著者

赤木 祐貴 荒井 碧 下村 斉 山本 康次郎 青山 隆夫

出版者

一般社団法人日本医療薬学会

雑誌

医療薬学 (ISSN:1346342X)

巻号頁・発行日

vol.41, no.6, pp.404-414, 2015-06-10 (Released:2016-06-10)

参考文献数

37

被引用文献数

1 1

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Low-dose aspirin inhibits cyclooxygenase-1 (COX-1) on platelets irreversibly, suppressing platelet aggregation.Nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit COX-1 reversibly by forming a salt bridge. However, there is little information on the antiplatelet effects of the chronic use of NSAIDs (other than aspirin). We performed pharmacokinetics/pharmacodynamics (PK/PD) analysis using in vitro experimental data obtained when NSAIDs were added to human blank blood, and estimated the antiplatelet effects of continuous NSAID administration.Ibuprofen, diclofenac, indomethacin and loxoprofen were studied in a one-compartment model, and etodolac was studied in a two-compartment model. Platelet aggregation was measured after adding NSAIDs to platelet-rich plasma at a range of concentrations containing the maximum plasma concentrations of one clinical dose. We calculated the platelet-aggregation threshold index (PATI) as an index of aggregation activity, which was defined as the putative stimulus concentration giving 50% aggregation, and performed PD analysis according to the sigmoidal Emax model. Simulated time-PATI curves of NSAIDs were compared to that of low-dose aspirin.Simulated values of increase in PATI for the maximum plasma concentration of each NSAID were lower than 3.9 µg/mL, which is the same as that of low-dose aspirin. Increases in PATI around the trough concentration were nearly zero for all NSAIDs except ibuprofen, thus suggesting that the antiplatelet effects of continuous NSAID administration are weaker and less persistent than those of low-dose aspirin. The simulation results indicate that continuous NSAID administration is less effective at preventing thrombosis and embolism than low-dose aspirin, and postoperative NSAID treatment needs to be careful of the occurrence of bleeding.

著者

下村 斉 青山 隆夫

出版者

一般社団法人日本医療薬学会

雑誌

医療薬学 (ISSN:1346342X)

巻号頁・発行日

vol.42, no.12, pp.781-794, 2016-12-10 (Released:2017-12-10)

参考文献数

53

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The incidence of pulmonary Mycobacterium avium complex (MAC) disease is increasing worldwide. Currently, clarithromycin is the key drug for treatment of pulmonary MAC disease, and multidrug therapy with rifampicin and ethambutol is recommended. However, the efficacy of this therapy is reported to be approximately 60-80%. Therefore, this disease is often difficult to treat, and there are some problems concerning this form of chemotherapy. Firstly, rifampicin decreases the serum clarithromycin concentration owing to CYP3A4-related interactions. Although this therapy needs to be administered for more than one year, to our knowledge, no study has investigated the long-term relationship between serum clarithromycin and rifampicin concentrations and CYP3A4 activity, together with treatment efficacy. Secondly, an alternative treatment to the recommended therapy of clarithromycin, rifampicin, and ethambutol has not been established. Therefore, fluoroquinolones are often used when the clinical efficacy of the recommended regimen is insufficient. However, very few previous studies have investigated the clinical efficacy of the combination of clarithromycin and fluoroquinolones, especially levofloxacin.Our recent study demonstrated that serum clarithromycin concentrations in patients with pulmonary MAC disease were continuously low because of rifampicin-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes observed. We also investigated the clinical outcomes achieved with the currently recommended dose of clarithromycin and levofloxacin, and suggested the possibility that combined administration of clarithromycin and levofloxacin did not improve clinical outcomes for the treatment of pulmonary MAC disease. In this mini-review, we summarize the findings of our clinical studies concerning chemotherapy for pulmonary MAC disease.

著者

下村 斉 青山 隆夫

出版者

一般社団法人日本医療薬学会

雑誌

医療薬学

巻号頁・発行日

vol.42, no.12, pp.781-794, 2016

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<p>The incidence of pulmonary <i>Mycobacterium avium</i> complex (MAC) disease is increasing worldwide. Currently, clarithromycin is the key drug for treatment of pulmonary MAC disease, and multidrug therapy with rifampicin and ethambutol is recommended. However, the efficacy of this therapy is reported to be approximately 60-80%. Therefore, this disease is often difficult to treat, and there are some problems concerning this form of chemotherapy. Firstly, rifampicin decreases the serum clarithromycin concentration owing to CYP3A4-related interactions. Although this therapy needs to be administered for more than one year, to our knowledge, no study has investigated the long-term relationship between serum clarithromycin and rifampicin concentrations and CYP3A4 activity, together with treatment efficacy. Secondly, an alternative treatment to the recommended therapy of clarithromycin, rifampicin, and ethambutol has not been established. Therefore, fluoroquinolones are often used when the clinical efficacy of the recommended regimen is insufficient. However, very few previous studies have investigated the clinical efficacy of the combination of clarithromycin and fluoroquinolones, especially levofloxacin.</p><p>Our recent study demonstrated that serum clarithromycin concentrations in patients with pulmonary MAC disease were continuously low because of rifampicin-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes observed. We also investigated the clinical outcomes achieved with the currently recommended dose of clarithromycin and levofloxacin, and suggested the possibility that combined administration of clarithromycin and levofloxacin did not improve clinical outcomes for the treatment of pulmonary MAC disease. In this mini-review, we summarize the findings of our clinical studies concerning chemotherapy for pulmonary MAC disease.</p>