Volume 52, No. 5/2014(May)
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Original Research
Drug-disease interaction in elderly patients in family practice
Peter Mand, Katharina Roth, Frank Biertz, Markus Kersting, Carsten Kruschinski, Guido Schmiemann, and Eva Hummers-Pradier
Price
42.00 $
Page No. 337
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (337-345)
Drug-disease interaction in elderly patients in family practice
Peter Mand1, Katharina Roth1, Frank Biertz2, Markus Kersting3, Carsten Kruschinski1, Guido Schmiemann4, and Eva Hummers-Pradier5
1Institute of General Practice, 2Institute for Biometry, 3Hannover Unified Biobank, Hannover Medical School, Hannover, 4Institute of Public Health and Nursing Research, Department for Health Services Research, University of Bremen, Bremen, and 5Institute of General Practice/Family Medicine, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany
Objective: To determine the frequency of potential drug-disease interaction in elderly patients in family practice. To assess which drugs and diagnoses are associated with a high risk related to drug-disease interaction and whether there are gender- or age-related differences. Methods: In routinely recorded electronic patient records, patients at least 65 years old with at least one diagnosis named in Beers list and one prescription were identified. Potential drug-disease interaction (PDDI) was presumed if within the same 3 months a “Beers” diagnosis and a potentially inappropriate prescription with respect to this diagnosis were documented for a patient. Multiple logistic regression analysis identified factors associated with a high risk of PDDI. Results: Of 24,619 patients (63.4% women) corresponding to our inclusion criteria, 10.4% were exposed to at least one PDDI. Almost no (0.0%) PDDI was associated with the most common Beers disorder hypertension (prevalence 49.2%). However, 23.4% of men suffering from bladder outflow obstruction (prevalence 17.6% in males) were exposed to at least one PDDI. PDDI was quite common in some rarer conditions, for example, indications for anticoagulation (prevalence 2.6%, 31.5% PDDI). PDDI was not influenced by gender, but associated with taking more than 4 drugs (OR 1.91 (1.83 – 2.00)), suffering from more than one Beers disorder (OR 1.24 (1.16 – 1.31)), and advanced age (OR 1.10 (1.05 – 1.15)). Conclusions: High risk patient groups could be identified. Some disorders as well as some drugs are particularly prone to risky constellations; these should be reflected in systems assisting prescribing with regard to patient safety.Correspondence to:
Prof. Dr., Eva Hummers-Pradier
Institute of General Practice/Family Medicine
University Medical Center, Georg-August-University
Humboldtallee 38, 37073 Göttingen, Germany
Email: [email protected]
Original Research
Efficacy evaluation of methotrexate in the treatment of ankylosing spondylitis using meta-analysis
Zibin Yang, Wei Zhao, Weihua Liu, Qiao Lv, and Xiliang Dong
Price
42.00 $
Page No. 346
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (346-351)
Efficacy evaluation of methotrexate in the treatment of ankylosing spondylitis using meta-analysis
Zibin Yang, Wei Zhao, Weihua Liu, Qiao Lv, and Xiliang Dong
Department of Spinal Surgery, The People’s Hospital of Dali Prefecture, Dali, China
The aim of this study was to evaluate the efficacy of methotrexate (MTX) in the treatment of ankylosing spondylitis (AS). The literature on controlled clinical trials was searched from MEDLINE, EMBASE, OVID, and Cochrane Library databases up to November 2012. The quality of the studies included was evaluated publicly by two reviewers. A meta-analysis was conducted to the homogeneous studies using Cochrane systematic review. Three trials involving 116 patients compared treatment with MTX against placebo. No statistically significant differences (p < 0.05) were found in the primary outcome measures of withdrawal rate, bath ankylosing spondilitis active index (BASDAI), C-reactive protein (CRP), patient global assessment, and side effects such as nausea and vomiting. Two trials involving 142 patients compared treatment with MTX plus infliximab (IFX) against IFX alone in the effect of treatment of AS. No statistically significant differences (p < 0.05) were found in the primary outcome measures of ASAS20 and withdrawal rate. Thus, we should choose the right drugs based on the specific situation in clinical applications. Randomized controlled trials designed rationally and implemented strictly with multi-center, large sample size and enough follow-up time are needed in future research.Correspondence to:
