A cross-sectional study clarifying profiles of patients with diabetes who discontinued pharmacotherapy: reasons and consequences.

BACKGROUND: Although diabetes is one of the fastest increasing diseases in prevalence worldwide and demands significant medical resources, more than half of all patients with diabetes do not achieve the expected target level of blood glucose. As a potential cause of poor glycemic control, insufficient adherence to medication has long been discussed and variably studied. However, dropout from treatment as another plausible cause has not been fully examined. The aim of this study was to clarify profiles of patients with diabetes who discontinued pharmacotherapy (Discont group) by extracting reasons of their decisions and by comparing with those who continued (Cont group) in terms of the related factors to glycemic control. METHODS: A cross-sectional, internet-based survey was conducted among Japanese with diabetes registered in a database. A self-administered questionnaire consisting of the 8-item version of the Morisky Medication Adherence Scale (MMAS-8), glycosylated haemoglobin (HbA1c) level, and demographic and disease characteristics was completed by all participants. Reasons for medication discontinuation and resumption were also received retrospectively from participants in the Discont group. To examine the risk of uncontrolled HbA1c, logistic regression analysis was conducted in each group. RESULTS: In the Discont group (148 cases), older age at resumption of pharmacotherapy and current smoking habit increased the probability of uncontrolled HbA1c, whereas in the Cont group (146 cases), a familial history of diabetes and better medication adherence in MMAS-8 scores decreased the probability of uncontrolled HbA1c. A relationship between medication adherence and HbA1c level was seen in the Cont but not in the Discont group. About 70 % of those in the Discont group made their decision to terminate diabetes treatment without consulting physicians and half of them perceived their situations inappropriately. CONCLUSIONS: Those who discontinued pharmacotherapy were less adherent to medication than those who did not discontinue. Risk factors for glycemic control also differed between those who discontinued and those who did not. More than one-third of participants with diabetes who discontinued pharmacotherapy had inappropriate perceptions of their disease, which medical professionals should be aware of for better interventions.

Effect of a lever aid on hand strength required for using a handheld inhaler correctly.

In the treatment of asthma and chronic obstructive pulmonary disease, using a lever aid to improve drug delivery from an inhaler is recommended for patients with poor muscle strength. However, no studies have investigated the effect on hand strength of using a lever aid. Here, we measured hand strength before and after operating a lever aid and tried to predict the required strength. We compared the pinch force required to activate a pressurized metered dose inhaler (pMDI) and a dry powder inhaler as well as the rotational torque required to activate a soft mist inhaler (SMI) before and after attaching a lever aid. We then assessed the correlation between the theoretical and measured pinch force after fitting the lever aid. Use of the lever aid significantly reduced the pinch force required for pMDI operation from 26.13-48.74 N to 4.90-16.87 N. In contrast, using a lever aid significantly reduced the force needed to rotate SMI, although the rotational torque required to operate did not change. There was a significant positive correlation between the theoretical and measured pinch forces required to activate a pMDI fitted with a lever aid. Using a lever aid will increase the number of patients who can use this device.

[Exploration of Education and Research on Drug Informatics].

I have been exploring methods for education and research on drug information for 43 years. There are various approaches to drug informatics research, which include collecting, evaluating, and analyzing information to solve drug related problems, sometimes producing new information from experiments and clinical research. All are based on information science. Drug informatics is information science from the viewpoint of pharmaceuticals. In addition to basic pharmacology, knowledge and skills such as epidemiology, data science, computer science, mathematical statistics, and communication studies are indispensable for the development of drug informatics.

Adverse event reports in patients taking psychiatric medication during pregnancy from spontaneous reports in Japan and the United States: an approach using latent class analysis.

