Poly(hydroxyurethane): catalytic applicability for the cyclic carbonate synthesis from epoxides and CO2.

We have developed a synthetic methodology using poly(hydroxyurethane) as an organocatalyst for the chemical fixation of CO2 into epoxides, leading to the formation of five-membered cyclic carbonates with remarkably high selectivity and yields. The catalyzed reaction was applicable to various epoxides.

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

Prevention of postprandial hypotension-related syncope by caffeine in a patient with long-standing diabetes mellitus.

A 74-year-old man who had type 2 diabetes mellitus of a duration of 20 years was admitted for syncope after eating a high carbohydrate meal. Although he had had episodes of pallor or syncope after carbohydrate-rich meals, such as with large amounts of white rice, several times within a year and he had been taken to hospitals emergently, the etiology of these episodes had remained unclear despite his undergoing several studies. Studies did show severe orthostatic hypotension during the head-up tilt test and a decrease in the coefficient of variation of the R-R interval (CVR-R) on resting electrocardiogram, suggesting severe autonomic nervous dysfunction. Because of the episodes of syncope after eating a carbohydrate-rich meal, we investigated whether he had postprandial hypotension (PPH). The 75 g oral glucose tolerance test revealed a significant decrease in his postprandial blood pressure by about 40 mmHg, leading to the diagnosis of PPH. The carbohydrate-rich meal test induced syncope with systolic blood pressure under 40 mmHg. Then 150 mg caffeine was administered before a second carbohydrate-rich meal. The marked decline in postprandial blood pressure was suppressed and plasma noradrenaline levels were gradually increased over a period of 60 minutes. Caffeine could be useful for prevention of postprandial hypotension-related syncope.

Systematic synthetic study of four diastereomerically distinct limonene-1,2-diols and their corresponding cyclic carbonates.

In order to produce versatile and potentially functional terpene-based compounds, a (R)-limonene-derived diol and its corresponding five-membered cyclic carbonate were prepared. The diol (cyclic carbonate) comprises four diastereomers based on the stereochemical configuration of the diol (and cyclic carbonate) moiety. By choosing the appropriate starting compounds (trans- and cis-limonene oxide) and conditions, the desired diastereomers were synthesised in moderate to high yields with, in most cases, high stereoselectivity. Comparison of the NMR data of the obtained diols and carbonates revealed that the four different diastereomers of each compound could be distinguished by reference to their characteristic signals.

Synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition.

The synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition and significantly improved MIC against Candida parapsilosis and echinocandin resistant-Candida is described.

Comparison of PPIs and H2-receptor antagonists plus prokinetics for dysmotility-like dyspepsia.

AIM: To compare efficacy of proton pump inhibitors (PPIs) with H(2)-receptor antagonists (H(2)RAs) plus prokinetics (Proks) for dysmotility-like symptoms in functional dyspepsia (FD). METHODS: Subjects were randomized to receive open-label treatment with either rabeprazole 10 mg od (n = 57) or famotidine 10 mg bid plus mosapride 5 mg tid (n = 57) for 4 wk. The primary efficacy endpoint was change (%) from baseline in total dysmotility-like dyspepsia symptom score. The secondary efficacy endpoint was patient satisfaction with treatment. RESULTS: The improvement in dysmotility-like dyspepsia symptom score on day 28 was significantly greater in the rabeprazole group (22.5% ± 29.2% of baseline) than the famotidine + mosapride group (53.2% ± 58.6% of baseline, P < 0.0001). The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status. Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine + mosapride group (87.7% vs 59.6%, P = 0.0012). Rabeprazole therapy was the only significant predictor of treatment response (P < 0.0001), defined as a total symptom score improvement ≥ 50%. CONCLUSION: PPI monotherapy improves dysmotility-like symptoms significantly better than H(2)RAs plus Proks, and should be the treatment of first choice for Japanese FD.

Successful remission of Evans syndrome associated with Graves' disease by using propylthiouracil monotherapy.

