Volume 42, No. 8/2004(August)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Drug utilisation
Safety and usage pattern of low-dose diclofenac when used as an over-the-counter medication: results of an observational cohort study in a community-based pharmacy setting
Abstract
J. Hasford, N. Moore and K. Hoye
1Department of Medical Informatics, Biometry and Epidemiology – IBE, University of Munich, Germany, 2Department of Pharmacology,
Université Victor Segalen, Bordeaux Cedex, France, and
3Hesetorget legesenter, Mart’n Seneteret, Elverum, Norway
Objective: The widespread and unsupervised nature of nonprescription drug usage makes it important that evidence of effectiveness and safety should be gathered in a real-world, over-the-counter (OTC) setting. This study was designed to evaluate the “real life” behavior of consumers with nonprescription access to low-dose diclofenac-K, with special focus on tolerability and the pattern of product usage. Participants and methods: Participants were recruited from consumers presenting at 62 community-based pharmacies in Norway after they had purchased low-dose diclofenac-K. Baseline data were collected from the participants in the pharmacy and information on diclofenac usage, the condition for which it was used, comprehensibility of the package insert, efficacy and safety were collected 5 days after commencing the medication. Follow-up safety data were collected 19 days after commencing study medication. Results: 446 individuals participated in the study with 383 taking medication and completing questionnaires at each time point. The directions for use were followed well with regard to recommended indications, contraindications and maximum dosages, but less well with respect to the recommended duration of use and concurrent medications. Most participants reported complete relief, a lot of relief, fair relief or some relief from the symptoms from which they were suffering and 70% were willing to purchase diclofenac-K again. Only 6.5% of participants reported adverse events and 6 participants (1.6%) were considered to have experienced a drug-related adverse event, none of which was considered to be severe. Conclusions: Overall, this study showed that low-dose diclofenac-K is efficacious, safe and commonly used in accordance with the directions for use when used as an OTC medication. It also demonstrated that the use of an OTC analgesic medication can be successfully monitored in a pharmacy-based cohort study. Correspondence to:
Prof. Dr. J. Hasford
Department of Medical Informatics
Biometry and Epidemiology – IBE
University of Munich, Marchioninistraße 15
D-81377 Munich, Germany
Email: has@ibe.med. uni-muenchen.de
Drug utilisation
The use of atorvastatin treatment in usual care environments: pooled analysis of six prospective, observational studies in 90,535 patients
Abstract
S. Vetter1, G. Ruf1, E. Regourd1 and W. März2
1Pfizer Ltd., Karlsruhe, Germany, and
2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University, Graz, Austria
Objective: We investigated the pattern of use as well as the efficacy and safety of atorvastatin in unselected inpatients and outpatients in routine clinical practice in Germany. Design: Six prospective, observational studies with a similar design were pooled. The studies lasted for up to 12 weeks and data from 90,535 patients (7,287 inpatients, 83,248 outpatients) were collected. The studies were performed in Germany in 2000 and 2001. Hospital or office-based physicians selected hyperlipemic patients with or without coronary heart disease (CHD) for once daily treatment with atorvastatin. Information on demographics, atorvastatin dosage, concomitant medication, concomitant diseases, cardiovascular risk factors, lipid profile as well as adverse events (AEs) and serious adverse events (SAEs) were obtained at 2 – 3 visits and descriptively analyzed. Main outcome measures: Absolute and relative changes in lipid parameters, percentage of patients with low-density lipoprotein cholesterol (LDL-C) values within target ranges according to the National Cholesterol Education Program (NCEP) criteria, and frequencies of AEs. Results: On average, patients were treated for 22.4 days (inpatients) and 106.0 days (outpatients), respectively. The overall mean atorvastatin dose of 14.4 mg/day was well tolerated by a heterogeneous patient population with a variety of concomitant diseases and medications. Overall, 0.8% of patients suffered from one or more AEs, 0.6% were considered as treatment-related. The corresponding figures for SAEs and treatment-related SAEs were 0.1% (131 patients) and 0.01% (13 patients), respectively. Subgroup analyses did not reveal a particular safety concern in any subgroup. In total, 99% of patients judged the tolerability of atorvastatin as very good or good. The mean percentages of reduction in