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Introduction: Two pilot studies for prescription-event monitoring in Japan (J-PEM) were launched in 1997 and 1998. Here we present data regarding adverse events that were reported in the second pilot J-PEM study where losartan was compared with ACE inhibitors and dihydropyridine calcium channel antagonists.Study Design: We conducted a cohort study with a concurrent control. METHODS/PATIENT GROUP: Study subjects prescribed losartan, an ACE inhibitor or a calcium channel antagonist were identified from prescriptions in hospital or community pharmacies. Events and other information were collected from doctors and pharmacists by mailed questionnaires. Events were coded and analysed using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Crude event rates were calculated and compared between patients treated with losartan and those receiving control drugs. When the difference was statistically significant, the event was further examined in several ways, including follow-up studies and by comparison with the data of the UK PEM study on losartan.Results: Pharmacists were sent 4344 questionnaires and returned 3591 (83%), while doctors were sent 3517 questionnaires and returned 1380 (39%). In the doctors' data, the adverse event rate for losartan treatment was greater than that for ACE inhibitors and/or calcium channel antagonists for the following seven events: headache, palpitations, anaemia, insomnia, feeling abnormal, increased blood pressure and asthma. Most of these are known adverse drug reactions (ADRs) of losartan except for two events: increased blood pressure and asthma. In pharmacists' data, the event rate for losartan was significantly greater than that for control drugs for the following ten events: hot flushes, abnormal hepatic function, oedema, peripheral swelling, decreased blood pressure, increased blood pressure, rhinitis, contact dermatitis, dry skin and heat rash. The first five events were known ADRs of losartan but the other five were not. When the two sets of data were combined, the rate of an additional event, increased blood creatinine phosphokinase, which is a known ADR of losartan, was significantly greater than that for the control drugs. The six events that were not documented as ADRs for losartan were not judged to be ADRs based on the results of follow-up studies and comparison with the UK PEM study on losartan. The crude rate of cough with losartan treatment was similar to that with calcium channel antagonists, but was significantly less than that with ACE inhibitors.Conclusion: No novel safety problems were found in this observational cohort study on losartan. The rates of some known ADRs differed significantly between patients treated with losartan and those in the control groups. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR -mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR -dependent resistance after osimertinib treatment, although these have not been prospectively investigated., Methods: The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023., Discussion: The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established., Registration: UMIN Clinical Trial Registry: UMIN000049225., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-12/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

The promotion of self-medication by pharmacies, with the aim of encouraging a patient's self-selection of proper OTC drug, is written about in the national action plan "Japan is Back". The subject of self-medication has been improved in the 2013 revised edition of "Model Core Curriculum for Pharmaceutical Education". At Tokyo University of Pharmacy and Life Sciences, the systematic education of self-medication was started from the onset of the six-year course in the third, fourth and fifth grade. We introduce here a new approach in our systematic education of self-medication. In the practice of the fourth grade, groups of around 5-6 students are formed. The pharmacy students assume various roles-of pharmacist, rater, observer, and chairman-and perform role-playing. We prepared a standardized patient (SP) showing various symptoms. The student of the role of pharmacist asks about the SP's symptoms, chooses an OTC drug suitable for the SP, and explains the OTC drug to the SP. After the role-playing, those in the roles of rater, observer, SP, and faculty give feedback to the student who played the role of pharmacist. Because we conduct this role-playing using SPs with a variety of symptoms, we can create a situation similar to a real drugstore.