A 46-year-old woman with Graves' disease was admitted for anemia and thrombocytopenia. She had previously been treated with methimazole but she self-discontinued the treatment 6 months prior to admission. She was diagnosed with Evans syndrome associated with Graves' disease and treated with propylthiouracil without corticosteroids, which normalized her thyroglobulin level. Surprisingly, while Evans syndrome is characterized by frequent relapses, this patient has been in remission of Evans syndrome for approximately 4 years. The remission of Evans syndrome associated with Graves' disease in the absence of immunosuppressive therapy suggests that these 2 diseases have a common pathogenetic mechanism.

Fulminant type 1 diabetes mellitus acutely emerged during pregnancy.

A pregnant woman at 32 weeks of gestation was emergently admitted to our hospital with symptoms of nausea, vomiting, and uterine contraction. Cardiotocogram demonstrated a loss of variability and late deceleration in fetal heart rate pattern. Emergency cesarean section was performed, and a male infant weighing 1750 g was born with Apgar scores of 1 at 1 min, and 3 at 5 min after delivery. After cesarean section, the patient developed an acetone breath odor, and blood examination demonstrated remarkable acidemia and an extremely high level of blood glucose. The patient was diagnosed with ketoacidosis with acute onset of fulminant type 1 diabetes mellitus. Intensive care was applied due to the severe diabetes mellitus conditions. The patient's general condition ameliorated during the postoperative period, although there was a possibility of neurological complications in the infant.

Tissue-specific mRNA expression profiles of drug-metabolizing enzymes and transporters in the cynomolgus monkey.

Pairs of forward and reverse primers and TaqMan probes specific to each of 19 drug-metabolizing enzymes (cytochrome P450s, UDP-glucuronosyltransferases, glutathione S-transferases, and sulfotransferases) and 5 transporters (ABC and SLC transporters) in the cynomolgus monkey were prepared. The expression level of each target mRNA was analyzed in total RNA obtained from three specimens of various cynomolgus monkey tissues (adrenal gland, brain, heart, kidney, large intestine, liver, lung, pancreas, prostate, small intestine, spleen, testis, and thymus) by real-time reverse transcription PCR using an Applied Biosystems 7500 Fast Real-Time PCR System. The data obtained in the present study provide useful information on tissue-specific profiles of the expression of these target mRNAs in the cynomolgus monkey, and the results are expected to be valuable in establishing drug metabolism- and transporter-mediated screening systems using the cynomolgus monkey for the evaluation of new chemical entities in new drug development.

FR290581, a novel sordarin derivative: synthesis and antifungal activity.

Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.

Comparison of inducibility of multidrug resistance (MDR)1, multidrug resistance-associated protein (MRP)1, and MRP2 mRNAs by prototypical microsomal enzyme inducers in primary cultures of human and cynomolgus monkey hepatocytes.

This study investigated the changes in the mRNA levels of the ATP binding cassette (ABC) transporters multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and multidrug resistance-associated protein 2 (MRP2) following exposure to the prototypical microsomal enzyme inducers rifampicin (Rif), dexamethasone (Dex), and omeprazole (Ome) in primary cultures of cryopreserved human and cynomolgus monkey hepatocytes. Analysis was performed by real-time reverse transcription-polymerase chain reaction using primers and TaqMan probes. First, the time course of the mRNA expression of these transporters in primary cultures of human and cynomolgus monkey hepatocytes was examined in detail. The ratio of MDR1 and MRP2 mRNA to beta-actin mRNA in both human and cynomolgus monkey hepatocytes remained constant from 48 to 72 h and from 24 to 72 h of culture, respectively. Second, the hepatocytes were exposed to the inducers and the changes in the levels of the transporter mRNAs were examined. Rif increased MDR1 and MRP1 mRNA levels in both human and cynomolgus monkey hepatocytes, while Ome slightly increased MDR1 and MRP1 mRNA levels in cynomolgus monkey hepatocytes. Rif and Ome increased MRP2 mRNA levels in both human and cynomolgus monkey hepatocytes. In contrast, Dex tended to decrease the mRNA levels of MDR1, MRP1, and MRP2 in both human and cynomolgus monkey hepatocytes. Cynomolgus monkey hepatocytes appeared to be more responsive than human hepatocytes to the inducers. These results indicate that primary cultures of cynomolgus monkey hepatocytes are as useful as primary cultures of human hepatocytes for evaluating the induction of MDR1, MRP1, and MRP2 mRNAs in preclinical studies.