LDL-C at the final visit ranged between 24.8% and 28.5%. Overall, 26.3% of patients reached the NCEP LDL-C goal compared to 4.9% at baseline. Inpatients achieved the target range for LDL-C more frequently than outpatients (35.3% vs 25.6%). An underuse of atorvastatin titration in clinical practice in Germany was apparent, particularly in outpatients. Conclusions: The use of atorvastatin in usual care environments is effective and safe. There is a gap between treatment guidelines and clinical practice in Germany as reflected by the number of patients outside the target range for LDL-C. A major opportunity exists to increase the number of patients who achieve LDL-C target ranges by appropriate dose titration and/or giving patients a higher initial dose. Available guidelines need to be implemented more stringently. Correspondence to:
S. Vetter, MD
Pfizer GmbH
Clinical Research, P.O. Box 4949
D–76032 Karlsruhe, Germany
Email: Silke.Vetter@Pfizer.com
Therapeutic drug monitoring
Monitoring methotrexate therapy in patients with rheumatoid arthritis
Abstract
A. Wiela-Hojenska, K. Orzechowska-Juzwenko, J. Swierkot, P. Wiland, M. Hurkacz and J. Szechinski
1Department of Clinical Pharmacology, 2Department of Rheumatology, Wroclaw Medical University, and 3Department of Internal Medicine and Rheumatology, Railway District Hospital, Wroclaw, Poland
Objective: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. Material and methods: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. Results: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-b-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. Conclusion: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug. Correspondence to:
Dr. A. Wiela-Hojenska
Department of Clinical Pharmacology
Wroclaw Medical University
Bujwida Str. 44
PL-50-345 Wroclaw, Poland
Email: wiela@farmklin.am.wroc.pl
Pharmacodynamics
Comparison of the acute pharmacodynamic responses after single doses of ephedrine or sibutramine in healthy, overweight volunteers
Abstract
A.M. Persky, C. Ng, M.H. Song, M.E. Lancaster, D.E. Balderson, M.A. Paulik and K.L.R. Brouwer
1Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, and 2GlaxoSmithKline, Research Triangle Park, NC, USA
Objective: With an increase in the incidence of obesity, tremendous effort has been devoted to the development of weight loss agents and the prospective surrogate markers of both a product’s efficacy and safety. The objective of the present study was to compare the pharmacodynamic responses of ephedrine and sibutramine using surrogate markers of weight loss potential and potential adverse events. Design and subjects: The study was designed as a 5-way, randomized, double-blinded, placebo-controlled trial with 3 single doses of ephedrine sulfate (0.25, 0.5 and 1 mg ´ kg–1) followed by an open-labeled sibutramine (10 mg) treatment. Healthy, mildly overweight (BMI = 25) subjects were administered the respective treatment and pharmacokinetic and pharmacodynamic measurements (body surface temperature, resting metabolic rate, blood pressure, heart rate, glucose, glycerol, nonesterified fatty acids, triglycerides) were obtained for 8 hours post dose and for an additional 4 measurements during the sibutramine treatment period. Results: Sibutramine treatment significantly increased resting metabolic rate compared to the placebo condition. Ephedrine significantly increased heart rate, systolic blood pressure and glucose but did not significantly affect other measurements. Conclusion: Both sibutramine and ephedrine have been shown to have weight loss potential, however, they elicit different metabolic and biochemical responses after a single dose. The nontherapeutic responses from these types of compounds may serve as a screening tool for the development of agents in the treatment of obesity. Correspondence to:
A.M. Persky, PhD
Division of Drug Delivery and Disposition,
Kerr Hall, CB #7360
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7360, USA
Pharmacokinetics
Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers
Abstract
R. Huupponen, M. Anttila, J. Rouru, H. Kanerva, T. Miettinen and M. Scheinin
1Department of Pharmacology and Clinical Pharmacology, and
2Clinical Research Services Turku, University of Turku, and
3Orion Corporation Orion Pharma, Turku, Finland
Objective: To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks. Methods: Sixteen healthy male subjects, age range of 20 – 29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings. Results: The mean (SD) AUC0-¥ of deramciclane was 1,251 (385) ng ´ h/ml after the first dose. The AUCt calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC0-¥ after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration. Conclusions: Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree. Correspondence to:
R. Huupponen, MD, PhD
Department of Pharmacology