Drug toxicity impedes drug development and its clinical use. In the present study, a toxicity risk index (TRI), which is an index for warning idiosyncratic drug toxicity (IDT), was proposed. The TRI of drugs was defined as a function of dose, pharmacokinetic parameters, and toxicokinetic data from covalent binding experiment. Twenty drugs, which were classified into three categories by a report (Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Kurihara A, Nagai Y, Nakai D, Okazaki O. 2009. Drug Metab Dispos 37:1970-1977), were studied with TRI. The three categories were BBW (drugs with a block box warning for IDT), WNG (drugs without a black box warning but with a warning for IDT), and SAFE (drugs without any warning). The TRIs of drugs classified as SAFE were distinctly different from those classified as BBW. The TRI of the SAFE drugs were lower than 0.456 (nmol/mg protein). In contrast, the TRI of the BBW drugs were higher than 1.10 (nmol/mg protein). These results warned us that a drug candidate, where the TRI is higher than 1.0 nmol/mg protein, should be categorized as a BBW drug. Further study with more data of TRI will give a cutoff value with a statistical meaning. Thus, TRI may be useful for decision making in drug development and its clinical use., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: In hypertensive patients with diabetes, antihypertensive therapy is important in reducing the risk of macro- and microvascular complications. In contrast to the guidelines issued by the American Diabetes Association (ADA) in and after 2002, the guidelines issued by the Japanese Society of Hypertension (JSH) in 2000 and 2004 maintained the traditional view that beta-blockers and thiazides should be rated as second-line drugs. However, both sets of guidelines recommended angiotensin converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as first-line agents for such patients., Methods: We examined the use of antihypertensives in hypertensive patients with and without diabetes using the prescription data for 1999, 2002 and 2005 from three Japanese university hospitals., Results: When compared with 1999, the proportion of patients with and without diabetes using ARBs was dramatically increased in 2005 from 1.5 to 55% and from 1.5 to 40%, while that of angiotensin converting enzyme inhibitors decreased from 52 to 32% and 35 to 23%, respectively. A relatively stable proportion of patients (around 10% with and without diabetes) used beta-blockers and around 60% of patients with and without diabetes used calcium channel blockers (CCBs) and very few (<5%) used thiazides., Conclusions: The rapid increase in use of ARBs and under-use of thiazides may be explained by the fee schedule in the Japanese health insurance system. The paucity of large-scale clinical trials may also hinder evaluation of the traditional view of the role of beta-blockers and thiazides in treatment of Japanese patients with diabetes.

Recently, medical institutions have been actively trying to reduce the number of inpatients. When inpatients make a transition to home care, the first step is to ensure that they have a homecare doctor, and that a visiting nursing station and pharmacy are available. Next, home care services must be determined once hospital care information has been obtained and the wishes of the patient and their family have been established. However, pharmacies are often only contacted the day or the day before a patient is discharged from the hospital, so they are burdened with a considerable amount of preparation. Based on the information pharmacies need, we therefore created an Information Supply Booklet that medical institutions can hand to pharmacies upon discharge of patients. The entries have been classified according to core and non-core issues for pharmacies. This type of Information Supply Booklet is needed to help patients efficiently adjust to their post-discharge environment. In the future, we would like to revise this booklet into a common national format which would incorporate the views of medical institutions.

A new method for measurement of myosin ATPase activity has been developed utilizing reversed-phase high-performance liquid chromatography (HPLC), which detects as low as 0.05 nmol of ADP hydrolyzed from ATP. After termination of the ATPase reaction by addition of perchloric acid, the hydrolysate ADP and substrate ATP were separated by reversed-phase HPLC. The absorbance of ADP was monitored at 259 nm, and the amount of ADP was quantified from its peak area on the chromatogram by use of the NIH Image computer software. Our method showed linearity over a wide range from 0.05 to 10 nmol of ADP per 20 microl with a coefficient of determination (r(2)) of 0.99. Myosin ATPase activities determined by the HPLC method were almost identical to those determined by the malachite green method, a widely used spectrophotometric method with range of detection from 1 to 8 nmol of phosphate. Because our method requires only a small volume of reaction solution, it will be a powerful tool for measuring ATPase activity of motor proteins, which are difficult to obtain in large amount., (Copyright 2001 Academic Press.)

Myosin light chain kinase (MLCK) is a regulatory protein for smooth muscle contraction, which acts by phosphorylating 20-kDa myosin light chain (MLC20) to activate the myosin ATPase activity. Although this mode of action is well-established, there are numerous reports of smooth muscle contraction that is not associated with MLC20 phosphorylation. The kinase activity for the phosphorylation is localized at the central part of MLCK, which is also furnished with actin-binding activity at its N terminal and myosin-binding activity at its C terminal. This article overviews as to how such multifunctional properties of MLCK modify the actin-myosin interaction and presents our observations that the phosphorylation is not obligatory in induction of smooth muscle contraction.

Myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of myosin in the presence of Ca(2+) and calmodulin (Ca(2+)-CaM) so that myosin can interact with actin filaments. MLCK has another activity that is not attributable to this kinase activity, i.e., it inhibits the ATP-dependent movement of actin filaments on a myosin-coated glass surface. MLCK itself can be phosphorylated at site A and site B with a few kinases. The phosphorylation at site A reduces kinase activity. However, we have no knowledge as to how phosphorylation of MLCK affects the inhibitory activity of MLCK. When MLCK was phosphorylated at site B, it exerted an inhibitory effect on the movement in much lower concentrations. When Ca(2+)-CaM or ML-9 was present, the inhibition was reduced. The reduction was less when the movement was arrested by the MLCK phosphorylated at site B. This observation was explained by the increase in the affinity of MLCK to myosin upon the phosphorylation at site B., (Copyright 1999 Academic Press.)

In addition to its kinase activity, myosin light chain kinase has an actin-binding activity, which results in bundling of actin filaments [Hayakawa et al., Biochem. Biophys. Res. Commun. 199, 786-791, 1994]. There are two actin-binding sites on the kinase: calcium- and calmodulin-sensitive and insensitive sites [Ye et al., J. Biol. Chem. 272, 32182-32189, 1997]. The calcium/calmodulin-sensitive, actin-binding site is located at Asp2-Pro41 and the insensitive site is at Ser138-Met213. The cyanogen bromide fragment, consisting of Asp2-Met213, is furnished with both sites and is the actin-binding core of myosin light chain kinase. Cross-linking between the two sites assembles actin filaments into bundles. Breaking of actin-binding at the calcium/calmodulin-sensitive site by calcium/calmodulin disassembles the bundles.

An efficient one-step affinity purification of bovine brain G protein betagamma subunits (betagamma's) is described. The betagamma's, in a detergent extract of brain membranes, are first dissociated from the alpha subunits (alpha's), reassociated with decahistidine-tagged alphail produced in bacteria, and then adsorbed onto Ni2+-nitrilotriacetic acid-agarose via the histidine tag. This mild adsorption retained the high activity of the ligand alpha's, in contrast to the commonly used chemical crosslinking methods. A wash step with a buffer containing chaotropic ions (SCN-) completely removed contaminating proteins that were refractory to washes with high concentrations of detergents, after which the highly purified betagamma's were eluted with a buffer containing Al3+, Mg2+, and F- ions. The obtained betagamma's were found to be fully functional, as assessed by their ability to support pertussis toxin-catalyzed ADP-ribosylation of alphail. Since the combination of the mild adsorption via the histidine tag and the wash with chaotropic ions can be easily applied to purifying betagamma's from various animal tissues, this new chromatographic method is expected to facilitate the purification of other membrane proteins that bind to Galpha and/or Galphabetagamma., (Copyright 1999 Academic Press.)

A new syringe-type minicolumn, called Extrashot-Silica (EXS-Silica), containing diatomaceous earth granules was described. The EXS-Silica differs from the conventional pretreatment column. Using the EXS-Silica we can execute the simultaneous extraction-injection to HPLC, column. Therefore, an analysis using the EXS-Silica is an easier and faster method than the general HPLC analysis method. In this study, we carried out the simultaneous determination of four xanthine derivatives, such as caffeine, theobromine, theophylline and paraxanthine, in serum specimens. We used dichloromethane containing 4% ethanol (v/v) for the extraction-injection and water-acetic acid-ethanol-dichloromethane (0.2:0.2:4:95.6, v/v) for the mobile phase of HPLC. The eluent was monitored with a UV detector at 275 nm. A linear relationship between the amount of drug and the peak height was confirmed in the range of 1-40 micrograms/ml for the above-mentioned four xanthine derivatives in the serum. When a 5 microliters aliquot of the serum was subjected to this method, the observed detection limits of the drug were far less than therapeutic concentrations. The analytical accuracy of our method was finally confirmed by comparing the obtained analytical data by the new method with those obtained using the fluorescense polarization immunoassay method. Serum concentrations of theophylline obtained by these two methods correlate satisfactorily. Except for minor modifications in the injector, the existing liquid-chromatographic equipment can be used.