International journal of clinical pharmacology and therapeutics (INT J CLIN PHARM TH )

Description

The International Journal of Clinical Pharmacology and Therapeutics appears monthly and publishes manuscripts containing original material with emphasis on the following topics: Clinical trials, Pharmacoepidemiology - Pharmacovigilance, Pharmacodynamics, Drug disposition and Pharmacokinetics, Quality assurance, Pharmacogenetics, Biotechnological drugs such as cytokines and recombinant antibiotics. Case reports on adverse reactions are also of interest.

  • Impact factor
    1.20
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    Impact factor
  • 5-year impact
    1.36
  • Cited half-life
    8.10
  • Immediacy index
    0.33
  • Eigenfactor
    0.00
  • Article influence
    0.35
  • Website
    International Journal of Clinical Pharmacology & Therapeutics website
  • Other titles
    International journal of clinical pharmacology and therapeutics, Clinical pharmacology and therapeutics
  • ISSN
    0946-1965
  • OCLC
    29934177
  • Material type
    Periodical
  • Document type
    Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: A patient presented with convulsive seizures when sodium valproate (VPA) and tebipenem pivoxil (Orapenem) were co-administered accidentally. The seizures were suspected to be caused by a reduced concentration of VPA in the blood. Case summary: A 6-year-old boy (weight: 16 kg, at the start of treatment) began sodium valproate (valproate syrup 5%) treatment for epilepsy in February 2012. At a dose of 350 mg/day, he experienced no convulsive seizures and maintained stable symptoms for the past 9 months. In December, he was prescribed 160 mg/day tebipenem pivoxil by an otolaryngologist for inflammation of the tympanic membrane. He experienced convulsive seizures the day after beginning co-administration. The concentration of VPA in his blood at this time was 30.0 μg/mL, which was lower than the optimal blood concentration. Discussion: Marked reduction of VPA concentration in the blood due to co-administration of VPA and injectable carbapenem antibiotics has been well-documented; however, this is the first report of such an interaction with tebipenem, which is an orally-administered carbapenem antibiotic. Although the mechanism of drug interaction between VPA and carbapenem antibiotics is not fully understood, it is thought that VPA blood concentrations decrease due to production of valproic acid glucuronic acid conjugates (VPA-Gluc) being promoted directly or indirectly by carbapenem antibiotics. When we assessed the patient according to the DIPS system, we calculated a score of +4 (possibility of interaction). Conclusions: The results suggest that co-administration of oral carbapenem antibiotics and VPA should be avoided.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: Objective: To determine the efficacy of the Anticonvulsant Screening Program (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) in identifying new anti-seizure drugs with new mechanisms of action (MOA). The ASP does not itself identify the nature of the MOA, but on further basic investigation, many of these drugs prove eventually to have a wide variety of new and novel MOA. Methods: Data were tabulated from multiple sources, including the ASP and the literature. Results: Since it was established in 1975, the ASP has contributed to the identification of at least 9 new anti-seizure drugs. The effectiveness of the program was evaluated by ascertaining the number of MOA of the anti-seizure drugs discovered by the ASP screening techniques. Considering the MOA of drugs marketed after 1975 - and the MOA of investigational compounds not yet marketed - the ASP has contributed to the identification of anti-seizure drugs that possess 16 distinctly different MOA. Conclusion: The ever-evolving screening approach of the ASP has many characteristics of a final common pathway for anti-seizure drug discovery.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetesmellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Methods: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4 - 12); study 2: canagliflozin 300 mg (days 1 - 17), probenecid 500 mg twice daily (days 15 - 17); and study 3: canagliflozin 300 mg (days 1 - 8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2 - 8 (study 3). Results: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Conclusion: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: Objectives: The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. Methods: Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm-2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. Results: