Safety profile of vonoprazan compared with proton pump inhibitors: insight from a pharmacovigilance study.

Proton pump inhibitors (PPIs) are used to treat acid-related disorders such as peptic ulcer and gastroesophageal reflux disease. Recently, vonoprazan, a novel potassium-competitive acid blocker (P-CAB), has been introduced as more effective treatment option. The purpose of this study was to clarify the adverse events associated with vonoprazan compared to PPIs using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. The database comprised 11,433 reports associated with PPIs, and 636 reports with vonoprazan. Hepatic and skin disorders were commonly detected in both PPIs and vonoprazan. There was a significant association of interstitial lung disease with PPIs as a class (ROR: 1.61, 95%CI: 1.47-1.77), but not with vonoprazan. Vonoprazan was strongly associated with haemorrhagic enterocolitis (ROR, 86.5; 95%CI, 59.7125). Among the PPIs, the signal score of microscopic colitis was noteworthy in the case of lansoprazole (ROR, 405; 95%CI, 348-472). It is suggested that there is a diversity in the strength of the association between PPIs and vonoprazan with adverse events. Our results may provide useful information for the treatment of acid-related disorders, but further research with more data is needed to finally clarify this.

Evaluation of adverse events associated with filgrastim originator and biosimilar using a spontaneous reporting system database.

Biosimilar products of filgrastim have become available for improved sustainability of cancer care; however, the real-world safety profile remains unknown. The purpose of this study was to clarify the adverse events associated with filgrastim originator and its biosimilar using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2014-2018 were extracted. We calculated the reporting odds ratio and 95% confidence interval for each adverse event. We obtained 584 reports of adverse events associated with filgrastim originator and 102 reports with its biosimilar. Signals were detected for bone marrow failure and febrile neutropenia with both filgrastim originator and its biosimilar; whereas those for drug resistance and hypoxia only involved filgrastim originator, and those for interstitial lung disease only involved its biosimilar. The safety profiles of filgrastim originator and its biosimilar were partly different. Further studies are needed to confirm these findings.

Beneficial effect of pretreatment of islets with fibronectin on glucose tolerance after islet transplantation.

The scarcity of available islets is an obstacle for clinically successful islet transplantation. One solution might be to increase the efficacy of the limited islets. Isolated islets are exposed to a variety of cellular stressors, and disruption of the cell-matrix connections damages islets. We examined the effect of fibronectin, a major component of the extracellular matrix, on islet viability, mass and function, and also examined whether fibronectin-treated islets improved the results of islet transplantation. Islets cultured with fibronectin for 48 hours maintained higher cell viability (0.146 +/- 0.010 vs. 0.173 +/- 0.007 by MTT assay), and also had a greater insulin and DNA content (86.8 +/- 3.6 vs. 72.8 +/- 3.2 ng/islet and 35.2 +/- 1.4 vs. 30.0 +/- 1.5 ng/islet, respectively) than islets cultured without fibronectin (control). Absolute values of insulin secretion were higher in fibronectin-treated islets than in controls; however, the ratio of stimulated insulin secretion to basal secretion was not significantly different (206.9 +/- 23.3 vs. 191.7 +/- 20.2% when the insulin response to 16.7 mmol/l glucose was compared to that of 3.3 mmol/l glucose); the higher insulin secretion was thus mainly due to larger islet cell mass. The rats transplanted with fibronectin-treated islets had lower plasma glucose and higher plasma insulin levels within 2 weeks after transplantation, and had more favorable glucose tolerance 9 weeks after transplantation. These results indicate that cultivation with fibronectin might preserve islet cell viability, mass and insulin secretory function, which could improve glucose tolerance following islet transplantation.

Diamide derivatives and cycloartanes from the leaves of Aglaia elliptica.

Chemical examination of the leaves of Aglaia elliptica led to the isolation of two new diamides, 10-O-acetylaglain B (1) and 4-epiaglain A (2), two known diamides, aglain A (3) and odorine (4), and three known cycloartanes (5-7). The structures of 1 and 2 were elucidated by interpretation of the spectral data.

Antimicrobial alkaloids from Zanthoxylum tetraspermum and caudatum.

