The Association between Molecular Initiating Events and Drug-Induced Hiccups.

Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous reports have revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence on its treatment or prevention. This study examined molecular initiating events (MIEs), which are the starting point of adverse events, to investigate the drug-induced pathways of hiccups. We extracted drugs suspected to cause hiccups using the FDA Adverse Event Reporting System, a large database on adverse drug reactions. Information on drugs suspected to be associated with hiccups was extracted from the overall population and sex-specific subgroups were divided. In each data table, the predicted activity values of nuclear receptors and stress response pathways for each drug were calculated using the Toxicity Predictor, a machine-learning model. Transforming growth factor-beta and antioxidant response elements were considered an independent factor for hiccups in the male and female subgroups, respectively. This report first examined one of the mechanisms of drug-induced hiccups and identified MIEs associated with drug-induced hiccups. The use of an adverse event database and the machine-learning model, Toxicity Predictor, may be useful for generating hypotheses for other adverse effects with unknown mechanisms.

Community Pharmacists' Experiences and Attitudes towards the Provision of Sexual and Reproductive Health Services: An International Survey.

Access to comprehensive sexual and reproductive health (SRH) services remains a challenge worldwide. Describing community pharmacists' SRH services in countries with different scopes of practice will aid in understanding how pharmacists view their roles and how to support them in providing needed services. A cross-sectional web-based survey was administered to pharmacists working in community pharmacies in Japan, Thailand, and Canada. The survey covered 7 SRH categories: pregnancy tests, ovulation tests, contraception, emergency contraception, sexually transmitted and blood-borne infections, maternal and perinatal health, and general sexual health. Descriptive statistics were used to analyze the data. A total of 922 eligible responses were included in the analysis (Japan = 534, Thailand = 85, and Canada = 303). Most Thai and Canadian participants reported dispensing hormonal contraceptives (Thailand = 99%, Canada = 98%) and emergency contraceptive pills (Thailand = 98%, Canada = 97%). Most Japanese participants provided patient education on barrier contraceptives for men (56%) and information on the safety of medications in pregnancy (74%) and breastfeeding (76%). The majority of participants expressed interest in additional training and expanding their roles in SRH. Sharing international experiences can guide challenges faced by the evolution of pharmacists' practice in SRH. Providing pharmacists support could help their readiness for this role.

Reproductive Health Services: Attitudes and Practice of Japanese Community Pharmacists.

The provision of sexual and reproductive health (SRH) services is an important part of a community pharmacist's role in many countries. However, such services are not traditionally provided by pharmacists in Japan. We surveyed the practice and attitudes regarding the provision of SRH services among Japanese community pharmacists with a focus on reproductive health (RH) topics. The participants were asked about the provision of RH services, attitudes toward their role as SRH providers, and self-reported confidence in providing education to patients on RH topics. We obtained 534 effective responses. About half of the participants reported providing RH services, and only 21% were involved in dispensing emergency contraception pills. Although the proportion of pharmacists providing education on these topics was considerably lower, about 80% recognized the importance of their role as SRH advisors. Confidence in providing patient education about RH topics depended on their experience in providing such services. Most participants were interested in additional SRH training (80%). Our results suggest that training programs could help to expand Japanese community pharmacists' roles as SRH providers and increase their confidence in the education of patients. This study provides useful insights to expand pharmacists' roles in Japan as providers of comprehensive SRH services.

Perspectives on Continuing Education Programs for Foundation-Level Drugstore Pharmacists in Japan.

BACKGROUND: Continuing education (CE) is important for developing and updating pharmacists' knowledge, skills, and attitudes. CE programs should be developed according to social requirements but also based on personal requirements depending on the sectors the pharmacists work in. This research aims to explore perspectives on CE programs for foundation-level drugstore pharmacists in Japan. METHOD: Foundation-level drugstore pharmacists were asked what CE programs or training they needed to develop patient care or customer satisfaction. RESULTS: We obtained 417 opinions (multiple answers were allowed) in 280 responses from 460 pharmacists (male: 245 and female: 215). The products and goods about which drugstore pharmacists wanted to learn covered a wide range. They wanted to learn about taping skills, tests, and products and devices related to care of the elderly. Taping skill would be quite unique for drugstore pharmacists. For special populations, they wanted knowledge and skills related to pregnancy tests and the safe use of medication by pregnant or lactating women. CONCLUSION: Drugstore pharmacists in Japan have different CE and continuing professional development (CPD) requirements from community pharmacists. The benefits of CE programs meeting pharmacists' requirements should be evaluated in future research.

