Volume 48, No. 1/2010(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Phenotyping with sulfasalazine – time dependence and relation to NAT2 pharmacogenetics
U.D. Kuhn, M. Anschütz, K. Schmücker, B.S. Schug, M. Hippius and H.H. Blume
Abstract
U.D. Kuhn1, M. Anschütz2, K. Schmücker2, B.S. Schug2, M. Hippius1 and H.H. Blume2
1Institute of Pharmacology and Toxicology, Division of Clinical Pharmacology, Medical Faculty (Universitätsklinikum), Friedrich Schiller University Jena, Jena, and 2SocraTec R&D GmbH, Oberursel, Germany
Objective: N-acetyltransferase 2 (NAT2) genotype-phenotype relation with sulfasalazine as probe drug by means of detailed genotype analysis and kinetic data evaluation. Background: Though phenotype analysis of sulfasalazine metabolism has been described before, genotype investigations in this regard are scarce. The influence of different single point mutations on the metabolism of the sulfasalazine metabolite sulfapyridine (SP) should give more insight into the functionality of different alleles especially with those still under discussion. Methods: In two bioavailability studies performed under comparable conditions with 24 healthy subjects of both genders equally distributed, plasma levels of SP and acetylsulfapyridine (Ac-SP) were determined after oral intake of enteric coated formulations of sulfasalazine (500 mg and 1,000 mg, respectively). The resulting metabolic ratios were calculated. NAT2 genotype was analyzed in parallel for all subjects deducing haplotype set as well as putative functional phenotype as (homozygous or heterozygous) rapid acetylator (RA) or slow acetylator (SA) and correlated with the PK results. Results and discussion: RA genotype in the overall study population was seen with 45.5% (including 6.8% homozygous wildtype *4/*4) and SA genotype with 54.5%. Compared to RA genotype, apparent terminal elimination half-life of SP as well as of Ac-SP was prolonged in the SA genotype population, Cmax and AUC values of SP were higher whereas average Cmax value of Ac-SP was lower (with AUC only some tendency to lower values). In general, phenotype-genotype correlation was good with only few exceptions. Strongest functional effect on enzyme activity was noticed in slow acetylators carrying the 341T > C mutation, followed by 590G > A mutation whereas the influence of 857G > A was considerably less pronounced. Homozygous 803A > G mutation (lysine > arginine shift) did not reveal enzyme activity reduction.Correspondence to:
Dr. med. U.D. Kuhn
c/o Institute of Pharmacology and Toxicology
Division of Clinical Pharmacology
Friedrich Schiller University Jena
Medical Faculty (Universitätsklinikum)
Dornburger Straße 159, 07740 Jena, Germany
Email: urs.kuhn@uni-jena.de
Original Research
Population pharmacokinetic study of methotrexate in children with acute lymphoblastic leukemia
C. Zhang, S. Zhai, L. Yang, H. Wu, J. Zhang and X. Ke
Abstract
C. Zhang1, S. Zhai1, L. Yang2, H. Wu2, J. Zhang2 and X. Ke3
1Department of Pharmacy of Peking University Third Hospital, Beijing, China and Therapeutic Drug Monitoring & Clinical Toxicology Center of Peking University, Beijing, 2Department of Pharmacy of the First Affiliated Hospital of Kunming Medical School, Kunming, and 3Department of Hematology of Peking University Third Hospital, Beijing, China
