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Drug lag (DL) in Japan has decreased in the last few years as a result of the globalization of drug development in the past decade, and new molecule entities (NMEs) with short DL are on the rise. The purpose of this study was to investigate the influence of DL on postmarketing safety of NMEs, by comparing the length of DL and the chronological trend of package insert revisions.The number of label revisions occurring during 6 years after approval was investigated for 142 NMEs approved between 2000 and 2006. The NMEs were classified by the length of DL (2 years and 4 years), and the label revision trends by each label section and therapeutic categories were analyzed.The cumulative number of level revisions in the "Drug Interactions" and "Clinically Significant Adverse Reactions" sections in the first year after approval in the DL2 years group was significantly greater than in the DL ≥2 years group. In the chemotherapeutic category that showed the shortest DL, the first label revision occurred in 33.3% within the first year and in 66.7% by the second year, and label revisions were performed earlier than in any other therapeutic categories.These results suggest that the package inserts of NMEs with a shorter DL tend to be revised earlier and more frequently, and it requires more careful monitoring of safety information after product launch.

Rifampicin (RFP; 30 mg/kg) was orally administered to fasted or fed rats using ultrapure water as the vehicle, and the influence of food on its pharmacokinetics was investigated. To examine the influence of intragastric pH and RFP solubility, similar experiments were performed using 0.1 M HCl (pH 1.0), 0.1 M phosphate buffer (pH 6.8), or 10% Tween 80 vehicles. Plasma RFP concentrations were measured by HPLC-UV for 24 h. The administration of RFP to fed rats in ultrapure water (10% dissolved) resulted in a significant 40% reduction in the maximum plasma drug concentration (Cmax) and area under the concentration-time curve (AUC0-24), as compared with fasted rats (p

Background Low-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and suppresses platelet aggregation. It is effective for secondary prevention of cardiovascular events. Because nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly bind with COX-1, the antiplatelet effects of aspirin may be suppressed when NSAIDs are co-administered. This interaction could be avoided by avoiding simultaneous administration; however, the minimum interval that should separate the administration of aspirin and loxoprofen is not well known. In this study, we investigated how to avoid the influence of NSAIDs on the antiplatelet effects of aspirin. An in vitro experiment was performed to investigate the influence of ibuprofen and loxoprofen at various concentrations on aspirin’s antiplatelet action. Methods Platelet aggregation and thromboxane B2 (TXB2) levels were measured after addition of aspirin only and NSAIDs plus aspirin to platelet-rich plasma. NSAIDs were used at their maximum plasma concentrations, the assumed concentration after 6 h (for loxoprofen only), and the assumed concentration after 12 h of taking one clinical dose. Platelet aggregation threshold index (PATI), defined as the putative stimulus concentration giving 50% aggregation, was calculated as an index of aggregation activity. Results PATI decreased in ibuprofen plus aspirin group compared to that in the aspirin only group, regardless of ibuprofen concentration. Furthermore, PATI significantly decreased when aspirin was added after loxoprofen-trans-OH addition at the maximum concentration (4.1 ± 0.1 μg/mL), compared to that in aspirin only group (5.9 ± 0.1 μg/mL). PATI showed no significant difference after addition of loxoprofen at the assumed concentration after 6 h (aspirin only group, 5.0 ± 0.5 μg/mL; loxoprofen-trans-OH plus aspirin group, 4.9 ± 0.4 μg/mL).In addition, TXB2 concentration tended to decrease with increasing PATI. Conclusions It is desirable to avoid ibuprofen co-administration with the usual once-daily low-dose aspirin therapy; however, a 6-h interval between loxoprofen and aspirin could avoid this potential interaction when loxoprofen is taken before aspirin.

