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It is often necessary to modify the dose or schedule of eribulin mesilate (Eri) because of adverse events. Therefore, we retrospectively investigated the optimal approach for Eri dose adjustment and/or dosage interval adjustment. Patients who received Eri at the institutions affiliated with the Division of Oncology of the Aichi Prefectural Society of Hospital Pharmacists between July 2011 and November 2013 were enrolled in this study. We compared the group that underwent dose reduction without changes to their dosage interval (dose reduction group) with the group that had a change in their dosage interval (dose-interval prolongation group). The primary end-point was time to treatment failure (TTF), and the secondary end-points were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and adverse events. The TTF and OS of the dose reduction group were approximately two times longer than those of the dose-interval prolongation group. In addition, the dose reduction group had significantly improved ORR and CBR, which together indicate an antitumor effect (p=0.013 and 0.002, respectively). Although peripheral neuropathy occurred significantly more frequently in the patients in the dose reduction group (p=0.026), it was grade 1 and controllable in most of the cases. There were no differences in the occurrence of other adverse effects between the two groups. Therefore, we suggest that dose reduction with maintenance of the dosage interval is the preferred treatment approach in cases where Eri dose or schedule modification is necessary.

Basic principles for simulation of acute reference dose (ARfD) setting were defined based on the work of Solecki et al. (2005). The principles are: (1) Appearance of acute toxicity within 24 h after oral administration. (2) Rationale for setting toxicity that appears or could appear after single oral administration. (3) ARfD setting is assumed to be necessary for all pesticides. (4) ARfD setting is not necessary when the value is at or above the cutoff level. (5) The setting basically applies to the general population. (6) ARfD is set based on the lowest NOAEL among all the available study data concerning endpoints for acute effects. (7) Effects of exposure during critical periods should be considered as endpoints for ARfD setting. (8) The approach for the safety coefficient is the same as that for acceptable daily intake. (9) If available, human data are acceptable as an endpoint for ARfD setting.

Microdensitometry of the metacarpal bone on radiograph was first set up as the endpoint of the treatment in clinical trials in Japan in 1980s. Then, radial bone mineral content obtained by single photon absorptiometry was used. In 1990s, lumbar spine BMD measured by DXA became the major endpoint of the study which was designed as prospective, randomized, double-blind, controlled trial. In 2000s, assessments on the incidences of the vertebral fractures have become mandatory as the primary endpoint of the placebo-controlled trial. The numbers of the subjects required in the study are getting larger and the subtleties in the study including adverse events more important along the progress of evidence-based medicine.

The worldwide situations of drug safety have changed dramatically. Drugs are used based on the evaluation of safety data collected in clinical practice worldwide. US Food Drug Administration collects spontaneous reports and requires manufacturers to report adverse drug reactions (ADRs) of US marketed drugs occurring worldwide. These worldwide data are available through the Adverse Event Reporting System (AERS) (about 4.1 million reports on about 3,073,340 patients, for 13 years: 1997.4th qr-2010.4th qr.). The current issues are how to analyze and utilize such large-scale safety data. Potential biases should always be kept in mind, because AERS is based on spontaneous reports. However, its huge volumes and exhaustiveness allow for sufficient scientific evaluation with the aid of current IT technology. Therefore, analysis of large-scale ADR database becomes a new research area not only from the medical science but also from the statistical viewpoint. In this report, I introduce some case studies in which we analyzed the AERS data on psychotropics including antipsychotics, antiepileptics, and antidepressants. Antipsychotics caused ADRs specific to each drug, and, in combination therapy, increased the incidences of diabetes mellitus, pancreatitis, and neuroleptic malignant syndrome; antiepileptics caused AEs (adverse events) including serious skin reactions such as Stevens-Johnson syndrome (SJS), congenital anomaly, and closed-angle glaucoma; and antidepressants caused AEs including serotonin syndrome, suicidal events, and congenital anomaly, and AEs occurring at a higher incidence for other indications, drugs often used in the elderly and AEs in combination therapy. We have analyzed ADRs associated with concomitant drug therapies using Bayesian approach. In the analysis we faced difficulties of overdispersion and we have to estimate a number of parameters, given a large number of target drugs as well as ADRs. In addition, ADR reports are not collected from uniform populations, we also have to consider the variations in the target populations. So, we use Bayesian statistics. Bayesian analysis has become feasible with advances in computer technologies and the Markov chain Monte Carlo (MCMC) methods. It allows us to analyze ADRs associated with concomitant drug therapies and estimate the ADR signals for each drug. Therefore, the analysis and evaluation of large-scale ADR database can provide important safety information in clinical practice and the studies on ADR database are the most important issues in ensuring the postmark safety of pharmaceutical products.