BACKGROUND: Little is known regarding the association between adverse events (AEs) and psychiatric medications administered to pregnant women in clinical trials during the pre-marketing period. This study analyzes reports of AE association with psychiatric medication administrated during pregnancy using post-marketing spontaneous reports of AE from the Japanese Adverse Drug Event Report (JADER) database and Food and Drug Administration Adverse Event Reporting System in the United States (FAERS-US). METHODS: We summarized AE reports of psychiatric medication administrated during pregnancy by comparing data obtained from JADER and FAERS-US databases with medication patterns determined as classes via latent class analysis. The odds ratios (ORs) of AE reports categorized into system organ classes in which each class was compared with those without psychiatric medications. RESULTS: The proportions of AE reports under psychiatric medication in pregnancy among all AE reports were 22.0% and 16.6% in JADER and FAERS-US, respectively. The 10,389 reports of psychiatric medication during pregnancy were classified into 11 classes. The proportion of patients receiving four or more psychiatric drugs in JADER was larger than that in FAERS-US. The maximum number of reports in combinations of AE and medication pattern in JADER was 169, for 'general disorders and administration site conditions' from the class of four or more medications (OR = 9.1), while that in FAERS-US was 1,654, for 'injury, poisoning, and procedural complications' from the class of single psychiatric medication (OR = 2.8). CONCLUSIONS: The main AE reports and associated AE differed depending on medication patterns in pregnant women taking psychiatric medication. This study may provide a prediction of AEs that are likely to be reported with each medication pattern. Our findings of the association between AE reports and medication patterns could help improve the administration of psychiatric medications during pregnancy, though further research on additional datasets is needed to clarify these results.

Factors contributing to the systemic clearance of infliximab with long-term administration in Japanese patients with Crohn's disease: Analysis using population pharmacokinetics
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OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. MATERIALS AND METHODS: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. RESULTS: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. CONCLUSION: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing.

Growth factors can stimulate tissue regeneration, but the side effects and low effectiveness associated with suboptimal delivery systems have impeded their use in translational regenerative medicine. Physiologically, growth factor interactions with the extracellular matrix control their bioavailability and spatiotemporal cellular signalling. Growth factor signalling is also controlled at the cell surface level via binding to heparan sulfate proteoglycans, such as syndecans. Here we show that vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) that were engineered to have a syndecan-binding sequence trigger sustained low-intensity signalling (tonic signalling) and reduce the desensitization of growth factor receptors. We also show in mouse models that tonic signalling leads to superior morphogenetic activity, with syndecan-binding growth factors inducing greater bone regeneration and wound repair than wild-type growth factors, as well as reduced tumour growth (associated with PDGF-BB delivery) and vascular permeability (triggered by VEGF-A). Tonic signalling via syndecan binding may also enhance the regenerative capacity of other growth factors.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

[The Report: Promotion of Social Contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences].

The Science Council of Japan issued "The report: Promotion of Social Contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences" on September 29, 2017. This report was prepared based on the analysis of current situation of the four-year doctoral course in the graduate school of pharmacy and the contents of the symposium of 137th annual meeting of the Pharmaceutical Society of Japan (PSJ), "Pharmaceutical Sciences in the Future: The Bridge Linking between Basic and Clinical Research". The goal of the 4-year doctoral program is to nurture the pharmacist-scientist who has both researcher mind and professionalism as a clinical pharmacist. Research on clinical pharmacy and pharmaceutical sciences is a core research area of the 4-year doctoral course, therefore its promotion is an important issue for the faculty of pharmacy. "Research on clinical pharmacy and pharmaceutical sciences" has to be based on various subjects and needs of the clinical site and be conducted not only at the clinical setting but also in universities, industries, research institutions and so on. Finally, the results have to be fed back to medical care and contribute to society. In this symposium, several representatives from various academic societies and one research institution which have important functions for academic interchanges, will give presentations on issues and initiatives for promoting research on clinical pharmacy and pharmaceutical sciences.

Positive predictive value of ICD-10 codes for acute myocardial infarction in Japan: a validation study at a single center.

BACKGROUND: In Japan, several large healthcare databases have become available for research since the early 2000's. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims. METHODS: We selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI. RESULTS: In a random sample of 200 patients, the average age was 67.7 years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%. CONCLUSION: The PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke.

Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn's disease.

Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn's disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn's Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.

Extraction and Standardization of Patient Complaints from Electronic Medication Histories for Pharmacovigilance: Natural Language Processing Analysis in Japanese.

