Health Care Cost Analysis of PPI or P-CAB-First Treatment in Patients With Gastroesophageal Reflux Disease.

GOALS: The aim was to examine actual health care cost in patients with gastroesophageal reflux disease (GERD) who were initiated on proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) as first-line therapy in Japanese real-world clinical settings. BACKGROUND: To date, cost-utility evaluation of acid-suppressants treatment in Japan has only been conducted by model analysis. STUDY: A cost utilization analysis was performed using a Japanese nationwide hospital-based claim database by extracting patients with GERD initiated on either PPI or P-CAB (242,102 pairs) and esomeprazole (EPZ) or P-CAB (241,825 pairs). Health care costs were compared in each comparison cohort with propensity-score matched pairs. The switching rates of initial acid-suppressants were also examined. RESULTS: Baseline characteristics were well-balanced after matching. The 3-year mean cumulative GERD-related and hospitalization costs per patient were ¥142,620 and ¥122,444 in PPI-first and P-CAB-first treatment groups, and ¥105,263 and ¥121,958 in EPZ-first and P-CAB-first treatment groups, respectively. Most hospitalization costs were non-GERD related in all the groups. The switching rates of PPI to P-CAB and P-CAB to PPI in 12 months were 7.5% and 20.2%, respectively. CONCLUSIONS: In this propensity-score matched analysis, health care cost was higher in patients with GERD initiated on PPI than in those initiated on P-CAB mainly owing to non-GERD-related hospitalization cost, whereas it was lower in those initiated on EPZ than in those initiated on P-CAB. When considering health care costs except hospitalization costs, PPI-first treatment was less expensive than P-CAB-first treatment. Low switching rate from PPI to P-CAB in the real-world practice may partially explain the discrepancy.

Immunogenicity and safety of the new MMR vaccine containing measles AIK-C, rubella Takahashi, and mumps RIT4385 strains in Japanese children: a randomized phase I/II clinical trial.

Domestic measles, mumps, and rubella combined (MMR) vaccines were discontinued in 1993 in Japan because of the unexpected high incidence of aseptic meningitis. The introduction of an effective MMR vaccine with lower reactogenicity has been expected. A new MMR vaccine (JVC-001) was developed, using mumps RIT4385 strain in combination with Japanese measles AIK-C strain and rubella Takahashi strain (MR) vaccine. An open-label, randomized, phase I/II clinical study was conducted in 100 healthy Japanese children equally randomized to a JVC-001 group and an MR with monovalent mumps vaccine (Hoshino strain) group. Immunogenicity was assessed using a neutralization test (NT) for measles, hemagglutination inhibition (HI) test for rubella, and NT and enzyme-linked immune-sorbent assay (ELISA) for mumps strain with different genotypes (genotype A, B, D and G) on Day 0 and Day 42-56. Solicited and unsolicited adverse events (AEs) were recorded. Seroconversion rates of measles and rubella were both 100%. JVC-001 induced higher immunogenicity against mumps virus genotype G with seroconversion rate of 77.1% (95% confidence interval [CI]: 62.7-88.0%) compared to 65.3% (95% CI: 50.4-78.3%) in the control group. Geometric mean titer (GMT) was 12.5 (95% CI: 8.6-18.3) in the JVC-001 group and 7.1 (95% CI: 5.0-10.1) in the control group. JVC-001 also induced good immunogenicity against other genotypes (A, B and D). There was no apparent difference in the incidence of AEs between JVC-001 and the control groups. JVC-001 is safe and induces effective immunogenicity against measles, mumps, and rubella compared with the currently marketed vaccines in Japan.

Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged ≥50 years when administered subcutaneously vs. intramuscularly.

The impact of alternate routes of vaccine administration, subcutaneous (SC) or intramuscular (IM), on the safety and immunogenicity of herpes zoster subunit candidate vaccine (HZ/su) was assessed in Japanese adults aged ≥ 50 y. During this phase III open-label study, 60 subjects were randomized (1:1) to receive HZ/su through SC or IM routes in a 0, 2 month schedule. Vaccine response rates (VRRs) and geometric mean concentrations (GMCs) of varicella zoster virus glycoprotein E (gE)-specific antibodies were determined by ELISA. Solicited and unsolicited symptoms were recorded for 7 and 30 d after each vaccination and graded 1-3 in severity. Serious adverse events (SAEs) were recorded throughout the study. At one month post-dose 2, VRRs were 100% (95% Confidence Interval (CI): 88.1-100) in both groups; anti-gE antibody GMCs were 44126.1 mIU/ml (95% CI: 36326.1-53601.0) and 45521.5 mIU/ml (95% CI; 37549.5-55185.9) in the SC and IM groups, respectively. Injection site reactions (pain, swelling and redness) were common, and observed more frequently following SC administration. Grade 3 redness and swelling were more frequently observed after SC administration. Fatigue and headache were the most frequently reported general symptoms for both routes of administration. Ten and 7 unsolicited AEs were reported in the SC and IM group, respectively. Two unsolicited AEs (1 in SC; 1 in IM) were considered related to vaccination by the investigator. Three non-fatal SAEs considered unrelated to vaccination were reported during the study. Administration of the HZ/su vaccine candidate resulted in a substantial immune response that was comparable between SC and IM subjects, but local reactogenicity may be greater for SC.