Nicorandil significantly reducted the incidence of major coronary events in patients with stable angina in a long-term trial, although there are few reports on its short-term efficacy in the treatment and prevention of angina symptoms. We performed a meta-analysis of the short-term efficacy of nicorandil compared with antianginal drugs for stable angina. We selected 20 reports (vs. β-blockers, n=6; vs. nitrates, n=6; vs. calcium antagonists, n=8) of prospective controlled trials from MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. The trials were short in duration (median 5 weeks). We combined the results using odds ratios (OR) for discrete data and weighted mean differences (WMD) for continuous data. Compared with antianginal drugs, nicorandil did not show significant reduction of angina episodes per week (vs. β-blockers, -1.50 [95% confidence interval (CI): -4.09, 1.09]; vs. nitrates, 0.22 [95% CI: -1.22, 1.65]; vs. calcium antagonists, -0.23 [95% CI: -1.37, 0.90]). Furthermore, there were no significant differences in time to ischemia (total exercise duration, time to 1-mm ST depression, time to onset of pain). Although the total numbers of adverse events with each antianginal drug were similar, heart rate and blood pressure were significantly decreased by calcium antagonists but not changed by nicorandil (8.09 [95% CI: 3.20, 12.98] and 8.64 [95% CI: 3.28, 13.99], respectively). Thus this study suggests that short-term therapy with nicorandil is as effective as standard therapy and that nicorandil can also be used as a first-line agent in patients with stable angina.

A new definition of transient ischemic attack (TIA) was proposed by the working group of the American Heart Association and the American Stroke Association in 2009. In this definition, TIA is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. This definition is currently much argued, and has not yet been globally accepted. There would be no meaning to differentiate TIA from ischemic stroke only by the duration of symptoms. Because, TIA in acute setting and acute ischemic stroke share the same spectrum. Therefore, we proposed a new clinical concept termed acute cerebrovascular syndrome (ACVS), which includes acute TIA and acute ischemic stroke. Patients early after TIA are at high risk of stroke and thus should be immediately evaluated and treated as a medical emergency, that is, ACVS. An international multicenter cooperative registry study is ongoing in 5,000 patients with TIA or minor stroke within 7 days after the onset, who will be followed up for 5 years, involving Japanese patients.

Molecular targeted drugs have been developed and have come to play a part in the standard treatment of cancers. However, issues such as the optimum dose, selection of patients, and verification of the molecular targets remain to be discussed, because unexpected clinical problems related to the clinical efficacy, adverse events, and development of resistance have appeared. Therefore, proof of principle (POP) studies and pharmacodynamic or pharmacogenomic research to explore new bio-markers for the drugs are essential for clinical progress. On the other hand, the higher cost of development and care must also be discussed as new problems.

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.

The number of prostate cancer patients is rapidly increasing in Japan, as aging people are more common and the lifestyle is more westernized. Another reason is that prostate specific antigen (PSA) is prevalent and PSA test can detect organ-confined prostate cancer in the early stage. In the past, endocrine therapy was the main treatment modality since many prostate cancer patients were diagnosed in the advanced stage. However, endocrine therapy is not suitable for young patients with organ-confined prostate cancer. Surgery and radiation therapy are becoming standard therapy for these patients. Although retropubic radical prostatectomy is widely performed,urinary incontinence and sexual dysfunction are still problems. Other approaches such as laparoscopic prostatectomy, portless endoscopic prostatectomy and perineal prostatectomy are also performed. Radiation therapy is commonly used for organ-confined prostate cancer in Europe and the U.S.A. The advancement in computer technology has made it possible to accumulate enough radiation dose to target without damaging the surrounding organs (3 D conformal, intensity-modulated radiotherapy). Heavy ion particle radiotherapy is also attempted in some institutes. Moreover, brachytherapy can be another choice in radiation therapy. In Japan, only high-dose brachytherapy with (192)Ir has been performed. In July 2003, permanent seed brachytherapy with (121)I was legally approved in Japan, and more organ-confined prostate cancer patients are expected to undergo this treatment. There are several treatment modalities for organ-confined prostate cancer patients these days. Therefore, not only tumor grade and stage, but also patients'lifestyle and thought should be considered in determining treatment.