Volume 52, No. 10/2014(October)
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Original
Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: determining statistical equivalence according to evidence-based methods
Andrea Messori, Valeria Fadda, Dario Maratea, Roberta Gatto, Sabrina Trippoli, Mauro De Rosa, and Claudio Marinai
Price
42.00 $
Page No. 825
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (825-829)
Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: determining statistical equivalence according to evidence-based methods
Andrea Messori1, Valeria Fadda3, Dario Maratea3, Roberta Gatto1, Sabrina Trippoli1, Mauro De Rosa3, and Claudio Marinai2
1HTA Unit, 2Department of Pharmaceutical Logistics, ESTAV Toscana Centro, Regional Health Service, Florence, and 3The BW Project, Sifact, Società Italiana di Farmacia Clinica e Terapia, Milan, Italy
Background: Although intravenous proton pump inhibitors (PPIs) are considered at least as effective as H2-receptors antagonists for stress ulcer prophylaxis (SUP) in critically ill patients, there is no data on whether there is also the proof of no difference among these agents. Methods: The clinical material was the same as that reported in previous meta- analyses and included all trials comparing intravenous PPIs vs. H2-receptor antagonists for SUP in critically ill patients. Our methodology was a combination of meta-analysis and equivalence testing based on confidence intervals (CIs). The end-point was the rate of overt bleeding. All PPIs evaluated in the included trials were separately studied. The equivalence margins were derived from power calculation data of the original trials. Results: Our analysis involved 8 randomized trials for 851 patients. Two comparisons were made (pantoprazole vs. H2-receptor antagonists and omeprazole vs. H2-receptor antagonists). The following RDs were estimated: pantoprazole, RD = –1.2%, 95% CI: –3.5% to +1.2%; omeprazole, RD = –3.0%, 95% CI: –7.2% to +1.3%. The 95% CIs confidence intervals for RDs remained within the ± 6% margin. These results indicate that intravenous pantoprazole and intravenous omeprazole are equivalent, Conclusion: These two PPIs, when administered by intravenous route, are equivalent according to reasonable equivalence margins. This conclusion can be the basis to develop local acquisition tenders on these drugs. One advantage of this approach is that the feasibility of administrative decisions can directly be tested on clinical grounds and on the basis of standard evidence-based methods.Correspondence to:
Dr. Andrea Messori, HTA Unit
Area Vasta Centro Toscana, Regional Health System
Via San Salvi 12, 50100 Florence, Italy
Email: [email protected]
Original
Open-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjects
Alice I. Nichols, Shannon Lubaczewski, Yali Liang, Kyle Matschke, Gabriel Braley, and Tanya Ramey
Price
42.00 $
Page No. 830
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (830-841)
Open-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjects
Alice I. Nichols1, Shannon Lubaczewski1, Yali Liang2, Kyle Matschke1, Gabriel Braley2, and Tanya Ramey2
1Pfizer Inc, Collegeville, PA and 2Pfizer Inc, Groton, CT, USA
Background: Potential drugdrug interactions are a concern for patients taking tamoxifen. Objective: This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. Materials and methods: This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUCinf), AUC to the last measurable concentration (AUClast), peak plasma concentration (Cmax)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 – 125%. Results: Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUCinf, AUClast, and Cmax, as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUClast and Cmax, respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). Conclusions: Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.Correspondence to:
Alice I. Nichols, PhD
Department of Clinical Pharmacology
Primary Care Business Unit, Pfizer Inc
500 Arcola Road, Collegeville, PA 19426, USA
Email: [email protected]
Original
A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers
Maurizio Caserini, Milko Radicioni, Chiara Leuratti, Ottavia Annoni, and Renata Palmieri
Price
42.00 $
Page No. 842
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (842-849)
A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers
Maurizio Caserini1, Milko Radicioni2, Chiara Leuratti2, Ottavia Annoni2, and Renata Palmieri1
1Polichem S.A., Lugano-Pazzallo, and 2CROSS Research S.A., Arzo, Switzerland
Objective: Finasteride, a selective inhibitor of type 2 5-α reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. Methods: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. Results: After multiple doses, mean (± SD) finasteride Cmax and AUC0–t corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL×h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL×h for the tablet. Plasma DHT was reduced by ~ 68 – 75% with the topical solution and by ~ 62 – 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred. Conclusions: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).Correspondence to:
Dr. Renata Palmieri
Polichem S.A.