Structural and functional analysis of tomato ß-galactosidase 4: insight into the substrate specificity of the fruit softening-related enzyme.

Plant ß-galactosidases hydrolyze cell wall ß-(1,4)-galactans to play important roles in cell wall expansion and degradation, and turnover of signaling molecules, during ripening. Tomato ß-galactosidase 4 (TBG4) is an enzyme responsible for fruit softening through the degradation of ß-(1,4)-galactan in the pericarp cell wall. TBG4 is the only enzyme among TBGs 1-7 that belongs to the ß-galactosidase/exo-ß-(1,4)-galactanase subfamily. The enzyme can hydrolyze a wide range of plant-derived (1,4)- or 4-linked polysaccharides, and shows a strong ability to attack ß-(1,4)-galactan. To gain structural insight into its substrate specificity, we determined crystal structures of TBG4 and its complex with ß-d-galactose. TBG4 comprises a catalytic TIM barrel domain followed by three ß-sandwich domains. Three aromatic residues in the catalytic site that are thought to be important for substrate specificity are conserved in GH35 ß-galactosidases derived from bacteria, fungi and animals; however, the crystal structures of TBG4 revealed that the enzyme has a valine residue (V548) replacing one of the conserved aromatic residues. The V548W mutant of TBG4 showed a roughly sixfold increase in activity towards ß-(1,6)-galactobiose, and ~0.6-fold activity towards ß-(1,4)-galactobiose, compared with wild-type TBG4. Amino acid residues corresponding to V548 of TBG4 thus appear to determine the substrate specificities of plant ß-galactosidases towards ß-1,4 and ß-1,6 linkages.

Synthesis and Biological Evaluation of Cyclopentaquinoline Derivatives as Nonsteroidal Glucocorticoid Receptor Antagonists.

The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo.

Expression, purification, crystallization and preliminary X-ray crystallographic analysis of tomato ß-galactosidase 4.

Plant ß-galactosidases play important roles in carbohydrate-reserve mobilization, cell-wall expansion and degradation, and turnover of signalling molecules during ripening. Tomato ß-galactosidase 4 (TBG4) not only has ß-galactosidase activity but also has exo-ß-(1,4)-galactanase activity, and prefers ß-(1,4)-galactans longer than pentamers as its substrates; most other ß-galactosidases only have the former activity. Recombinant TBG4 protein expressed in the yeast Pichia pastoris was crystallized by the sitting-drop vapour-diffusion method using PEG 10,000 as a precipitant. The crystals belonged to the orthorhombic space group P212121, with unit-parameters a = 92.82, b = 96.30, c = 159.26 Å, and diffracted to 1.65 Å resolution. Calculation of the Matthews coefficient suggested the presence of two monomers per asymmetric unit (VM = 2.2 Å(3) Da(-1)), with a solvent content of 45%.

Enzymatic activity and substrate specificity of the recombinant tomato ß-galactosidase 1.

The open reading frame of tomato ß-galactosidase 1 was expressed in yeast, and the enzymatic properties and substrate specificity were investigated. The enzyme had peak activity at pH 5.0 and 40-50°C. TBG1 was active on ß-(1,3)- and ß-(1,6)-galactobiose and lactose. TBG1 released galactose from lupin galactan, tomato fruit alkali soluble pectin, arabinogalactan, gum arabic and methyl ß-(1,6)-galactohexaoside, but not from labeled ß-(1,4)-galactoheptaose. TBG1 was assessed for its ability to degrade three galactosyl-containing cell wall fractions purified from different development and ripening stages of tomato fruit. TBG1 released galactose from all of the fractions from all of the stages tested. TBG1 activity was highest on the hemicellulose fraction at the 10 and 20d after pollination stage. This result is not correlated the with TBG1 expression pattern. TBG1 might act on a small but specific set of polysaccharide containing galactose.