Photochemical Mechanism of Riboflavin-Induced Degradation of Famotidine and a Suggested Pharmaceutical Strategy for Improving Photostability.

The present study aimed to clarify the mechanism of photodegradation of famotidine with riboflavin (FMT/RF), and to develop a photochemically stabilized formulation of FMT/RF. Photochemical properties of RF were characterized by UV-VIS spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. Pharmacokinetic study was conducted in rats after intravenous administration of FMT (1 mg/kg) formulation containing RF (0.01 mg/kg). The UV-VIS spectral pattern of RF partly overlapped with the sunlight spectrum, and ROS generation from photoirradiated RF was remarkable; thus, RF had high photoreactive potential. In the photostability testing, after irradiation (250 W/m(2)), degradation rate for FMT in FMT/RF was ca. 11-fold higher than that in FMT alone. The addition of radical scavengers to FMT/RF led to attenuated photodegradation of FMT/RF; in particular, the addition of L-ascorbic acid (vitamin C; VC) to FMT/RF showed ca. 86% inhibition of the photodegradation of FMT/RF. The pharmacokinetic study on FMT indicated that the addition of VC (1 mg/kg) to FMT/RF had no significant impact on the pharmacokinetic behavior of FMT. These findings suggest that ROS-mediated photochemical reaction would be involved in the photodegradation pathway of FMT/RF, and the complementary use of VC might be an attractive approach to improve the photostability of FMT/RF.

The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly.

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients.

Dissolution profile of 24 levofloxacin (100 mg) tablets.

Although there are 23 generic levofloxacin (100 mg) tablets (LVFX tablets) and 1 brand name LVFX tablet (supply now discontinued) in Japan, there have been no reports that have evaluated and compared the dissolution profiles of LVFX tablets using the same dissolution method. We studied the dissolution profile of LVFX tablets by the Paddle method, a standard dissolution test method. Among 23 generic LVFX tablets, 2 LVFX tablets had lower dissolution rates and 14 had higher dissolution rates than the brand name LVFX tablet. It is suggested that LVFX tablets have different dissolution profiles, which could cause different pharmacokinetic profiles.

Effect of switching tiotropium HandiHaler® to Respimat® Soft Mist™ Inhaler in patients with COPD: the difference of adverse events and usability between inhaler devices.

BACKGROUND: Recently, tiotropium Respimat® Soft Mist™ Inhaler has been developed. Respimat is a multidose and propellant-free kit. The aerosol generated from Respimat improved lung drug deposition and required a lower dose of drug than HandiHaler®. The aim of this study is to assess the effect of switching from tiotropium HandiHaler to Respimat in patients with chronic obstructive pulmonary disease (COPD). METHODS: Thirty-four patients with COPD who received 18 µg of tiotropium delivered by the HandiHaler once daily were enrolled in this study between May and September 2010. Symptoms, adverse events, pulmonary functions, and usability of inhaler devices were assessed before and 12 weeks after switching from HandiHaler to 5 µg of tiotropium delivered by the Respimat. Symptoms and adverse events were also assessed 4 and 12 weeks after switching. Dyspnea was evaluated using the British Medical Research Council dyspnea scale. The usability of inhaler devices was scored using a 12-step checklist. RESULTS: Twenty-nine patients were followed until 12 weeks after switching. The median FEV1 (forced expiratory volume in 1 sec) values before and 12 weeks after switching to Respimat were 1.41 L and 1.60 L, respectively. Dry mouth appeared to improve after switching to Respimat. Cough just after inhalation was observed in seven patients until 4 weeks after switching. However, six patients overcame cough as they got used to Respimat. Regarding the handling of inhaler devices, patients were not good at breathing out before inhalation and holding their breath just after inhalation both with HandiHaler and with Respimat. However, in general, both inhalers were considered to be easy to use. Twenty-one patients replied that handling of Respimat was easier than that of HandiHaler. CONCLUSIONS: There was no major problem in switching from tiotropium HandiHaler to Respimat. Respimat and HandiHaler showed similar effects and usability. However, we should be aware of cough just after inhalation with Respimat.

Doubling of serum creatinine: is it appropriate as the endpoint for CKD? Proposal of a new surrogate endpoint based on the reciprocal of serum creatinine.