A population pharmacokinetic model was developed to describe the factors that may affect the pharmacokinetics of methotrexate (MTX) in Chinese child patients with acute lymphoid leukemia (ALL) and to predict the individual pharmacokinetic parameters in these patients. One hundred and eighteen children with ALL who received MTX at the dose of 2 – 3.5 g/m2 were enrolled in this study. 96 children were enrolled in the index group and 22 children in the validation group. The data were analyzed using nonlinear mixed effect model (NONMEM) software. A linear two-compartment model with linear elimination best described the data. The forward inclusion-backward elimination method was used to investigate the different covariates, including age, body weight, gender, etc. The Bayesian method was used to predict the individual pharmacokinetic parameters. Validation was applied using an internal and external approach. The population pharmacokinetic parameters and 95% confidence interval (CI) were obtained as follows: The clearance of central compartment (CL1), apparent volume of distribution of central compartment (V1), the clearance between central and peripheral compartment (CL2), and apparent volume of distribution of peripheral compartment (V2) were 5.04 (3.93 – 6.15) l/min, 16.1 (12.5 – 19.7) l, 0.203 (0.102 – 0.304) l/min and 7.05 (3.86 – 10.20) l, respectively. The inter-individual variability of CL1, V1, CL2, and V2 were 49.60%, 29.36%, 137.64%, and 107.70%, respectively. Gender, body surface area and the amount of alkalinization agent during 24 hours before MTX administration had significant effects on CL1. A strong relationship was found in this study between CL2 and age, as well as between V2 and age. A good correlation was further proved through the validation model. Moreover, some secondary pharmacokinetic parameters were estimated: the elimination half-life t1/2 was 2.34 h (CV = 36.7%), elimination constant ke was 0.33 h-1 (CV = 33.2%), and the area under plasma concentration versus time curve AUC was 582.92 mg·h·l-1 (CV = 55.9%). Our model combine Bayesian approach enabled a satisfactory estimation of MTX concentration in individual patients. The results of this study allowed clinicians to assess the MTX pharmacokinetic parameters based on the specific demographic characteristics of patients.Correspondence to:
Prof. S. Zhai
Department of Pharmacy
Peking University Third Hospital
49 Huayuan North Road
Haidian District, Beijing, 100191, China
Email: laural_chao@hotmail.com
Original Research
Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway
M. Nakamuta, T. Fujino, R. Yada, K. Yasutake, T. Yoshimoto, N. Harada, M. Yada, N. Higuchi, M. Kato, M. Kohjima, A. Taketomi, Y. Maehara, T. Nishinakagawa, K. Machida, K. Matsunaga, M. Nakashima, K. Kotoh and M. Enjoji
Abstract
M. Nakamuta1,2, T. Fujino2, R. Yada2, K. Yasutake2, T. Yoshimoto1, N. Harada1, M. Yada3, N. Higuchi3, M. Kato3, M. Kohjima3, A. Taketomi4, Y. Maehara4, T. Nishinakagawa5, K. Machida5, K. Matsunaga5, M. Nakashima5, K. Kotoh3 and M. Enjoji5
1Department of Gastroenterology, 2Clinical Research Center, Kyushu Medical Center, National Hospital Organization, 3Department of Medicine and Bioregulatory Science, 4Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, and 5Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
Objective: Bezafibrate (BF) has been used to treat biliary damage, particularly in patients with primary biliary cirrhosis (PBC), and its clinical efficacy has been demonstrated. The mechanism of action is thought to involve activation of the PPARα-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. Methods: The levels of serum γ-glutamyl transpeptidase and alkaline phosphatase, and those of bile components were examined before and after BF administration in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage (PTBD). Hepatic expression of PPARα and MDR3 was quantified by real-time PCR in patients with PBC or non-alcoholic fatty liver disease (NAFLD). Results: In patients with obstructive jaundice, BF decreased the serum levels of biliary enzymes and increased the bile concentration of PL. In patients with PBC or NAFLD, the expression levels of MDR3 were already up-regulated before starting the BF treatment. Although BF treatment