A randomized double-blind comparative study of sublingual immunotherapy for cedar pollinosis.

BACKGROUND: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollen is a substantial problem in Japan. Sublingual immuno-therapy (SLIT) is safer than conventional antigen-specific immunotherapy, the only treatment modality by which complete cure of the disease can be expected. We investigated the safety and efficacy of SLIT in the treatment of cedar pollinosis patients compared to placebo. METHODS: A randomized, placebo-controlled, double-blind study was conducted in 61 cedar pollinosis patients. Increasing doses of standardized Japanese cedar extract or placebo were administered sublingually in intervals ranging from daily to once a week after six weeks. The primary efficacy variable was the mean of the daily total symptom scores (TSS) during the pollen dispersing period. Secondary efficacy variables included the QOL scores and related variables. RESULTS: Primary efficacy variable scores were significantly lower for some days in the SLIT group than in the placebo group (P < .01 or P < .05). Secondary efficacy for the QOL score in SLIT group was almost of half of placebo group. There was no significant difference in the overall incidence of side effects between the SLIT group and the placebo group. CONCLUSIONS: SLIT was effective and safe in the treatment of cedar pollinosis.

The effects of montelukast on tissue inflammatory and bone marrow responses in murine experimental allergic rhinitis: interaction with interleukin-5 deficiency.

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin-5 (IL-5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL-5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL-5 deficiency. Three groups of age-matched BALB/c mice with or without IL-5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast-treated groups (2.5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony-forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose-dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL-5-replete mice compared to controls. In IL-5-deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL-5-responsive Eo/B-CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL-5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.

Bottom-up synthesis of optically active oligonaphthalenes: three different pathways for controlling axial chirality.

The oxidative homocoupling of optically active binaphthalenes 1a-d with a stoichiometric amount of CuCl2 and amines afforded quaternaphthalenes 2a-d in up to 93% de. The high diastereoselectivities were achieved through three different pathways (epimerization of the axis together with diastereoselective crystallization, thermodynamic, and kinetic control pathways). The type of side chains on the naphthalene influenced which pathway dominates. Three pathways were applicable to octinaphthalenes (8a-d) and hexadecanaphthalene 10a with 46-99% de. The absolute configuration of the newly formed axial bond was determined by (1) X-ray crystallographic analysis, (2) transformation to known compounds 15 and 16, (3) CD spectra of oligonaphthalenes with two pyrene rings as exciton parts, and (4) the shift values in 13C NMR spectra of 13C-enriched derivatives 29-31 toward chiral shift reagent Eu(+tfc)3.

[Outcome of treatment with surgical resection of the remaining tumor after modified M-VAC treatment for advanced urothelial carcinoma].

We retrospectively evaluated the effect of the surgical resection of the remaining tumor after modified M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) (m-M-VAC) treatment for locally advanced or metastatic urothelial carcinoma. In m-M-VAC therapy, methotrexate and vinblastine on 15 and 22 days were omitted from the classical M-VAC to avoid the discontinuation and the dose reduction, and duration of 1 course was shortened to 21 days from 28 days of the classical M-VAC. Seven patients with locally invasive or metastatic carcinoma of the renal pelvis, ureter, and bladder, 6 males and 1 female, with a median age 64.1 years, ranging from 49 to 77 years received m-M-VAC chemotherapy without severe side effects. In all patients, the residual viable carcinoma was completely resected and they achieved complete remission. The median survival time was 20 months (range, 7 to 61). Five of these 7 patients were still alive. Two patients had no recurrence and achieved long-term survival (survival duration; 61 and 39 months). Although further studies and long-term follow up are required, these results suggest that patients who present with locally advanced or metastatic urothelial carcinoma may benefit from surgical resection after m-M-VAC.