Via Senago 42D
CH-6912, Lugano-Pazzallo, Switzerland
Email: [email protected]
Original
Effects of genetic polymorphisms of CYP2C19*2/*3 and MDR1 C3435T on the pharmacokinetics of lansoprazole in healthy Chinese subjects
Yu-Xin Zhang,·Shi-Jie Wei,·Xiao-Ying Yang,·Wen-Ping Zhang, Xin-Yu Wang, and·Hong-Wan Dang
Price
42.00 $
Page No. 850
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (850-855)
Effects of genetic polymorphisms of CYP2C19*2/*3 and MDR1 C3435T on the pharmacokinetics of lansoprazole in healthy Chinese subjects
Yu-Xin Zhang,·Shi-Jie Wei,·Xiao-Ying Yang,·Wen-Ping Zhang, Xin-Yu Wang, and·Hong-Wan Dang
1Institute of Clinical Pharmacology & Department of Pharmacy, General Hospital of Ningxia Medical University, and 2School of pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
Objectives: To evaluate the influence of CYP2C19*2/*3 and MDR1 C3435T polymorphisms on the pharmacokinetics of lansoprazole (LPZ) in healthy Chinese subjects. Methods: All 24 subjects were from a study of bioequivalence. Plasma concentrations of LPZ were determined by liquid chromatography/mass spectrometry. Cytochrome P450 (CYP) 2C19*2/*3 and multidrug resistance transporter gene 1 (MDR1) C3435T of the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: Significant differences were found in the area under the concentration-time curve from predose to T (AUC0–T), area under the concentration-time curve from predose to infinity (AUC0–∞, t1/2), and apparent oral clearance (CL/F) of LPZ between CYP2C19 extensive metabolizers and intermediate metabolizers (p < 0.05). The AUC0–T, AUC0–∞, maximum plasma concentration, and CL/F of LPZ were significantly different between subjects with the MDR1 C3435T C/C, C/T, and T/T polymorphisms (p < 0.05). Conclusion: CYP2C19*2/*3 and MDR1 C3435T polymorphisms are important determinants of LPZ pharmacokinetics.Correspondence to:
Prof. Hong-Wan Dang
Institute of Clinical Pharmacology and Department of Pharmacy
General Hospital of Ningxia Medical University
Yinchuan 750004, Ningxia, China
Email: [email protected]
Original
Implications of different application sites on the bioavailability of a transdermal contraceptive patch containing ethinyl estradiol and gestodene: an open-label, randomized, crossover study
Joachim Höchel, Barbara Schuett, Matthias Ludwig, and Christian Zurth
Page No. 856
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (856-866)
Implications of different application sites on the bioavailability of a transdermal contraceptive patch containing ethinyl estradiol and gestodene: an open-label, randomized, crossover study
Joachim Höchel, Barbara Schuett, Matthias Ludwig, and Christian Zurth
Bayer Pharma AG, Berlin, Germany
Objectives: A novel once-aweek contraceptive patch delivers the same systemic exposure seen with a combined oral contraceptive pill containing 0.02 mg ethinyl estradiol (EE) and 0.06 mg gestodene (GSD). This study evaluated the relative bioavailability of EE and GSD after application of this patch to three different sites. Methods: In this phase I, open-label, randomized, intra-individual comparison, crossover study, 43 women (aged 18 – 45 years) were randomized to one of six treatment sequences. Patches were applied to two test sites (buttocks and outer, upper arm) and one comparator site (lower abdomen). In each treatment period, four patches were worn for 7 days each, followed by a 7-day, patch-free interval. The primary objective was to investigate the relative bioavailability of transdermally administered EE and GSD between test and comparator sites using the primary variable area under the concentration- time curve (AUC(0–168)) during week 4 of each period. Results: Of the 43 women who were randomized, 43 were included in the set for safety evaluation and 40 were included in the set for pharmacokinetic (PK) analysis. Three subjects were excluded from the PK analysis as they failed to complete the study. AUC(0–168) for EE and GSD were equal when the patch was applied to buttocks or abdomen (AUC(0–168) ratios: