Volume 46, No. 1/2008(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Adverse Drug Reactions
Risk of hypoglycemia associated with thyroid agents is increased in patients with liver impairment
N. Iihara, Y. Kurosaki, M. Takada and S. Morita
Abstract
N. Iihara, Y. Kurosaki, M. Takada and S. Morita
1Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa, 2Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 3Division of Practical Pharmacy, School of Pharmacy, Kinki University, Osaka, and 4Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan
Objective: To determine the risk of developing hypoglycemia from drugs that affect glucose homeostasis and evaluate the elevation of that risk by liver impairment as judged by a decrease of liver reserve or the severity of abnormal values in liver function tests. Methods: A hospital-based case-control study was carried out. The base population consisted of all patients aged 20 years and older attending a university hospital in Japan from 2002 – 2004 who had received drugs and serum glucose measurements. Cases were defined as having had at least one episode of hypoglycemia as determined by a serum glucose concentration below 70 mg/dl. Up to 5 controls for each case were matched for the year of serum glucose measurement, out- or inpatient status, clinical departments visited, and age difference within 5 years, taken randomly from the base population without hypoglycemia. The odds ratio for developing hypoglycemia was estimated using conditional logistic regression analysis. Results: From a base population of 10,011, 245 cases and 1,194 controls were enrolled. Of the drugs investigated, levothyroxine use was associated with an increased risk of hypoglycemia in patients with liver impairment (adjusted odds ratio; non-use with normal liver (reference), non-use with liver impairment 0.91 (95% CI 0.62, 1.33), use with normal liver 4.50 (0.58, 34.76), use with liver impairment 14.68 (1.57, 137.4), p for trend 0.007). The risk elevation likely depended on the lowering of liver reserve. Conclusion: Clinicians and pharmacists should carefully monitor serum glucose concentrations in levothyroxine users with liver impairment, especially those with lower liver reserve.Correspondence to:
N. Iihara, PhD; Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki-city, Kagawa 769-2193, Japan
Email: iiharan@kph.bunri-u.ac.jp
Therapeutics
Long-term remission in schizophrenia and related psychoses with long-acting risperidone: Results obtained in an open-label study with an observation period of 18 months
P.-M. Llorca, E. Sacchetti, K. Lloyd, W. Kissling and R. Medori
Abstract
P.-M. Llorca, E. Sacchetti, K. Lloyd, W. Kissling and R. Medori
1CMP B, CHU Clermont-Ferrand, Clermont-Ferrand, France, 2University Psychiatric Unit, Brescia University School of Medicine and the Department of Mental Health, Brescia Spedali Civili, Brescia, Italy, 3CHIRAL, School of Medicine, Swansea University, Swansea, UK, 4Inpatient and Outpatient Clinic for Psychiatry and Psychotherapy, Munich, Germany, and 5Janssen-Cilag, Medical Affairs EMEA, Beerse, Belgium
Objective: To monitor long-term symptomatic tolerability and remission in patients with stable but suboptimally treated psychoses after switching to risperidone long-acting injectable (RLAI). Method: This subgroup analysis of the Switch to Risperidone Microspheres (StoRMi) open-label trial followed up patients with psychoses who were converted to RLAI for a period of 18 months or until RLAI became commercially available in their country of residence. It included patients from seven European countries. Dosage adjustments were performed as clinically necessary. The efficacy endpoint was achieving and maintaining remission, defined as absent to mild core schizophrenia symptoms for >= 6 months. A schizophrenia assessment was also completed and patients were monitored for the development of adverse events (AEs). Discontinuation rates were calculated based on Kaplan-Meier estimates where patients switching to commercial RLAI were used as censored observations. Results: A total of 529 patients were followed for up to 18 months. At 18 months, the discontinuation rate was 55.7% based on Kaplan-Meier estimates. The median time to discontinuation was 15.7 months (95% CI (14.0; 17.5)). RLAI was generally well tolerated with most AEs mild-to-moderate in severity. 