did not further up-regulate MDR3 expression in NAFLD patients, PPARα expression was significantly increased. Conclusions: BF enhanced the secretion of PL into bile in cholestatic patients undergoing PTBD. However, in patients with PBC or NAFLD, diseases that represent cholesterol overload, MDR3 was already expressed at a high level to compensate for bile acids overproduction, and its expression was hardly affected by BF. In patients with chronic liver diseases such as PBC, BF may induce clinical effects via mechanisms independent of PL secretion.Correspondence to:
M. Enjoji, MD, PhD
Department of Clinical Pharmacology
Faculty of Pharmaceutical Sciences
Fukuoka University
8-19-1 Nanakuma, Jonan-ku
Fukuoka 814-0180, Japan
Email: enjoji@adm.fukuoka-u.ac.jp
Original Research
Appropriate dosing in patients with impaired renal function on medical wards before and after an educational intervention
S. Baum and S. Harder
Abstract
S. Baum and S. Harder
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
Context: Whereas in larger hospitals individualized dose adjustment in renal insufficiency can be provided by expert systems and pharmacists, these options are often not available in smaller hospitals. Aims: We evaluated whether one short educational session for the medical staff of internal wards of a community hospital, focusing on creatinine clearance and dosing in renal insufficiency, and providing a list of frequently used drugs and their dosing schedule does reduce the rate of patients with unadjusted doses. Material and methods: In patients with a creatinine clearance < 60 ml/min, dosing schedules for 92 drugs were determined. After a 6-month observation period (Cohort 1), an educational intervention and the abovementioned list were delivered to the medical staff. This intervention was followed by a further 6-months observation period (Cohort 2). Results: In Cohort 1, 55/85 patients (median age 79 y) had at least one initially inappropriately adjusted medication, and 47/85 remained so at discharge, whereas in Cohort 2 (median age 77 y), 28/85 patients had at least one initially inappropriately adjusted medication (p = 0.014 compared to Cohort 1) and 27/85 remained so at discharge (p = 0.05). In Cohort 1, 46.0% of all prescriptions with drugs which need dose adjustment (n = 220) were not adjusted. After the intervention (Cohort 2), 25.6% of all prescriptions (n = 176) followed an unadjusted dosage (p < 0.001). Conclusion: This intervention was on a “low key”-level, and no further support e.g. academic detailing was effected. Despite this, we found a considerable reduction in the number of inappropriate doses in patients with impaired renal function.Correspondence to:
Prof. Dr. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt
University Hospital
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany
Email: harder@em.uni-frankfurt.de
Original Research
Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects
Y.J. Lee, M.G. Lee, L.A. Lim, S.B. Jang, and J.Y. Chung
Abstract
Y.J. Lee, M.G. Lee, L.A. Lim, S.B. Jang, and J.Y. Chung
Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea
Objective: This study aimed to evaluate the effect of genetic polymorphisms of SLCO1B1 and ABCB1 on the pharmacokinetics of atorvastatin and its metabolites. Methods: 290 Koreans were genotyped for SLCO1B1, ABCB1 and CYP3A5, and 28 subjects were selected for the pharmacokinetic study. Each subject received a single oral dose of 20 mg atorvastatin and blood samples were collected up to 48 hr after dosing. The relationship between the genotypes and atorvastatin pharmacokinetics was examined. Results: For SLCO1B1 genotypes, the mean area under the concentration-time curve from time 0 to infinity (AUC0-∞) of atorvastatin was 148.2 ng × hr/ml for *15/*15 