Z-360, a novel therapeutic agent for pancreatic cancer, prevents up-regulation of ephrin B1 gene expression and phosphorylation of NR2B via suppression of interleukin-1 β production in a cancer-induced pain model in mice

<p>Abstract</p> <p>Background</p> <p>Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, <it>N</it>-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production.</p> <p>Results</p> <p>In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region.</p> <p>Conclusions</p> <p>We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.</p

Chronic administration of citalopram inhibited El mouse convulsions and decreased monoamine oxidase-A activity.

Serotonin (5-HT) is thought to play an important role in the seizures of El mice because the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by chronic administration of citalopram (80 mg/kg/day, p.o. for 2 weeks), but were not inhibited by acute administration of citalopram (80 mg/kg, i.p., 2 h after single injection). Both chronic and acute administration of citalopram decreased the concentration of 5-hydroxyindolacetic acid in the brain, whereas the concentration of 5-HT was not changed by treatment with citalopram. Tryptophan hydroxylase activity was not different between the citalopram and control groups, although the monoamine oxydase-A activity was lowered by chronic administration of citalopram. These findings suggest that both acute and chronic administration of citalopram depresses the 5-HT turnover rate, however chronic administration is necessary to inhibit El mouse convulsions.</p

The x-ray microcalorimeter spectrometer onboard Athena

Trabajo presentado a la conferencia: "Space Telescopes and Instrumentation: Ultraviolet to Gamma Ray" celebrada en Amsterdam (Holanda) el 1 de julio de 2012.-- et al.One of the instruments on the Advanced Telescope for High-Energy Astrophysics (Athena) which was one of the three missions under study as one of the L-class missions of ESA, is the X-ray Microcalorimeter Spectrometer (XMS). This instrument, which will provide high-spectral resolution images, is based on X-ray micro-calorimeters with Transition Edge Sensor (TES) and absorbers that consist of metal and semi-metal layers and a multiplexed SQUID readout. The array (32 x 32 pixels) provides an energy resolution of < 3 eV. Due to the large collection area of the Athena optics, the XMS instrument must be capable of processing high counting rates, while maintaining the spectral resolution and a low deadtime. In addition, an anti-coincidence detector is required to suppress the particle-induced background. Compared to the requirements for the same instrument on IXO, the performance requirements have been relaxed to fit into the much more restricted boundary conditions of Athena. In this paper we illustrate some of the science achievable with the instrument. We describe the results of design studies for the focal plane assembly and the cooling systems. Also, the system and its required spacecraft resources will be given. © (2012) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.Peer Reviewe

Z-350, A Novel Compound with ␣ 1 -Adrenoceptor Antagonistic and Steroid 5␣-Reductase Inhibitory Actions: Pharmacological Properties In Vivo

ABSTRACT The ␣ 1 -adrenoceptor-antagonistic and steroid 5␣-reductaseinhibitory actions of Z-350 [(S)-4-{3-{4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy}benzoyl}indole-1-yl}butyric acid hydrochloride] were investigated in rabbits and rats in vivo. Z-350 (1-30 mg/kg), administered intraduodenally, dosedependently inhibited phenylephrine-induced increases in prostatic urethral pressure with an ED 50 value of 3.8 mg/kg in anesthetized male rabbits, whereas the effects on mean blood pressure and orthostatic hypotensive response were weaker when compared with other ␣ 1 -adrenoceptor antagonists, tamsulosin and prazosin. Z-350 (1-10 mg/kg p.o.) dose-dependently inhibited the prostatic steroid 5␣-reductase activity in rats with an ED 50 value of 2.8 mg/kg. The daily oral administration of Z-350, at м10 mg/kg for 7 days, significantly reduced the prostatic growth induced by testosterone in castrated rats, with no effect on dihydrotestosterone-induced prostatic growth. These results indicate that Z-350 exhibited ␣ 1 -adrenoceptor-antagonistic and 5␣-reductase inhibitory actions at almost equal doses in vivo, and was expected to improve the bladder outlet obstruction associated with benign prostatic hyperplasia with smaller cardiovascular adverse effect. Benign prostatic hyperplasia (BPH) is a frequent disorder in elderly men, characterized by the progressive enlargement of prostatic tissue, resulting in an obstruction of the proximal urethra and disturbance of urinary flow. Symptomatic BPH is generally considered to consist of the following two components: a static component related to prostatic tissue mass, and a dynamic component related to prostatic smooth muscle tone. The ability of an ␣ 1 -adrenoceptor antagonist to improve the clinical symptoms of BPH was first demonstrated by In contrast, other approaches to reduce prostatic enlargement had also been made previously. It is well known that the growth of the prostate gland is dependent on tissue androgen Simultaneous ␣ 1 -adrenoceptor-antagonistic and steroid 5␣-reductase inhibitory actions are thus expected to be more effective than each action alone

The development of the ICIQ-UAB: A patient reported outcome measure for underactive bladder

Aims: To present the development of the International Consultation on Incontinence Questionnaire-underactive bladder (ICIQ-UAB) as the first patient reported outcome measure for the assessment of the symptoms and impact on the health-related quality of life of UAB developed in-line with the Food and Drug Administration Guidance for Industry.Methods: Draft items were developed following 44 semi-structured concept elicitation interviews in the UK and refined using 36 cognitive interviews. A pilot study was designed to assess the draft ICIQ-UAB's initial psychometric properties with 54 patients recruited from European hospitals. Further concept elicitation interviews were also carried out with 11 patients in the US and 10 patients in Japan. All participants had a prior urodynamic diagnosis of detrusor underactivity.Results: The cognitive interviews confirmed the initial items to be understood and interpreted as intended. Pilot testing showed that both internal consistency (Cronbach's α ≥ 0.85) and test-retest reliability (stable patients; intraclass correlation coefficient ≥ 0.88) werehigh. The interviews in the US and Japan elicited symptoms and impacts that support previous findings in the UK and provided further insight into the experiences of patients in those countries. The developmental ICIQ-UAB was refined using the evidence from all substudies.Conclusions: The validity and reliability of the ICIQ-UAB were supported in a pilot study settingand the wider cultural applicability by the additional interviews in the US and Japan. Following further validation in future clinical trials, the developmental ICIQ-UAB is envisaged as an important tool for the monitoring of future UAB treatment strategies