BACKGROUND: Despite the growing number of studies using natural language processing for pharmacovigilance, there are few reports on manipulating free text patient information in Japanese. OBJECTIVE: This study aimed to establish a method of extracting and standardizing patient complaints from electronic medication histories accumulated in a Japanese community pharmacy for the detection of possible adverse drug event (ADE) signals. METHODS: Subjective information included in electronic medication history data provided by a Japanese pharmacy operating in Hiroshima, Japan from September 1, 2015 to August 31, 2016, was used as patients' complaints. We formulated search rules based on morphological analysis and daily (nonmedical) speech and developed a system that automatically executes the search rules and annotates free text data with International Classification of Diseases, Tenth Revision (ICD-10) codes. The performance of the system was evaluated through comparisons with data manually annotated by health care workers for a data set of 5000 complaints. RESULTS: Of 5000 complaints, the system annotated 2236 complaints with ICD-10 codes, whereas health care workers annotated 2348 statements. There was a match in the annotation of 1480 complaints between the system and manual work. System performance was .66 regarding precision, .63 in recall, and .65 for the F-measure. CONCLUSIONS: Our results suggest that the system may be helpful in extracting and standardizing patients' speech related to symptoms from massive amounts of free text data, replacing manual work. After improving the extraction accuracy, we expect to utilize this system to detect signals of possible ADEs from patients' complaints in the future.

Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Hospital-Based Cohort Study.

Methotrexate (MTX) is used widely as a first-line drug for the treatment of rheumatoid arthritis (RA) worldwide. There are large interindividual differences in the therapeutic response to MTX, but it is not known which factors influence them. We therefore investigated predictive factors associated with the therapeutic response to MTX in a hospital-based cohort study. Japanese adult RA outpatients prescribed MTX were enrolled and their characteristics were collected from the electronic medical records. The European League Against Rheumatism (EULAR) response criteria were used as the response to MTX therapy. The observation period was 1 year after beginning MTX administration. Sixteen types of single-nucleotide polymorphisms were investigated using the real-time PCR method. Associations between the MTX response and patient characteristics were evaluated using the multivariate logistic regression model. Among 70 Japanese adult RA outpatients, 52 were classified as MTX responders. In multivariate analysis, patients with the solute carrier family 19 member 1 (SLC19A1) 80G>A A/A genotype had a better response than those with the A/G or G/G genotype, and patients with the C allele of γ-glutamyl hydrolase (GGH) 16T>C had a better response than those with the T/T genotype.This study showed that the therapeutic response to MTX in Japanese RA patients was associated with the genetic polymorphisms of SLC19A1 80G>A and GGH 16T>C in actual clinical practice.

Possible associations of personality traits representing harm avoidance and self-directedness with medication adherence in Japanese patients with type 2 diabetes.

BACKGROUND: Insufficient medication adherence in diabetes patients, of which numbers continue to increase globally, remains a critical issue. Medication adherence is multifactorial and determined by interactions among factors including socioeconomic status, health care team and system, condition, therapy, and patient-specific factors. On the other hand, personality traits have been studied in adherence other than to medication. Using the instruments of Temperament and Character Inventory (TCI), Harm Avoidance (TCI-HA) and Self-directedness (TCI-SD) showed distinguishing associations with adherence of health-related programs. However, few studies have been performed to elucidate psychometric properties related to medication adherence. We investigated how TCI-HA and TCI-SD of patients with diabetes are related to medication adherence. METHOD: A cross-sectional survey was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Personality traits were assessed using the established scales of TCI-HA and TCI-SD. Univariate and multivariate regression analyses of the MMAS-8 scores were performed in addition to assessing demographic and disease characteristics and TCI-HA and TCI-SD. RESULTS: A total of 358 responses were analyzed. Multivariate regression analysis of MMAS-8 scores revealed that higher TCI-SD was related to better adherence and experiencing drug-related side effects was related to poor adherence. Aging was significantly associated with better medication adherence in univariate regression analysis but became insignificant in multivariate regression. CONCLUSIONS: In diabetes patients, the anxiety reflected in TCI-HA tends to lower and the self-control reflected in TCI-SD tends to promote medication adherence. TCI-SD has a greater effect than TCI-HA.

