Volume 52, No. 9/2014(September)
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Original Research
Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations
Lai San Tham, Crystal Mei Fen Zhao, Fanni Natanegara, Stephen Lowe, Christopher Chen, Chay Ngee Lim, Helle Linnebjerg, Brian A. Willis, Malcolm . Mitchell, and Stephen D. Wise
Price
42.00 $
Page No. 717
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (717-725)
Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations
Lai San Tham1, Crystal Mei Fen Zhao2, Fanni Natanegara3, Stephen Lowe4, Christopher Chen5, Chay Ngee Lim6, Helle Linnebjerg3, Brian A. Willis3, Malcolm I. Mitchell7, and Stephen D. Wise8
1Lilly – NUS Centre for Clinical Pharmacology, Level 5 Clinical Research Centre (MD11), National University of Singapore, Singapore, 2Drug Evaluation Unit, Clinical Pharmacology and Therapeutics Unit, Department of Medicine, Austin Health and Northern Health, The University of Melbourne, Victoria, Australia, 3Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA, 4Lilly – NUS Centre for Clinical Pharmacology, Level 6, National University of Singapore, Singapore, 5Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Clinical Research Center, Singapore, 6University of Minnesota, Department of Experimental and Clinical Pharmacology, Minneapolis, MN, USA, 7Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK, and 8Eli Lilly and Company (retired), Singapore
Objectives: A modified insulintolerance test (ITT) can be used to simulate a physiological stress state through the induction of controlled hypoglycemia in healthy volunteers. This allows for evaluation of hypothalamic-pituitary-adrenocortical axis response to stress via a surge in cortical release. However, a consequence of severe, prolonged hypoglycemia is QT interval prolongation. The aim of this analysis was to confirm that blood glucose lowering to 60 mg/dL (previously identified as adequate for inducing stress) has low risk of inducing clinically significant QT prolongation. Materials and methods: Continuous ECG monitoring was conducted as a planned substudyof an open-label, 2-period study involving 18 healthy male subjects. The QTcF response to hypoglycemia was measured over 2 identical periods, ~ 7 days apart. Results: An indirect- response model adequately described the pharmacological relationship between blood glucose and QTcF intervals over the time-course of the ITT. The model correctly identified the steep glucose-QT relationship as an on-off response with a large Hill coefficient of 59 and the threshold glucose, EC50, as ~ 57 mg/dL with narrow between-subject variability of 10%. Simulated QTcF profiles over the course of an ITT did not demonstrate any QTcF interval changes of clinical concern, defined as QTcF observation > 500 ms, if hypoglycemia did not reach below 60 mg/dL. The statistical prediction that the chance of a mean QTcF observation > 500 ms was < 0.0001. Conclusions: Results support that an ITT maintained at or above 60 mg/dL is unlikely to cause QT prolongation in healthy volunteers and does not warrant continuous ECG monitoring in this group of subjects.Correspondence to:
Dr. Lai San Tham, PharmD
Lilly-NUS Centre for Clinical Pharmacology,
Level 5 Clinical Research Centre (MD 11)
National University of Singapore
10 Medical Drive, 117597 Singapore
Email: [email protected]
Original Research
Impact of comorbidities on the treatment of atopic dermatitis in clinical practice
Alexandra Werner-Busse, Karel Kostev, Guido Heine, and Margitta Worm
Price
42.00 $
Page No. 726
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (726-731)
Impact of comorbidities on the treatment of atopic dermatitis in clinical practice
Alexandra Werner-Busse1, Karel Kostev2, Guido Heine1, and Margitta Worm1
1Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin Berlin, Berlin, and 2IMS Health Epidemiology and Pharmacovigilance, Frankfurt am Main, German