13% of patients discontinued treatment because of an AE. Body weight of patients increased by a mean ± SD of 1.0 ± 6.1 kg from treatment initiation to endpoint (p = 0.0001). Glucose-related AEs occurred in four patients (0.8%). Among those patients not meeting severity remission criteria at baseline, 44.8% were in remission at endpoint. Among those patients meeting severity criteria for remission at baseline, 84.2% were in remission at endpoint. A total of 93.7% of the patients who achieved or maintained remission at 6 months were in remission at endpoint. Conclusions: RLAI is safe during long-term treatment up to 18 months in adults requiring antipsychotics. Conversion to RLAI resulted in improved symptom control. Most patients achieved and maintained a sustained remission (>= 6 months) after conversion to RLAI.Correspondence to:
R. Medori, MD; Janssen-Cilag, Medical Affairs EMEA, Turnhoutseweg 30, 2340 Beerse, Belgium
Email: rmedori@jacde.jnj.com
Drug Utilization
Influence of medical training on self-medication by students
H. James, S.S. Handu, K.A.J. Al Khaja and R.P. Sequeira
Abstract
H. James, S.S. Handu, K.A.J. Al Khaja and R.P. Sequeira
Department of Pharmacology and Therapeutics, College of Medicine
and Medical Sciences, Arabian Gulf University, Kingdom of Bahrain
Objective: To examine the influence of medical training on the knowledge, attitude and practice of self-medication by medical students. Subjects and methods: This was a cross-sectional, descriptive study. A self-developed, pre-validated questionnaire containing open-ended and close-ended items was used for data collection. Medical students in the 2nd and 4th year of the medical course at the Arabian Gulf University Bahrain filled in the questionnaire anonymously. Data were analyzed using SPSS and results expressed as counts and percentages. 2-tailed Chi2-test was applied and p < 0.05 was considered significant. Results: The respondents (n = 141) had a mean age of 19.94 ± 1.21 years. Overall, they had a fair knowledge about appropriate self-medication but knowledge of the benefits and risks of self-medication was adequate. Self-medication was perceived to be time-saving, providing quick relief in common illnesses, a learning experience, economical, and convenient. Among the perceived disadvantages were adverse drug reactions, inappropriate drug use, and the risk of making a wrong diagnosis. Majority of the respondents had a positive attitude favoring self-medication and read the package insert. The practice of self-medication was common and often inappropriate. The commonest indications for self-medication were cough, cold and sore throat (63.2% in Year 2) and headache (78.3% in Year 4). Mild illness, previous experience, and lack of time were the most frequent reasons for resorting to self-medication. Analgesics were the commonest drugs used, and drugs were mostly obtained from private pharmacies. Students of Year 4 had better knowledge about appropriate self-medication (58.7% versus 35.8%, p = 0.02), had greater awareness of the risks of self-medication and would discourage others from practicing self-medication (58.7% versus 40.4%, p = 0.04). They had a more confident attitude (54.3% versus 35.1%, p = 0.03) and a smaller number of them would seek a prescription (34.8% versus 54.3%, p = 0.03). They practiced self-medication more often (73.3% versus 52.6%, p = 0.02) and more appropriately (58.7% versus 35.8%, p = 0.02). Conclusion: This cross-sectional study shows that senior medical students tend to have greater knowledge of appropriate self-medication, have a more confident as well as concerned attitude towards self-medication, and tend to practice self-medication more often and appropriately.Correspondence to:
Dr. H. James; Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 22979, Kingdom of Bahrain
Email: DrHenryJames@hotmail.com
Pharmacodynamics
Characterization of vascular reactivity in dorsal hand veins after oral rosiglitazone treatment in healthy subjects
C. Schindler, C.M. Ferrario, C. Jatzke, K. Ahner, K.B. Brosnihan, P. Bramlage, U. Maywald, R. Oertel, W. Boecking and W. Kirch
Abstract
