Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor (AS-1763) as a next-generation noncovalent BTK inhibitor.

Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846.

Background: Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise.

Methods: Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes.

TNIK inhibition abrogates colorectal cancer stemness.

Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours.

[In vivo activity of liposomal amphotericin B against Exophiala dermatitidis in a murine lethal infection model].

This study evaluated the in vivo activity of liposomal amphotericin B (L-AMB) and deoxycholate amphotericin B (D-AMB) in a murine model of disseminated infection caused by Exophiala dermatitidis. Cyclophosphamide-treated neutropenic ddY mice were inoculated intravenously with conidial suspensions of E. dermatitidis IFM 4827 or IFM 53409.

[Case of muscle rigidity by remifentanil just before the end of surgery].

This report shows a rare case of muscle rigidity by remifentanil just before the end of surgery. A 71-year-old man was scheduled for microvascular decompression to cure trigeminal neuralgia. Anesthesia was induced with propofol, suxamethonium and remifentanil 0.

The critical velocity and 1500-m surface performances in Finswimming.

The purpose of this investigation was to determine whether the concepts of critical velocity (CV) and anaerobic swimming capacity (ASC) could be used by coaches as a reliable index in order to monitor 1500-m Surface (SF) performances in Finswimming. Thirteen Finswimmers (6 males and 7 females, 24+/-6 years), members of the Japanese national team, were instructed to swim three different swimming distances (400-, 800-, and 1500-m) at maximal effort in a 50m long course swimming pool. CV and the ASC were calculated using 400-m and 800-m swim times.

Pleuromutilin derivatives having a purine ring. Part 2: influence of the central spacer on the antibacterial activity against Gram-positive pathogens.

Structural modification of the 4-piperidinethio moiety, as a spacer of the first pleuromutilin analogues 2A and 2B having a purine ring, led to discovery of the novel pleuromutilin derivatives 14B and 17B. These compounds with good solubility in water showed promising in vitro antibacterial activity against various Gram-positive bacteria including MRSA, PRSP, and VRE and have potent in vivo efficacy.

Pleuromutilin derivatives having a purine ring. Part 3: synthesis and antibacterial activity of novel compounds possessing a piperazine ring spacer.

SAR studies on the water-soluble thioether pleuromutilin analogue 6, which has excellent in vitro and in vivo antibacterial activities, led to discovery of the novel pleuromutilin derivatives having a piperazine ring spacer. These derivatives displayed potent and well-balanced in vitro antibacterial activity against various drug-susceptible and -resistant Gram-positive bacteria. In particular, the promising pleuromutilin analogues 37 and 40 were found to exhibit strong in vivo efficacy against Staphylococcus aureus Smith.

Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models.

Purpose: Voreloxin, formerly known as SNS-595 or AG-7352, is a novel naphthyridine analog currently under investigation for the treatment of ovarian and hematologic malignancies. Voreloxin mechanism of action includes DNA intercalation and inhibition of topoisomerase II that causes selective DNA damage. In this study, we describe the anti-proliferative activity of voreloxin in a wide range of in vitro and in vivo models of human cancers.

Pleuromutilin derivatives having a purine ring. Part 1: new compounds with promising antibacterial activity against resistant Gram-positive pathogens.

In the course of our research aimed at the discovery of metabolic stable pleuromutilin derivatives with more potent antibacterial activity against Gram-positive pathogens than previous analogues, a series of compounds bearing a purine ring were prepared and evaluated. From SAR studies, we identified two promising compounds 85 and 87, which have excellent in vitro activity against a number of Gram-positive pathogens, including existing drug-resistant strains, and potent in vivo efficacy.

Water-soluble pleuromutilin derivative with excellent in vitro and in vivo antibacterial activity against gram-positive pathogens.

Although earlier pleuromutilin analogues showed potent in vitro antibacterial activity against some Gram-positive pathogens, their in vivo efficacy was low because of insufficient pharmacokinetic properties. We designed novel thioether pleuromutilin derivatives having a purine ring as a polar and water solubilizing group and identified a promising pleuromutilin analogue 6 with good solubility in water ( approximately 50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens.

A comparison of three different concentrations of ropivacaine with fentanyl for patient-controlled epidural analgesia.

Background: The optimal concentration of ropivacaine in combination with fentanyl for patient-controlled epidural analgesia focusing on preservation of bowel function, analgesia, and motor function remains unclear.

Methods: Three hundred-twelve women scheduled to undergo gynecologic lower abdominal surgery, were randomly allocated to receive ropivacaine 0.05, 0.

Intrathecal landiolol inhibits nociception and spinal c-Fos expression in the mouse formalin test.

