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The microscopic effects of each substituent of the Hf catalyst and the growing polymer on the monomer insertion process were investigated for Hf-pyridyl amido-catalyzed coordinative chain transfer polymerization using the Red Moon method. Since the Hf catalyst has two reaction sites, cis - and trans -sites, we separately applied the appropriate analysis methods to each one, revealing that the naphthalene ring influenced monomer insertion at the cis -one, while the i -Pr group and the hexyl group of the adjacent 1-octene unit did the trans -one. It was interesting to find that the hexyl group of the 1-octene-inserted catalyst (oHfCat) pushes the naphthalene ring toward the cis -site and narrows the space at the cis -site, thus indirectly creating a steric hindrance to cis -insertions. Further, the relative position of the Hf catalyst and the growing polymer was found to be strongly influenced by the patterns of insertion reactions, i.e., cis - or trans -insertions. In particular, it was clarified that, after trans -insertions, the growing polymer on the Hf atom covers the cis -site, making cis -insertion less likely to occur. These studies reveal the microscopic effects of the catalyst substituents and the growing polymer on the catalyst during the polymerization reaction process; these microscopic analyses using the RM method should provide atomistic insights that are not easy to obtain experimentally for advanced catalyst design and polymerization control.

The Hf-pyridyl amido complex ((pyridylamido)Hf(IV)) is a cationic catalyst activated by ion-pairing with auxiliary catalyst B(C 6 F 5 ) 4 to show high activity for α-olefin polymerization. Previously, it was experimentally observed that the consumption rate of 1-octene in the 1-octene/ethene copolymerization is 3-fold compared to the 1-octene homopolymerization in coordinative chain transfer polymerization using the catalyst HfCat + -B(C 6 F 5 ) 4 - ion pair (IP) and the chain transfer agent (CTA) ZnEt 2 . In the present study, we have performed atomistic chemical simulations of the IP-catalyzed homopolymerization of 1-octene and copolymerization of 1-octene and ethene on the basis of the Red Moon (RM) methodology. Using the analysis by polymer propagation diagrams (PPDs), in the 1-octene homopolymerization and the 1-octene/ethene copolymerization with the 1-octene-inserted catalyst (oHfCat), it is theoretically shown that the propagation reactions intermittently pause due to the steric hindrance of two hexyl groups of the oHfCat and the 1-octene inserted adjacent to the Hf atom. On the other hand, in the polymerizations with the ethene-inserted catalyst (eHfCat), it is reasonably recognized that the propagation reactions occur smoothly at a constant rate, and the polymerization continuously proceeds due to the relatively smaller steric hindrance. In conclusion, it was shown, for the first time, that the RM method can be used to reveal the microscopic effects of monomers and substituents in the polymerization reaction processes. Therefore, our current work using PPDs demonstrates the promising potential of the RM methodology in studying catalytic olefin polymerizations and complex chemical reaction systems in general.

Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability. A proposed flowchart is presented as a guidance tool to be used by the practicing medicinal chemist when facing a phototoxicity risk. The description of available tools to consider in the drug design process will include an overview of the evolution of in silico methods and their application as well as structure alerts for consideration as potential phototoxicophores.

Background: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic (IC) assay (APD1806) using monoclonal antibodies against the matrix (M) protein of human metapneumovirus (hMPV) for detection of hMPV from nasopharyngeal swab samples based on the results of real-time RT-PCR., Methods: Nasopharyngeal swab samples taken from 189 patients aged 0 - 5 years who were suspected of having respiratory tract infections associated with hMPV were used in this study. The samples were tested both by the IC assay and by real-time RT-PCR for detection of hMPV., Results: The sensitivity and specificity of the IC assay for detection of hMPV were 88.8% (95/107) and 92.7% (76/82), respectively., Conclusions: The IC assay using monoclonal antibodies against the M protein of hMPV is an accurate and fast assay that is suitable as a diagnostic tool for hMPV infection. The optimal timing of the IC assay is 12 hours or more after the onset of fever due to hMPV infection.

Background: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic assay (ICA) kit, ALSONIC® Adeno (Alfresa Pharma Co., Osaka, Japan), for the detection of human adenovirus (HAdV) from throat swab samples based on the results of real-time PCR. The incubation time required for the novel assay kit (5 minutes) is shorter than that required for other ICA kits that are available in Japan., Methods: Throat swab samples were taken from 151 patients aged 6 months to 15 years who were suspected of having respiratory tract infections caused by HAdV., Results: The sensitivity and specificity of the ICA for detection of HAdV were 92.2% (83/90) and 95.1% (58/61), respectively, and the assay showed positive and negative predictive values of 96.5% (83/86) and 89.2% (58/65), respectively., Conclusions: ALSONIC® Adeno is suitable as a diagnostic tool in the acute phase of HAdV infection.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012)., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: Spontaneous pneumothorax combined with thoracic endometriosis is a rare condition during pregnancy. We present a case of chemical pleurodesis with autologous blood and freeze-dried concentrated human thrombin during pregnancy., Case Report: This report presents a case of spontaneous pneumothorax combined with thoracic endometriosis that arose at 22 weeks' gestation in a 35-year-old female. The initial chest drainage was unsuccessful. At 25 weeks' gestation, video-assisted thoracoscopic surgery was performed and revealed endometriosis in the thoracic cavity. Since the leak persisted, chemical pleurodesis was performed with autologous blood and freeze-dried concentrated human thrombin at 28 weeks' gestation. The leak improved markedly and did not recur., Conclusion: This is the first case report about chemical pleurodesis with autologous blood and freeze-dried concentrated human thrombin during pregnancy. This procedure might contribute to the management of pneumothorax in pregnant women., (Copyright © 2018. Published by Elsevier B.V.)