Xiliang Dong, MM
Department of Spinal Surgery
The People’s Hospital of Dali Prefecture,
No. 35 Renmin Road, Dali 671000, China
Email: [email protected]
Original Research
Gender differences in persistency to bisphosphonates in patients with metastatic breast and prostate cancer
Peyman Hadji, Jannis Kyvernitakis, Ute Albert, Joachim Jockwig, and Karel Kostev
Price
42.00 $
Page No. 352
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (352-359)
Gender differences in persistency to bisphosphonates in patients with metastatic breast and prostate cancer
Peyman Hadji1, Jannis Kyvernitakis1, Ute Albert1, Joachim Jockwig2, and Karel Kostev1,2,3
1Philipps-University of Marburg, Department of Gynecology, Gynecological Endocrinology and Oncology, Marburg, 2Fresenius University of Applied Sciences, Health and Social faculty, Idstein, and 3IMS Health, Frankfurt, Germany
Background: Bisphosphonates (BIS) treatment is a standard of care in metastatic bone disease (MBD) and regular intake is of upmost importance to ensure the effectiveness. The aim of this study was to investigate gender specific differences in persistence with BIS in MBD for the first time in this regard. Patients and methods: Out of the original database of 16 million patients, we extracted first-time metastatic cancer related BIS prescriptions from January 2001 to December 2011 in patients diagnosed with MBD following breast cancer (BC) or prostate cancer (PC). Patients were matched (1 : 1) in accordance to age. For persistence analyses, 1,007 patients with metastatic BC and PC were available. Results: After 1 year of follow-up, 35.3% of BC and 26.6% of PC patients treated with BIS discontinued their treatment (p < 0.001). The differences were irrespective of increased refill gaps and route of BIS administration. The multivariate hazard ratios of the Cox regression models for 1-year risk of BIS discontinuation (adjusting for multiple variables) showed no increased risk for treatment discontinuation for BC vs. PC patients (HR: 0.87; 95% CI: 0.65 – 1.17). The use of co-medications decreased, regional and insurance aspects increased the risk of treatment discontinuation (HR of 0.88, 1.50, and 1.42). Conclusions: Although apparent in the primary analysis, we found no significant difference in the gender specific persistency after 12 months of first BIS treatment in MBD. Only co-medication, geographical and insurance aspects were associated with differences in discontinuation rates. Further studies are needed to investigate this clinically important relationship.Correspondence to:
Dr. Karel Kostev
IMS Health
Darmstädter Landstraße 108
60598 Frankfurt/Main, Germany
Email: [email protected]
Original Research
Active vitamin D analogs, maxacalcitol and alfacalcidol, as maintenance therapy for mild secondary hyperparathyroidism in hemodialysis patients – a randomized study
Hirokazu Honda, Fumihiko Koiwa, Hiroaki Ogata, Kanji Shishido, Takashi Sekiguchi, Tetsuo Michihata, Hajime Ogawa, Masanori Mukai, Keiko Takahashi, Ryuji Suzuki, Kyoko Kino, Kenichi Kato, Koji Yamamoto, Eriko Kinugasa, and Tadao Akizawa
Price
42.00 $
Page No. 360
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (360-368)
Active vitamin D analogs, maxacalcitol and alfacalcidol, as maintenance therapy for mild secondary hyperparathyroidism in hemodialysis patients – a randomized study
Hirokazu Honda1, Fumihiko Koiwa2, Hiroaki Ogata3, Kanji Shishido4, Takashi Sekiguchi5, Tetsuo Michihata6, Hajime Ogawa7, Masanori Mukai8, Keiko Takahashi4, Ryuji Suzuki9, Kyoko Kino10, Kenichi Kato11, Koji Yamamoto12, Eriko Kinugasa3, and Tadao Akizawa1
1Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, 2Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, 3Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, 4Kawasaki Clinic, Kawasaki, 5Sekiguchi Naika Clinic, Hachinohe, 6Ebara Clinic, 7Ogawa Clinic, 8Yukigaya Sanwa Clinic, 9Hitotsubashi Hospital, Tokyo, 10Bousei Hospital, Saitama, 11Yamanashi Red Cross Hospital, Minamituru, and 12Hatanodai Koike Clinic, Tokyo, Japan
Background: The present randomized study was designed to compare the efficacy between two active vitamin D analogs, alfacalcidol (ACD) and maxacalcitol (OCT), for the management of mild secondary hyperparathyroidism (SHPT) in dialysis patients. Methods: SHPT in all 32 patients analyzed in the study was initially treated with OCT. Once patients’ intact PTH levels decreased to the target range of 150 – 180 pg/mL, they were randomized either to switch to ACD at 0.5 μg/day (n = 14), or to remain on an effectively unchanged dose of OCT (n = 13). Phosphate, calcium, and intact PTH levels were measured every 2 weeks for 12 weeks and vitamin D doses were changed according to target ranges of phosphate (3.5 – 6.0 mg/dL), calcium (albuminadjusted calcium: 8.4 – 10.0 mg/dL), and intact parathyroid hormone (60 – 180 pg/mL). Achievement rates of the target ranges of the parameters were estimated. Results: Baseline calcium levels in the OCT group were significantly higher than in the ACD group. Changes in achievement rates of target ranges of intact PTH and calcium during the study did not differ significantly between the vitamin D drugs. Changes in calcium levels in the OCT and ACD groups were similar during the study. Achievement rates of the target range of phosphate in both groups were also similar until 8 weeks, although the rate in the OCT group declined at 10 weeks. Conclusions: The efficacy and safety of OCT for the treatment of mild SHPT are similar to those of ACD in hemodialysis patients.Correspondence to:
Hirokazu Honda, MD, PhD
Division of Nephrology, Department of Medicine
Showa University School of Medicine
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 141-8666, Japan
Email: [email protected]
Original Research
Effect of dual bronchodilation with QVA149 on cardiac safety in healthy volunteers
Anton Drollmann, Matthew Brown, Romain Sechaud, Sheryl Perry, Hisanori Hara, Ieuan Jones, and Salvatore Febbraro
Price
42.00 $
Page No. 369
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (369-380)
Effect of dual bronchodilation with QVA149 on cardiac safety in healthy volunteers
Anton Drollmann1, Matthew Brown2, Romain Sechaud1, Sheryl Perry2, Hisanori Hara1, Ieuan Jones1, and Salvatore Febbraro3
1Novartis Institutes for BioMedical Research, Basel, Switzerland, 2Novartis Institutes for BioMedical Research, Horsham, and 3Simbec-Altasciences, Merthyr Tydfil, UK
Objectives: QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects. Methods: This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs. placebo in healthy subjects. Similar analyses were done for QVA149 vs. indacaterol 600 μg, glycopyrronium 200 μg, and salmeterol 200 μg. The time-matched and average change from baseline in QT interval corrected for HR using Fridericia’s formula (QTcF), effects on serum potassium and blood glucose, pharmacokinetic (PK) parameters, and safety were also assessed. Results: Of 50 subjects randomized, 43 completed the study. QVA149, when compared with placebo, showed the time-matched largest mean increase and decrease in HR of 5.69 bpm and –2.51 bpm, respectively, and average HR change from baseline of 0.62 bpm. QVA149 showed no tachycardic potential compared with indacaterol and no relevant tachycardic effect compared with glycopyrronium. No consistent differences were seen in the time-matched largest mean change and average change from baseline in QTcF for QVA149 vs. other treatments. There were no relevant effects of QVA149 on serum potassium and blood glucose. There was no apparent PK/PD relationship between the observed exposures to indacaterol and glycopyrronium in QVA149 on HR and QTcF. There were no deaths or serious adverse events. Conclusion: Overall, short-term administration of QVA149 showed a good cardiovascular safety and tolerability profile in healthy subjects.Correspondence to:
Anton Drollmann
Translational Medicine
Novartis Institutes for BioMedical Research
Building WSJ 386.12.48.50, Postfach
4002 Basel, Switzerland
Email: [email protected]
Original Research
Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg × 2 tablets) fixeddose combination tablet in healthy male volunteers
Hee Youn Choi, Yook-Hwan Noh, Yo Han Kim, Mi Jo Kim, Shi Hyang Lee, Jeong-Ae Kim, Bogyeong Kim, Hyeong-Seok Lim, and Kyun-Seop Bae
Price
42.00 $
Page No. 381
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (381-391)
Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg × 2 tablets) fixeddose combination tablet in healthy male volunteers
Hee Youn Choi1, Yook-Hwan Noh1, Yo Han Kim1, Mi Jo Kim1, Shi Hyang Lee1, Jeong-Ae Kim2, Bogyeong Kim2, Hyeong-Seok Lim1, and Kyun-Seop Bae1
1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, and 2LG Life Sciences, Ltd., Seoul, Korea
Objectives: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. Materials and methods: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. Results: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 – 1.006) and 1.021 (90% CI 0.949 – 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 – 0.923) and 1.144 (90% CI 1.013 – 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. Conclusion: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.Correspondence to:
Kyun-Seop Bae, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Asan Medical Center
88, Olympic-ro 43-gil, Songpa-gu
Seoul, 138-736, Korea
Email: [email protected]
Original Research
A 6-year retrospective study of adverse drug reactions due to drug-drug interactions between nervous system drugs
Qing-ping Shi,, Xian-di He, Mei-ling Yu, Jin-xiu Zhu, Yan Liu, Feng Ding, Rang Sang, Xiao-dong Jiang, and Shu-qiang Zhang
Price
42.00 $
Page No. 392
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (392-401)
A 6-year retrospective study of adverse drug reactions due to drug-drug interactions between nervous system drugs
Qing-ping Shi1,2, Xian-di He3*, Mei-ling Yu1, Jin-xiu Zhu1, Yan Liu1, Feng Ding1, Rang Sang1, Xiao-dong Jiang1, and Shu-qiang Zhang4
1Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 2Education and Research Center, Bengbu Medical College, 3Intensive Care Unit, The First Affiliated Hospital of Bengbu Medical College, and 4Center of Adverse Drug Reaction Monitoring, Bengbu Food and Drug Administration, Bengbu, China
Objective: The primary objective of this study was to determine the frequency and characteristics of adverse drug reactions (ADRs) due to drug-drug interactions (DDIs) between nervous system drugs recorded for hospitalized patients in China. The secondary objective was to identify and record the possible mechanisms underlying these DDIs. Methods: In this retrospective study performed from January 2007 to December 2012, we detected and analyzed ADRs caused by potential or actual DDIs between nervous system drugs, by using the Center of Adverse Drug Reaction Monitoring, Bengbu Food and Drug Administration (CADRMBFDA) database. Results: The CADRMBFDA database contained 1,207 reports of ADRs due to nervous system drugs, involving 1,079 hospitalized patients. Of the ADRs reported, 131 (12.14%) were associated with potential and actual DDIs. There were 259 (21.46% of the total ADR reports) reports on potential and actual DDIs. The proportion of serious ADRs (6 out of 131) was significantly higher among actual DDI reports (p < 0.001) than among the remaining reports (6 out of 942). Conclusions: The results of our study confirmed that the CADRMBFDA database was a valuable resource for detecting actual DDIs. Moreover, the database helps identify drugs that can cause serious ADRs, thus indicating focus areas for healthcare education.Correspondence to:
Xian-di He
Intensive Care Unit
The First Affiliated Hospital of Bengbu Medical College
287 Changhuai Road, Bengbu, 233004, China