In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. Conclusions: The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: Objective: Drug effects on the function of smell and taste are occasionally mentioned in prescription information however, most originate from anecdotal reports without even distinguishing between gustatory or olfactory deteriorations. This includes the antifungal fluconazole. Material and methods: In a randomized, placebocontrolled, double-blind, two-way crossover study, 12 healthy men and 9 healthy women (age 26.8 ± 3.7 years) took oral doses of 400 mg fluconazole or placebo once daily for 8 days. Gustatory and olfactory functions were tested before and after the treatment using clinically validated tests ("Taste Strips" and "Sniffin' Sticks", respectively). Results: Baseline taste scores of 12.3 ± 2.2 and 12.5 ± 1.7 for the fluconazole and placebo conditions, respectively, corresponded to normative values. Similarly, baseline (pretreatment) composite olfactory TDI scores (odor "threshold discrimination identification") of 35.0 ± 3.2 and 35.7 ± 4.3 for men and 34.8 ± 4.2 and 35.5 ± 2.8 for women during the fluconazole or placebo conditions, respectively, corresponded to normative values. Neither gustation nor olfaction was significantly affected by the fluconazole treatment. Conclusions: The present study provided a negative result regarding fluconazole effects contrasting, for example, with those of sildenafil in a comparatively powered study [1]. Up to the tested dose of 400 mg/d, fluconazole does not have general and reproducible effects on taste and smell in healthy humans. However, it was unlikely to detect rare disturbances with the present study cohort size, and, therefore, rare fluconazole side effects on human chemosensation, as occasionally reported, remain a possibility.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.
    International journal of clinical pharmacology and therapeutics 11/2014;
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    ABSTRACT: Aim: To discuss the available data regarding the off-label uses of anti-TNF agents in non-infectious uveitis. Data source: A literature search was performed in Medline through PubMed from January 2001 to January 2014. Study selection and data extraction: English-language articles about uveitis treatment with anti-TNF drugs in adult patients were reviewed. Data synthesis: The use of anti-TNF-α drugs for treatment of several refractory manifestations of refractory uveitis in adult patients is increasing. However, due to the lack of evidence from randomized controlled trials, the use of anti-TNF in uveitis remains "off-label"in most countries. There is no trial-based evidence to support it except for the experience provided by cases and case series. This experience, which is continuously increasing, has yielded encouraging results. Anti-TNF-α drugs, such as infliximab, adalimumab, and golimumab, are reasonably effective for controlling ocular inflammation and sparing patients corticosteroid treatment in non-infectious refractory uveitis. Approximately 80% of patients on infliximab, adalimumab, or golimumab were able to achieve sustained control of inflammation by 6 months. Conclusion: Anti-TNF-α therapy is effective in inducing clinical remission for refractory uveitis, with a relatively low rate of treatment-ending adverse events. However, randomized and controlled trials are required to adequately assess the maintained clinical efficacy and safety profile in the long term of anti-TNF agents for non-infectious refractory uveitis.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Background: The formulation investigated as reference contains thioctic acid which is known to be poorly soluble in water and have some instability during storage at high temperature. To overcome these limitations, a new piperazine dithioctate (PDT) tablet formulation was developed by a domestic pharmaceutical company in Korea. Objective: The aim of this clinical study was to evaluate the pharmacokinetic characteristics of PDT in healthy volunteers. Methods: This study consisted of two clinical trials. In the part 1 study, a randomized, singledose, parallel study was performed with 24 healthy volunteers. All of the subjects were administered one of the three study formulations, Thioctacid® HR (High Release) as the reference, PDT-1 or PDT-2 (each containing thioctic acid 600 mg), respectively. To determine the harmacokinetic characteristics, blood samples were serially collected at pre-dose and at pre-defined timepoints after dosing. In the part 2 study, a randomized, single-dose, two-way crossover study was conducted with 48 subjects. All of the subjects were administered both the reference and PDT-2 formulations, with a 7-day washout period between the two medications. Blood samples were collected at the same timepoints as in the part 1 study. Tolerability was evaluated throughout the study. Results: 23 volunteers completed the part 1 study. The maximum plasma concentration (Cmax) of thioctic acid after administration of the reference tablet was 4.08 ± 2.35 μg/mL (means ± SD), and the Cmax of PDT-1 and PDT-2 was 3.53 ± 2.87 μg/mL and 4.15 ± 1.62 μg/mL, respectively. The AUClast value was 2.96 ± 1.13 μg x h/mL for the reference, 2.84 ± 1.12 μg x h/mL for PDT-1, and 3.30 ± 1.32 μg x h/mL for PDT-2. 