Background and aim: Atopic dermatitis is often associated with atopic comorbidities such as allergic rhinitis, allergic asthma and food allergy. The aim of the present study was to analyze treatment data pertaining to atopic dermatitis patients in Germany with regard to the presence of other atopic comorbidities in the primary care and to investigate whether the presence of atopic codiagnoses has an impact on the treatment of atopic dermatitis (AD) patients. Methods: We used data from the Disease Analyzer database (IMS HEALTH, Germany) including 1,631 physicians (general practitioners, dermatologists and pediatricians) and 3.3 million patients. 39,642 (7.5%) of these patients were treated by dermatologists, 17,124 (5.2%) by pediatricians and 15,774 (0.9%) by general practitioners and had a documented diagnosis of atopic dermatitis. Results: 46.4% of AD patients treated by general practitioners, 42.5% by dermatologists and 32.0% by pediatricians were codiagnosed with one defined atopic diseases (allergic asthma, urticaria, allergic rhinitis and food allergy). In patients without AD, the proportion of atopic diseases was significantly smaller (41.4% for those treated by general practitioners, 38.4% for those treated by dermatologists, 26.4% for those treated by pediatricians). AD patients with another atopic comorbidity received topical corticosteroids (CS) (42.5%) more frequently than those without comorbidity (46.4% vs. 41.4% for patients treated by general practitioners, 42.5% vs. 38.4% for patients treated by dermatologists, 32.0% vs. 26.4% for patients treated by pediatricians). The general practitioners and pediatricians prescribed systemic corticosteroids to 13.2% and 7.8% of AD patients with additional atopic diseases, while the rate was only 5.1% and 3.0% in patients without comorbidities. Conclusion: In AD patients, the share of patients diagnosed with atopic diseases is significantly higher than in patients without AD. AD outpatients with concomitant atopic comorbidities receive topical, but also systemic corticosteroid prescriptions more frequently.Correspondence to:
Dr. Karel Kostev
IMS Health – Epidemiologie and Pharmacovigilance
Darmstädter Straße 108
60598 Frankfurt am Main, Germany
Email: [email protected]
Original Research
Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro
Sai-Zhen Chen, Pei-Pei Pan, Lei-Bin Shen, Shan-Shan Xu, Da-Peng Dai, Pei-Wu Geng, Jie Cai, Jian-Ping Cai, and Guo-Xin Hu
Price
42.00 $
Page No. 732
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (732-738)
Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro
Sai-Zhen Chen1,2*, Pei-Pei Pan1*, Lei-Bin Shen3, Shan-Shan Xu2, Da-Peng Dai4, Pei-Wu Geng1, Jie Cai1, Jian-Ping Cai4, and Guo-Xin Hu1
1School of Pharmacy, Wenzhou Medical University, 2Taizhou Central Hospital, Taizhou, 3The First Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang, and 4The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China
Objective: Co-administration of anti-hypertension and anti-diabetic drugs is common in clinical settings. Methods: In this study, we characterized the drug-drug interactions of losartan (LOS) and glimepiride (GLP) using recombinant cytochrome P450 (CYP) 2C9 enzymes (CYP2C9*1, CYP2C9*3, CYP2C9*13, and CYP2C9*16). Results: Metabolism of losartan by recombinant CYP2C9* 1, CYP2C9*3, CYP2C9*13, and CYP2C9* 16 was inhibited by glimepiride competitively with IC50 values of 0.669 ± 0.055 μM, 0.424 ± 0.032 μM, 2.557 ± 0.058 μM, and 0.667 ± 0.039 μM, respectively. The inhibitory effect of glimepiride on losartan metabolism by CYP2C9*13 was marginal. The apparent Ki value of glimepiride with CYP2C9*3 (0.0416 ± 0.0059 μM) was significantly lower than with CYP2C9*1 (0.1476 ± 0.0219 μM) and CYP2C9*16 (0.2671 ± 0.0456 μM). On the other hand, losartan weakly inhibited the hydroxylation of glimepiride by P450 2C9 enzymes competitively. The potencies for inhibition of glimepiride hydroxylation were determined to be CYP2C9*1≈CYP2C9*3≈CYP2C9*16 > CYP2C9*13 by 4 μM losartan. No significant inhibition was observed when 0.5 μM losartan was used. Conclusions: Given these results, the potential inhibition of losartan metabolism by CYP2C9*3, CYP2C9*13, and CYP2C9*16 in vivo by glimepiride deserves further investigation. These results may provide valuable information for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.
