Volume 43, No. 9/2005(September)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacodynamics
Effect of rofecoxib on the glomerular filtration rate, proteinuria and the renin-angiotensin-aldosterone system in elderly subjects with chronic renal impairment
Abstract
M. Horackova, O. Sch
1Department of Medicine, 2nd Medical Faculty of Charles University, 2Department of Nephrology, and 3Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Considering the increasing popularity and prescribing of specific COX-2 inhibitors, a new class of NSAIDs lacking gastrointestinal side effects, the evaluation of their effects on renal function has become very important. Objective: The aim of the study was to evaluate the effect of rofecoxib on GFR, proteinuria and the renin-angiotensin-aldosterone system (RAAS) in elderly patients with chronic renal impairment under controlled conditions of water and salt intake. Subjects: There were ten patients (average age 67 years, range 53 ? 80 years) with analgesic or vascular nephropathy (average GFR 54 ml/min/1.73 m2, range 30 ? 79 ml/min/ 1.73 m2) given 25 mg rofecoxib daily for seven days under balanced conditions of water and sodium metabolism (salt intake 6 ? 8 g/24 hours). Methods: The effect of rofecoxib on GFR measured using inulin clearance (Cin), creatinine clearance (CCr) serum cystatin C concentration (Scystatin), tubular creatinine secretion (using the ratio CCr/Cin), 24-hour urinary excretion of albumin (UalbV) and prostaglandins (UPGE2V and UPGF2aV), basal and stimulated plasma renin activity (PRA) and serum aldosterone concentration (Saldosterone) was evaluated before and on Day 7 during rofecoxib treatment. Results: Rofecoxib did not significantly change Cin, CCr, Scystatin, CCr/Cin and UalbV. However, UPGE2V and UPGF2aV were decreased during rofecoxib administration (p = 0.059 and p = 0.024, respectively). Rofecoxib attenuated the stimulated rise of PRA and Saldosterone (p = 0.019 and p = 0.008, respectively). Conclusions: Short-term rofecoxib administration was not associated with significant change in GFR in elderly patients with moderate chronic renal impairment under conditions of balanced salt and water metabolism despite significant attenuation of RAAS activity. Since the CCr/Cin ratio did not change in our study, we assume rofecoxib to have no influence on creatinine tubular secretion.Correspondence to:
Dr. M. Horackova
Department of Medicine
2nd Medical Faculty of Charles University
University Hospital Motol
V Uvalu 84
150 06 Prague 5, Czech Republic
Email: horackov@czn.cz
Immunopharmacology
Safety monitoring of a polyvalent immunoglobulin preparation: documentation of 15,548 administrations
Abstract
W.G. Struff, M. Klasser, V. Eckert and R.L.J. Dietrich
1Blood Transfusion Service Northrhine-Westfalia, German Red Cross, M
Between 1997 and 2002, a postmarketing surveillance study was conducted throughout Germany to evaluate IntraglobinCorrespondence to:
Dr. W.G. Struff
German Red Cross Blood Transfusion Service
Institute M
Email: w.struff@bsdwest.de
Education
Assessing prescription writing skills of pre-clerkship medical students in a problem-based learning curriculum
Abstract
K.A.J. Al Khaja, S.S. Handu, H. James, V.S. Mathur and R.P. Sequeira
Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
Objective: To audit the acquisition of prescribing skills of pre-clerkship medical students in a problem-based learning (PBL) curriculum that incorporates a prescribing program. Material and methods: Student performance in pharmacotherapy stations included in six out of eight end-of-unit-objective structured practical examinations (OSPE) was evaluated using a rating checklist. Results: Prescription writing skills of 539 students (66.2% female and 33.8% male) were appraised. With the exception of refill element, the other physician-related components including prescriber?s identity, date of prescription order, patient?s identity, the symbol Rx ?Take Thou?, and prescriber?s signature were written by 96.1% of the students (95% confidence interval (CI) 94.1 ? 97.5). However, the drug-related components such as the appropriateness of drug(s) selected, strength, dosage form, quantity to be dispensed and directions for use were written satisfactorily by 50.2% of the students (95% CI 46.0 ? 