Predictors for delayed encephalopathy following acute carbon monoxide poisoning.

BACKGROUND: In Japan, many carbon monoxide (CO) poisoning cases are transported to emergency settings, making treatment and prognostic assessment an urgent task. However, there is currently no reliable means to predict whether "delayed neuropsychiatric sequelae (DNS)" will develop after acute CO poisoning. This study is intended to find out risk factors for the development of DNS and to characterize the clinical course following the development of DNS in acute CO poisoning cases. METHODS: This is a retrospective cohort study of 79 consecutive patients treated at a single institution for CO poisoning. This study included 79 cases of acute CO poisoning admitted to our emergency department after attempted suicide, who were divided into two groups consisting of 13 cases who developed DNS and 66 cases who did not. The two groups were compared and analyzed in terms of clinical symptoms, laboratory findings, etc. RESULTS: Predictors for the development of DNS following acute CO poisoning included: serious consciousness disturbance at emergency admission; head CT findings indicating hypoxic encephalopathy; hematology findings including high creatine kinase, creatine kinase-MB and lactate dehydrogenase levels; and low Global Assessment Scale scores. The clinical course of the DNS-developing cases was characterized by prolonged hospital stay and a larger number of hyperbaric oxygen (HBO) therapy sessions. CONCLUSION: In patients with the characteristics identified in this study, administration of HBO therapy should be proactively considered after informing their family, at initial stage, of the risk of developing DNS, and at least 5 weeks' follow-up to watch for the development of DNS is considered necessary.

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole.

BACKGROUND: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. RESULTS: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. CONCLUSIONS: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

YCM1008A, a novel Ca2+-signaling inhibitor, produced by Fusarium sp. YCM1008.

In the course of screening for drugs that suppress the Ca(2+)-mediated growth inhibition in a yeast mutant, we found that the metabolite of Fusarium sp. strain YCM1008 inhibited Ca(2+)-signaling. A novel pyrano-pyridone, YCM1008A was isolated from the fermentation broth using HLB column chromatography followed by HPLC, and the structure was elucidated by spectral analysis. YCM1008A suppressed Ca(2+)-induced growth inhibition of the Saccharomyces cerevisiae (Deltazds1Deltasyr1) mutant.

EI-1941-1 and -2, novel interleukin-1beta converting enzyme inhibitors produced by Farrowia sp. E-1941. I. Biochemical characterization of EI-1941-1 and -2.

EI-1941-1 and -2 isolated from the culture broths of Farrowia sp. selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively, without inhibiting elastase and cathepsin B. EI-1941-1 and -2 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 values of 5.0 and 10.3 microM, respectively. Biochemical characterizations of EI-1941-1 and -2 are described in this article.

EI-1941-1 and -2, novel interleukin-1 beta converting enzyme inhibitors Produced by Farrowia sp. E-1941. II. Taxonomy of producing strain, fermentation, isolation, physico-chemical properties, and biological properties.

EI-1941-1 and -2, novel interleukin-1 beta converting enzyme (ICE) inhibitors, were isolated from the culture broths of Farrowia sp. E-1941. EI-1941-1 and -2 selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively. Taxonomy and fermentation of the producing strain and isolation, physico-chemical properties, structure elucidation, and biological properties of EI-1941-1 and -2 are described.

EI-2346, a novel interleukin-1beta converting enzyme inhibitor produced by Streptomyces sp. E-2346. I. Taxonomy of producing strain, fermentation, isolation, physico-chemical properties, and biological properties.

EI-2346, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was isolated from the culture broths of Streptomyces sp. E-2346. EI-2346 selectively inhibited the human recombinant ICE activity with an IC50 value of 3.9 microM, without inhibiting elastase and cathepsin B. EI-2346 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with an IC50 value of 5.2 microM.

EI-2128-1, a novel interleukin-1beta converting enzyme inhibitor produced by Penicillium sp. E-2128.

EI-2128-1, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was isolated from the culture broths of Penicillium sp. E-2128. EI-2128-1 selectively inhibited human recombinant ICE activity with IC50 value of 0.59 microM, without inhibiting elastase and cathepsin B. EI-2128-1 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 value of 0.28 microM.

Structurally unique inhibitors of human mitogen-activated protein kinase phosphatase-1 identified in a pyrrole carboxamide library.

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates cardinal mitogen-activated protein kinase (MAPK) substrates, such as p38, c-Jun NH(2)-terminal kinase, and extracellular signal-regulated kinase. Although these MAPK substrates regulate many essential cellular processes associated with human diseases, few pharmacological inhibitors have been described. The lack of readily available selective MKP-1 inhibitors has severely limited interrogation of its biological role and was one rationale for using a recently described tricyclic pyrrole-2-carboxamide library in our screening efforts. In this report we demonstrate the pharmacological richness of the pyrrole carboxamide library by the finding that 10 of 172 members inhibited human MKP-1. Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC(50) values of 8.0 +/- 0.9 and 8.3 +/- 0.8 microM, respectively. Both showed some selectivity for MKP-1 over the closely related phosphatases MKP-3, Cdc25B, VHR, and PTP1B. Computational examination of the surface properties near the catalytic site revealed that the phosphatases studied differ significantly in their electrostatic potential at the substrate binding site. The compounds inhibited MKP-1 reversibly but displayed mixed kinetics. Phosphatase inhibition was retained in the presence of physiologically relevant concentrations of glutathione. Molecular docking studies suggested that PSI2106 may interact with His(229) and Phe(299) on MKP-1. These results reveal the power of using a small focused library for identifying pharmacological probes.

Two new analogues of the cytotoxic substance BE-52211 from Streptomyces sp.

Two new beta-hydroxy acetamides, BE-52211 B and BE-52211 C, which were structural analogues of BE-52211, were obtained as an inseparable mixture from an actinomycete, Streptomyces sp. Their structures were elucidated on the basis of spectroscopic data. They inhibited cell division of starfish embryos at a concentration of 2.5 microg/mL or greater.

Piericidins C5 and C6: new 4-pyridinol compounds produced by Streptomyces sp. and Nocardioides sp.

Piericidins C5 (1) and C6 (2), two new members of the piericidin family, were isolated from a Streptomyces sp. and a Nocardioides sp., together with known piericidins C1 (3), C2 (4), C3 (5), C4 (6), D1 (7), and A3 (8). The structures were determined on the basis of their spectroscopic data. Both new compounds inhibited cell division of fertilized starfish (Asterina pectinifera) eggs at the minimum inhibitory concentration of 0.09 microg/mL.