Pneumococcal vaccine coverage in Japan among patients with a history of splenectomy: Results of a retrospective administrative database study.

BACKGROUND: Splenectomy results in immune deficiency and increases the risk of clinically significant infections, termed overwhelming post-splenectomy infection (OPSI). In Japan, vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is covered by the Japanese National Health Insurance (NHI) for post-splenectomy patients, but there are limited data about whether these patients receive PPSV23 vaccination. METHODS: We performed retrospective analyses of the JMDC Claims Database comprising employees (including some retired individuals) and their families in Japan. We identified patients who underwent splenectomy (registration period: January 1, 2005-June 30, 2019) at ≥ 2 to ≤ 64 years old, and obtained information about PPSV23 vaccination, reasons for splenectomy, and prevalence/complications of pneumococcal infectious diseases (including OPSI-related disorders). RESULTS: Among 7,394,182 registered individuals, splenectomy was performed in 475, with an incidence rate of 1.6 cases per 100,000 person-years. Of 414 patients who underwent splenectomy at ≥ 2 to ≤ 64 years of age, their mean ± standard deviation age was 45.4 ± 15.7 years and 63.3% were 45-64 years old. Splenectomy was incidental in 55.3%. Overall, 123/414 patients were prescribed PPSV23 vaccination, resulting in vaccination coverage of 29.7%. The median interval from splenectomy to vaccination was 1.0 month (range: -1 to 85 months). CONCLUSION: This was the first study to document PPSV23 vaccination coverage after splenectomy in a Japanese real-world setting. PPSV23 coverage is quite low in Japan relative to that in other countries.

A Japanese nationwide survey of 23-valent pneumococcal capsular polysaccharide vaccine (PPSV23) revaccination coverage rate among elderly adults aged 65 and older and physician's attitude.

In July 2017, the Japanese Association for Infectious Diseases issued guidance for the administration of the PPSV23 revaccination. Despite increasing recognition of its protective benefits, levels of PPSV23 revaccination coverage rate in Japanese elderly population are unclear at present. Here, we report the results of a survey to know PPSV23 revaccination rates among elderly patients aged 65 and older. We asked an array of questions related to PPSV23 revaccination to Elderly adults and doctors across Japan via Web-based surveys in June 2018. The sampled population consisted of 5,085 men and women aged 65 and older. The PPSV23 revaccination coverage rate was estimated by survey questions regarded vaccination counts, intervals, and vaccine type. In addition, 400 internal medicine physicians were surveyed and asked about their reasons for recommending PPSV23 revaccination to elderly patients. In total, 1,648 elderly adults had received at least one PPSV23 dose; of these, 58 had received it at least twice (revaccination coverage rate: 3.5%). The most commonly cited justification for revaccination with PPSV23 among the surveyed physicians was that the benefits of revaccination exceed the risks of revaccination. In addition, multivariate analysis showed revaccinated status was most strongly associated with recommendations from peers (e.g. spouse, family, friends) among elderly subjects. This study reports PPSV23 revaccination coverage rate among Japanese adults aged 65 and older for the first time and concludes that the coverage rate is very low.

A Japanese nationwide survey of 23-valent pneumococcal capsular polysaccharide vaccine (PPSV23) coverage among patients with chronic medical condition aged 50 and older.

The 23-valent capsular polysaccharide pneumococcal vaccine (PPSV23) was introduced in Japan's routine immunization schedule October 2014. It was recommended for adults aged 65 years (including those ≥65 during the transition period), and for adults 60-64 with cardiac, renal, or respiratory dysfunction equivalent to Level 1 physical disability. Several studies have shown that patients aged 50+ with chronic medical conditions (CMC) are at elevated risk of pneumococcal infection. Nonetheless, PPSV23 vaccination rates among this population remains low. In our study, we report the results of a survey investigation into PPSV23 vaccination rates among Japanese patients aged 50+ with CMC. Patients aged 50+ comprised the patient population (n = 5,078) and internal medicine physicians comprised the doctor population (n = 400) located all over Japan were asked an array of questions relevant to PPSV23 immunization in June 2018 via Web-based surveys. PPSV23 coverages among chronic patients aged 50-59, 60-64, and 65+ years were respectively 1.3%, 2.9%, and 37.8%. The high disease-specific PPSV23 rates seen in the 65+ group was 50.0% and 49.4%, for chronic liver disease and chronic lung disease, respectively. Doctors most frequently cited a lack of municipal subsidies as justification for recommending the vaccine to patients with CMC aged 50-64 years, and deference to patients' wishes as justification for patients with CMC aged 65+. In conclusion, PPSV23 has poor coverage among Japanese adults aged 50-64 with CMC. Doctors and local authorities need to raise public awareness to improve the vaccination rate, given the high risk of pneumococcal infectious disease among patients with CMC.