42 volunteers completed the part 2 study. The Cmax of reference and PDT-2 was 5.59 ± 3.07 μg/mL and 5.14 ± 3.18 μg/mL, respectively. The AUClast value was 4.01 ± 1.65 μg x h/mL for the reference and 3.96 ± 1.47 μg x h/mL for PDT-2. The geometric mean ratios (PDT-2/reference) and the 90% CI for Cmax and AUClast were 0.93 (0.78 - 1.11) and 1.01 (0.94 - 1.09), respectively. Conclusion: Both studies suggested that the pharmacokinetic profile of the newly developed piperazine dithioctate formulation was comparable to the pharmacokinetic profile of the reference tablet. Both study tablets were well tolerated in all of the subjects.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. Methods: All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 μg) + ethinyl estradiol (30 μg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). Results: Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin's PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. Conclusion: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were welltolerated.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: Peramivir is a neuraminidase inhibitor having activity against various influenza A and B subtypes. The main route of elimination is the kidney and a dose reduction is justified for multipleday therapy when the creatinine clearance is < 50 mL/min. Before the 2009 influenza pandemic, dosing guidelines did not exist for patients receiving continuous renal replacement therapy (CRRT). This case report provides data on the dialysis membrane saturation coefficient (SA) and pharmacokinetic parameters of peramivir in a 29-year-old female receiving continuous veno-venous hemodiafiltration (CVVHDF), a mode of CRRT. Methods: Plasma and effluent samples were collected to calculate the saturation coefficient, plasma half-life, maximum and minimum plasma concentrations, and area under the plasma drug concentrationtime curve (AUC) for peramivir. CVVHDF was performed using a Prisma pump and an AN69 filter. During peramivir sampling, the dialysate flow rate was 16.7 mL/min. The mean total ultrafiltrate produced was 14.2 mL/min. To calculate a saturation coefficient (SA), simultaneous sampling of blood and effluent was performed. Pre- and post-filter as well as effluent samples were obtained 4.5 and 8.5 hours following the 3rd dose of 480 mg. Plasma concentrations were also obtained at several time points and the AUC estimated from 0 to 24 hours (AUC0-24). Results: The maximum plasma concentration (C30min,) was 19,477 ng/mL, the minimum plasma concentration (Cmin) 2,750 ng/mL, and AUC0-24 196,166 ng x h/mL. The estimated plasma half-life was 8.2 hours with a log-linear decrease over the 24-hour period suggesting significant extracorporeal clearance. The calculated SA was 0.98, similar to an estimated SA of 1. Conclusion: Peramivir is readily cleared by CVVHDF having a calculated SA close to 1. The maximum and minimum plasma concentrations, AUC0-24, and plasma half-life was similar to those previously reported. These data will be useful in determining appropriate peramivir dosing regimens for severely ill influenza patients with acute renal impairment managed by CVVHDF.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objectives: To better characterize the risk profile of the intravenous immunoglobulin (IVIG) Intratect®, a non-interventional study was undertaken to systematically collect large-scale safety information under real-life conditions in patients with primary and secondary immunodeficiency. Secondary objectives were data on treatment modalities. Methods: A prospective, non-interventional study was performed at 95 centers. Results of an interim analysis are reported here. Intratect® (50 g/L) was administered at the physician's discretion. Data were captured from patients with different causes of immunodeficiency (61.5% with malignancy) at routine clinic visits, with a particular focus on the frequency and causality of adverse events. Results: 1,313 patients were