*These authors contributed equally to this work.Correspondence to:
Dr. Guo-Xin Hu
Department of Pharmacology
Wenzhou Medical College
Wenzhou, Zhejiang 325035, China
or
Dr. Jian-ping Cai
The Key Laboratory of Geriatrics
Beijing Hospital and Beijing Institute of Geriatrics
Ministry of Health
No. 1, Dahua Road, Dongdan, Beijing 100730, China
Email: [email protected] or [email protected]
Original Research
Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study
Anton Drollmann, Romain Sechaud, Parasar Pal, Hisanori Hara, Susan Uziel-Fusi, and Peter Winkle
Price
42.00 $
Page No. 739
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (739-745)
Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study
Anton Drollmann1, Romain Sechaud1, Parasar Pal2, Hisanori Hara1, Susan Uziel-Fusi3, and Peter Winkle4
1Novartis Institutes for BioMedical Research, Basel, Switzerland, 2Integrated Information and Sciences, Novartis Healthcare Private Ltd, Hyderabad, India, 3Novartis Pharmaceutical Corporation, East Hanover, NJ, and 4Advanced Clinical Research Institute, Anaheim, CA, USA
Objective: Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. Methods: This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 μg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. Results: A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of –2.88 (90% CI: –3.78, –1.99) beats per minutes (bpm) and a maximum of –5.87 (90% CI: –7.82, –3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events. Conclusion: A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.Correspondence to:
Dr. Anton Drollmann, Executive Director
Translational Medicine- Respiratory Profiling Head
Novartis Pharma AG, Building WSJ 386.12.48.50
Postfach, 4002 Basel, Switzerland
Email: [email protected]
Original Research
Association of MDR1 C3435T and RFC1 G80A polymorphisms with methotrexate toxicity and response in Jordanian rheumatoid arthritis patients
Sima A. Samara, Yacoub M. Irshaid, and Khader N. Mustafa
Price
42.00 $
Page No. 746
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (746-755)
Association of MDR1 C3435T and RFC1 G80A polymorphisms with methotrexate toxicity and response in Jordanian rheumatoid arthritis patients
Sima A. Samara1, Yacoub M. Irshaid1, and Khader N. Mustafa2
Departments of 1Pharmacology and 2Internal Medicine (Rheumatology Division), Faculty of Medicine, The University of Jordan, Amman, Jordan
Objectives: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 G80A) and multi-drug resistance-1 (MDR1 C3435T) might affect MTX response and/or toxicity. The aim of this study was to find out if there is an association between those polymorphisms and MTX toxicity and/or response in Jordanian RA patients. Method: A genotyping approach was used to determine the studied polymorphisms in 159 RA patients. Results: There was an association between RFC1 G80A and MDR1 C3435T polymorphisms with MTX toxicity. Patients with RFC1 80GG genotype were at higher risk for gastrointestinal toxicity (p = 0.036). Patients carrying at least one MDR1 3435T variant allele were at higher risk for MTX overall toxicity (p = 0.04), especially hepatotoxicity (p = 0.028). Furthermore, the distribution of RFC1 G80A polymorphism between males and females was significantly different. The variant genotype 80AA was found to be more in males than in females (60% vs. 31%) (p = 0.011). Conclusions: Our results suggest that genetic polymorphisms in methotrexate transporters affect the toxicity but not the response of MTX treatment. Further studies should be performed to have more conclusive results.Correspondence to:
Yacoub M. Irshaid, MD, PhD
Department of Pharmacology, Faculty of Medicine
The University of Jordan, Amman, 11942, Jordan
Email: [email protected] and [email protected]
Original Research
A randomized study of intranasal vs. intravenous infusion of dexmedetomidine in gastroscopy
Guang Han, Wei-wei Yu, and Ping Zhao
Price
42.00 $
Page No. 756
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (756-761)
A randomized study of intranasal vs. intravenous infusion of dexmedetomidine in gastroscopy
Guang Han, Wei-wei Yu, and Ping Zhao
Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