EE, 1.07 (94% confidence interval, CI: 0.994 – 1.16); GSD, 1.02 (94% CI: 0.946 – 1.10)). Relative bioavailabilities for EE and GSD were 31% and 24% higher, respectively, for arm vs. abdomen. AUC(0–168) 94% CI for the arm/abdomen ratio exceeded the pre-defined bioequivalence range of 80 – 125% (EE: 1.21 – 1.42; GSD: 1.15 – 1.34). Other PK parameters were correspondingly higher for arm vs. buttocks or abdomen. Patch adhesion and tolerability were good, with no relevant differences between sites. Conclusion: Differences in systemic EE/GSD exposure following patch application to the outer, upper arm vs. lower abdomen and buttocks are unlikely to be clinically relevant, and there were no relevant safety concerns.Correspondence to:
Dr. Joachim Höchel
Bayer Pharma AG, Clinical Sciences
Müllerstraße 178, 13342 Berlin, Germany
Email: [email protected]
Original
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects
Prafull Mistry, Juliet Reid, Isabelle Pouliquen, Simon McHugh, Lee Abberley, Stephen DeWall, Adam Taylor, Xin Tong, Marian Rocha del Cura, and Elizabeth McKie
Price
42.00 $
Page No. 867
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (867-879)
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects
Prafull Mistry1, Juliet Reid1, Isabelle Pouliquen2, Simon McHugh3, Lee Abberley4, Stephen DeWall4, Adam Taylor1, Xin Tong1, Marian Rocha del Cura1, and Elizabeth McKie1
1GlaxoSmithKline, Stevenage, 2GlaxoSmithKline, Uxbridge, 3GSK R&D, Addenbrooke’s Centre for Clinical Investigation, Cambridge, UK, and 4GlaxoSmithKline, King of Prussia, PA, USA
Objective: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK1070806, a novel IgG1 mAb that neutralizes human interleukin (IL)-18. Methods: In this first-timein-human (FTIH) study, cohorts of healthy and obese subjects were randomly allocated to receive single doses of GSK1070806 (0.008 – 10 mg/kg) or placebo. Blood was sampled ≤ 274 days post-dosing, and safety monitored. Results: GSK1070806 was generally well tolerated. The most common AEs were nasopharyngitis and headache, arising as frequently in the placebo as in the active drug groups; most AEs were mild to moderate and unrelated to dose level. There were no allergic, delayed-type hypersensitivity, or infusion-related reactions and the incidence of immunogenicity was low. GSK1070806 plasma pharmacokinetic profiles were comparable in healthy and obese subjects; there was no major deviation from dose proportionality for AUC∞ and Cmax although a trend for dose-dependent increase in t1/2 was observed. Serum drug-bound IL-18 levels increased post-dosing and were sustained for a long time-period following GSK1070806 administration. Ex-vivo whole blood assay demonstrated prolonged pharmacological activity of GSK1070806 as determined by its primary immunological mechanism of action, inhibition of IL-18-induced IFN-γ production.Conclusion: GSK1070806 warrants clinical investigation in patients.Correspondence to:
Dr. Elizabeth McKie
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
Email: [email protected]
Original
Leishmanicidal and apoptotic activities of oleuropein on Leishmania major
Maha H. Elamin and Salyha S. AL-Maliki
Price
42.00 $
Page No. 880
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (880-888)
Leishmanicidal and apoptotic activities of oleuropein on Leishmania major
Maha H. Elamin and Salyha S. AL-Maliki
Department of Zoology, College of Science, King Saud University, University Center for Women Students, Riyadh, Saudi Arabia
