Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First-in-Human Phase 1 Study.

A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To evaluate its safety, tolerability, and pharmacokinetics, double-blind, placebo-controlled, single ascending dose (SAD), and multiple ascending dose (MAD) phase 1 studies were conducted in 126 healthy adults. The food effect was evaluated in a randomized, open-label, crossover manner (n = 5). ME3183 was safe and tolerable up to 25 mg in the SAD part and up to 10 mg twice daily in the MAD part. Frequently observed treatment-emergent adverse events included diarrhea and headache, as commonly reported for approved PDE4 inhibitors, providing no novel safety concerns. Pharmacokinetic analysis showed dose-dependent increases in Cmax and AUC, with later tmax and longer t1/2 than apremilast, an approved PDE4 inhibitor. The food effect study showed slightly decreased systemic exposure. In the MAD part, plasma exposure levels of ME3183 were higher even at the minimal dose (2.5 mg twice daily) than the estimated therapeutically effective level. These results show the safe profile of ME3183 and support further studies to confirm the safety and efficacy of the drug in patients with psoriasis and other inflammatory diseases.

Safety and Pharmacokinetic Characterization of Nacubactam, a Novel ß-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.

Nacubactam is a novel ß-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine ß-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential ß-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).

Purification and characterization of a glycoside hydrolase family 5 endoglucanase from Tricholoma matsutake grown on barley based solid-state medium.

An endoglucanase was isolated from solid-state culture of the ectomycorrhizal fungus Tricholoma matsutake (TmEgl5A) grown on rolled barley and vermiculite. The enzyme was purified by ammonium sulfate fractionation, ion-exchange, hydrophobic, and gel filtration. TmEgl5A showed a molecular mass of approximately 40 kDa as determined by SDS-PAGE. The single band of the protein was analyzed by peptide-mass-finger-printing using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the trypsin-digested peptide sequences were matched to a putative endoglucanase sequence (protein ID1465229) in the JGI T. matsutake 945 v3.0 genome database. Based on the sequence information, the gene encoding TmEgl was cloned and expressed in Pichia pastoris KM71H. The deduced amino acid sequence was similar to GH5 family endoglucanases from Basidiomycetes. The enzyme acts on barley ß-glucan, lichenan, and CMC-Na. The hydrolyzation products from these substrates were detected by thin-layer chromatography as oligosaccharides with minimal disaccharides. These results suggested that T. matsutake produces a typical endoglucanase in solid-state culture, and the fungus has the potential to degrade ß-linkage polysaccharides.

Evaluation of computer-aided detection of lesions in mammograms obtained with a digital phase-contrast mammography system.

A computer-aided detection (CAD) system was evaluated for its ability to detect microcalcifications and masses on images obtained with a digital phase-contrast mammography (PCM) system, a system characterised by the sharp images provided by phase contrast and by the high resolution of 25-µm-pixel mammograms. Fifty abnormal and 50 normal mammograms were collected from about 3,500 mammograms and printed on film for reading on a light box. Seven qualified radiologists participated in an observer study based on receiver operating characteristic (ROC) analysis. The average of the areas under ROC curve (AUC) values for the ROC analysis with and without CAD were 0.927 and 0.897 respectively (P = 0.015). The AUC values improved from 0.840 to 0.888 for microcalcifications (P = 0.034) and from 0.947 to 0.962 for masses (P = 0.025) respectively. The application of CAD to the PCM system is a promising approach for the detection of breast cancer in its early stages.

Characteristics of elderly people using the psychiatric emergency system.

We investigated the differences between elderly and under-65-year-old patients using the psychiatric emergency system. The following characteristics were more common in elderly patients than in younger patients: organic mental disorder, mood disorder, dementia, disturbed consciousness, no excitation, physical complications, no history of visiting a psychiatrist and no history of hospitalization. In addition, significantly more elderly patients with mood disorder attempt suicide.

Moderate hyperventilation prolongs electroencephalogram seizure duration of the first electroconvulsive therapy.

Although it is controversial that seizure duration can influence the efficacy of electroconvulsive therapy (ECT), a missed or brief seizure is considered less effective ECT. Of the background in the practice of ECT, hyperventilation may augment the seizure duration. To elucidate these hypotheses, we performed double-blind randomized controlled trial for 19 patients. They were divided into 2 groups, according to the end-tidal pressure of carbon dioxide (ETCO2): The moderate hyperventilation group with ETCO2 of 30 mm Hg and the normal ventilation group with ETCO2 of 40 mm Hg. ECT was performed under general anesthesia with propofol and suxamethonium. During ECT electroencephalogram (EEG) and electromyogram were recorded. The Global Assessment of Functioning scores were also analyzed before and after 6 sequential ECT. The moderate hyperventilation group showed a significant increase in EEG seizure duration in the first treatment compared with the normal ventilation group (P < 0.05). However, EEG seizure duration in the subsequent treatments and electromyogram seizure duration in all the treatments did not differ between 2 groups. The moderate hyperventilation did not prevent the increase in seizure threshold or shortening of seizure duration. No complications or sever adverse effects were observed after ECT in any of the 6 treatments. The Global Assessment of Functioning scores were not significantly changed with moderate hyperventilation. We conclude that moderate hyperventilation is safe and may be useful for seizure augmentation before the restimulation with higher intensities.

Structure-activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridines.

The synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.

Effect of temporal subtraction technique on the diagnosis of primary lung cancer with chest radiography.

PURPOSE: The purpose of this study was to assess the diagnostic accuracy of the temporal subtraction technique in the detection of primary lung cancers by readers with different levels of experience. METHODS: Previous and current chest radiographs from 40 patients with histologically proven lung cancer and 40 controls were studied. Temporal subtraction images were produced using an automated digital subtraction technique. We evaluated the effect of temporal subtraction images in the diagnosis of lung cancer with chest radiographs via an observer performance study with the use of receiver operating characteristic analysis. Six experienced radiologists and six residents participated as observers. RESULTS: Observer performance for all observers was superior when temporal subtraction images were used (mean Az value increased from 0.764 to 0.836, p=0.0006). Although the average Az value for residents increased significantly, from 0.707 to 0.795 (p=0.0038), the average Az value for experienced radiologists increased only from 0.821 to 0.878 (n.s.). CONCLUSION: In conclusion, the temporal subtraction technique clearly improves diagnostic accuracy for the detection of primary lung cancer. The results indicated that the use of temporal subtraction images was more beneficial for the residents than for the experienced radiologists. This method would compensate to some extent for experience-dependent diagnostic accuracy in the detection of lung cancer.