Objective: To compare the respiratory and circulatory parameters between intranasal and intravenous dexmedetomidine in gastroscopy. Methods: 60 patients undergoing elective gastroscopy were randomly divided into group D1 and D2. Dexmedetomidine (0.5 μg/kg, 1 mL) and normal saline (NS, 1 mL) were given by intranasal route 40 minutes before induction, and then NS (20 mL) and dexmedetomidine (0.5 μg/kg, 20 mL) were given intravenously 10 minutes before induction, respectively, in groupsD1 and D2. Propofol (1.5 – 2 mg/kg) was used for induction. Heart rate (HR), meanarterial pressure (MAP), pulse oxygen saturation(SpO2), and respiratory rate (RR) were monitored. The latent period of falling asleep, the duration of gastroscopy, the time of awakening, and the total dose of propofol consumption were also recorded. Postoperative sedation scale and adverse reactionswere observed. Results: One patient in group D1 was excluded from the study due to atrioventricular block. The HR and SpO2 were significantly lower, but RR was significantly higher in group D2 than in group D1(all p < 0.05). The time of awakening was significantly longer and the rates of respiratory depression were significantly higher in group D2 than in group D1 (all p < 0.05) There were no significant differences in other parameters between both groups. Conclusion: Intranasal dexmedetomidine is a new, safe, and effective approach for gastroscopy because it has more stable respiratory and circulatory parameters and less adverse reactions than intravenous dexmedetomidine.Correspondence to:
Ping Zhao, MD
Department of Anesthesiology
Shengjing Hospital of China Medical University
No 36, Sanhao Street, Herping District, Shenyang 110004, China
Email: [email protected]
Original Research
Association of statin use with storage lower urinary tract symptoms (LUTS): data mining of prescription database
Mai Fujimoto, Tomoya Higuchi, Kouichi Hosomi, and Mitsutaka Takada
Price
42.00 $
Page No. 762
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (762-769)
Association of statin use with storage lower urinary tract symptoms (LUTS): data mining of prescription database
Mai Fujimoto, Tomoya Higuchi, Kouichi Hosomi, and Mitsutaka Takada
Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, Osaka, Japan
Objective: The efficacy and safety of statins have been studied in a number of clinical trials and epidemiological studies. In recent years, the Medicine and Healthcare Products Regulatory Agency (MHRA) has assessed the evidence available on the following adverse reactions associated with the use of statins: sleep disturbances, memory loss, micturition disorders (problems with urination), sexual disturbances, depression, and interstitial pneumopathy. However, the association between statin use and the risk of these adverse reactions remains unclear. To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) or the disorder causing LUTS, we carried out data mining using a prescription database. Methods: A large organized database of prescriptions constructed by a database vendor was used in the study. Symmetry analysis was used to identify the risk of LUTS after using statins over the period January 2006 to August 2013. Statin use in combination with drugs administered for storage LUTS was examined by prescription sequence symmetry analysis (PSSA). Results: A significant association between statins and drugs for storage LUTS was found, with adjusted sequence ratios (ASRs) of 1.21 (95% CI, 1.00 – 1.46), 1.19 (95% CI, 1.04 – 1.38), and 1.17 (95% CI, 1.05 – 1.30) for intervals of 91, 182, and 365 days, respectively. In the analyses of individual statins, significant associations were found only for pravastatin. Significant associations with individual drugs for storage LUTS were found for solifenacin succinate with ASRs of 1.36 (95% CI, 1.02 – 1.81), 1.48 (95% CI, 1.19 – 1.84), and 1.47 (95% CI, 1.25 – 1.73) for intervals of 91, 182, and 365 days, for flavoxate hydrochloride with an ASR of 1.56 (95% CI, 1.13 – 2.17) at an interval of 182 days, and for oxybutynin hydrochloride with ASRs of 2.06 (95% CI, 1.11 – 3.94) and 1.71 (95% CI, 1.09 – 2.72) at intervals of 182 and 365 days. Significant associations with gender were found only in females with ASRs of 1.25 (95% CI, 1.04 – 1.51) and 1.23 (95% CI, 1.07 – 1.41) at intervals of 182 and 365 days, respectively. Conclusions: Analysis of the prescription database showed significant association for storage LUTS in statin users.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kink University
577-8502, 3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email: [email protected]
Original Research
Investigation of the relationship between a starting dose in first-in-human studies and no observed adverse effect level in nonclinical studies
Akihide Sato and Mamoru Narukawa
Price
42.00 $
Page No. 770
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (770-775)
Investigation of the relationship between a starting dose in first-in-human studies and no observed adverse effect level in nonclinical studies
Akihide Sato and Mamoru Narukawa
Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