Two benzophenanthrene alkaloids, 8-acetonyldihydronitidine and 8-acetonyldihydroavicine were isolated from Zanthoxylum tetraspermum stem bark along with liriodenine, sesamin, lichexanthone and (+)-piperitol-gamma,gamma-dimethylallylether. The species endemic to Sri Lanka, Z. caudatum, contained sesamin, savinin, liriodenine, decarine and 8-O-desmethyl-N-nornitidine. 8-Acetonyldihydronitidine and 8-acetonyldihydroavicine showed significant antibacterial activity while the former along with liriodenine was strongly antifungal. Savinin exhibited potent spermicidal activity. Both savinin and sesamin exhibited significant insecticidal activity.

(24R)-24,25-Dihydroxycycloartan-3-one.

In the title compound, C(30)H(50)O(3), the three six-membered rings adopt chair, twist and twist-boat conformations. The five-membered ring is in a slightly distorted envelope conformation. The substituent on the five-membered ring is in an extended conformation, with its two hydroxyl O atoms forming an intramolecular hydrogen bond. One of these O atoms also forms an intermolecular hydrogen bond with the oxygen of the carbonyl group in a neighbouring molecule.

Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression.

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.

Sustained enhancement of Ca(2+) influx by glibenclamide induces apoptosis in RINm5F cells.

Cytosolic Ca(2+) elevations are known to be involved in triggering apoptosis in many tissues, but the effect of sustained enhancement of Ca(2+) influx on apoptosis in beta cells remains unknown. We have found that the viability of RINm5F cells is decreased dose-dependently by continuous exposure to glibenclamide at concentrations from 10(-7) to 10(-4) M, and that this effect is partially ameliorated by pretreatment with cycloheximide. Electrophoresis of the cells exposed to glibenclamide revealed ladder-like fragmentation characteristic of apoptosis, and which also is suppressed by cycloheximide pretreatment. By using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, we detected increased DNA fragmentation in the nuclei of the cells exposed to glibenclamide, and staining with Hoechst 33342 and propidium iodide showed a dose-dependent increase in the number of cells with the chromatin condensation and fragmentation in their nuclei that is characteristic of apoptosis. The effects of glibenclamide on cell viability and apoptotic cell death were partially inhibited by treatment with Ca(2+) channel blocker, and by reducing the extracellular Ca(2+) concentration during glibenclamide exposure, suggesting that they may be derived from increased Ca(2+) influx. Furthermore, only the percentage of apoptotic cells, and not that of necrotic cells, increased with the increasing intracellular Ca(2+) concentration during glibenclamide exposure. In conclusion, we have demonstrated that the sustained enhancement of Ca(2+) influx caused by glibenclamide exposure can induce apoptotic cell death in a pure beta cell line.

Three putrescine bisamides from the leaves of Aglaia grandis.

Three putrescine (i.e. 1,4-butanediamine) bisamides were isolated from the leaves of Aglaia grandis. Their structures were elucidated by interpretation of spectral data.

Constituents of a fern, Diplazium subsinuatum. III. Four new hopane-triterpene lactone glycosides.

From a whole plant of a fern, Diplazium subsinuatum, three new hopane-triterpene lactone glycosides, diplaziosides V-VII (1-3), were isolated, together with a new monoacetyl derivative (4) of diplazioside VII (3). Compounds 1-3 were defined as the respective 3-O-[beta-D-glucopyranosyl-(1-->2)]-beta-D-glucopyranosides of 3beta,24-dihydroxyhopan-28,22-olide (1), of 3beta,17,24-trihydroxyhopan-28,22-olide (2), and of (22R)-3beta,24,30-trihydroxyhopan-28,22-olide (3), and 4 as the 6"-O-acetate of 3, respectively, on the basis of spectral evidence. 1-3 are new in their glycoside structures but also in their triterpene structures. Furthermore, in compounds 1-4, the coupling between the 24-hydroxy proton and one of the 24-methylene protons showed a very large J-value (11.4 Hz); based on this 1H-NMR evidence, etc., preferred conformations of the 24-hydroxymethylene groups in 1-4 are also inferred. In a similar manner, 1H-NMR coupling patterns of the 24-hydroxymethylene in the monoglucoside (2a) and aglycone (2b), derived from 2, are also reported and discussed here.

The cyclic AMP response element modulator family regulates the insulin gene transcription by interacting with transcription factor IID.