C. Schindler, C.M. Ferrario, C. Jatzke, K. Ahner, K.B. Brosnihan, P. Bramlage, U. Maywald, R. Oertel, W. Boecking and W. Kirch
1Institute of Clinical Pharmacology, Medical Faculty, Technical University Dresden, Dresden, Germany, and 2Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Objective: In clinical studies with diabetic patients thiazolidinediones have been shown to restore abnormal vascular function which might be attributed to improved blood sugar control or to restoration of vascular endothelium and smooth muscle responsiveness. The present study was undertaken to investigate whether rosiglitazone modulates vascular responsiveness to different vasoactive agents and exerts renin-angiotensin-system (RAS)-inhibiting properties in healthy subjects in vivo. Methods: 24 healthy male subjects were randomized to receive either rosiglitazone or placebo. Venoconstrictor responses to angiotensin II (Ang II) and phenylephrine, and endothelium-dependent response to histamine and insulin, and endothelium-independent response to glyceroltrinitrate were compared using the dorsal hand vein compliance method. Effects on the RAS were investigated by plasma level determinations of Ang II and angiotensin-(1-7). Treatment effects on the systemic arterial system were investigated by standardized pulse-wave-analysis. Results: Rosiglitazone significantly inhibited venoconstrictor responses to Ang II by 19% (–70% vs. –51% constriction, p = 0.034) and in the presence of rosiglitazone the ED80 for phenylephrine was increased (ED80: 317 ± 86 ng vs. 531 ± 102 ng; p = 0.010). Rosiglitazone treatment was without effect on endothelium-dependent dilation, blood pressure, pulse-wave-velocity and plasma angiotensin peptide levels. Conclusions: The data of the present study in veins of healthy subjects are consistent with data from in vitro and animal studies supporting a direct effect of rosiglitazone on venous tone by modulation of the vascular smooth muscle response via AT1-receptor-downregulation.Correspondence to:
Dr. C. Schindler; Institute of Clinical Pharmacology, Medical Faculty of the Technical University Dresden, Fiedlerstrasse 27, 01307 Dresden, Germany
Email: christoph.schindler@tu-dresden.de
Letter to the Editor
Relationship between an increase in serum creatinine or a doubling in serum creatinine and a decrease in glomerular filtration rate estimated using prediction equations
O. Schück and M. Horackova
Abstract
O. Schück and M. Horackova
Department of Internal Medicine, 2nd Faculty of Medicine, University Hospital, Charles University in Prague, Czech Republic
Correspondence to:
M. Horackova, MD, PhD; Department of Internal Medicine 2nd Faculty of Medicine, University Hospital, Motol V Uvalu 84, 150 06 Prague 5, Czech Republic
Email: Horackov@email.cz
Bioavailability Section
Bioequivalence study of two limaprost alfadex 5 µg tablets in healthy subjects: moisture-resistant tablet (dextran formulation) versus standard tablet (lactose formulation)
S. Nakade, J. Komaba, T. Ohno, J. Kitagawa, K. Furukawa and Y. Miyata
Abstract
S. Nakade, J. Komaba, T. Ohno, J. Kitagawa, K. Furukawa and Y. Miyata
1Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki, and 2Project Coordination & Data Management, Ono Pharmaceutical Co., Ltd., Osaka, Japan
Objective: A study was conducted to assess the bioequivalence of two limaprost alfadex 5 µg tablets, a moisture-resistant tablet (dextran formulation) and a standard tablet (lactose formulation). Materials and methods: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 120 healthy male volunteers. One tablet of either formulation was administered with 200 ml of water after 10-hour overnight fast. After dosing, serial blood samples were collected for a period of 6 hours. Plasma harvested from blood was analyzed for limaprost by a validated LC/MS/MS method. The peak plasma concentration (Cmax) values and time associated with the maximal concentration (tmax) were obtained from the observed data. The elimination rate constant (lambda z) was obtained as the slope of the linear regression of the log-transformed concentration values vs. time data in the terminal phase, and the elimination half-life (t1/2) was calculated as 0.693/lambda z. The area under the curve to the last measurable point (AUC0-t) was estimated by the linear trapezoidal