A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors

Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.     

Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma‐shock

Gando S, Wada H, Kim HK, Kurosawa S, Nielsen JD, Thachil J, Toh C‐H, Scientific and Standardization Committee on DIC of the ISTH. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma‐shock. J Thromb Haemost 2012; 10: 2593–5.     

The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine

Purpose  

To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes.     

Development of a technique for the investigation of folding dynamics of single proteins for extended time periods

A technique was developed for the detection of fluorescence signals from free single molecules for extended time periods and was applied to the characterization of the unfolded states of iso-1-cytochrome c (cyt c). Protein molecules labeled with fluorescent dye were slowly injected into a capillary at concentrations that allow for the observation of one molecule at a time. A laser was introduced into the capillary coaxially, and the fluorescence was imaged as traces by using a lens with a large focal depth and wide field of view. Thus, the traces reflect the time-dependent changes in the fluorescence signals from single proteins. Cyt c was labeled with Alexa Fluor 532 at the C-terminal cysteine (cyt c-Alexa). In bulk experiments, cyt c-Alexa was shown to possess different fluorescence intensity for the native state, the unfolded state (U), and the intermediate state. Single-molecule traces of cyt c-Alexa were recorded by using the device. Intensity histograms of the traces revealed two distributions with broad and narrow widths, which were interpreted to correspond to the U and intermediate state, respectively, observed in the bulk measurements. The broad width of the U suggested the existence of a relatively slow conformational dynamics, which might be consistent with the correlation time ( approximately 15 ms) estimated from the traces assignable to the U. The technique was expected to reveal dynamics of proteins along the folding processes without artifacts caused by immobilization.     

Prognosis and clinical features of intractable epilepsy: A prospective study

Abstract  Of the epileptic patients who were treated for ≥ 5 years until the end of 1990 and had more than four seizures in 1990, 63 patients had been treated without interruption until the end of 1995. We analyzed their clinical courses from 1990 to 1995 prospectively. More than half the subjects were diagnosed with temporal lobe epilepsy. Twenty cases had presumed etiology, and 32 had neuropsychiatric complications. Of the subjects whose seizures were not controlled with conventional antiepileptic drugs (AED), 11 cases demonstrated significant improvement when new AED; that is, lamotrigine, vigabatrin, clobazam, topiramate, tiagabine or CGP33101 were added. However, 10 patients did not respond to new AED. Presumed etiology, neuropsychiatric complications, multiple epileptic foci in EEG and abnormalities on head CT or MRI were characteristics of the patients whose seizures were resistant to new AED.     

Probucol inhibits intercellular adhesion molecule-1 expression on cultured rat mesangial cells

SUMMARY: Interleukin-1 (IL-1) has been reported to participate in the progression of glomerulonephritis by, in part, up-regulating intercellular adhesion molecule-1 (ICAM-1) expression in experimental glomerulonephritis. In the present study, we examined whether probucol, an antihyperlipidemic agent, inhibited IL-1-induced inflammatory processes in mesangial cells in culture. Northern blot analysis demonstrated that 200 U/mL IL-1 up-regulated ICAM-1 messenger RNA (mRNA) expression with its peak at 4-6 h after stimulation. Ten μg/mL lipopolysaccharide (LPS), a stimulant to release IL-1 from mesangial cells, induced ICAM-1 mRNA expression by five-fold within 6 h and 10 μg/mL probucol notably reduced this induction. Immunoblotting also confirmed that LPS increased ICAM-1 protein by two-fold within 24 h and probucol inhibited this increase. IL-1 receptor antagonist (IL-1ra; 1–100 ng/mL) suppressed LPS-induced ICAM-1 mRNA expression in a dose-dependent manner and 100 ng/mL IL-1ra completely inhibited ICAM-1 induction, indicating that LPS increased ICAM-1 expression through the action of secreted IL-1. Interleukin-1 activity in culture media, measured by thymocyte proliferation assay, was significantly enhanced by LPS and inhibited by probucol. However, neither LPS nor probucol substantially affected IL-1 mRNA expression, suggesting that the IL-1 activity might be regulated at post-translational level. These results suggest that probucol may act as an anti-inflammatory drug by suppressing IL-1 activity from mesangial cells in the progression of glomerulonephritis.     

Embryonal carcinoma producing DU-PAN-2 with burned-out phenomenon in the testis

A burned-out testicular tumor with lung and lymph node metastases presented high serum levels of DU-PAN-2. However, the serum levels of CA19-9, alpha-fetoprotein, beta-human chorionic gonadotropin, and sialyl Lewis X were normal. A biopsy of the cervical lymph nodes revealed embryonal carcinoma. Four courses of chemotherapy, including cisplatin, etoposide, and bleomycin, normalized the level of DU-PAN-2, and the metastatic lesions disappeared. This is the second reported case of an embryonal carcinoma producing DU-PAN-2. The secretor and Lewis gene typings, which affect the normal serum ranges of CA19-9 and DU-PAN-2, were determined.     

Oral Sustained-release Cisplatin Capsule

An oral sustained-release cisplatin preparation was prepared by combining microporous water-insoluble pharmaceutical polymer, ethylcellulose, a membrane and a gel-forming polymer, poly(acrylic) acid (Carbopol). As cisplatin is an extremely hydrophilic and small compound, it was difficult to control the release rate solely by the micropores on the ethylcellulose capsule. To retain cisplatin within the capsule, gel-forming polymer was formulated inside the capsule. The release rate of cisplatin was dependent both on the number of micropores of the capsule and the formulated amount of Carbopol. The number of micropores ranged from 20 and 30 to 60, and the formulated amount of Carbopol varied from 15 to 100 mg. In-vitro release experiments suggested that the release rate decreased as the formulated amount of Carbopol increased when the pore number was 60 and 30. However, when pore number was decreased to 20, the effect of the amount of Carbopol was not clearly observed. In the in-vivo study using rabbits, the sustained-release cisplatin capsule was evaluated in comparison with solution after oral administration of 20 mg drug. With the pore number of 60, C_max was 0.46 ± 0.02 μg mL^?1 at 4 h and thereafter serum concentrations declined rapidly. When the pore number was 30, serum cisplatin level-time profiles showed long-acting patterns and AUC was reversely correlated with the formulated amount of Carbopol. C_max and t_max were 0.41 ± 0.02 μg mL^?1 and 3.33 ± 0.88 h, respectively and 0.23 ± 0.01 μg mL^?1 was obtained at 24 h after oral administration of capsule having 30 pores and 15 mg of Carbopol. We conclude that the possibility of developing an oral sustained-release cisplatin preparation is feasible.