Background: Leishmania is a unicellular protozoan parasite causing a wide range of human diseases ranging from localized self-healing cutaneous lesions to fatal visceral infections. Objective: The aim of the present study is to assess the cytotoxic, anti-proliferative, and apoptotic effects of oleuropein on Leishmania major promastigotes (MHOM/SA/84/JISH) and to compare its effects with the reference drug sodium stibogluconate (pentostam). Methods: Cytotoxicity and promastigote proliferation were measured using MTT colorimetric assay. Furthermore, the Annexin V/propidium iodide staining technique followed by flow cytometry was used for studying the cell death properties of oleuropein. Results: In the present report we have shown that oleuropein, a pharmacologically safe, natural product of olive leaf, has a potent leishmanicidal effect. Indeed, oleuropein exhibits cytotoxic and anti-proliferative effects against Leishmania major promastigotes. Moreover, oleuropein triggers death through apoptosis, whereas pentostam induces death mainly via necrosis on Leishmania major promastigotes. Conclusion: Here we demonstrate for the first time that the non-toxic, natural product oleuropein has apoptotic properties against Leishmania major promastigotes. Further studies are needed to investigate its molecular pathway.Correspondence to:
Maha H. Elamin, Associate Professor
College of Science, Department of Zoology
University Centre for Women Students
King Saud University
P.O. Box 22452, Riyadh 11495, Saudi Arabia
Email: [email protected]
Original
Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects
Xia Chen, Teddy Kosoglou, Paul Statkevich, Bharath Kumar, Jing Li, Marissa F. Dockendorf, Guoqin Wang, Robert S. Lowe, Ji Jiang, Hongzhong Liu, Zaiqi Wang, David L. Cutler, and Pei Hu
Price
42.00 $
Page No. 889
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (889-899)
Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects
Xia Chen1, Teddy Kosoglou2, Paul Statkevich2, Bharath Kumar2, Jing Li2, Marissa F. Dockendorf2, Guoqin Wang3, Robert S. Lowe2, Ji Jiang1, Hongzhong Liu1, Zaiqi Wang3, David L. Cutler2, and Pei Hu1
1Phase 1 Unit, Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China, 2Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA, and 3MSD R&D (China) Co., Ltd., Chaoyang District, Beijing, China
Aim: Vorapaxar is a proteaseactivated receptor (PAR)-1 antagonist being developed for the prevention and treatment of thrombotic vascular events. To evaluate race/ethnic differences between Caucasians and Chinese in the pharmacokinetics of vorapaxar and its active metabolite SCH 2046273 (M20) or in the metabolite/parent ratio, we conducted a cross-study comparison on pharmacokinetic data of vorapaxar and M20 obtained from two similarly designed studies: one in healthy Chinese subjects and the other in a healthy Western (United States, [U.S.]) population. Methods: The pharmacokinetic profiles of vorapaxar and M20 were characterized using open label, two treatment parallel group designs in men and women aged 18 – 45 years. Vorapaxar was administered orally as a single dose of 40 mg in Chinese subjects (n = 14) or 120 mg in U.S. subjects (n = 14), or 2.5 mg QD for 6 weeks in both studies (Chinese, n = 14; U.S., n = 23). Results: Vorapaxar was rapidly absorbed in both Chinese and U.S. subjects. Vorapaxar and M20 had similar elimination half-lives. The range of metabolite/parent ratios after single dose or daily administration was largely overlapped in Chinese and U.S. subjects. Steady state was attained by day 21 for vorapaxar and M20 in both race/ethnic groups. The accumulation ratios for vorapaxar and M20 during daily administration were similar in Chinese and U.S. subjects. Vorapaxar was well-tolerated in Chinese and U.S. subjects. Conclusion: The pharmacokinetic profiles of vorapaxar and M20 and the metabolite/parent ratios in healthy Chinese were generally comparable to those in a healthy Western population.Correspondence to:
Pei Hu, MD
Phase 1 Unit, Clinical Pharmacology Research Center
Peking Union Medical College Hospital (PUMCH)
Floor 8, Middle building, West Yard of PUMCH,
No.41 Damucang, Xidan, Xicheng District, Beijing 100032, China
Email: [email protected]
Original
Tetrandrine induces apoptosis in gallbladder carcinoma in vitro
Ronghua Zhu, Tianyu Liu, Zhujun Tan, Xiangsong Wu, Maolan Li, Lin Jiang, Runfa Bao, Yijun Shu, Aiguo Lu, and Yingbin Liu
Price
42.00 $
Page No. 900
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (900-905)