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.

This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure-activity relationships. Intranasal administration of PTP1B inhibitors at ≥0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action.

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive WNK1-4 kinase inhibitors, the optimization of which enabled cocrystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

Pituitary stalk transection syndrome (PSTS) is a rare complication that can accompany breech delivery. Early diagnosis of this syndrome is difficult, and it may cause a serious delay in the diagnosis. We present a case of PSTS ascertained after breech delivery. A 20-year-old woman presented with primary amenorrhea. The patient was born by breech delivery and had a history of treatment for pituitary dwarfism. Her laboratory findings showed pituitary hypothyroidism, and hormone replacement therapy was initiated. At 28 years old, she became pregnant and had a normal delivery at 38 weeks' gestation. One year after delivery, her thyroid hormone level changed. Laboratory test showed adrenocortical insufficiency, and magnetic resonance imaging of the pituitary gland showed transection of the pituitary stalk and development of an ectopic posterior lobe. These findings were compatible with PSTS. When a patient who has been born by breech delivery presents with symptoms of pituitary deficiency, PSTS should be considered in the differential diagnosis., (© 2015 Japan Society of Obstetrics and Gynecology.)

Various conservative treatments for cervical pregnancy have been reported. However, unlike tubal ectopic pregnancy, the treatment of cervical pregnancy has not been well established. For patients who desire fertility preservation, treatment with methotrexate chemotherapy carries a high success rate for preservation of the uterus. When methotrexate is injected i.v. or i.m., expulsion of pregnant tissue occasionally takes up to 1 month. In this report, we present four cases of cervical pregnancy which were successfully managed by methotrexate injection into the bilateral uterine arteries. In cases presenting with massive bleeding, embolization of the bilateral uterine arteries was performed. Cervical pregnancy was aborted within 8 days safely, and fertility could be preserved without harmful side-effects., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Several etiologies have been proposed for erythrocytosis associated with uterine leiomyoma. We report a case of erythrocytosis associated with a large uterine leiomyoma, in which specific immunostaining for erythropoietin was positive. A 55-year-old woman, gravida 0, para 0, was referred to our hospital for treatment for a large uterine myoma and erythrocytosis. She had no vaginal bleeding after she reached menopause at 50 years old. She had severe polycythemia: hemoglobin (Hb), 19.9 g/dL; red blood cell count (RBC), 6.65 × 10(6)/mm(3); hematocrit, (Hct) 59.1%. An abdominal simple hysterectomy was performed, and a pathological examination confirmed the diagnosis of leiomyoma of the uterus. In addition, immunostaining demonstrated that the cytoplasm of the leiomyoma cells was strongly positive for erythropoietin. After the operation, the patient's hemoglobin and hematocrit levels normalized, and we diagnosed her condition as myomatous erythrocytosis syndrome.

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.

1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.

A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.

The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC(50): 4.2 nM).

Purpose: To evaluate the metabolic fate of UCN-01, a signal transduction inhibitor, blood and plasma concentrations, distribution, metabolism and excretion were investigated in rats and dogs after intravenous administration of [3H]UCN-01., Methods: The radioactivity in plasma, blood and tissues was measured after intravenous administration of UCN-01. In addition, the radioactivity excreted in bile, urine and feces was also determined., Results: The radioactivity in rat and dog plasma disappeared triphasically with terminal half-lives of 21.3 and 27.2 h, respectively. The ratios of the blood-to-plasma concentrations ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [3H]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The highest concentration was observed in the lungs followed by the liver and kidneys. The radioactivity was mainly excreted in feces, reaching 96.0% of the radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct-cannulated rats, most of the radioactivity excreted in feces was from biliary radioactivity. There were several metabolites in bile samples, but little UCN-01., Conclusions: UCN-01 is mainly eliminated by the liver, and there are high concentrations of radioactivity derived from [3H]UCN-01 in all tissues except the brain and testes.