We analyzed a mechanism of transcriptional regulation of the human insulin gene by cyclic AMP response element modulator (CREM) through four cyclic AMP response elements (CREs). We isolated two novel CREM isoforms (CREMDeltaQ1 and CREMDeltaQ2), which lack one of the glutamine-rich domains, Q1 and Q2 respectively, and six known isoforms (CREMtaualpha, CREMalpha, inducible cyclic AMP early repressor (ICER) I, ICER Igamma, CREM-17X, and CREM-17) from rat pancreatic islets and the RINm5F pancreatic beta-cell line. CREM isoforms functioned as efficient transcriptional activators or repressors to modulate insulin promoter activity by binding to all of the insulin CREs. The binding activity of repressors is higher than that of activators and suppressed not only basal activity but also activator-induced activities. Furthermore, CREM activator interacted directly with the transcription factor IID components hTAF(II)130 and TATA box-binding protein (TBP). These results suggest that the activation of the insulin gene transcription by CREM activator is mediated by not only direct binding to the CREs but also by recruiting transcription factor IID to the insulin promoter via its interaction with hTAF(II)130 and TBP. On the other hand, the CREM repressor ICER competitively interrupts the binding of the activators to CREs and does not interact with either TBP or hTAF(II)130; therefore, it might fail to stabilize the basal transcriptional machinery and repress transactivation.

Induction of apoptosis by hinokitiol, a potent iron chelator, in teratocarcinoma F9 cells is mediated through the activation of caspase-3.

Hinokitiol, a potent iron chelator, has been reported to induce differentiation in teratocarcinoma F9 cells with a reduction of viable cells. In this study, we examined the steps leading to eventual cell death by hinokitiol during differentiation. Hinokitiol induced DNA fragmentation of F9 cells in a concentration- and time-dependent manner. This effect was also observed in a cell-free system using the nuclei from intact cells and the cytosols from hinokitiol-treated cells. In contrast, hinokitiol methyl ether and hinokitiol-Fe (III) complex, which are deficient in iron-chelating activity, showed no DNA fragmentation activity in both cell culture and cell-free systems. These results suggest that iron deprivation by hinokitiol may be involved in the induction of apoptosis of F9 cells. Caspase-3, one of the key enzymes in the apoptotic cascade, was specifically activated by hinokitiol treatment, but not by the other two derivatives. In addition, its specific inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, strongly blocked hinokitiol-induced DNA fragmentation. These results indicate that iron deprivation by hinokitiol can induce apoptosis of F9 cells through the activation of caspase-3.

The MH1 domains of smad2 and smad3 are involved in the regulation of the ALK7 signals.

The biological responses of the transforming growth factor beta (TGF-beta) superfamily are induced by activation of a receptor complex and Smad proteins. We surveyed the TGF-beta superfamily receptors using the degenerate PCR strategy, and found activin receptor-like kinase 7 (ALK7) to be abundantly expressed in fetal rat pancreatic islets. ALK7 is also expressed in adult rat islets and pancreatic beta-cell-derived MIN6 cells. The constitutively active form of ALK7, ALK7(T194D), activated Smad3 and a chimeric Smad protein, Smad3-2, containing the MH1 domain of Smad3 and the MH2 domain of Smad2, and translocated them to nuclei and then induced activation of the human PAI-1 promoter. However, neither Smad2 nor Smad2-3 protein, containing the MH1 domain of Smad2 and the MH2 domain of Smad3 were activated. These results indicate that the ALK7 signal regulates nuclear localization and activation of Smad2 and Smad3, and the MH1 domain of Smad2 has inhibitory effects on the nuclear localization.

Induction of differentiation and apoptosis by dithizone in human myeloid leukemia cell lines.

We investigated the effect of diphenylthiocarbazone (dithizone) and its structurally related compounds on the differentiation and apoptosis of two human myeloid leukemia cell lines. Dithizone caused a time- and concentration-dependent induction of differentiation in both the promyelocytic leukemia cell line HL-60 cells and the myeloblastic leukemia cell line ML-1 cells, as measured by nitroblue tetrazolium (NBT) reducing activity. Morphological changes and esterase activities confirmed that this differentiation took place. The induction of differentiation required the addition of dithizone to the culture medium for at least 12 h. The differentiation inducing activity was inhibited by the preincubation of dithizone with various metal ions such as Pb2+, Zn2+, Cu2+ and Mn2+ ions, but not with Fe3+ and Mg2+ ions. In addition, the DNA extracted from dithizone-treated HL-60 cells showed a typical ladder pattern characteristic of apoptosis in agarose gel electrophoresis. A quantitative analysis of DNA fragmentation revealed that this apoptosis was concentration- and time-dependent in both the HL-60 and ML-1 cells. Dithizone-induced apoptosis was also inhibited by preincubation with Mn2+ ions, but not with Mg2+ ions. These results indicate that dithizone induces both differentiation and apoptosis in HL-60 and ML-1 cells through a unique mechanism including metal chelation.