Objective: A starting dose in first-in-human (FIH) studies has been determined carefully to guarantee the safety of participants in the study but sometimes it seems to be too conservative. The objective of the present study is to investigate a reasonable safety factor to enable effective drug development without serious safety problems in study participants. Methods: No-observedadverse-effect levels (NOAELs) in nonclinical studies, starting doses in FIH studies, and approved doses in Japan were reviewed by documents disclosed by health authorities, and the relationships among each parameter were analyzed retrospectively. Results: The present study suggested that the starting doses in the past FIH studies had been determined very prudently, and revealed that there were significant differences between the starting dose and approved dose. Conclusion: It would be possible to develop new drugs effectively without serious safety risks if a reasonable safety factor had been applied to determine a starting dose in FIH studies.Correspondence to:
Akihide Sato, MSc
Department of Clinical Medicine (Pharmaceutical Medicine)
Graduate School of Pharmaceutical Sciences
Kitasato University
Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan
Email: [email protected]
Original Research
Evaluation of etanercept dose reduction in patients with rheumatoid arthritis using pharmacokinetic/pharmacodynamic modeling and simulation
Li-feng Hsu and Jin-ding Huang
Price
42.00 $
Page No. 776
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (776-786)
Evaluation of etanercept dose reduction in patients with rheumatoid arthritis using pharmacokinetic/pharmacodynamic modeling and simulation
Li-feng Hsu and Jin-ding Huang
Department of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Medical College, Tainan, Taiwan
Objectives: In this study, we attempt to explore the feasibility of alternative dosing regimens of etanercept in patients with rheumatoid arthritis (RA) using pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. Methods: All data used for estimation of PK/PD model parameters were collected from previously published literatures. American College of Rheumatology (ACR) 20/50/70 response rate and a disease activity score in 28 joints (DAS28) was selected as the principal clinical endpoint for further PK/PD modeling. The cumulative AUC (area under the concentration-time curve) of etanercept for different dosing regimens was calculated based on the final PK model and was then linked to the time course of clinical endpoints. Ten different dosing regimens were simulated in this study. Results: The PK model that best fit the serum concentration-time data for etanercept was a one-compartment model with first order absorption and elimination. Based on the PK/PD analysis, the relationship between the predicted cumulative AUC of etanercept to the ACR 20/50/70 response rate and DAS28 score was well characterized by Emax logistic and inhibitory Emax model, respectively. In our simulations, the following dosing regimens that are equally effective to current recommended dosage of 25 mg twice weekly (b.i.w.): (1) 25 mg once weekly (q.w.); (2) 50 mg every 2 weeks (q2w); (3) 25 mg b.i.w. for 3 months and 25 mg q2w thereafter; and (4) 50 mg q.w. for 3 months and 50 mg q2w thereafter. Conclusion: In this study, the clinical data was well described by the models developed, and several alternative dosing regimens were proposed. Further clinical studies in patients are still needed to confirm our findings.Correspondence to:
Jin-ding Huang, PhD
Department of Clinical Pharmacy and Pharmaceutical Sciences
National Cheng Kung University, MedicalCollege
1 University Road, Tainan 70101, Taiwan
Email: [email protected]
Original Research
Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells
David Díaz-Carballo, Ali Haydar Acikelli, Walter Bardenheuer, Sebastian Gustmann, Sascha Malak, Raphael Stoll, Thorsten Kedziorski, Mhd Ali Nazif, Holger Jastrow, Gunter Wennemuth, Philip Dammann, Martin Feigel, and Dirk Strumberg
Price
42.00 $
Page No. 787
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (787-801)
Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells
David Díaz-Carballo1*, Ali Haydar Acikelli1*, Walter Bardenheuer1, Sebastian Gustmann1, Sascha Malak1, Raphael Stoll2, Thorsten Kedziorski2, Mhd Ali Nazif2, Holger Jastrow3, Gunter Wennemuth3, Philip Dammann4, Martin Feigel5, and Dirk Strumberg1
1Institute of Molecular Oncology and Experimental Therapeutics. Marienhospital Herne, Herne, 2Faculty of Chemistry and Biochemistry, Biomolecular NMR Spectroscopy of Ruhr-University Bochum, Bochum, 3Institute of Anatomy, 4Central Animal Laboratory, University of Duisburg-Essen Medical School, and 5Workgroup Natural Product Chemistry, Faculty of Chemistry and Biochemistry. Ruhr-University Bochum, Bochum, Germany
Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis which could be promising therapeutics or lead structures against therapy-refractory neuroblastoma entities.