subjects (n = 3), which was significantly larger than for 1a/*15 and *1b/*15 (n = 8) (80.7 ng × hr/ml, p = 0.0121) and also larger than for *1a/*1a, *1a/*1b and *1b/*1b (n = 17) (66.3 ng × hr/ml, p = 0.0018). The mean AUC0-∞; of 2-hydroxyatorvastatin for *15/*15 was also larger than in *1a/*1a, *1a/*1b and *1b/*1b (p = 0.012). In lactone forms, no significant pharmacokinetic difference was found among the genotypes. For ABCB1 genotypes, the half-lives of atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin and 2-hydroxyatorvastatin lactone were significantly longer in c.2677TT-c.3435TT (n = 3) vs. c.2677GG-c.3435CC and c.2677GT-c.3435CT (n = 10), yielding p = 0.049, 0.007, 0.007 and 0.007, respectively. Conclusion: This study shows that the SLCO1B1*15 allele may be associated with the individual difference in the AUC0-∞ of atorvastatin whereas the ABCB1 TT-TT diplotype may affect the elimination half-life of the drug in the Korean population.Correspondence to:
J.Y. Chung, MD, PhD
Department of Pharmacology
College of Medicine, Yonsei University
134 Shinchon-dong, Seodaemun-gu
Seoul 120-752, Republic of Korea
Email: jychung@yuhs.ac
Original Research
Pharmacokinetics of alogliptin when administered with food, metformin, or cimetidine: a two-phase, crossover study in healthy subjects
A. Karim, P. Covington, R. Christopher, M. Davenport, P. Fleck, X. Li, E. Wann* and Q. Mekki
Abstract
A. Karim1, P. Covington2, R. Christopher3, M. Davenport4, P. Fleck1, X. Li4, E. Wann5* and Q. Mekki1
1Takeda Global Research & Development Center, Inc., Lake Forest, IL, 2Pharmaceutical Product Development, Inc., Wilmington, NC, 3Takeda San Diego, San Diego, California, 4Pharmaceutical Product Development, Inc., Richmond, VA, and 5Takeda Pharmaceuticals North America, Inc., Deerfield, IL, USA
Objective: The dipeptidyl peptidase-4 inhibitor alogliptin, under development for treatment of Type 2 diabetes, primarily is excreted renally. This study investigated (1) the effect of food on alogliptin pharmacokinetics and tolerability and (2) pharmacokinetic interactions between alogliptin and metformin or cimetidine and tolerability of alogliptin when administered with either drug. Methods: This randomized, open-label, two-phase, crossover study recruited healthy adults. In the single-dose phase, 36 subjects received an oral dose of alogliptin 100 mg under fed or fasted conditions. In the multiple-dose phase, subjects in one arm (n = 17) received 6 days each of alogliptin 100 mg once daily (q.d.), metformin 1,000 mg twice daily (b.i.d), and alogliptin q.d. + metformin b.i.d; subjects in the other arm (n = 18) received 6 days each of alogliptin 100 mg q.d., cimetidine 400 mg q.d., and alogliptin q.d. + cimetidine b.i.d. Pharmacokinetic parameters were determined after the last dose in each period. Tolerability was assessed through adverse events and clinical findings. Results: Food had no effect on alogliptin area under the concentration-time curve (AUC) from 0 h to infinity and a small, clinically insignificant effect on maximum plasma concentration (Cmax) (fed/fasted least squares (LS) geometric mean ratio, 0.856; 90% confidence interval (CI), 0.798 – 0.917). Metformin and cimetidine did not affect alogliptin pharmacokinetics. Alogliptin had no effect on metformin Cmax and a small, clinically insignificant effect on AUC over the dosing interval ((alogliptin + metformin)/metformin LS geometric mean ratio, 1.19; 90% CI, 1.095 – 1.291). Alogliptin did not affect cimetidine pharmacokinetics. Alogliptin tolerability was similar under all conditions. Conclusion: Alogliptin can be administered without regard to meals and with metformin or cimetidine without the need for dose adjustment.Correspondence to:
A. Karim, PhD
Takeda Global Research & Development Center, Inc.