Objective: Inflammatory malignant fibrous histiocytoma (IMFH) is composed of fibroblastic and histiocytic elements with a marked inflammatory cell infiltrate. The authors examined the case of a 43-year-old woman with IMFH of the ovary., Methods: The serum interleukin-6 (IL-6) levels were examined and immunohistochemical analysis of the tumor was performed using monoclonal antibodies against lysozyme, alpha 1-antitripsin, vimentin, and IL-6., Results: The patient had marked general inflammatory reactions of fever (38.0 degrees C), leukocytosis with 78.3% neutrophils, elevated CRP (23.5 mg/dl), and accelerated ESR (166 mm/h). The serum IL-6 concentration was 499 pg/ml. The right ovary was occupied by the solid tumor, composed of both fibrous and histiocytic elements with a marked inflammatory cell infiltrate. These inflammatory reactions disappeared after surgical resection and recurred when the tumor reappeared. The immunohistochemical staining of lysozyme, alpha 1-antitrypsin, vimentin, and IL-6 was localized to the malignant cells, suggesting their histiocytic origin., Conclusions: This is the first case of IMFH of the ovary producing IL-6. Expression of IL-6 in the IMFH may account for both the local and the systemic inflammatory effects of tumors with these morphological features., (Copyright 1999 Academic Press.)

We identified a DAX1 missense mutation, a substitution of arginine for leucine at codon 466 (Leu466Arg), in an infant with X-linked congenital adrenal hypoplasia (AHC). A heterozygous substitution, Leu466Arg, was also identified in his mother and sister. Since leucine at position 466 is well conserved among other orphan nuclear hormone receptor superfamilies and Leu466Arg was not detected among 50 normal Japanese control individuals, the mutation is most likely responsible for X-linked AHC. It is interesting to note that Leu466Arg among all mutations ever reported is located at the most C-terminal region of the DAX-1 protein. Most mutations identified previously were located in the C-terminal presumptive ligand binding domain. Hence, the C-terminal end of the DAX-1 protein may play an important role in the biological function, such as in normal adrenal embryogenesis.

A cell line derived from human endometrial clear cell adenocarcinoma was newly established and named TEN. The tumor cells were obtained from uterine body of a 74-year-old who had been undergone an abdominal simple hysterectomy. The histologic features of the tumor cells showed abundant clear cytoplasm with diastase digested glycogen granule growing in solid nest and tubular pattern. The TEN cells were continuously propagated in vitro during the past 45 months and they were at 75th passage. They grew in a monolayered sheet with a doubling time of about 53 hours. The TEN cells resembled the structure of the original tumor and had abundant glycogen granules, lipid droplets in the cytoplasm. The histopathology of the transplanted tumor in SCID mice resembled that of the original tumors. The TEN cells secreted a high content of CA125. Immunohistochemically, the TEN cells had c-erbB-2 and Cathepsin D immunoreactivity in some parts of the cell population. But they did not have estrogen, progesterone and EGF receptor. Sensitivities of the TEN cells to a variety of anti-cancer drugs were examined. In in-vitro tests, MTT assays employed. The results suggested that the TEN cells were not sensitive to any of 13 agents. On the other hand, in-vivo sensitivity test of transplanted tumor in SCID mice, the tumors were sensitive to CPT-11 and paclitaxel. We conclude that the TEN cell line will be effective material for chemosensitivities against the endometrial clear cell adenocarcinoma.

We measured serum ECP levels in infants during first wheezing episode. Serum ECP in these infants are significantly higher than in control infants, although much higher in children with asthma. Serum ECP in these infants with high serum IgE and/or positive RAST score are higher than in infants with normal serum IgE and negative RAST score. In children with bronchial asthma serum ECP is correlated with peripheral eosinophil counts, but in infants during first wheezing episode serum ECP is often elevated not associated with increased peripheral eosinophil counts. These suggest that activated eosinophils could be responsible for bronchoconstriction in wheezing patients with atopic diathesis even in very early phase and that these eosinophilic inflammations could contribute to formation of increased airway reactivity and bronchial asthma.

The mechanisms of water transport across the upper portion of the descending limb of long-looped nephron (LDLu) were examined by microperfusion of segments isolated from hamster kidneys. Because of cation permselectivity a streaming voltage was generated when a transmural osmotic gradient was imposed. When 100 mmol/l urea was added to the bath, the streaming voltage was -4.9 +/- 0.4 mV. Addition of 10(-4) mol/l parachloromercuribenzene sulfonate (PCMBS) decreased the voltage to -2.4 +/- 0.7 mV. This effect was associated with changes in osmotic water permeability (Pf, 10(-3) cm/s) from 243 +/- 42 to 47 +/- 15. PCMBS also decreased the transmural diffusional water permeability (Pdw, 10(-3) cm/s) from 9.4 +/- 0.6 to 7.2 +/- 0.6. The inhibitory effect of PCMBS was prevented by pretreatment with dithiothreitol. N-Butanol permeability was measured as an index of cellular resistance for diffusion. Large differences between Pf and Pdw can be explained both by cellular resistance to diffusion and by resistance through a water channel with a single file mechanism. The apparent activation energy for water transport, 13.3 x 10(3) joule/mol (3.16 kcal/mol), was low. These findings are compatible with the hypothesis that a water channel exists in this segment. PCMBS also inhibited the NaCl diffusion voltage, a parameter indicating cation permselectivity, in parallel with suppression of the streaming voltage, suggesting that the water channel is in part associated with cation permselectivity. The possibility that the PCMB-sensitive cation-permselective pathway exists in parallel cannot be ruled out.