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Abstract

T.D.J. Smilde, G.C.M. Linssen, D. Gallemann, T. Kuhn, T. Machnig, P.G.M. Mol, H.L. Hillege, L.M. Van Wijk, R.B. Van Dijk and D.J. Van Veldhuisen

¹Department of Cardiology, Thoraxcenter, University Medical Center Groningen, Groningen, ²Department of Cardiology, Twenteborg Hospital, Almelo, The Netherlands, ³Merck KGaA, Darmstadt, Germany, ⁴Department of Pharmacology, University Medical Center Groni
Background: Chronic heart failure (CHF) is a potential indication for the administration of EMD 87 580, a selective Na⁺/H⁺ exchange inhibitor. CHF is often accompanied by renal dysfunction, which is known to affect the pharmacokinetics of compounds predominately cleared by the kidneys. We examined the influence of renal dysfunction on the pharmacokinetics of EMD 87 580 in patients with CHF. Methods: 21 patients with CHF and normal renal function (Group 1) and 9 patients with CHF and renal dysfunction (Group 2) received EMD 87 580 orally over 8 days. The mean creatinine clearance (CrCl) in Group 1 was 99.7 ml/min. 12 patients in this group were randomized to receive two doses of EMD 87 580 (7 patients 2 Correspondence to:
T.D.J. Smilde, MD Department of Cardiology Thoraxcenter University Hospital Groningen Hanzeplein 1 P.O.Box 30001 9700 RB Groningen, The Netherlands
Email: t.d.j.smilde@thorax.azg.nl

Abstract

A. Meinitzer, M. Zink, W. M

¹Clinical Institute of Medical and Chemical Laboratory Diagnostics, ²Department of Anesthesiology and Intensive Care Medicine, Medical University, Graz, Austria
Objective: There is only limited knowledge on the pharmacokinetics of midazolam and its active metabolites in potential organ donors. Before establishing the diagnosis of brain death, drugs interfering with the neurological assessment have to be washed out. National guidelines advise a waiting time of 12 hours. The aim of our study was to evaluate whether it is sufficient to rely on a calculated waiting time. Methods: As examples of typical pharmacokinetics of midazolam and its metabolites, we followed the concentration over time in four potential organ donors with immunoassays and high-performance liquid chromatography (HPLC). Results and conclusions: In each of the 4 patients studied, the elimination of midazolam and/or midazolam metabolites was delayed. As long as brain death diagnosis requires that drugs interfering with the clinical assessment must be at levels below the therapeutic range, monitoring of midazolam and metabolites appears mandatory.
Correspondence to:
Univ.-Prof. Dr. Gabriele Halwachs-Baumann Clinical Institute of Medical and Chemical Laboratory Diagnostics Auenbruggerplatz 29 8036 Graz, Austria
Email: gabriele.halwachs@meduni-graz.at

Abstract

W. Dieterle, S. Corynen, S. Vaidyanathan and J. Mann

¹Drug Disposition Consultants, L
Objective: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities. Methods: Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18 ? 45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data. Results: Mean AUC and t_1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean C_max was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, C_max and t_1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib. Conclusions: Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.Correspondence to:
Dr. J. Mann Speedel Pharma AG Department of Clinical Research and Development Hirschg
Email: jessica.mann@speedel.com

Abstract

A.H. Zwinderman and T.J. Cleophas

European Interuniversity College of Pharmaceutical Medicine, Lyon, France
Background: Clinical investigators, although they are generally familiar with testing differences between averages, have difficulty testing differences between variabilities. Objective: To give examples of situations where variability is more relevant than averages and to describe simple methods for testing such data. Results: Examples include: (1) testing drugs with small therapeutic indices, (2) testing variability in drug response, (3) assessing pill diameters or pill weights, (4) comparing patient groups for variability in patient characteristics, (5) assessing the variability in duration of clinical treatment, (6) finding the best method for patient assessment. Various fields of research, particularly in clinical pharmacology, make use of test procedures that implicitly, address the variability in the data. Tests specially designed for testing variability in data include the c²-test for one sample, the F-test for 2 samples and Bartlett?s or Levene?s test for 3 or more samples. Additional methods include (1) the comparison of confidence intervals, and (2) testing confidence intervals against prior defined intervals of therapeutic tolerance or equivalence. Many of these tests are available in Excel and other statistical software programs and one such program is described. Conclusions: In the analysis of clinical data the variability in the data is often more important than averages. Eight simple methods for assessment variability are described to illustrate the value and importance of putting more emphasis on and this parameter.Correspondence to:
T.J. Cleophas, MD, PhD, Assoc. Professor European College of Pharmaceutical Medicine, Lyon, France c/o Albert Schweitzer Hospital Box 444 3300 AK Dordrecht, Netherlands
Email: ajm.cleophas@wxs.nl

Abstract

F.

¹Ankara University School of Medicine, Clinical Microbiology and Infectious Diseases Department, Ibni Sina Hospital, Ankara, ²Ankara University School of Medicine, Nephrology Department, Ibni Sina Hospital, Ankara, Turkey
A case is presented involving a female patient who experienced rhabdomyolysis following high-dose therapy with a statin. Acute renal failure was a complicating factor necessitating the use of hemodialysis. The patient recovered fully within about 6 weeks.Correspondence to:
F.
Email: cokcaf@infeksiyon.org

Abstract

X. Zhu and W.G. Shin

¹Clinical Pharmacy, College of Pharmacy, Seoul National University, South Korea, ²College of Pharmacy, Yanbian University, China
A bioequivalence study of diclofenac injection (test formulation (diclofenac potassium): HANA, reference formulation (diclofenac sodium): Shinpoong) was conducted in 18 healthy male Korean volunteers who received each medicine at a dose of 75 mg in a 2 Correspondence to:
W.G. Shin, Pharm. D., Ph.D. College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University San 56-1, Shinlim-Dong Kwanak-Gu, Seoul 151-742, Republic of Korea
Email: wgshin@snu.ac.kr

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Volume 43, No. 11/2005(November)