followed for a median of 294 days. At study entry, 836 patients (63.7%) were receiving therapy, most frequently IVIG treatment (37.2%). In total, 21,995 Intratect® infusions were documented (median 11 infusions per patient, median dose 200 mL). Median serum IgG level increased from 5.78 (interquartile range 3.70, 8.87) g/L at month 1 to 6.58 (4.82, 9.48) g/mL at month 12. Altogether, 689 adverse events were collected, irrespective of causality. From these, 225 (32.7%) were assessed as related to Intratect® and thus considered suspected adverse drug reactions (ADRs). Thus, the ADR rate was 1.0% per infusion. Seven ADRs (7/225, 3.1%) were graded serious. In all cases, the patients had recovered or were recovering at the time of reporting. Conclusions: Use of Intratect® for immunoglobulin substitution in primary and secondary immunodeficiency under real-life conditions is associated with a low rate of suspected ADRs. Serious ADRs are rare and manageable.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: Clinical information on tigecycline use in serious nosocomial infections is limited, and the efficacy is uncertain. The aim of this retrospective study was to assess the utilization pattern and the effectiveness of tigecycline in a tertiary medical center in Taiwan. Methods: A retrospective study of the clinical and microbiological outcome of all patients treated with tigecycline for at least 72 hours over a 2-year period was conducted in a 730-bed teaching hospital. Results: Data from 133 patients with 149 cases of nosocomial infection were analyzed in this assessment. The mean APACHE II score at the initiation of tigecycline therapy was 22.5 ± 8.8, and the mean duration of treatment was 11.4 ± 5.6 days. Pneumonia was the most frequently diagnosed clinical indication for tigecycline use (113 cases, 76%). An overall positive clinical outcome was observed in 75 cases (50%). Multidrug-resistant Acinetobacter baumannii (MDRAB) is the most common organism for tigecycline therapy (n = 59), with a positive clinical outcome of 38% in tigecycline monotherapy, 66% in dualtherapy, and 17% in triple-therapy (p = 0.031). The most commonly used combining agents with tigecycline to treat MDRAB infections were intravenous colistin, inhaled colistin, and cepoferazone/sulbactam, with positive clinical outcome rates of 53%, 100%, and 80%, respectively. Admission to intensive care unit was identified as a predictive factor for negative clinical outcome. Conclusion: Our pneumonia-dominated study population demonstrated a lower clinical improvement rate of tigecycline compared to previous published data. Tigecycline monotherapy is not recommended for MDRAB infection, but colistin or cephoperazone/ sulbactam combined with tigecycline seemed to yield a good clinical outcome for MDRAB infection.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: The Food and Drug Administration (FDA) only requires bioequivalence testing of generic substitutions in order for them to be deemed equivalen to the original product. There may be a large difference of bioavailability among the generic drugs that especially have a narrow therapeutic index, and this may affect clinical outcomes. We aimed to determine whether switching from generic-to-generic equivalent anti-epileptic drugs (AEDs) in patients with epilepsy is associated with clinical outcomes. Methods: We performed a retrospective study using the electronic medical records of a tertiary hospital. Adults with a history of epilepsy who used a generic phenytoin and whose therapy was switched to another generic phenytoin between January 2012 and June 2013 were included (n = 80). We compared the drug concentration of phenytoin and seizure events before and after the switch. Results: After switching their generic phenytoin, 33 out of 80 patients (41%) suffered from increasing seizure events (pre-interchange period, 0.44 ± 0.97; post-interchange period, 1.24 ± 2.05; p < 0.0001). The number of medical visits for acute seizure significantly increased in the post-interchange period. The phenytoin serum concentration of all the patients was lesser in the post-interchange period than in the pre-interchange period. (pre-interchange period, 12.79 μg/mL; post-interchange period, 6.36 μg/mL; p < 0.0001). Among the patients with drug resistant epilepsy (DRE), 17 patients (84.2%) had increasing seizure events in the post-interchange period. Conclusions: We confirmed that there was a significant difference in bioavailability between generic phenytoin. Therefore, when using or switching generic anti-epileptic drugs, therapeutic drug monitoring must be done, and the patients' condition must be considered.