New fixed-dose combination drugs (FDCs) had been developed in limited numbers in Japan. Since regulatory requirements were relaxed in 2005, 73 new FDCs have been approved by PMDA since 2006. In this study, we investigate trends in new FDCs and their benefits through a questionnaire survey provided to patients and pharmacists.The new FDCs were analyzed by therapeutic categories, first approval country and drug lag (DL). Questionnaire surveys were conducted on hypertension, bronchial asthma, and glaucoma in approximately 300 patients and 700 pharmacists in 66 hospitals to investigate the benefits of new FDCs.The highest number of FDCs approved by the therapeutic category was 15 cardiovascular agents. The DL (median) was less than 1 year in several therapeutic categories including cardiovascular agents. The survey results showed that patient compliance improved in 30.8% of the bronchial asthma. Regarding the time and effort required to prescribe these drugs, 32.5% of pharmacists reported "slightly decreased" in bronchial asthma, while 32.0% reported "slightly increased" in hypertension. More than one-third (70.6%) responded "recommend" in bronchial asthma.The number of new FDCs markedly increased since 2006, and this presented new opportunities for the Japanese pharmaceutical industry. FDCs not only increase convenience to the patient but also improve patient compliance and the efficiency of pharmacist prescription processes. However, the rapid increase in new FDCs may cause confusion in the medical field, and new FDCs should be developed not only to improve convenience but also to consider the benefits they provide to patients, pharmacists, and physicians.

Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex(®) (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, p

Background Fluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients. Methods Pulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate. Results There were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events. Conclusion The possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.

Background Concomitant use of clarithromycin (CAM) and rifampicin (RFP) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease affects the systemic concentrations of both drugs due to CYP3A4–related interactions. To date, however, there has been no report that investigates the long–term relationship between the drug concentrations, CYP3A4 activity, and clinical outcomes. Our aim was to investigate the time course of the drug levels in long–term treatment of subjects with pulmonary MAC disease, and examine the correlation of these concentrations with CYP3A4 activity and clinical outcomes. Methods Urine and blood samples from nine outpatients with pulmonary MAC disease were collected on days 1, 15, and 29 (for four subjects, sample collections were continued on days 57, 85, 113, 141, 169, 225, 281, 337, and 365). Serum drug concentrations and urinary levels of endogenous cortisol (F) and 6 beta-hydroxycortisol (6βOHF), the metabolite of F by CYP3A4, were measured, and evaluated 6βOHF/F ratio as a CYP3A4 activity marker. In addition, the clinical outcomes of 4 subjects were evaluated based on examination of sputum cultures and chest images. Results The mean 6βOHF/F ratio increased from 2.63 ± 0.85 (n = 9) on the first day to 6.96 ± 1.35 on day 15 and maintained a level more than double initial value thereafter. The serum CAM concentration decreased dramatically from an initial 2.28 ± 0.61 μg/mL to 0.73 ± 0.23 μg/mL on day 15. In contrast, the serum concentration of 14-hydroxy-CAM (M-5), the major metabolite of CAM, increased 2.4-fold by day 15. Thereafter, both CAM and M-5 concentrations remained constant until day 365. The explanation for the low levels of serum CAM in pulmonary MAC disease patients is that RFP-mediated CYP3A4 induction reached a maximum by day 15 and remained high thereafter. Sputum cultures of three of four subjects converted to negative, but relapse occurred in all three cases. Conclusions Our study demonstrated that serum CAM concentrations in pulmonary MAC disease patients were continuously low because of RFP-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes.

CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone (DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16alpha-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu(210) to Glu(279) were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16alpha-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.

Polypyromellitimides show excellent thermal stability due to their rigid aromatic chain molecules. In the present paper, the viscoelastic properties of such polymers are correlated to their rigid chain structure. The viscoelastic properties of polypyromellitimides prepared with various degrees of cyclization from polypyromellitamic acid film are measured with a tensile oscillating apparatus at 5Hz in the range of -60∼90°C. And the viscoelastic properties of polypyromellitimide, Kapton H film, are also measured at a higher temperature range of 20∼500°C by means of a torsional pendulum. Three mechanical ralaxations were found at -60°C and 70°C by tensile measurement, and at 60°C and 330°C by torsional measurement. The lowest one is ascribed to the absorbed water as previously pointed out. The middle one is found also to be related to the absorbed water. The highest one, which is revealed in this work for the first time, is assigned to rearrangement of the oriented molecules at higher temperatures.

2015