BackgroundLow-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.MethodsPlatelet 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.ResultsPATI 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.ConclusionsIt 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.

Direct oral anticoagulants (DOACs) are available for nonvalvular atrial fibrillation patients. The advantage of DOACs is that regular anticoagulation monitoring is not required. However, adherence to the recommended regimen is essential. We investigated the association between medication adherence and the risk of cerebral infarction in patients taking DOACs. Patients admitted to any of the participating hospitals for cerebral infarction from September 2018 to February 2020 and prescribed DOACs before admission were defined as the case group, and patients hospitalized for diseases other than cerebral infarction, except for bleeding disorders, and prescribed DOACs before admission were defined as the control group. A nested case–control study was adapted, and 58 and 232 patients were included in the case and control groups, respectively. Medication adherence was assessed by the pharmacists through standardized interviewing. The adjusted odds ratio for the risk of cerebral infarction for low-adherence patients (<80% adherence rate) against good-adherence patients (100% adherence rate) was 9.69 (95% confidence interval, 3.86–24.3; p < 0.001). The patients’ age and other background characteristics were not found to be risk factors for cerebral infarction. In conclusion, low adherence is a risk factor for cerebral infarction in patients taking DOACs. Pharmacists should focus on maintaining ≥80% adherence to DOAC therapy to prevent cerebral infarction.

Alendronate, an oral bisphosphonate (e.g., Fosamax ), is eŠective in the treatment of osteoporosis, and the Fosamaxpackage insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca 2＋ , Mg 2＋ , etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the in‰uence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-‰uorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with ‰uorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in theˆrst 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h -1/2 ) among the water samples. Cumulative urinary excretion recoveries with tap water, evian  and 100％ deep ocean water were 0.98±0.17％, 0.80±0.18％ and 1.01±0.16％ (mean±S.E., n＝4). Those with Contrex (0.33±0.07％) were signiˆcantly lower when compared with ultrapure water (1.56±0.35％, p＜0.01). Theseˆndings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken.

Background Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. Methods Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. Results A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55–21.2; p = 0.009 ), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. Conclusions The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

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. Key words risedronate; mineral water; drug interaction; urine excretion; rat Osteoporosis is a systemic disease characterized by reduced bone mass and structural deterioration of bone tissue, leading to an increased risk of fracture. According to the 2011 Guidelines for the Treatment of Osteoporosis, the number of patients with osteoporosis in the rapidly aging population of Japan is increasing and is now estimated at about 13 million. 1)The occurrence of a fracture significantly impacts a person's daily activities, so pharmacotherapy for the prevention of osteoporosis is recommended for patients who are at high risk of bone fracture. A variety of drugs are available for treating osteoporosis, including calcium agents, active vitamin D 3 , raloxifene, and bisphosphonates (BPs). BPs exhibit particularly potent bone resorption inhibitory activity and are therefore the first-choice drug for treating osteoporosis. 1)Because they inhibit resorption and thus increase bone mineral density, BPs play an important role in treating postmenopausal osteoporosis. The resorption-inhibiting activity of risedronate, a third-generation BP, is reported to be approximately 3000 times that of etidronate, a first-generation BP.2) Recently, risedronate began to be marketed for once per month (75 mg), in addition to daily (2.5 mg) and weekly (17.5 mg) dosing.The variety of mineral waters sold and consumed in Japan has increased in recent years. Annual consumption of mineral water per person in Japan was 25.7 L in 2014 (approximately 3 times that of 15 years ago).3) The consumption of mineral waters in Japan is predicted to increase further in coming years. For orally administered BPs, the package inserts advise patients and health care workers that the bioavailability of the drug may be reduced when taken with mineral waters containing high levels of metal cations (Ca 2+ , Mg 2+, etc.), as a result of chelation (Ajinomoto Co., Inc., Actonel ® package insert [2013/2]). As the hardness of a mineral water depends on its calcium and magnesium conten...