Japan PGx Data Science Consortium Database: SNPs and HLA genotype data from 2994 Japanese healthy individuals for pharmacogenomics studies.

Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing.

Increased expression of vascular endothelial growth factor protein in dorsal root ganglion exposed to nucleus pulposus on the nerve root in rats.

STUDY DESIGN: An experimental rat study. OBJECTIVE: To assess pain-related behavior and vascular endothelial growth factor (VEGF) expression induced by nucleus pulposus (NP) applied to nerve roots in rats. SUMMARY OF BACKGROUND DATA: Radiculopathy from disc herniation is caused by nerve compression and chemical inflammation. In experimental studies, a decrease in mechanical withdrawal threshold, blood flow, and nerve root dysfunction was reported when the NP was applied to nerve roots. However, neuron reproduction and changes in nerve root blood vessels have not been clearly understood. METHODS: NP harvested from the tail was applied to the left L5 dorsal root ganglion (NP group; n = 77). As a control, sham-operated animals were used (n = 77). Behavioral testing with von Frey hairs was performed for 35 days. Immunoreactivity (IR) for VEGF, activating transcription factor-3, growth-associated protein-43 (GAP-43), factor VIII, and hypoxia-inducible factor-1[alpha] (HIF-1 a) were studied by immunohistochemistry. Western blot analyses of VEGF and GAP-43 were also performed. RESULTS: The mechanical withdrawal threshold significantly decreased from 7 to 28 days in the NP group versus the sham group (P < 0.05). In the NP group, activating transcription factor-3-IR cells increased from 3 to 14 days (P < 0.05), hypoxia-inducible factor-1[alpha]-IR cells increased at 14 days (P < 0.05), and blood vessels with Factor VII-IR cells increased at 28 days (P < 0.05) compared with the sham group. The expression levels of VEGF and GAP-43 in the NP group significantly increased at 14 and 28 days (P < 0.05). CONCLUSION: Neuron damage induced by NP applied to the nerve root at the early stage, and axon extension occurred from 14 days. VEGF increased at 14 and 28 days, and the numbers of blood vessels increased 28 days after surgery. The mechanical withdrawal threshold improved at 35 days. Regeneration and vascularization by VEGF might be associated with pain-related behavior.

Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers.

BACKGROUND: Avanafil is a selective phosphodiesterase type 5 inhibitor being developed for the treatment of erectile dysfunction. OBJECTIVE: This study was conducted to meet Korean regulatory requirements for the marketing of avanafil. To this end, tolerability and pharmacokinetic properties of single and multiple oral doses of avanafil in healthy Korean male volunteers were assessed. METHODS: A double-blind, randomized, placebo-controlled, parallel-group, dose-escalation study was conducted at the Asan Medical Center (Seoul, Korea). Subjects were randomized to receive either drug or placebo in blocks according to each dose. Subjects were randomly allocated to receive 50-, 100-, or 200-mg tablets of avanafil or placebo once daily for 7 days (avanafil:placebo, 8:2 in each dose group). Tolerability was assessed by monitoring vital signs and results of laboratory tests, 12-lead ECGs, and color discrimination tests. Blood samples of approximately 6 mL were collected in heparinized tubes before and 0.1, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration on days 1 and 7. Plasma concentrations of avanafil were measured using LC-MS/MS. Pharmacokinetic parameters of avanafil on days 1 and 7 were determined by noncompartmental analysis and compared among the 3 dose groups. RESULTS: Of the 32 healthy male subjects initially enrolled, 30 completed the study. The mean (SD) age, height, and weight of the participants were 23.4 (1.7) years, 175.0 (5.4) cm, and 70.3 (8.9) kg, respectively. Adverse events were reported by 20 of 25 subjects (80%) taking avanafil and by 4 of 6 (67%) taking placebo. No serious adverse events were reported, and there were no clinically relevant changes in vital signs, ECG recordings, physical examination findings, or color discrimination test results. All the adverse events resolved spontaneously. Avanafil reached a mean T(max) at 0.33 to 0.52 hour after dosing and then declined, with a mean apparent t1/2 of 5.36 to 10.66 hours. AUC and C(max) were proportional to dose, and the mean accumulation index on day 7 after a single daily dose of avanafil was 0.98. CONCLUSION: Avanafil was generally well tolerated and had linear pharmacokinetic properties at daily doses of 50 to 200 mg over 7 days in these healthy Korean male volunteers. Korean National Study Registration Number: 3466.

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor.

A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA(+/+)/SCID(+/+) mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log(10) h(-1). During the initial phase of treatment, the log(10) reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10(8) virions per day, and this may be comparable to HCV production in the human liver.