and Clinical Pharmacology
University of Turku,
Itäinen Pitkäkatu 4B
20520 Turku, Finland
Email: risto.huupponen@utu.fi
Pharmacokinetics
Safety and pharmacokinetics of inhaled morphine delivered using the AERx System in patients with moderate-to-severe asthma
Abstract
B. Otulana, J. Okikawa, L. Linn, R. Morishige and J. Thipphawong
Aradigm Corporation, Hayward, CA, USA
Objective: The safety and pharmacokinetics of inhaled morphine in asthmatic subjects were investigated using the AERx System, a novel aerosol system. Methods: Twenty subjects with asthma received inhaled placebo and inhaled morphine sulfate, 2.2 mg, 4.4 mg and 8.8 mg, on separate days in a single-blind crossover study. Six of the subjects received an additional open-label dose of 17.6 mg on a separate day. Plasma morphine concentrations and safety evaluations including pulmonary function testing were performed. Results: Mean tmax values were similar following all dose groups at ~ 1 – 2 minutes. Mean AUC(0à1) values showed dose proportionality for the first 3 dose groups (6.3, 12.3 and 24.3 ng ´ h ´ ml–1), the mean AUC(0à1) for the 17.6 mg dose group was 1.6 × that of the 8.8 mg dose group. No statistically significant differences in forced expiratory volume in 1 sec (FEV1) were found for the 2.2 mg, 4.4 mg, or 8.8 mg dose groups; at 17.6 mg, a statistically significant but not clinically meaningful reduction in mean FEV1 (–8.18%) from baseline occurred at 10 minutes compared to placebo, spontaneously returning to baseline by 60 min. Four subjects experienced significant but reversible decreases in FEV1 of ³ 20% compared to baseline and across all dose levels including after placebo, but with no associated increase in dyspnea, wheezing or other adverse events. Conclusions: Inhaled morphine using the AERx System was absorbed rapidly and demonstrated dose-dependent plasma concentrations. It was well-tolerated and did not cause clinically significant bronchoconstriction in most subjects with moderate-to-severe asthma. Correspondence to:
B. Otulana, MD
Aradigm Corporation
3929 Point Eden Way
Hayward, CA, USA 94545
Email: totulana@aradigm.com
Bioavailability section
Sex-related differences in the pharmacokinetics of isosorbide-5-mononitrate (60 mg) after repeated oral administration of two different prolonged release formulations
Abstract
T.B. Vree, E. Dammers and R. Valducci
1Institute for Anesthesiology, University Medical Centre, Nijmegen Sint Radboud, 2DADA Consultancy, Nijmegen, The Netherlands, and 3Valpharma S.A., Serravalle, Republic of San Marino
Objective: To identify differences in the disposition of isosorbide-5-mononitrate between male and female volunteers. Method: Plasma concentration and area under the concentration-time curve (AUCss) data of isosorbide-5-mononitrate were obtained in a randomized, crossover, multiple-dose bioequivalence study in 24 subjects (12 females and 12 males). Participants received a single oral dose of 60 mg isosorbide-5-mononitrate prolonged-release tablet formulation (formulations I and II) on each of 6 consecutive days. Plasma isosorbide-5-mononitrate concentrations were determined according to validated methods involving liquid chromatography mass spectrometry. Results: A total of 2 × 24 plasma concentration-time curves of the parent drug could be analyzed. The intersubject variation in plasma concentrations ranged from 25 – 50% (coefficient of variation). With both formulations, the mean plasma concentration-time curves for males and females ran parallel. The parameters Cmax, Cmin, AUCss, and AUCss/kg in females were significantly higher than in males (p < 0.0001). This difference was solely attributed to the difference in body weight (p = 0.0024) and body mass index between males and females (p = 0.0113). Seven females showed a t = 0 = 24 h (Cmin) plasma concentration that was twice as high as the other 5 females and all the males; 125 ± 12.2 ng/ml versus 59.3 ± 9.2 ng/ml, respectively, in females (p < 0.0001) and 56.3 ± 6.9 ng/ml in males (p < 0.0001). With both formulations, females in the n = 7 group had a longer t1/2 and MRT than females in the n = 5 group, 5.06 ± 0.76 h, 11.2 ± 0.55 h versus 4.19 ± 0.56, 9.40 ± 0.62 h (p = 0.0057). The male group did not show this phenomenon, their disposition was similar to that of the female group of n = 5. Conclusion: The difference found in the Cmax and AUCss/kg of isosorbide-5-mononitrate between male and female subjects must be due to the difference in dose/kg, following a standard dose of 60 mg. Fixed dose administration is common practice due to the available pharmaceutical formulations, while in the ideal situation the dose should be based on dose/kg or titrated to the required clinical effect.Correspondence to:
Dr. T.B. Vree
DADA Consultancy,
PO Box 38121,
NL-6503 AC Nijmegen,
The Netherlands
Email: T.Vree@anes.umcn.nl