Validation study of a method for assaying DE-310, a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, and the free drug in tumor tissue by high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry.

DE-310 is a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, DX-8951, which is conjugated to a water-soluble polymer via a peptide spacer. Assay methods have been developed for the determination of a polymer-bonded DX-8951 conjugate, DX-8951, and Glycyl-DX-8951 concentrations in murine Meth A tumor tissue. Free DX-8951 and Glycyl-DX-8951 were extracted from tumor tissue homogenates by protein precipitation and analyzed by LC/MS/MS (method I). Conjugated DX-8951 was isolated by solid-phase extraction after digestion with a thermolysin. The productive phenylalanyl-glycyl-DX-8951 was analyzed by LC/MS/MS (method II). The lower limits of quantitation of DX-8951, Glycyl-DX-8951, and conjugated DX-8951 were 1.36, 1.34 and 73.7 ng/g (as DX-8951 equivalent). These two methods showed satisfactory sensitivity, precision and accuracy. To study the pharmacokinetics of DE-310, it would be of great help to assay the polymer-bonded DX-8951 and its released drugs in tumor tissue.

[Clinical study of modified M-VAC therapy with one 21-day cycle for advanced urothelial cancer].

Although M-VAC therapy is a standard chemotherapy for advanced transitional cell carcinoma, the treatment schedule has to be delayed or cancelled in many patients because of the toxicity. To reduce the toxicity we modified the treatment schedule of M-VAC treatment. The dosages of this simplified M-VAC therapy were 30 mg/m2 methotrexate (on day 1), 3 mg/m2 vinblastine (on day 2), 30 mg/m2 doxorubicin (on day 2) and 70 mg/m2 cisplatin (on day 2), with courses repeated every 21 days for four cycles as a principle. Seventeen patients with histologically proven advanced transitional cell carcinoma were treated with this simplified M-VAC therapy without dose modification or delay. The median number of cycles was 4. Neutropenia, anemia and thrombopenia (grade 4) was observed in 2, 1 and 2 patients respectively, but no drug-related deaths were observed. Complete response and partial response were achieved in 2 (12%) and 10 (59%) patients respectively. Of 2 complete responders one patient was alive without evidence of disease at 12 months and another patient died of the disease at 42 months. Of 10 partial responders 6 patients underwent the additional surgical resection of residual tumors. Of these 6 patients 3 patients are alive without evidence of disease at 6, 30 and 31 months. The remaining 3 developed recurrence and 2 died of the disease at 13 and 29 months. Five non-responders died of the disease at 5 months after the start of the therapy. Response rate of simplified M-VAC therapy was excellent and treatment duration was short. However, relapses were commonly observed as well as the original M-VAC treatment.

Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis.

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1-R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1-R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2.5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)-5-, but not IL-3-, or granulocyte-macrophage colony-stimulating factor-responsive eosinophil/basophil colony-forming units, and IL-5-stimulated eosinophil maturation. These results indicate that cysLT1-R antagonism in vivo limits both IL-5-responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti-allergic effects of cysLT1-R antagonists are consistent with the concept that cysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.

Synthesis of optically active oligonaphthalenes via second-order asymmetric transformation.

Synthesis of numerous optically active rod-shaped oligo(2,3-dioxyfunctionalized)naphthalenes connected at their 1,4-positions was achieved using oxidative coupling under CuCl2/alpha-methylbenzylamine conditions by second-order asymmetric transformation. We believe this method is practical and should contribute to the field of material science.