Aim: We aimed to investigate the relationship between genetic polymorphisms and mRNA expression of dihydrofolate reductase (DHFR) in a healthy Japanese population.
Method: Two gene polymorphisms of DHFR (19-bp deletion allele and 3′UTR 829C>T) and mRNA expression of DHFR were evaluated in 100 unrelated healthy Japanese adults (47 men and 53 women). The genotype for DHFR 19-bp deletion was determined using the complete deletion/insertion method and that for DHFR 3′UTR 829C>T using the PCR-restriction fragment length polymorphism method. The mRNA expression of DHFR was determined by real-time PCR using RNA extracted from peripheral blood mononuclear cells.
Results: Allelic frequencies of DHFR 19-bp deletion in healthy Japanese adults were: wild allele 38% and deletion allele 62%. Allelic frequencies of DHFR 3′UTR 829C>T were: C allele 83% and T allele 17%. Median (25th-75th percentile) mRNA expression levels of DHFR intron 1 in wild/wild, wild/deletion, and deletion/deletion individuals were 0.53 (0.33-0.61), 0.28 (0.20-0.44), and 0.33 (0.24-0.52), respectively, with a significant difference between wild/wild and wild/deletion (P=0.010). Median mRNA expression of DHFR 3′UTR 829C>T in C/C and C/T genotypes were 0.29(0.20-0.45) and 0.41(0.25-0.62), respectively, with a significant difference between C/C and C/T (P=0.024).
Conclusion: Our healthy Japanese adults showed statistically significant differences in distribution of allelic frequencies for DHFR 19-bp deletion and 3′UTR 829C>T, and in mRNA expression of DHFR according to genotype. Therefore, the genetic polymorphisms and/or differences in mRNA expression of DHFR might contribute to the variation in efficacy and toxicity of methotrexate in patients with rheumatoid arthritis and other diseases. (Jpn J Clin Pharmacol Ther 2013; 44(3): 185-192)

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Background: Healthcare information databases are available in Japan for drug safety evaluations. Adverse drug reactions(ADRs) can be predicted from diagnosis codes, medications/procedures, or laboratory test results that are available from the databases.
Objective: The validity of prediction of statin-related ADRs from healthcare information database was evaluated by comparing with doctor's diagnoses and abnormal laboratory test results in patients receiving statin therapy.
Methods: A Drug Use-Results Survey database for statins was used. The predictability of well known ADRs caused by statins, such as rhabdomyolysis and liver disorder, from laboratory test results available from the database was evaluated. Abnormal results were observed; creatine kinase(CK) levels increased to 10 times the normal upper limit (1,500 IU/L or higher) and aspartate aminotransferase/alanine transaminase(AST/ALT) levels increased to 3 times the normal upper limit (120 IU/L/135 IU/L or higher). Positive predictive values(PPV) were calculated using doctor's diagnoses as the gold standard.
Results: Among 26,849 participants in post-marketing studies on statins (study period: 1989–2008), 64% were females and 81% were aged between 50 and 79 years. Four cases of rhabdomyolysis were reported (0.017%). CK levels were elevated in 20 patients and the PPV was 10.0%. Two hundred and four cases of liver disorder were reported (0.890%). AST/ALT levels were elevated in 98 patients and the PPV was 44.9%.
Conclusion: PPVs of statin-related ADRs from abnormal laboratory test results were relatively low and many false-negative or false-positive cases were observed. Both quantitative and qualitative information is required for conducting database analyses of drug safety profiles. Each ADR case should be described in detail, and the threshold of abnormal values should be examined to increase the validity of ADR predictions. (Jpn J Clin Pharmacol Ther 2013; 44(3): 193-200)

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The Ethical Guideline for Clinical Research, issued by the Ministry of Health, Labor and Welfare of Japan in 2003 and revised in July 2008, requires compensation for subjects' injury related to investigator-initiated clinical studies. At the Osaka University Hospital, contracts with insurance companies were included in 26, 16, and 15 protocols in 2009, 2010 and 2011, respectively. These insurance products cover transient payment but do not include the cost of medical care. Since the implementation of the revised guideline, several issues on the contracts with insurance companies have been encountered during three years. The insurance fee estimates varied greatly among the companies. In some cases, all four companies rejected to insure due to high risk. In other cases, three rejected and one company requested high insurance fee. In multi-center studies, the compensation frameworks may differ for each hospital. The compensation for clinical trials aiming at ameliorating side effects caused by cancer treatment showed a gap between the guideline and the actual situation. The insurance for clinical trials using devices showed challenges in evaluating the risk and benefit. Considering these issues, better compensation frameworks including cost of medical care should be established to protect human subjects. (Jpn J Clin Pharmacol Ther 2013; 44(3): 201-206)

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The University Hospital Clinical Trial Alliance(UHCT Alliance) was established in 2006 with the goal to conduct global studies in Japan, and is presently organized by 7 national university hospitals in the Kanto and Shin-Etsu area. To promote more efficient and safer clinical trials, we have been considering the possibility of a centralized IRB(CIRB) system in the Alliance. The outline of our plan is as follows: One of the university hospitals selected for a clinical trial is responsible for both Cooperative Hearing and CIRB, resulting in a shift of the site in charge of member hospitals in the Alliance. The CIRB should review not only “ethical and scientific issues” but also “local issues” such as qualifications of the investigators and the institutions. The CIRB should conduct continuing review of each ongoing trial. In the case of occurrence of significant adverse events in a member hospital, the site voluntarily offers opinions to the CIRB. Low efficiency caused by a small number of member hospitals and the CIRB shifting system seems to be the most serious problem in our plan. A CIRB for three Alliance members, similar to the Alliance system, has been working in an investigator-initiated clinical trial since July 2010. This ongoing system will provide more information about the advantages and disadvantages of our CIRB plan. When the number of member hospitals increases markedly, the methods of reviewing “local issues” should be reconsidered in order to safeguard the rights, safety, and well-being of trial subjects. (Jpn J Clin Pharmacol Ther 2013; 44(3): 207-215)

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We have studied and reported the influences of CYP2C19 polymorphism on the clinical efficacy of proton pump inhibitors(PPI), such as acid inhibition and cure rates of H.pylori infection and gastroesophageal reflux diseases(GERD) by PPI-based regimens. We linked the SS-MIX information and CYP2C19 genotypes on the computer disconnected to anything else and found that dose of PPI depended on CYP2C19 genotypes in patients with GERD. We studied the effect of CYP2C19 polymorphisms on the symptomatic recurrences of GERD in patients treated with a low dose of a PPI. We found that patients with rapid metabolizer genotypes of CYP2C19 had a higher risk of symptomatic recurrence of GERD when treated with a low dose of a PPI. (Jpn J Clin Pharmacol Ther 2013; 44(3): 263-265)

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