Purpose: The purpose of this study was to determine if intrathecal landiolol, a beta1-blocker, can modulate formalin-induced nociception and spinal c-Fos expression in mice, in the absence of anesthesia.

Methods: Thirty-two mice were randomly assigned to one of four groups: the control group (n = 8) received intrathecal normal saline 10 microL, while the other three groups (n = 8 for each) received intrathecal landiolol at escalating doses of 250 microg.kg(-1), 500 microg.

Clonidine-ephedrine combination reduces pain on injection of propofol and blunts hemodynamic stress responses during the induction sequence.

Study Objectives: To evaluate the effects of clonidine and ephedrine on propofol-induced pain and on hemodynamic changes during the induction sequence.

Design: This was a prospective, randomized, double-blind study.

Setting: The study was conducted at a university hospital.

Isoflurane and sevoflurane during reperfusion prevent recovery from ischaemia in mitochondrial KATP channel blocker pretreated hearts.

Background And Objective: Inhalation anaesthetics given only during post-ischaemic reperfusion have some protective effect against reperfusion injury in the heart. Adenosine triphosphate-regulated mitochondrial potassium channels have been shown to be an important mediator of cardioprotection. Thus, we investigated whether 5-hydroxydecanoate, a putative mitochondrial potassium channel blocker, prevents the cardioprotective effect of volatile anaesthetics.

Are the incidences of cardiac events during noncardiac surgery in Japan the same as in the United States and Europe?

In Japan, an ever-present problem in the preoperative evaluation of patients with ischemic heart disease is that although such evaluations are based on Western data, these data serve as the basis for determining perioperative risk in Japanese patients. To remedy this problem, the Cardiac Ischemia and Anesthesia Research Committee was formed in 1997 and has conducted studies of perioperative complications in noncardiac surgery in Japan. In two retrospective studies in 1997, the proportions of patients with ischemic heart disease were 3.

Epidural ropivacaine anesthesia decreases the bispectral index during the awake phase and sevoflurane general anesthesia.

The sedative effects of epidural anesthesia without volatile and IV anesthetics and quantification of the degree of epidural anesthesia-induced sedation have not been investigated. In the current study we evaluated the effects of epidural anesthesia on the bispectral index (BIS) during the awake phase and during general anesthesia. After placing the epidural catheter, the patients were randomly allocated to 2 groups receiving either 5 mL of epidural saline (group S) or the same volume of 0.

Effects of melatonin and superoxide dismutase on free radical formation in the postischemic reperfused heart.

Purpose: Melatonin has been reported to protect against oxygen free radicals. We investigated whether melatonin or superoxide dismutase (SOD) would decrease hydroxyl radical concentration in the postischemic reperfused heart.

Methods: An isolated rat heart-lung preparation was used.

Synthesis and structure-activity relationships of 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines as novel antitumor agents.

In order to obtain clinically useful antitumor agent, we have designed and synthesized various 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines, and evaluated their cytotoxic activity. The series of novel 3-substituted derivatives synthesized in this study showed good antitumor activity against murine P388 leukemia. Particularly, the 3-formyl 1,8-naphthyridine displayed an antitumor activity equal to that of the 3-carboxy 1,8-naphthyridine against murine and human tumor cell lines as well as in vivo test for mouse leukemia.

Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2.

We have previously reported that a series of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids possess moderate cytotoxic activity. In a further attempt to find clinically useful antitumor agents, we investigated the structure-activity relationships (SARs) of a new series of compounds obtained by changing the C-6 position of the fluorine atom in addition to the C-5 and C-7 positions and evaluating their cytotoxic activity against several murine and human tumor cell lines. Our results showed that the 6-unsubstituted 1,8-naphthyridine structure had the most potent cytotoxic activity against murine P388 leukemia twice that of the 6-fluoro analogue.

Sevoflurane reduces dysrhythmias during reperfusion in the working rat heart.

Purpose: The effects of sevoflurane on myocardial reperfusion injury have not been well studied. The purpose of this study was to determine the effects of sevoflurane on myocardial function, arrhythmia, and metabolism during reperfusion in an isolated working rat heart model.

Methods: Thirty-two hearts were divided into four groups according to the timing of 2.

Effects of epidural fentanyl and intravenous flurbiprofen for visceral pain during cesarean section under spinal anesthesia.

Purpose: Despite adequate levels of sensory blockade, patients sometimes complain of abdominal pain during cesarean section performed under spinal anesthesia. The aim of this study was to evaluate the effects of epidural fentanyl and intravenous flurbiprofen on visceral pain during cesarean section in patients having spinal anesthesia.

Methods: Thirty ASA physical status I and II patients undergoing elective cesarean section were studied.