*Contributed equallyCorrespondence to:
Dr. David Díaz-Carballo
Institute of Molecular Oncology and Experimental Therapeutics
Marienhospital Herne
Hölkeskampring 40, 44625 Herne, Germany
Email: [email protected]
Case Report
Peripheral mononeuropathy associated with valproic acid poisoning in an adult patient
Srecko Marusic, Paulo Roque Obreli Neto, Vladimira Vuletic, and Marijan Kirin
Price
42.00 $
Page No. 802
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (802-804)
Peripheral mononeuropathy associated with valproic acid poisoning in an adult patient
Srecko Marusic1, Paulo Roque Obreli Neto2, Vladimira Vuletic3, and Marijan Kirin4
1Department of Clinical Pharmacology, University Hospital Dubrava, Zagreb, Croatia, 2Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, Brazil, 3Department of Neurology, and 4Intensive Care Unit, University Hospital Dubrava, Zagreb, Croatia
Objective: To present the case of axillary nerve neuropathy associated with valproic acid (VPA) poisoning. Case report: A 26-year-old man was hospitalized because of a suicide attempt with VPA overdose. Toxicology analysis revealed high serum VPA level (2,896 μmol/L; therapeutic range: 350 – 690 μmol/L). Three days after admission, the patient complained of weakness in his right arm. Neurological examination revealed weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. A nerve conduction velocity test was normal in the ulnar, radial, median, musculocutaneous, and suprascapular nerves. Compoundmuscle action potential showed reduced amplitudeand prolonged latencies in the right axillary nerve taken from Erb’s point and absent taken from distal stimulation point. Right axillary nerve paresis was diagnosed and the patient underwent a physical therapy program, which resulted in gradual recovery. Discussion: In the presented case, other possible causes of neuropathy were excluded by medical history, laboratory and radiological tests, and clinical course of the disease.The temporal relationship between the VPA poisoning and the occurrence of neuropathy supports the hypothesis of a VPA-caused axillary neuropathy. According to the Naranjo’s Adverse Drug Reaction (ADR) ProbabilityScale, VPA-induced neuropathy was rated “probable”. Conclusion: VPA-induced neuropathy may be a serious ADR, but it is potentially preventable and reversible. Thus, clinicians should be aware of this rare ADR.Correspondence to:
Srecko Marusic
Department of Clinical Pharmacology
University Hospital Dubrava
Av. Gojka Suska 6, 10000 Zagreb, Croatia
Email: [email protected]
Bioavailability Section
Bioavailability and bioequivalence of a darunavir 800-mg tablet formulation compared with the 400-mg tablet formulation
Thomas N. Kakuda, Lorant Leopold, Maarten Timmers, Tom Van De Casteele, Vera Hillewaert, Frank L. Tomaka, and Richard M.W. Hoetelmans
Price
42.00 $
Page No. 805
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (805-816)
Bioavailability and bioequivalence of a darunavir 800-mg tablet formulation compared with the 400-mg tablet formulation
Thomas N. Kakuda1, Lorant Leopold1, Maarten Timmers2, Tom Van De Casteele3, Vera Hillewaert2, Frank L. Tomaka1, and Richard M.W. Hoetelmans3
1Janssen Research & Development, LLC, Titusville, NJ, USA, 2Janssen Research & Development, and 3Janssen Infectious Diseases BVBA, Beerse, Belgium
Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden. Objectives: To assess the relative oral bioavailability (NCT01052883) and bioequivalence (NCT01308658) of a darunavir 800-mg tablet vs. 2 × 400-mg tablets. Methods: In two phase I, open-label, randomized, crossover, single-center studies, healthy volunteers received once-daily ritonavir (100 mg, days 1 – 5) and a single 800-mg darunavir dose: 2 × 400-mg tablets (reference) or 1 × 800- mg tablet (test) on day 3 and vice versa after a ≥ 7-day wash-out. Each study had fasted (n = 16 (bioavailability); n = 83 (bioequivalence)) and fed panels (n = 16; n = 45, respectively). Pharmacokinetic profiles and tolerability were assessed. Results: No volunteers discontinued for treatment-related reasons. Least-square mean ratios (test vs. reference) for darunavir maximum plasma concentrations (Cmax), area under the concentration-time curve from zero to infinity (AUC0–∞) were: 1.06 and 1.15 (bioavailability), and 1.02 and 1.00 (bioequivalence), respectively (fasted); 0.89 and 0.88 (bioavailability), and 0.96 and 0.98 (bioequivalence), espectively (fed). 