Email: [email protected]
Original Research
Zopiclone induced methemoglobinemia and hemolytic anemia
Thomas Y.K. Chan
Price
42.00 $
Page No. 402
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (402-406)
Zopiclone induced methemoglobinemia and hemolytic anemia
Thomas Y.K. Chan
Division of Clinical Pharmacology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
Objective: To characterize the risk of methemoglobinemia and hemolytic anemia following large overdoses of zopiclone, a cyclopyrrolone hypnotic-sedative and a racemic mixture of R-zopiclone and S-zopiclone (eszopiclone). Methods: This review included all reports of zopiclone induced methemoglobinemia, hemolytic anemia, and oxidative stress that had been published in medical journals or discussed in continuous medical education (CME) programs. These reports were identified by searching the Medline (1980 – December 9, 2013), China Journal Net (1994 – December 2013), and Google Scholar, using zopiclone, eszopiclone, methemoglobinemia, hemolytic anemia, and oxidative stress as the search terms. Results: Six cases of methemoglobinemia, one case of methemoglobinemia, with concomitant hemolytic anemia, and one case of hemolytic anemia were identified. These complications occurred after large zopiclone overdoses (450 – 3,750, 1,125 – 1,500, and 375 – 750 mg, respectively, i.e., 60 – 500, 150 – 200, and 50 – 100 times the daily dose of 7.5 mg). The resulting methemoglobinemia could be severe (19.4 – 24.5%), while the hemolytic anemia was mild (Hb 9.0 – 9.6 g/dL). Molecular modelling analyses indicate that eszopiclone and its two metabolites will be kinetically labile. Their molecular surfaces have significant amounts of electron-deficient regions. All three compounds are expected to react with cellular nucleophiles, such as glutathione, causing its depletion and oxidative stress. Conclusions: After large overdoses, zopiclone, alone or together with its metabolites, most probably causes oxidative stress in erythrocytes to account for the methemoglobinemia and hemolytic anemia. Further studies are required to determine their incidence and the dose-related capacity of zopiclone and its metabolites in producing erythrocyte oxidative stress.Correspondence to:
Thomas YK Chan, MD, PhD
Division of Clinical Pharmacology
Department of Medicine and Therapeutics
Faculty of Medicine
The Chinese University of Hong Kong, Prince of Wales Hospital
Shatin, New Territories, Hong Kong, China
Email: [email protected]
Original Research
Pharmacokinetics and safety profiles of novel diethylstilbestrol orally dissolving film in comparison with diethylstilbestrol capsules in healthy Chinese male subjects
Hong Zhang, Hong Chen, Xiao-Jiao Li, Qi Zhang, Yan-Fu Sun, Cheng-Jiao Liu, Li-Zhi Yang, and Yan-Hua Ding
Price
42.00 $
Page No. 407
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (407-415)
Pharmacokinetics and safety profiles of novel diethylstilbestrol orally dissolving film in comparison with diethylstilbestrol capsules in healthy Chinese male subjects
Hong Zhang, Hong Chen, Xiao-Jiao Li, Qi Zhang, Yan-Fu Sun, Cheng-Jiao Liu, Li-Zhi Yang, and Yan-Hua Ding
Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China
Objective: We compared the pharmacokinetic (PK) profiles of diethylstilbestrol orally dissolving film (DES ODF) and DES-capsule as well as assessing the safety, local tolerability, taste, and disintegration time of DES ODF. Materials and methods: Twelve healthy male volunteers receiving a single administration of 2.0 mg of DES ODF or DES-capsule were included in the study. The tolerability, taste, and time to dissolution of DES ODF were assessed after dosing. Safety assessments included adverse events, hematology and biochemistry tests, urinalysis, vital signs, and electrocardiography. Results: The PK parameters of DES ODF were all greater than those of DEScapsule. The Cmax values were 5.64 ± 1.1 and 3.4 ± 1.93 ng/mL for DES ODF and DES-capsule, respectively. Assessment of bioequivalence was based on the 90% CIs of the treatment ratios of the log-transformed Cmax, AUC0–t, and AUC0–∞ (DES ODF to DES-capsule), with the mean values being 1.93 (141 – 264), 1.24 (98 – 156), and 1.59 (121 – 207), respectively, indicating that DES ODF had a significantly high bioavailability. The mean DES ODF disintegration time was 14 ± 5 minutes. DES ODF was well tolerated and no serious adverse events or clinically relevant changes were observed. Conclusions: The DES ODF is well tolerated and better absorbed in comparison with DES-capsule.Correspondence to:
Dr. Yan-Hua Ding
Phase I Clinical Trial Unit, The First Hospital
Jilin University, Changchun 130021, China
Email: [email protected]
Original Research
Tetrandrine enhances the anticancer effects of arsenic trioxide in vitro
Youran Chen, Peichun Li, Shen Yang, Nannan Tong,·Jie Zhang and Xiaoyan Zhao
Price
42.00 $
Page No. 416
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (416-424)
Tetrandrine enhances the anticancer effects of arsenic trioxide in vitro
Youran Chen1, Peichun Li1, Shen Yang1, Nannan Tong1,·Jie Zhang3 and Xiaoyan Zhao1,2
1College of Pharmaceutical Sciences, Southwest University, Chongqing, 2Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, and 3Department of Neurology, The Ninth People’s Hospital of Chongqing, Chongqing, China
Arsenic trioxide (As2O3), an effective agent to treat leukemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden death have been implicated in the cardiotoxicity of As2O3. The present study was designed to assess whether the combination of As2O3 and tetrandrine could generate a more powerful anti-cancer effect. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed for detecting the proliferation of HepG2 and A549 cells treated with tetrandrine and As2O3. Fluorescent microscopy measurements and flow cytometry were carried out to evaluate the apoptosis in HepG2 cells. The cell cycle arrest of HepG2 cells was also determined by flow cytometry. The cell proliferation assay in HepG2 and A549 cells indicated that tetrandrine significantly enhanced the inhibit effect of As2O3. In addition, the following Isobolograms further demonstrated that combining As2O3 with tetrandrine generated synergism action. Tetrandrine also enhanced the apoptosis, necrosis and cell cycle arrest in As2O3-treated HepG2 cells. Our present study showed that tetrandrine can dramatically enhance the anti- cancer effect induced by As2O3. Combining As2O3 with tetrandrine would be a novel strategy to treat cancer in clinical practice.Correspondence to:
Dr. Xiaoyan Zhao
College of Pharmaceutical Sciences
South west University
Chongqing 400716, China
and to
Dr. Jie Zhang
Depatment of Neurology
The 9th People’s Hospital of Chongquing
Chongquing 400700, China
Email: [email protected] and [email protected]
Bioavailability Section
Bioequivalence study of two commercial amoxicillin suspension formulations in healthy human volunteers
Gilson C.N. Franco, Sinvaldo Baglie, Ana P.B. Ruenis, Luiz M. Franco, Karina Cogo, Yoko Oshima-Franco, Paulo Silva, Francisco C. Groppo, and Pedro Luiz Rosalen
Price
42.00 $
Page No. 425
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (425-430)
Bioequivalence study of two commercial amoxicillin suspension formulations in healthy human volunteers
Gilson C.N. Franco1,8, Sinvaldo Baglie2, Ana P.B. Ruenis3, Luiz M. Franco4, Karina Cogo5, Yoko Oshima-Franco6, Paulo Silva7, Francisco C. Groppo8, and Pedro Luiz Rosalen8
1Department of General Biology, Area of Physiology and Pathophysiology, 2Department of Pharmaceutical Sciences, Area of Pharmacology, State University of Ponta Grossa, Ponta Grossa, 3Activa-CRO do Brasil, São Paulo, 4Faculty of Health Sciences, Methodist University of Piracicaba, Piracicaba, 5Department of Dentistry, Implantology Area, University of Santo Amaro, São Paulo, 6Post Graduate Course in Pharmaceutical Sciences, University of Sorocaba, Sorocaba, 7Bioagri Laboratórios Ltda, and 8Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Purpose: To compare the pharmacokinetic profiles and to evaluate the bioequivalence of two commercial amoxicillin suspension formulations (500 mg/5 mL AMOXIL®, reference formulation and AMOXI-PED®, test formulation) in