. Davidoff, M.D. Hill, S.C. Cramer, Y. Yang and A. Moore
Abstract
A.W. Davidoff1, M.D. Hill2, S.C. Cramer3, Y. Yang1 and A. Moore1
1Stem Cell Therapeutics Corp., 2University of Calgary, Calgary, Alberta, Canada and 3Departments of Neurology and Anatomy & Neurobiology, University of California, Irvine, CA, USA
The current study was designed to compare blood and cerebrospinal fluid (CSF) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (hCG): Pregnyl®, derived from human urine, and Ovitrelle® a recombinant form. Two separate groups, each with six older male human subjects, were dosed with either form of the drug at 10,000 IU intramuscularly (IM), and followed over a 36-hour period. No significant difference in the serum level of hCG was observed for either preparation of hCG (Peak serum conc.: 316 ± 53 vs. 270 ± 60 at 12 hours, 311 ± 38 vs. 321 ± 60 IU/l at 24 hours; AUC: 10,053 ± 1,268 vs. 8,793 ± 1,768, Pregnyl and Ovitrelle, mean ± SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (CNS) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/l; range 1.9 – 2.1 and 1 – 1.4 IU/l for Pregnyl and Ovitrelle, resp.). This preliminary study in normal human volunteers suggests that the two forms of hCG tested, Ovitrelle® and Pregnyl®, when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, we conclude that these two drugs demonstrate no statistical significant difference with respect to the CSF.Correspondence to:
Dr. A.W. Davidoff, PhD
Stem Cell Therapeutics Corp., Suite 1000
1520- 4th St. SW
Calgary, T2R 1H5, Canada
Email: adavidoff@stemcellthera.com
Original Research
Renoprotect and blood pressure lowering effect of low-dose hydrochlorothiazide added to intensive renin-angiotensin inhibition in hypertensive patients with chronic kidney disease
M. Abe, K. Okada, T. Maruyama and K. Matsumoto
Abstract
M. Abe, K. Okada, T. Maruyama and K. Matsumoto
Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
Objectives: Combination therapy with angiotensin II Type I receptor blocker 50 mg of losartan and a fixed combination of losartan (50 mg)/hydrochlorothiazide (12.5 mg) was administered to hypertensive patients with Stage 3 – 4 chronic kidney disease to investigate its renoprotective effect. Methods: Subjects already being administered the angiotensin I-converting enzyme inhibitor enalapril and losartan 100 mg daily were enrolled in this open-labeled trial (n = 40). Administration of 100 mg losartan twice daily was replaced with losartan (50 mg)/hydrochlorothiazide (12.5 mg) once daily after the morning meal and losartan at 50 mg once daily after the evening meal for the 24-week study period. Results: The mixture of losartan/hydrochlorothiazide significantly reduced systolic and diastolic blood pressures by 14.7 and 7.4 mmHg, respectively, compared with the baseline values. No significant changes were observed in the serum creatinine levels and estimated glomerular filtration rate. The urinary protein/creatinine ratio was, however, significantly decreased. Similarly, the regression line of 1/serum creatinine level was significantly increased after administration of losartan/hydrochlorothiazide. None of the patients exhibited a significant increase in the occurrence of adverse effects. Conclusions: Our results demonstrated that a low dose of hydrochlorothiazide had a renoprotective effect due to its blood pressure-lowering effect. We accordingly propose that a low dose of hydrochlorothiazide should be administered to those patients in whom the blood pressure is not well controlled by intensive renin-angiotensin system inhibition therapy using the maximum recommended doses of angiotensin II Type I receptor blockers and angiotensin I-converting enzyme inhibitors.Correspondence to:
M. Abe, MD
Division of Nephrology, Hypertension and Endocrinology
Department of Medicine
Nihon University School of Medicine
30-1, Oyaguchi-Kamimachi, Itabashi-ku
Tokyo 173-8610, Japan
Email: mabe@med.nihon-u.ac.jp
Original Research
Influence of L-arginine on the nitric oxide concentration and level of oxidative stress during ischemia-reperfusion injury in a rat model
H. Krauss, A. Jablecka, P. Sosnowski and P. Bogdanski
Abstract
H. Krauss1, A. Jablecka2, P. Sosnowski1 and P. Bogdanski3
1Department of Physiology, Collegium Anatomicum, 2Departament of Clinical Pharmacology and 3Department of Internal Medicine, Metabolic Disorders and Hypertension, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