Tetrandrine induces apoptosis in gallbladder carcinoma in vitro
Ronghua Zhu1*, Tianyu Liu2*, Zhujun Tan2, Xiangsong Wu2, Maolan Li2, Lin Jiang2, Runfa Bao2, Yijun Shu2, Aiguo Lu1, and Yingbin Liu2
1Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, and 2Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Objective: The aims of this study were to observe the apoptosis effects of tetrandrine on human gallbladder carcinoma cell line (SGC-996), and to explore its related mechanism. Methods: First, the anti-proliferative activities of tetrandrine on SGC-996 cells were determined by using the MTT assays. Then, cell cycle changes were detected by flow cytometry analysis. The apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay. Detection of mitochondrial membrane potential was used to validate the ability of tetrandrine on inducing apoptosis. Finally, the expressions of the apoptosis-related proteins (caspase-3, PARP, Bcl-2, and Bax) were analyzed by western blot. Statistical analyses were performed using the Student’s t-test for comparison of the results obtained from cells with or without treatment of tetrandrine. Results: The MTT assay revealed a significant inhibition of cell proliferation in a dose- and time-dependent manner. Cells treated with tetrandrine were arrested at the S phase, according to the flow cytometric analysis. Tetrandrine produced a dose-dependent increase in the apoptotic cell population compared with control cells. Tetrandrine can also affect mitochondrial function by changing the mitochondrial membrane potential. Furthermore, western blot assay demonstrated that the tetrandrine induced apoptosis in SGC-996 cells by regulating the ratio of Bcl-2/Bax and activating the expression of cleaved caspase-3. Conclusions: The results indicate that tetrandrine may be a potential agent for the treatment of gallbladder carcinoma.
*These authors contributed equally to this work.Correspondence to:
Dr. Ying-bin Liu
Department of General Surgery, Xinhua Hospital
Shanghai Jiaotong University School of Medicine
No. 1665 Kongjiang Road, Shanghai 200092, China
Email: [email protected]
Original
Adverse drug reactions in elderly patients following discharge from an internal medicine clinic
Srecko Marusic, Mario Sicaja, Paulo Roque Obreli Neto, Miljenko Franic, Ivana Marinovic, and Vesna Bacic-Vrca
Price
42.00 $
Page No. 906
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (906-913)
Adverse drug reactions in elderly patients following discharge from an internal medicine clinic
Srecko Marusic1, Mario Sicaja2, Paulo Roque Obreli Neto3, Miljenko Franic4, Ivana Marinovic5, and Vesna Bacic-Vrca5
1Department of Clinical Pharmacology, 2Department of Cardiology, University Hospital Dubrava, Zagreb, Croatia, 3Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, Brazil, 4Department of Orthopedic Surgery, and 5Department of Clinical Pharmacy, University Hospital Dubrava, Zagreb, Croatia
Objective: The aim of this study was to evaluate the incidence and type of adverse drug reactions (ADRs) and identify risk factors for ADRs in elderly patients within 30 days following discharge from an internal medicine clinic. Methods: A prospective observational study was conducted at the Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia, between September 1st and November 30th 2012. Patients aged ≥ 65 years discharged from the clinic during the study period were eligible for inclusion in the study. The follow-up visit was scheduled ~ 30 days after discharge. During the visit, the patients were assessed for the occurrence of ADRs. Two independent physicians evaluated each possible ADR by using the Naranjo ADR probability scale. Multivariate logistic regression analysis was used to identify predisposing factors for ADRs. Results: There were 209 patients included in this study. A total of 72 ADRs were detected in 63 (30.1%) patients. The most frequent ADRs were bleeding disorders associated with warfarin therapy, followed by hypoglycemia associated with antidiabetics. Five (6.9%) ADRs, which resulted in hospital admission, were classified as serious. Multivariate logistic regression analysis indicated number of prescribed drugs ≥ 4 and prescription of furosemide and warfarin to be associated with increased risk of ADRs. Conclusions: Our study showed that ADRs are an important cause of morbidity in elderly patients after hospital discharge. Judicious prescription of drugs and careful and frequent monitoring of drug therapy are necessary to reduce the risk of ADRs.Correspondence to:
Srecko Marusic
Department of Clinical Pharmacology
University Hospital
Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia
Email: [email protected]
Case Report
A novel therapeutic use of HFA-BDP metereddose inhaler for asthmatic patients with rhinosinusitis: Case series
Yoshiki Kobayashi, Mikiya Asako, Akira Kanda, Koich Tomoda, and Hirotaka Yasuba
Price
42.00 $
Page No. 914
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (914-919)
A novel therapeutic use of HFA-BDP metereddose inhaler for asthmatic patients with rhinosinusitis: Case series
Yoshiki Kobayashi1,2, Mikiya Asako2, Akira Kanda2, Koich Tomoda2, and Hirotaka Yasuba1
1Department of Airway Medicine, Mitsubishi Kyoto Hospital, Kyoto, and 2Department of Otolaryngology, Kansai Medical University, Osaka, Japan
Objective: Most asthmatics have been found to have rhinosinusitis (RS). Patients with ethmoid sinusitis, in particular, often suffer from an impaired sense of smell; this is clinically important and necessitates concurrent treatment for both asthma and RS. As a rational therapeutic strategy, we focused on a fine particle HFA-134abeclomethasone dipropionate (HFA-BDP) metered-dose inhaler. Because of its small size, the medication is still present in the exhaled breath after inhalation. Methods: Five mild-to-moderate asthmatics with ethomoidpredominant sinusitis characterized by an impaired sense of smell and mild peripheral blood eosinophilia received a single-agent treatment with orally-inhaled HFA-BDP which was then exhaled through the nose. In addition, the stained small particles were created by an ultrasonic nebulizer and flow image of them during oral inhalation and nasal exhalation was evaluated by using nasal endoscopy. Results: After treatment, the sense of smell was restored in all cases with a concomitant improvement in sinusitis as confirmed by computerized tomography. In addition, amelioration of peripheral blood eosinophilia as well as small airway obstruction as indicated by pulmonary function tests was observed. Macroscopical imaging revealed that small particles flow toward olfactory cleft during both the inhalation and exhalation phases. Conclusion: We have presented 5 cases of asthmatic patients with RS treated with a concurrent single therapy, HFA-BDP exhaled through the nose (ETN). A clinical trial must be considered to establish this new therapeutic strategy based on the concept of “one airway, one disease.”Correspondence to:
Yoshiki Kobayashi, MD, PhD
Department of Otolaryngology
Kansai Medical University
2-5-1 Shinmachi, Hirakata, Osaka 573-1191, Japan
Email: [email protected]
Bioavailability Section
Pharmacokinetics and bioequivalence study of three oral formulations of ambroxol 30 mg: a randomized, three-period crossover comparison in healthy volunteers
Bo Jiang, Jin-Liang Chen, Hong-Gang Lou, Ling-Yan Yu, Hua-Hao Shen, and Zou-Rong Ruan
Price
42.00 $
Page No. 920
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (920-926)
Pharmacokinetics and bioequivalence study of three oral formulations of ambroxol 30 mg: a randomized, three-period crossover comparison in healthy volunteers
Bo Jiang, Jin-Liang Chen, Hong-Gang Lou, Ling-Yan Yu, Hua-Hao Shen, and Zou-Rong Ruan