54.4). With respect to prescribing skills, the mean total score of Year 4 students did not significantly differ from that of Year 2 (69.4 (CI 65.7 ? 73.1) vs. 66.3 (CI 62.7 to 69.9); p = 0.237). However, the mean scores of individual drug-related components such as appropriateness of drug(s) selected, dosage form, and direction for use were significantly higher in Year 4 than that of Year 2 students (p < 0.05). Of 381 rationally prescribed drugs, 81.1% were written with generic names. Conclusion: This study revealed that the students acquire prescribing skills to a limited extent during the pre-clerkship phase in a PBL program. Prescribing errors and deficits were found to be mainly associated with drug-related components. Further training and assessment of prescribing skills during the clerkship and internship period are needed to achieve mastery of this skill as a terminal competency of graduating physicians.Correspondence to:
Prof. R.P. Sequeira
Chairman, Department of Pharmacology and Therapeutics
Arabian Gulf University
P.O. Box 22979
Manama, Kingdom of Bahrain
Email: sequeira@agu.edu.bh
Adverse Drug Reactions
Unsuspected rhabdomyolysis associated with phenytoin
Abstract
F.J. Santos-Calle, J. Borr
1Intensive Care Medicine Service, 2Pharmacy Service, and 3Neurology Section, General University Hospital Elche, Elche, Spain
Case summary: A case of rhabdomyolysis, in which the etiology could be associated with phenytoin administration is presented and guidelines are described which may assist the early recognition, treatment and prevention of renal failure when such patients are treated in intensive care units. A 46-year-old white man experienced a generalized tonic-clonic seizure at home lasting approximately two minutes. The patient presented with similar crises when seen by the emergency services and had a neurological status of seven points on the Glasgow scale. He was intubated orotracheally and mechanically ventilated. Administration of a 1,250 mg loading dose of phenytoin in 250 ml 0.9% sodium chloride injection were administered intravenously according to guidelines approved by the hospital. These require administration of the loading dose over 30 ? 60 minutes followed by phenytoin 150 mg/8 h i.v. administered as a drip diluted in 0.9% NaCl 50 ml over 30 ? 60 minutes. Obtained plasma levels were within the therapeutic range but on Day 3 the level of creatine kinase (CK) increased. We initiated treatment to prevent renal failure but the level doubled daily reaching a peak of 54,000 U/l on the fifth day. It was suspected that the increase in CK was due to the treatment with phenytoin which was stopped and replaced by valproic acid 500 mg/8 h orally. The cumulative total dose of phenytoin was 3,050 mg. The subsequent serial determinations of CK showed a decrease beginning on the day phenytoin was stopped and levels falling to 14,229 U/l on the day the patient left the ICU. The patient had no recurrence of the convulsive episodes after the day of admission. In the neurology ward, the patient recovered satisfactorily and the CK value gradually returned to normal. The patient was asymptomatic when released on the ninth day. Discussion: The most likely cause of the rhabdomyolysis was phenytoin treatment because of the close temporal relationship between exposure to the drug and onset of symptoms and the rapid resolution of the symptoms and signs after phenytoin was discontinued. An objective causality assessment concluded that a possible adverse drug reaction had occurred.
Correspondence to:
J. Borr
Email: jborrasb@sefh.es
Adverse Drug Reactions
Interferon-induced pulmonary sarcoidosis
Abstract
R. Farah, R. Farah and N. Makhoul
1Department of Internal Medicine F, Western Galilee Hospital, Nahariya, Israel, 2Leumit Health Service, Western Galilee, Israel, and 3Intensive Care Unit, Western Galilee Hospital, Nahariya, Israel
A further new case of sarcoidosis associated with the use of interferon (IFN) in the classical treatment of chronic hepatitis C (CHC) is reported. During the last two years, more than 20 cases of interferon-induced sarcoidosis have been described in the literature and about half of these cases have involved CHC. Therefore this disorder appears more common than originally thought two years ago, possibly due to the more frequent use of interferon therapy and an improvement in the methods of diagnosis.Correspondence to:
R. Farah, M.D.
Department of Internal Medicine F
Western Galilee Hospital
P.O.Box 21
Nahariya 22100, Israel
Email: raymond_farah@yahoo.com, Raymond.Farah@naharia.health.gov.il
Pharmacokinetics
The single-dose pharmacokinetics of the novel CCK1 receptor antagonist, dexloxiglumide, are not influenced by age and gender
Abstract
P. Roy, J. Wangsa, A. Patel, A. Nolting, St. Persiani, W. Abramowitz and R. Kapil
1Department of Clinical Pharmacology and Drug Dynamics, Forest Research Institute, Harborside Financial Center, New Jersey, USA, 2Department of Bioanalytical and Drug Metabolism, Forest Research Institute, Farmingdale, New York, USA, 3Rotta Research Labor
Objective: The effects of age and gender on the single-dose pharmacokinetics of dexloxiglumide, a selective cholecystokinin (CCK1-subtype) receptor antagonist, were assessed in healthy young and elderly male and female subjects. Methods: In total, 24 males and 24 females (12 young and 12 elderly subjects per gender group) received a single oral dose of 200 mg dexloxiglumide under fasted conditions. Mean (range) ages were 23.8 (18 ? 32) and 71.3 (66 ? 88) years for young and elderly subjects, respectively. Analysis of covariance (ANCOVA) with age group and gender as factors and body weight as a covariate was performed on the dexloxiglumide pharmacokinetic parameters of peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC). The p values obtained from ANCOVA were considered for the assessment of age and gender effects. Results: A small (~ 18%) but statistically significant (p Correspondence to:
R. Kapil, PhD
Forest Research Institute
Harborside Financial Center, Plaza V
Jersey City, NJ 07311, USA
Email: ram.kapil@frx.com
Bioavailability Section
Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point
Abstract
J. Splawinski, J. Kuzniar, R. Kurianowicz and P. Wanczura
1National Institute of Public Health, Warsaw, and
2District Hospital Nr. 2, Rzesz
Objective: To evaluate the bioequivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a phar-macodynamic end point, i.e the platelet aggregation test ex vivo. Subjects, materials and methods: The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 Correspondence to:
Prof. J. Splawinski
Narodowy Instytut Zdrowia Publicznego
ul. Chelmska 30/34
00725 Warszawa, Poland
Email: splawinski@il.waw.pl
Bioavailability Section
Bioequivalence studies with metformin: comparability of reference tablets from different origins
Abstract
V. Vlahov, U. Thyroff-Friesinger, R. Koytchev, N. Bakracheva and E. Gatchev
1Chair of Clinical Pharmacology, Multidisciplinary Hospital for Active Treatment Queen Giovanna, Sofia, Bulgaria, 2HEXAL Pharmaforschung GmbH, Holzkirchen, and 3CCDRD AG, Neuenhagen, Germany
Background: The choice of an appropriate reference product is still a problem within the European Union. When no direct comparisons between originator products in different countries are available, registration authorities are sometimes only prepared to grant registration for a generic product on the basis of a comparison with the originator product in the respective country. The aim of the investigation was therefore to evaluate the bioequivalence of reference products from different origins in two different bioequivalence trials with the same test drug. Methods: Two separate bioequivalence trials were performed involving the oral administration of one test and two reference products containing 500 mg metformin. Both studies had a randomized, open, single-dose, three-period crossover design and were carried out in 24 healthy volunteers. The reference products in the first trial were Glucophage mite (Germany) and Diabex (Australia). In the second trial the reference drugs were Glucophage mite (France) and Glucophage mite (Switzerland). The results of each trial were analyzed regarding the bioequivalence of the respective reference drugs. Findings: The reference drugs in each of both trials were bioequivalent: the 90% confidence intervals for both AUC0 ? tlast and Cmax were entirely within the acceptance range for bioequivalence trials (0.80 ? 1.25 for both parameters). Interpretation: In the case of metformin, the reference products available in the countries examined were very similar. This retrospective analysis involving two studies, therefore, confirmed bioequivalence between these reference products.Correspondence to:
R. Koytchev
CCDRD AG
Fontanestra
Email: rkoytchev@ccdrdag.com