rule. The analysis of variance (ANOVA) was carried out using log-transformed AUC0-t, AUC0-¥ and Cmax and untransformed tmax, and 90% confidence intervals for AUC0-t and Cmax were calculated. If the 90% confidence intervals (CI) for both AUC0-t and Cmax fell fully within the interval 80 – 125%, the bioequivalence of the two formulations was established. Results: The means of AUC0-t were 0.779 vs. 0.754 pg × h/ml (test vs. reference), and the means of the Cmax were 1.26 vs. 1.12 pg/ml (test vs. reference). The geometric mean ratios of the test formulation to reference formulation for AUC0-t and Cmax were 104.0 and 112.4%, respectively, and the 90% CI for AUC0-t and Cmax were 100.7 – 107.4% and 105.6 – 119.6%, respectively. Both 90% CI for AUC0-t and Cmax fell within the Ministry of Health, Labour and Welfare of Japan accepted bioequivalence range of 80 – 125%. Conclusions: Based on the results, the moisture-resistant tablet was determined to be bioequivalent to the standard tablet.Correspondence to:
J. Komaba, MS; Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 17-2 Wadai Tsukuba, Ibaraki 300-4247, Japan
Email: komaba@ono.co.jp
Bioavailability Section
A randomized, crossover study to determine bioequivalence of two brands of dexibuprofen 400 mg tablets in healthy Asian adult male subjects of Indian origin
S. Menon, N. Kadam, G. Patil and P. Mhatre
Abstract
S. Menon, N. Kadam, G. Patil and P. Mhatre
Therapeutic Drug Monitoring Laboratory, Sion Koliwada, Sion (E), Mumbai, India
Aim: To estimate the bioavailability and evaluate bioequivalence of a single dose of a dexibuprofen tablet (test formulation, containing dexibuprofen 400 mg, manufactured by Emcure Pharmaceuticals Ltd., Pune, India) and to compare it with that of a single dose of a Seractil tablet (reference formulation, containing dexibuprofen 400 mg, manufactured by Genus Pharmaceuticals, Bershire, UK) under fasting conditions. Subjects and methods: Using a two-treatment, two-period, two-sequence, randomized crossover design, test and reference formulations were administered as individual single doses to 24 healthy adult Asian male subjects of Indian origin under non-fed conditions, with 4 days washout period between dosing. 17 blood samples were drawn from each subject over a 12-hour period. Pharmacokinetic parameters, Cmax, AUC0-t, AUC0-¥ and Cmax/AUC0-¥ were calculated from the plasma concentration-time data of each individual and during each period by applying non-compartmental analysis. Analysis of variance was carried out using logarithmically transformed and non-transformed values of the stated pharmacokinetic parameters. Data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. Results: All 24 subjects who received the two formulations on two occasions with a washout period of 4 days, completed the study and provided an adequate amount of blood at each sampling point. After oral administration the values of Cmax (µg/ml), tmax (h), AUC0-t (µg/ml × h), AUC0-¥ (µg/ml × h) for reference and test formulations were 23.501 and 22.948, 1.156 and 1.281, 69.795 and 68.455, and 72.454 and 70.208, respectively. ANOVA and CI test showed no significant (p > 0.05) variation in these pharmacokinetic parameters of test and reference formulations. When the AUC0-t values for both formulations for non-transformed and log-transformed data were compared, the test formulation showed a bioavailability of 98.08% and 99.56%, respectively, as compared to reference formulation. These values are within the acceptance limit of 80 – 120%. No adverse events were observed in any of the subjects during the two runs of the study. Both clinical and laboratory parameters of all subjects showed no clinically significant changes. Conclusion: The test formulation containing dexibuprofen 400 mg (manufactured by Emcure Pharmaceuticals Ltd., Pune, India) was bioequivalent to reference formulation (Seractil, manufactured by Genus Pharmaceuticals, Berkshire, UK). Both formulations were well tolerated. The test formulation can be considered a pharmaceutically and therapeutically equivalent alternative to Seractil.
Correspondence to:
Dr. S. Menon; Therapeutic Drug Monitoring Laboratory, 194, Scheme No. 6, Road No. 15, Sion Koliwada, Sion (E), Mumbai-40002, India
Email: tdmlab@vsnl.net