healthy Brazilian volunteers. Methods: Under fasting condition, 25 volunteers (13 males and 12 females) were included in this randomized, open-label, two-period crossover (1-week washout interval) bioequivalence study. Blood samples were collected at pre-dose (0 hour) and 0.5, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, and 12 hours after drug ingestion. Pharmacokinetic parameters (Cmax, tmax, t1/2, AUC0–tlast, and AUC0–∞) were calculated from plasma concentrations for both formulations in each subject. Results: Arithmetic mean values of the pharmacokinetic parameters were: Cmax = 12.004 (± 2.824) μg×mL–1; tmax = 1.118 (± 0.396) h; t1/2 = 1.226 (± 0.179) h; AUC0–tlast = 29.297 (± 6.007) μg×h×mL–1; and AUC0–∞ = 29.299 (± 6.007) μg×h×mL–1 for reference formulation and Cmax = 11.456 (± 2.825) μg×mL–1; tmax = 1.331 (± 0.509) h; t1/2 = 1.141 (± 0.133) h; AUC0–tlast = 28.672 (± 5.778) μg×h×mL–1; and AUC0–∞ = 28.693 (± 5.796) μg×h×mL–1 for test formulation. The confidence intervals (90% CI) for reference and test formulations were, respectively, 90.74 – 100.46% for Cmax and 93.62 – 103.61% for AUC0–t. Conclusion: Based on the results, both formulations of amoxicillin evaluated in this study were considered bioequivalent according to FDA and ANVISA/Brazil criteria.Correspondence to:
Prof. Pedro Luiz Rosalen
Department of Physiological Sciences
Piracicaba Dental School, University of Campinas
Av. Limeira, 901, 13414-903 Piracicaba, SP, Brazil
Email: [email protected]
Bioavailability Section
Pharmacokinetics and bioequivalence study of irbesartan tablets after a single oral dose of 300 mg in healthy Thai volunteers
Supeecha Wittayalertpanya, Pajaree Chariyavilaskul, Nantaporn Prompila, Nonlanee Sayankuldilok and Wanna Eiamart
Price
42.00 $
Page No. 431
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (431-436)
Pharmacokinetics and bioequivalence study of irbesartan tablets after a single oral dose of 300 mg in healthy Thai volunteers
Supeecha Wittayalertpanya1, Pajaree Chariyavilaskul1, Nantaporn Prompila2, Nonlanee Sayankuldilok2, and Wanna Eiamart2
1Department of Pharmacology, and 2Chula Pharmacokinetic Research Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Objective: Pharmacokinetics and bioequivalence of 300 mg irbesartan tablets were studied in 26 healthy Thai male volunteers. Methods: A single oral dose of one 300 mg tablet of the test product and the reference product was given to each volunteer according to a randomized two-way crossover design with 1-week wash out period. Blood samples were collected at predetermined time intervals until 72 hours post dose and irbesartan concentration was quantified with a validated HPLC method. Individual plasma irbesartan concentration-time profile was analyzed for pharmacokinetic parameters. Results: Maximum plasma concentrations (Cmax) of 3,617.19 and 3,295.77 ng/mL for test and reference, respectively, were achieved. Areas under the plasma concentration-time curve; AUC0–t and AUC0–∞ were 15,304.65 and 15,638.90 ng×h/mL for test and 15,389.21 and 15,730.34 ng×h/mL for reference. The median tmax was 1.50 hours and 1.25 hours for test and reference, respectively. Plasma elimination half-lives (t1/2) were 7.35 hours and 8.09 hours for test and reference, respectively. Primary pharmacokinetic parameters Cmax, AUC0–t, and AUC0–∞ were tested parametrically by analysis of variance (ANOVA), and it revealed no statistically significant difference (defined as p < 0.05) between the corresponding Cmax, AUC0–t, and AUC0–∞ with respect to sequence, volunteers, period and formulation. The 90% confidence intervals for the ratio of test and reference product of the parameters Cmax, AUC0–t, and AUC0–∞ were within 80 – 125% (100.13 – 121.40% for Cmax, 90.83 – 106.86% for AUC0–t and 91.11 – 106.55% for AUC0–∞). Conclusion: The two products were bioequivalent in terms of both rate and extent of drug absorption into systemic circulation.Correspondence to:
Supeecha Wittayalertpanya
Department of Pharmacology, Faculty of Medicine
Chulalongkorn University, Bangkok 10330, Thailand
Email: [email protected]