Time interval of revaccination with 23-valent pneumococcal polysaccharide vaccine more than 5 years does not affect the immunogenicity and safety in the Japanese elderly.

In the previous study, revaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in a total of 161 elderly subjects (≥70 years of age) who had received the initial vaccination at least 5 years before (range: 5 to11 years) showed an acceptable safety profile and induction of immune responses to the serotypes in PPSV23. The optimal interval between the initial vaccination and revaccination with PPSV23 is of interest to protect elderly from pneumococcal disease over the long-term. In this post-hoc analysis, we analyzed that the immunogenicity and safety of revaccination with PPSV23 by time interval after the initial vaccination. The level of serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic killing activity (OPA) geometric mean titers (GMTs) at 4 weeks after revaccination with PPSV23 in each subgroup based on time interval (5, 6, 7, 8 and 9-11 years) after the initial vaccination were comparable to those after the primary vaccination and vaccine-induced serotype-specific IgG and OPA levels were similar regardless of the time interval after the initial vaccination. There was no difference in the safety profiles among the subgroups. In conclusion, administration of a second dose of PPSV23 at least 5 years after the initial vaccination was immunogenic and well-tolerated in the elderly ≥70 years of age regardless of the time interval after the initial vaccination.

Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs.

Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic ß cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 µM MK-0941 lowered the S(0.5) of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC(50) values for activation of GK by MK-0941 were 0.240 and 0.065 µM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 µM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ~2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0-2 h) plasma glucose levels by up to 48% compared with vehicle-treated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.

A small-molecule glucokinase activator lowers blood glucose in the sulfonylurea-desensitized rat.

Glucokinase activators increase insulin release from pancreatic beta-cells and hepatic glucose utilization by modifying the activity of glucokinase, a key enzyme in glucose-sensing and glycemic regulation. Sulfonylureas are antihyperglycemic agents that stimulate insulin secretion via a glucose-independent mechanism that is vulnerable to secondary failure through beta-cell desensitization. The present study determined whether glucokinase activator treatment retains its glucose-lowering efficacy in male, adult, non-diabetic Sprague-Dawley rats desensitized to sulfonylurea treatment and whether glucose-lowering during chronic glucokinase activator treatment is subject to secondary failure. Animals were given food containing either glimepiride (a sulfonylurea), Compound B (3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide, an experimental glucokinase activator), or no drug for up to 5 weeks. Food containing 0.04% of either drug produced acute (within 4-8 h) and significant (P<0.05) reductions in blood glucose to approximately 50% of control levels. Chronic treatment with either 0.01% or 0.04% glimepiride resulted in complete failure of glucose-lowering efficacy within 3 days whereas the efficacy of Compound B was sustained throughout the entire study. Glipizide, also a sulfonylurea, had no glucose-lowering effect when given by gavage (3mg/kg) to glimepiride-desensitized animals whereas Compound B retained full glucose-lowering efficacy in glimepiride-desensitized animals. Oral glucose tolerance was significantly impaired, compared with controls, in animals treated with glimepiride for two weeks but was enhanced to a small extent in animals treated with Compound B. Compound B also significantly increased pancreatic insulin content, compared with controls. These findings suggest that Compound B has sustained glucose-lowering effects in a rat model of sulfonylurea failure.

Metabolic activation of N-thiazol-2-yl benzamide as glucokinase activators: Impacts of glutathione trapping on covalent binding.

Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.

Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators.

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).

Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy.

The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.

A selective small molecule glucagon-like peptide-1 secretagogue acting via depolarization-coupled Ca(2+) influx.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca(2+) release from intracellular stores, but to extracellular Ca(2+) influx. The response was inhibited by the presence of either L-type Ca(2+) channel blockers or K(+) ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Galphas- nor Galphaq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca(2+) influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.

Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.

Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.

Identification of novel and potent 2-amino benzamide derivatives as allosteric glucokinase activators.

The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.

Structure-activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridines.

The synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.