Division of Clinical Pharmacology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Objective: To compare the pharmacokinetic properties of two newly developed generic ambroxol formulations with a branded innovator product in healthy Chinese male volunteers. Methods: This was a single-dose, randomized, open-label, threeperiod crossover study in healthy volunteers aged 18 – 45 years under fasting conditions. Subjects were assigned to receive 1 of 2 test formulations or a reference tablet of ambroxol 30 mg. Each study period was separated by a 1-week washout phase. Blood samples were collected at pre-specified times. A non-compartmental mmethod was employed to determine pharmacokinetic properties (Cmax, tmax, AUC0–tlast, AUC0–∞) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80 – 125%. Results: 24 subjects were enrolled in and completed the study. The geometric mean Cmax values for the test tablet, test capsule, and reference product were 82.73, 85.36, 84.56 ng/mL, and their geometric mean AUC0–tlast (AUC0–∞) were 660.87 (753.49), 678.98 (756.79), and 639.41 (712.14) ng × h/mL, respectively. For test tablet vs. reference, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0–tlast, and AUC0–∞ were 91.2% to 104.9%, 96.5% to 110.7%, and 98.8% to 113.4%, respectively. For test capsule, the corresponding values were 94.1% to 108.3%, 99.2% to 113.7%, and 99.2% to 113.9%, respectively. No adverse events occurred during the study. Conclusions: The ambroxol 30 mg tablets and capsules were considered bioequivalent to the reference formulation in accordance with predetermined regulatory criteria.Correspondence to:
Dr. Zou-rong Ruan
Division of Clinical Pharmacology
2nd Affiliated Hospital, School of Medicine
Zhejiang University
Jiefang Road 88# Hangzhou, 310009, China
Email: [email protected]
Bioavailability Section
Dermatopharmacokinetic bioequivalence study of two types of topical patches containing loxoprofen sodium
Xia Chen, Qian Zhao, Ei Hitsu, Ji Jiang, Wen Zhong, Takayasu Matsuzawa, and Pei Hu
Price
42.00 $
Page No. 927
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 10/2014 (927-932)
Dermatopharmacokinetic bioequivalence study of two types of topical patches containing loxoprofen sodium
Xia Chen1, Qian Zhao1, Ei Hitsu2, Ji Jiang1, Wen Zhong1, Takayasu Matsuzawa3, and Pei Hu1
1Phase I unit, Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China, 2China Business Division, EPS Corporation, Tokyo, and 3Research and Laboratories, Lead Chemical Co., Ltd., Toyama, Japan
Purpose: This study evaluated the bioequivalence of two types of topical loxoprofen patches, LX-A and LX-P, in healthy Chinese volunteers through a dermatopharmacokinetic approach. Method: Based on a pilot study, this study was designed as an open-label, self-controlled trial in 20 males. Subjects received application of two 3.2 × 3.2 cm2 pieces of LX-A and LX-P patches on their backs at randomly assigned positions simultaneously. Stratum corneum (SC) samples were taken with adhesive stripping tapes prior to patch application and at 20 hours and 24 hours postdose following removal of each loxoprofen patch, respectively. Bioassay was performed with a validated high performance liquid chromatography-tandem mass spectrometry method. Bioequivalence was evaluated through a power model on the total amount of loxoprofen at each post-application point and on the percentage change of SC loxoprofen content between the two time-points. Results: Mean (± standard deviation) total amount of SC-sampled loxoprofen was similar between LX-A and LX-P at 20 hours (38,722 ± 7,171 ng vs. 39,309 ± 9,688 ng) and 24 hours (36,638 ± 8,149 ng vs. 37,426 ± 9,029 ng) post-administration. The corresponding point estimate (90% confidence interval, 90%CI) of LX-P to LX-A was 1.00 (0.92, 1.09) and 1.02 (0.93, 1.12), respectively. In addition, the 24 hour/20 hour ratio for SC content of loxoprofen was statistically comparable between LX-A and LX-P, with both the point estimate and the 90% CI falling into the range of (0.80, 1.25). Conclusion: Our study indicated that LX-P and LX-A are two bioequivalent topical formulations of loxoprofen.Correspondence to:
Pei Hu, MD
Phase I unit, Clinical Pharmacology Research Center
Peking Union Medical College Hospital
41#, Damucang Hutong, Xicheng District, Beijing, 100032, China
Email: [email protected]