675 North Field Drive
Lake Forest, IL 60045, USA
Email: akarim@tgrd.com
Original Research
Storage, utilization and cost of drug products in Palestinian households
W.M. Sweileh, A.F. Sawalha, S.H. Zyoud, S.W. Al-Jabi, F.F. Bani Shamseh and H.S. Khalaf
Abstract
W.M. Sweileh1, A.F. Sawalha1,2, S.H. Zyoud2, S.W. Al-Jabi1, F.F. Bani Shamseh2 and H.S. Khalaf2
1College of Pharmacy and 2Poison Control and Drug Information Center (PCDIC), An-Najah National University, Nablus, Palestine
Background and objective: Appropriate storage and use of medications in households may decrease drug wastage and unnecessary hazard. The objective of this study was to investigate storage, utilization habits and cost of medications in households in Palestine. Methods: This is a cross sectional, anonymous, questionnaire-based study of 465 households in northern Palestine. The drug product inventory in the surveyed households was investigated and family members were interviewed. Results: A total of 465 households were assessed, 50 were excluded. The total number of drug products in the 415 households was 5,505; the mean ± SD was 13.3 ± 7.8. Level of father’s education, presence of chronic disease and insurance coverage were the variables that showed a significant relationship with the amount of drug products found in the households. Most of the drug products (43.4%) were stored in relatively unsafe places in the house within the reach of children. Approximately one third (32.5%) of the drug products were not in their original container. The percentages of unused drug products, expired, or those with no clear expiry date were 32.7%, 17.7% and 11% respectively. Estimated drug wastage in the 415 households and nationwide would be 16,100 and 19 million USD respectively. The most common drug categories encountered in households were alimentary, musculoskeletal and anti-infective agents. The most common individual drugs encountered were: paracetamol (8.5%), ibuprofen (4.9%) and diclofenac (3.7%). Conclusion: Medications were stored in large quantities in Palestinian households, and a large percentage was being wasted. Drug-use assessments and a comprehensive evaluation of the current national drug policies are warranted to curtail this problem.Correspondence to:
W.M. Sweileh, PhD
Associate Professor
Clinical Pharmacology, College of Pharmacy
An-Najah National University
Nablus, Palestine
Email: waleedsweileh@najah.edu
Original Research
Antihypertensive drug utilization and conformity to guidelines in a sub-Saharan African hypertensive population
T.O. Olanrewaju, A. Aderibigbe, O.A. Busari and E.O. Sanya
Abstract
T.O. Olanrewaju1, A. Aderibigbe1, O.A. Busari2 and E.O. Sanya3
1Division of Nephrology, Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, 2Department of Medicine, Federal Medical Center, Ido-Ekiti, and 3Division of Neurology, Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria
Background: Despite availability and usage of wide array of antihypertensive drugs, blood pressure has remained poorly controlled in most health care settings particularly in Africa. The cost of these drugs among other factors strongly determines the prescription and usage pattern which ultimately affects control of blood pressure particularly in sub-Saharan Africa. The aim of this study was to describe the current utilization pattern of antihypertensive drugs in a tertiary hospital in Nigeria in line with the regional and international guidelines for hypertension management and to compare with similar studies in other parts of the country to generate the national outlook. Methods: This is a cross sectional study of 805 adult hypertensive patients who were on treatment at the Medical Out-Patient Department of University of Ilorin Teaching Hospital in Nigeria, a country with the most populous black hypertensive patients. Data were collated from the patients’ records and evaluated according to drug classifications. Results: 787 patients out of the 805 evaluated were eventually included in the analysis. Mean age was 57.88 ± 12.59 years with 490 (62.3%) females. Frequency of use of classes of antihypertensive was: diuretics (D, 84%), calcium channel blockers (CCB, 66%), angiotensin converting enzyme inhibitors (ACEI, 65%), a-methyldopa (ALD, 26%), beta-blockers (BB, 11.9%) and angiotensin