90% confidence intervals (CI) were within 80.00 – 125.00%, except bioavailability AUC0–∞(fed and fasted conditions). Median time to Cmax was comparable for both formulations. No clinically relevant differences in adverse events or laboratory abnormalities occurred between formulations. Conclusions: Bioequivalence was demonstrated for the 800-mg darunavir tablet (fasted and fed conditions). This formulation can reduce pill burden and potentially increase adherence for HIV-1-infected patients in whom once-daily darunavir/ritonavir 800/100 mg is appropriate.Correspondence to:
Dr. Thomas N. Kakuda
Janssen Research & Development, LLC
1125 Trenton-Harbourton Road, K20605
Titusville, NJ 08560-0200, USA
Email: [email protected]
Bioavailability Section
Pharmacokinetic and bioequivalence assessment of two formulations of tianeptine sodium in healthy male volunteers
Renhua Zheng and Bo-Hyung Kim
Price
42.00 $
Page No. 817
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (817-823)
Pharmacokinetic and bioequivalence assessment of two formulations of tianeptine sodium in healthy male volunteers
Renhua Zheng1 and Bo-Hyung Kim1,2
1Department of Clinical Pharmacology and Therapeutics, and 2East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Republic of Korea
Background: Tianeptine is widely used for controlling depressive symptoms. Objective: The aim of this study was to evaluate the bioequivalence between the generic (test) formulation containing tianeptine sodium 12.5 mg and the branded (reference) formulation Stablon® with regard to their pharmacokinetic profiles. Methods: A randomized, two-sequence, two-treatment crossover study was conducted in healthy male Korean volunteers. All of the enrolled subjects were allocated to one of two sequence groups. They were administered a tablet of the test or reference formulation and then administered the alternative formulation after a 7-day washout period. The blood samples were taken before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 10 hours after dosing. The plasma concentrations of tianeptine were analyzed using high-performance liquid chromatography with tandem mass spectrometer. Tolerability was assessed throughout the study. Results: The pharmacokinetic parameters were assessed in the 40 subjects who completed the study. The tianeptine Cmax for the test formulation was 283.13 ± 57.58 ng/mL (mean ± SD) and that for the reference formulation was 272.50 ± 59.00 ng/mL. The AUClast of tianeptine was 803.24 ± 180.94 ng×h/mL for the test formulation and 792.27 ± 180.93 ng×h/mL for the reference formulation. The geometric mean ratio (%) of the test to reference formulation was 104.04 (90% CI, 99.66 – 108.61) for Cmax and 101.30 (98.01 – 104.71) for AUClast. Clinically significant adverse events were not reported during the study. Conclusion: The test and reference formulations of tianeptine were bioequivalent with regard to the pharmacokinetic parameters of Cmax and AUClast. Both formulations were tolerated by all of the participants.Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
East-West Medical Research Institute
Kyung Hee University College of Medicine and Hospital Seoul
23 Kyungheedae-ro, Dongdaemun-gu, Seoul
130-872, Korea
Email: [email protected]
Letter to the Editor
Effects of sugammadex on coagulation: it does not represent a bleeding risk in surgical patients
Michele Carron
Page No. 824
Abstract
Intern. Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 – Letter to the editor
Effects of sugammadex on coagulation: it does not represent a bleeding risk in surgical patients
Michele Carron
Department of Medicine, Anesthesiology and Intensive Care, University of Padova, Padova, Italy
Correspondence to:
Michele Carron, MD, PhD
Department of Medicine, Anesthesiology and Intensive Care
University of Padova
Via C. Battisti, 267, 35121 Padova, Italy
Email: [email protected]