Objective: This study aimed at evaluating whether supplementation of L-arginine in the course of ischemia and reperfusion syndrome after acute, experimental ischemia of the hind legs of the rat, could influence nitric oxide (NO) concentration and selected biochemical parameters concentration related to the oxidative stress. Material and methods: The study included 64 male Wistar rats. The animals were divided into four groups: Group I = control, Group II = placebo, Group III = L-arginine (500 mg/kg body mass/day for 5 days, p.o.), Group IV = L-arginine and nonspecific nitric oxide synthase (NOS) inhibitor – N(G)-Nitro-L-arginine-methyl ester (L-NAME) (75 µmol/ rat/day for 5 days, p.o.). Each group was further divided into subgroups: 1 = animals not subjected to ischemia and reperfusion, 2 = animals underwent 4-hour ischemia and subsequent reperfusion. Animals from Subgroup 2 were anesthetized and submitted to acute tourniquet ischemia of the hind limb. Blood samples were collected from all anesthetized rats by puncturing the right ventricle to assess total antioxidant status, lipids’ peroxide concentration and nitric oxide concentration before ischemia and at 4th hour of ischemia and at 30th, 60th or 120th minute of reperfusion. Results: We found that administration of L-arginine to rats resulted in significant increase of NO, level of total antioxidant status (TAS), and decrease of lipid’ peroxide concentration when compared to the control and placebo groups. All these laboratory changes were progressing along with lengthening of reperfusion time. Simultaneous application of L-NAME led to reversal of phenomena caused by L-arginine. Conclusions: The present results suggest that L-arginine may protect tissues and organs against ischemia-reperfusion injury. The potential therapeutic role of L-arginine administration in prevention and treatment of ischemia-reperfusion syndrome consequences needs further investigation in humans.Correspondence to:
P. Bogdanski, PhD
Department of Internal Medicine,
Metabolic Disorders and Hypertension
University of Medical Sciences
Poznan, Poland
Email: pawelbogdanski@wp.pl
Bioavailability Section
Oseltamivir oral suspension and capsules are bioequivalent for the active metabolite in healthy adult volunteers
S. Lennon, J. Barrett, C. Kirkpatrick and C. Rayner
Abstract
S. Lennon1, J. Barrett1, C. Kirkpatrick1 and C. Rayner2
1Roche Products Ltd., Welwyn Garden City, Hertfordshire, United Kingdom, and 2F. Hoffmann-La Roche Ltd., Basel, Switzerland
Aims: The objective of this study was to assess the relative bioavailability of oseltamivir carboxylate (active metabolite) following oral administration of the market suspension, the clinical trial suspension and the market capsule formulations of oseltamivir (prodrug) in healthy subjects. Methods: In this single-center, open-label, three-period crossover study, 24 healthy adult volunteers were randomized to receive one dose (150 mg oseltamivir) of each of the three formulations (market suspension, clinical trial suspension, market capsule formulation), with a 7-day washout period between each administration. Blood samples, collected for up to 48 h post-dosing, were analyzed for plasma oseltamivir and oseltamivir carboxylate. Adverse events were monitored. Results: Pharmacokinetic parameters for oseltamivir and oseltamivir carboxylate were similar for the three formulations. Bioequivalence for oseltamivir carboxylate was demonstrated between the market capsule and the two suspensions: 90% confidence intervals for the log-transformed Cmax, AUClast and AUCinf ratios fell within the 80 – 125% criteria. Similarly, the two suspensions were also demonstrated as bioequivalent for oseltamivir carboxylate. Oseltamivir was well tolerated. The majority of adverse events observed were mild in intensity, with the most common being nausea and headache. Conclusions: This study demonstrates that the market suspension, the clinical trial suspension and the market capsule formulations of oseltamivir are bioequivalent for the active metabolite, oseltamivir carboxylate. Based on this finding, the market suspension may be used to achieve comparable exposure in patients unable to take capsules.Correspondence to:
Dr. S. Lennon
Clinical Pharmacologist
Pharma Development Exploratory Pharmacology
Roche Products Ltd.
6 Falcon Way, Welwyn Garden City
Hertfordshire, AL7 1TW, United Kingdom
Email: sian.lennon@roche.com