receptor blockers (3.8%). Proportions of number of drugs usage per patient were: 0 (2.2%), 1 (9.1%), 2 (37.1%), 3 (35.8%), 4 (15.6%), and 5 (0.1%). The most commonly used combinations of drugs were ACEI + CCB + D (21.6%), followed by CCB + D (14.5%), ACE + D (11.4%) and ACEI + D + ALD (9.8%). Other recent studies in Nigeria revealed diuretics and multiple agents as the prevalent prescription pattern. Conclusion: Antihypertensive utilization in Ilorin, Nigeria like some parts of the country conforms to the guidelines for the management of hypertension in blacks with majority of patients on diuretics particularly in combination with other agents. Angiotensin converting enzyme inhibitors are increasingly being used whereas beta-blockers and angiotensin receptor antagonists are still less utilized.Correspondence to:
Dr. T.O. Olanrewaju
Division of Nephrology, Department of Medicine
University of Ilorin Teaching Hospital
PMB 1459, Ilorin, Nigeria
Email: timothysegun@yahoo.com
Case Reports
Sildenafil induced choreoathetosis in men with Parkinson’s disease
O. Perkovic, D. Vitezic, J. Rudez, M. Vitezic, M. Kovacevic, J. Mrsic-Pelcic, D. Ljubicic, and A. Jurjevic
Abstract
O. Perkovic1,2, D. Vitezic1,2, J. Rudez1,2, M. Vitezic2, M. Kovacevic1,2, J. Mrsic-Pelcic2, D. Ljubicic1,2 and A. Jurjevic1,2
1University Hospital Centre Rijeka and 2University of Rijeka Medical School, Rijeka, Croatia
Objective: The present report describes a case of choreoathetotic movements which were most probably induced by sildenafil in a patient with Parkinson’s disease (PD) treated with levodopa/carbidopa (LD/CD). Case summary: A 56-year-old retired man was admitted to hospital because of bizarre, involuntary movements and anxiety. Before admission he had taken sildenafil 100 mg. He had a previous history of PD for 5 years and during the last 3 years he was stable with long-acting LD/CD and selegiline. He is in Stage 2 according to Hoehn and Yahr Staging of PD. The patient did not have any problems with erectile function and he took sildenafil 50 minutes after the last daily dose of LD/CD. The patient was discharged from the hospital 12 hours after the admittance without any symptoms of choreoathetosis. Conclusion: Choreoathetotic dyskinesia is an adverse effect which was provoked by sildenafil administration (drug abuse) in a previously stabile responder to LD therapy, but probably had a lower threshold for dyskinesia. Predisposition for this pharmacokinetic interaction could be a short time interval between LD and sildenafil applied in high dosage.Correspondence to:
Dr. O. Perkovic, PhD
Department of Neurology
University of Rijeka School of Medicine
Krešimirova 42
51000 Rijeka, Croatia
Email: Olivio.Perkovic@medri.hr
Case Reports
Protracted deep coma after bromazepam poisoning
K. Lakhal, S. Pallancher, J.-C. Mathieu-Daude, P. Harry and X. Capdevila
Abstract
K. Lakhal1, S. Pallancher1, J.-C. Mathieu-Daude2, P. Harry3 and X. Capdevila1
1Réanimation Polyvalente, Département d’Anesthésie-Réanimation A, 2Service de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, Centre Hospitalier Universitaire de Montpellier, and 3Centre Antipoison des régions Centre et Pays de la Loire, Centre Hospitalier Universitaire d’Angers, France
Background: Bromazepam intoxication is very common but surprisingly rarely reported. Case description: We describe the case of a 73-year-old woman who suffered from a prolonged coma after acute self poisoning with bromazepam (serum concentration of 2,000 ng/ml at admission, 2 – 10 hours after ingestion of up to 180 mg) and zolpidem (900 ng/ml at admission). Only the former lasted at toxic concentrations. Recovery of consciousness allowed extubation on Day 16. Repeat-dose activated charcoal (25 g every 6 h from Day 14 to 16) resulted in minimal effects on bromazepam grossly estimated kinetics. Conclusion: Despite its relatively low theoretic half-life, bromazepam may induce a prolonged life-threatening coma, even in the absence of renal or hepatic failure.Correspondence to:
K. Lakhal, MD
Réanimation Polyvalente
Département d’Anesthésie-Réanimation A
Hôpital Lapeyronie, Centre Hospitalier Universitaire
34000 Montpellier, France
Email: lakhal_karim@yahoo.fr
Letter to the Editor
Metabolic syndrome in mental illness: evidence and way out
S. Saddichha