Transcriptional repressors are increased in pancreatic islets of type 2 diabetic rats.

To further clarify the mechanism of impaired insulin gene transcription in the diabetic state, we investigated the expression and function of the transcriptional repressor CREM (CRE modulator) in rat pancreatic islets. The CREM gene generates both transcriptional activators and repressors by alternative splicing and an intronic promoter. We isolated a novel alternatively spliced CREM isoform, CREM-17X, which efficiently represses insulin gene transcription, in addition to the three previously reported repressors. We also compared mRNA levels of insulin and the CREM repressors in pancreatic islets of Wistar and GK (Goto-Kakizaki) rats, the well-characterized spontaneous animal model of type 2 diabetes. The CREM repressor levels are increased, and the expression of insulin mRNA is decreased in GK rats, suggesting that increased CREM repressor expression in pancreatic islets could contribute to the decreased insulin gene transcription that results in impaired insulin secretion in type 2 diabetes.

Anti-tumor promoting activities of lantadenes on mouse skin tumors and mouse hepatic tumors.

Two-stage carcinogenesis of mouse skin papillomas induced by 7,12-dimethylbenz[alpha]anthracene and 12-O-tetradecanoylphorbol 13-acetate, and mouse hepatic tumors induced by N-nitrosodiethylamine and phenobarbital, were inhibited by lantadenes.

Constituents of a fern, Diplazium subsinuatum. II. Structure elucidation of five new hopane-triterpene glycosides.

From whole fern, Diplazium subsinuatum (Wall. ex Hook. et Grev.) Tagawa, two new hopane-triterpene glycosides named diplaziosides III and IV were isolated, together with three new hopane glycosides with acetylated sugars. The structures of diplaziosides III and IV were established as (22S)-24-O-alpha-L-arabinofuranosyl-(1 --> 2)- [beta-D-glucopyranosyl-(1 --> 6)]-beta-D-glucopyranosyl-20 alpha-O-beta-D-glucopyranosyl-30-hydroxyhopan-28-oic acid (1) and (22R)-24-O-alpha-L-arabinofuranosyl-(1-->2)-[beta-D-glucopyranosyl-(1--> 6)]-beta-D-glucopyranosyl-30-carboxy-17-hydroxy-hopano-28,22-lacto ne (2), respectively, on the basis of spectral evidence. Diplazioside III (1) is novel not only in its glycoside structure, but also in its triterpene structure and moreover, 1 provides the first instance of a naturally occurring bisdesmoside with a hopane aglycone. The structures (3a, 3b, and 4a) of the acetylated glycosides were also elucidated, and this is the first report of naturally occurring acetates of hopane glycosides.

New hydrolyzable tannins, shephagenins A and B, from Shepherdia argentea as HIV-1 reverse transcriptase inhibitors.

Two new hydrolyzable tannins, shephagenins A and B, were isolated along with hippophaenin A and strictinin from the leaf extract of Shepherdia argentea, which showed a remarkable inhibitory activity against human immunodeficiency virus (HIV)-1 reverse transcriptase. Their structures, having a gluconic acid core, have been elucidated on the basis of spectroscopic and chemical methods. The inhibitory effect of the leaf extract on HIV-1 reverse transcriptase was found to be due to tannins, and their activities were stronger than that of (-)-epigallocatechin gallate as a positive control.

Inhibitory effects of lantadenes and related triterpenoids on Epstein-Barr virus activation.

To search for possible antitumor promoters, inhibitory effects of lantadenes and related triterpenoids from Lantana camara L. (Verbenaceae) on Epstein-Barr virus activation, were tested. The substitutions on the carboxylic acid through an ester bond might play an important role in the activity.