Risk factors for rhabdomyolysis with HMG-CoA reductase inhibitors identified using a postmarketing surveillance database in Japan
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OBJECTIVE: To investigate quantitatively the risk factors for rhabdomyolysis or related symptoms associated with HMG-CoA reductase inhibitors (statins), we used the lipid-lowering drug database (32,157 patients) developed by the RAD-AR Council, Japan, based on the postmarketing surveillance (PMS) data of pharmaceutical companies to perform a nested case-control study. MATERIALS AND METHODS: Of 26,849 patients taking statins, the case group was composed of 51 patients who experienced rhabdomyolysis or related symptoms while taking statins, and the control group was 1,020 patients randomly selected from patients who did not experience rhabdomyolysis or related symptoms while taking statins. Relevant factors that can be extracted from the database were: sex, age, body mass index (BMI), statin use duration, complications, concomitant medication, and clinical laboratory test values. RESULTS: Among those taking statins, 51 experienced rhabdomyolysis or related symptoms. Factors differing significantly between the two groups by univariate analysis were age, duration of statin intake, combination drugs (Ca antagonists, angiotensin II receptor blocker (ARB), cardiac drugs, benzodiazepines, mucoprotective drugs, insulin, α-glucosidase inhibitors), clinical laboratory results (high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase, alkaline phosphatase, total bilirubin), and complications (alcoholic hepatitis). Conditional multivariate logistic analysis of these factors yielded adjusted/odds ratios of 8.82 for the concomitant administration of an ARB and 3.45 for increased AST and 3.20 for increased total bilirubin levels. CONCLUSION: Risk factors for rhabdomyolysis or related symptoms associated with taking statins were combination with ARB and increases in AST or total bilirubin levels.
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Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study.

OBJECTIVES: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study. METHODS: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model. RESULTS: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation. CONCLUSIONS: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan.

BACKGROUND AND PURPOSE: Internationalization of pharmacists, as well as pharmacy students, in terms of both the knowledge to care for international patients and to have medical information literacy, is a current concern in Japan. EDUCATIONAL ACTIVITY AND SETTING: Keio University Faculty of Pharmacy has developed an elective course for pharmacy students, based on written agreements with the United States and Thailand that establish a student clinical rotation exchange program. The exchange program lasts for four to six weeks and involves clinical rotations in hospitals abroad during the students' sixth year. Rotations follow a four-week didactic preparatory course. The course objectives are to acquire the knowledge, skills, and attitude needed to function as leading pharmacists with an international perspective. METHODS: We asked students to complete a feedback survey inquiring about the usefulness of preparatory courses, self-evaluation pre- and post-rotation satisfaction with the program, and overall self-assessment. FINDINGS: Twenty-four out of 41, i.e., 58.5% of the students replied with feedback. All respondents replied that the preparatory course was useful. They also replied that, based on their self-evaluation, they were satisfied with their level of English language skill improvement after the rotation. Pharmaceutical knowledge satisfaction, however, was slightly decreased. All respondents replied that this program was of a satisfactory nature, with 71%, 63%, and 92% of the respondents replying that they could acquire the knowledge, skills, and attitude program objectives respectively. SUMMARY: It is possible to successfully develop an overseas clinical rotation program. Students were quite satisfied upon completion and achieved the expected objectives.

Effect of everolimus on the glucose metabolic pathway in mouse skeletal muscle cells (C2C12).

INTRODUCTION: Everolimus selectively inhibits mammalian target of rapamycin complex 1 (mTORC1) and exerts an antineoplastic effect. Metabolic disturbance has emerged as a common and unique side effect of everolimus. OBJECTIVES: We used targeted metabolomic analysis to investigate the effects of everolimus on the intracellular glycometabolic pathway. METHODS: Mouse skeletal muscle cells (C2C12) were exposed to everolimus for 48 h, and changes in intracellular metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry. mRNA abundance, protein expression and activity were measured for enzymes involved in glycometabolism and related pathways. RESULTS: Both extracellular and intracellular glucose levels increased with exposure to everolimus. Most intracellular glycometabolites were decreased by everolimus, including those involved in glycolysis and the pentose phosphate pathway, whereas no changes were observed in the tricarboxylic acid cycle. Everolimus suppressed mRNA expression of enzymes related to glycolysis, downstream of mTOR signaling enzymes and adenosine 5'-monophosphate protein kinases. The activity of key enzymes involved in glycolysis and the pentose phosphate pathway were decreased by everolimus. These results show that everolimus impairs glucose utilization in intracellular metabolism. CONCLUSIONS: The present metabolomic analysis indicates that everolimus impairs glucose metabolism in muscle cells by lowering the activities of glycolysis and the pentose phosphate pathway.

Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population.

BACKGROUND: Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA. METHODS: Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and-401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR). RESULTS: Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients. CONCLUSION: The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.