BACKGROUND: The evaluation of the progression of renal insufficiency, or decline in glomerular filtration rate (GFR), has been approached more simply and precisely by converting measured serum creatinine value into the reciprocal of serum creatinine, estimated GFR, or other parameters. Doubling of serum creatinine (simple doubling) is conveniently used as a surrogate endpoint for progression of renal disease but is thought to be biased unfairly by the initial value of serum creatinine (Scr(Int)). We proposed the definite decline in the reciprocal of serum creatinine (2-4 doubling) as a surrogate endpoint, comparing simple doubling with this new endpoint to verify the effect of Scr(Int) on the endpoint. METHODS: For the purpose of comparison between endpoints, 194 patients in a historical cohort of chronic glomerulonephritis were investigated. Kaplan-Meier survival analysis was performed with the composite endpoint of need for dialysis and either simple doubling or 2-4 doubling. Then, the distribution of Scr(Int) was compared between total patients and patients developing each endpoint. RESULTS: The endpoint value of serum creatinine (Scr(End)) with 2-4 doubling was lower than that with simple doubling at Scr(Int) <2.00 mg/dl, and the difference of Scr(End) between simple doubling and 2-4 doubling was larger, as Scr(Int) became lower. In patients reaching simple doubling, Scr(Int) was higher than that of the total patients (1.66 vs. 1.07 mg/dl in median, respectively; p < 0.001). In patients reaching 2-4 doubling, there was no significant difference in Scr(Int). CONCLUSION: Patients with low serum creatinine concentration at baseline had a tendency of prolonged development into simple doubling. In contrast, with 2-4 doubling, there was no bias of Scr(Int).

Anti-inflammatory effect of theophylline in rats and its involvement of the glucocorticoid-glucocorticoid receptor system.

Although theophylline has been suggested to have an anti-inflammatory effect, there have been few reports to show the in vivo effect and the mechanism of anti-inflammatory activity of theophylline experimentally. To reveal the anti-inflammatory activity of theophylline, we studied the effect of theophylline and its metabolites on carrageenan-induced edema in rat foot pad. Subcutaneous injection of theophylline (5 - 100 mg/kg) inhibited carrageenan-induced edema dose-dependently. Theophylline metabolites, that is, 1-methylxanthine, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid (equimolar dose to 50 mg/kg of theophylline), did not inhibit the edema significantly. The inhibitory effect of theophylline on carrageenan-induced edema disappeared by pretreatment with aminoglutethimide, an inhibitor of glucocorticoid synthesis and with mifepristone, an antagonist of the glucocorticoid receptor. These results suggest that theophylline itself has anti-inflammatory activity and the glucocorticoid-glucocorticoid receptor system is involved in the anti-inflammatory activity of theophylline.

Establishment and pathophysiological characterization of type 2 diabetic mouse model produced by streptozotocin and nicotinamide.

This study was performed in order to establish a mouse model that represents the non-obese type 2 diabetes reflecting a majority of diabetic patients among Asian races and to show its pathophysiological profiles. Streptozotocin (STZ) was administered to C57BL/6J mice with or without nicotinamide (120 or 240 mg/kg, STZ/NA120 or STZ/NA240), twice with an interval of 2 d, and plasma glucose concentration, body weight, water intake, insulin contents and insulin signal-related proteins were monitored. STZ-induced hyperglycemia (fasting and non-fasting), body weight loss and polyposia were significantly depressed by NA dose-dependently. In STZ/NA120 and STZ/NA240 mice, pancreatic insulin content was retained by 28 and 43% of normal control (10.5+/-0.93 microU/ml), respectively, and histological damage of pancreatic beta cells was also less severe than that observed in STZ mice. When given the calorie-controlled high fat diet, the STZ/NA mice caused hyperlipidemia, and significantly increased insulin resistance. These observations suggest that the combined administration of STZ and NA causes partial depletion of pancreatic insulin and that the high fat constituents lead to insulin resistance in this model. The present mouse model, therefore, well exhibits the recent diabetic pathophysiological characteristics of a majority of Asian patients.

[Pilot study of the practical use of Internet in medical services: the questionnaire for pharmacists in Japan].

We performed a questionnaire survey to 260 pharmacists as a pilot study, in order to know the actual application of IN to medical services in Japan. The response rate of our questionnaire was 40% (105 persons), and 91% of the answers were from pharmacists who works in hospitals, community pharmacies, or clinics. According to the results, 90 of the 105 pharmacists had had some experience of using IN, and 68% of whom (58% of respondents) use IN daily as a means of problem solution on their works. IN was probably used as a relatively reliable information source something like text-books in such cases as acquiring the medical information for patients or other medical staffs. In addition, IN may have been esteemed its facilities and the informational usefulness and reliability. However, since this survey is just a pilot trial, the result dose not necessarily reflect a general situation around IT use. Consequently, this study result could be need by still further research.