    International journal of clinical pharmacology and therapeutics 10/2014;
  • International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/ NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Background: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. Objectives: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. Methods: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. Results: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. Conclusions: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: To compare the effects of postoperative patient-controlled intravenous analgesia (PCIA) with morphine, tramadol, or tramadol combined with lornoxicam on serum inflammatory cytokine production. Methods: 60 patients with an American Society of Anesthesiologists (ASA) physical status of I or II, undergoing radical correction of gastric cancer, were equally randomized to receive PCIA with morphine (M group), tramadol (T group), or tramadol combined with lornoxicam (L group). The visual analog scale (VAS) and Bruggemann comfort scale (BCS) scores were used to evaluate the postoperative analgesic efficacy. Serum levels of the interleukins (IL) IL-2, IL-6, and IL-10, and soluble IL-2 receptor (sIL-2R) were measured before anesthesia, 90 min after incision, and 24, 48, and 72 h after surgery. Results: No significant difference was found in the VAS, BCS, or baseline serum IL-2, IL-6, IL-10, or sIL-2R between the groups. At 90 min after incision, only the IL-6 levels increased (p < 0.05). At 24 h after surgery, the IL-2 levels decreased, with the M group having the lowest levels, while IL-6, IL-10, and sIL-2R levels increased, with the M group having the highest level and the L group having the lowest level (p < 0.05). At 48 h after surgery, the cytokine levels were starting to return to the baselines but still had statistical significance (p < 0.05). At 72 h after surgery, only the IL-6 levels had returned to their baseline. Conclusion: PCIA using tramadol combined with lornoxicam has less influence on inflammatory cytokines than morphine or tramadol alone in patients undergoing gastric cancer surgery.
    International journal of clinical pharmacology and therapeutics 10/2014;
  • International journal of clinical pharmacology and therapeutics 10/2014; 52 Suppl 1:1-64.
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    ABSTRACT: Objective: Sitafloxacin is a new fluoroquinolone with a broad spectrum of antibacterial activity, including grampositive and gram-negative bacteria. This study was to evaluate the pharmacokinetic characteristics of a single dose of sitafloxacin in healthy Chinese volunteers. Methods: This was a single-center, open-label, randomized-sequence study conducted in 12 subjects. Subjects were randomly assigned to receive single doses of 50, 100, and 200 mg of sitafloxacin in a 3-way crossover design with a 7-day washout period between administrations. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study. Results: After administration of single doses of 50, 100, and 200 mg, geometric mean estimate for sitafloxacin Cmax were 0.72, 1.62, and 2.73 μg/mL and the mean of AUClast were 3.97, 8.71, and 18.03 μg x h/mL, respectively. Sitafloxacin was rapidly absorbed, reaching Cmax ranged from 0.85 to 1.21 hours. The terminal half-life ranged from 5.19 to 6.28 hours. The Cmax and AUC last were proportional to the doses. The mean clearance, the half-life, and the volume of distribution were constant, irrespective of the dose. Conclusion: In healthy Chinese subjects, single dosing of sitafloxacin resulted in linear plasma pharmacokinetics.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Materials: Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. Methods: In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 to < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC0-inf), AUC from zero to last measurable concentration (AUC0-t), maximum plasma concentration (Cmax), time to Cmax (tmax), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. Results: 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing >= 20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 to < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC0-inf, 1.32 vs. 0.73 μmol x h/L respectively); children weighing =>20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC0-inf, 3.06 vs. 0.69 μmolx h/L). Cmax was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (=> 20 kg). Conclusions. The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing => 20 kg but not in children weighing 8 to < 20 kg.
    International journal of clinical pharmacology and therapeutics 09/2014;