A Double-blind, Placebo-controlled Study Evaluating the Pharmacodynamic Effects of Two Fixed Doses of SSR149415 (250 mg Bid and 100 mg Bid) on Hypothalamic-pituitary-adrenal Axis Function in Outpatients With Major Depressive Disorder

Primary Objective:
- To evaluate the effects of two fixed doses of SSR149415 (250 mg bid and 100 mg bid) on hypothalamic-pituitary-adrenal axis function in patients with major depressive disorder.
Secondary Objectives:
To evaluate the tolerability and safety of SSR149415 in patients with major depressive disorder.
To evaluate the efficacy of two fixed doses of SSR149415 compared to placebo in patients with major depressive disorder.
To evaluate plasma concentrations of SSR149415.

开始日期2006-12-01

申办/合作机构

Sanofi

NCT00374166 / Completed临床2期

An Eight-week, Multicenter, Double-blind, Placebo- and Paroxetine-controlled Study Evaluating the Efficacy and Tolerability of Two Fixed Doses of SSR149415 (250 mg Bid and 100 mg Bid) in Outpatients With Generalized Anxiety Disorder

The objective is to evaluate the efficacy and safety of two doses of SSR149415 (250 mg and 100 mg twice daily) compared to placebo and paroxetine 20 mg once daily in outpatients with generalized anxiety disorder

开始日期2006-08-01

申办/合作机构

Sanofi

NCT00361491 / Completed临床2期

An Eight-Week, Multicenter, Double-Blind, Placebo- and Paroxetine-Controlled Study Evaluating the Efficacy, and Tolerability of Two Fixed Doses of SSR149415 (250 mg Bid and 100 mg Bid) in Patients With Major Depressive Disorder

The purpose of the study is to evaluate the efficacy of SSR149415 in the treatment of Major Depressive Disorder, defined as a change from baseline to visit 7 in the Hamilton Depression Rating Scale.
To evaluate the tolerability, safety and efficacy on disability and quality of life in patients with major depressive disorder.To evaluate plasma concentrations of SSR149415.

开始日期2006-08-01

申办/合作机构

Sanofi SA

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100 项与 Nelivaptan 相关的转化医学

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100 项与 Nelivaptan 相关的专利（医药）

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项与 Nelivaptan 相关的文献（医药）

2022-01-01·Neuroendocrinology2区 · 医学

Exercise-Induced Adrenocorticotropic Hormone Response Is Cooperatively Regulated by Hypothalamic Arginine Vasopressin and Corticotrophin-Releasing Hormone

2区 · 医学

Article

作者: Okamoto, Masahiro ; Soya, Mariko ; Shima, Takeru ; Yook, Jang Soo ; Jesmin, Subrina ; Koizumi, Hikaru ; Soya, Hideaki ; Saito, Tsuyoshi ; Takahashi, Kanako

Introduction: Exercise becomes a stress when performed at an intensity above the lactate threshold (LT) because at that point the plasma adrenocorticotropic hormone (ACTH), a marker of stress response, increases. It is possible that the exercise-induced ACTH response is regulated at least by arginine vasopressin (AVP) and possibly by corticotropin-releasing hormone (CRH), but this remains unclear. To clarify the involvement of these factors, it is useful to intervene pharmacologically in the regulatory mechanisms, with a physiologically acceptable exercise model. Methods: We used a special stress model of treadmill running (aerobic exercise) for male Wistar rats, which mimic the human physiological response, where plasma ACTH levels increase at just above the LT for 30 min. Animals were administered the AVP V1b receptor antagonist SSR149415 (SSR) and/or the CRH type 1 receptor antagonist CP154526 (CP) intraperitoneally before the exercise, which allowed the monitoring of exercise-induced ACTH response. Immunohistochemical evaluation of activated AVP and CRH neurons with exercise was performed for the animals’ hypothalami. Results: A single injection of either antagonist, SSR or CP, resulted in inhibited ACTH levels after exercise stress. Moreover, the combined injection of SSR and CP strongly suppressed ACTH secretion during treadmill running to a greater extent than each alone. The running-exercise-induced activation of both AVP and CRH neurons in the hypothalamus was also confirmed. Conclusion: These results lead us to hypothesize that AVP and CRH are cooperatively involved in exercise-induced ACTH response just above the LT. This may also reflect the stress response with moderate-intensity exercise in humans.

2022-01-01·Neuroscience Letters4区 · 医学

Spinal neurochemical mechanisms of acute stress-induced visceral hypersensitivity in healthy rats

4区 · 医学

Article

作者: Ness, Timothy J ; DeBerry, Jennifer J ; DeWitte, Cary

Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 μg) and IT phentolamine hydrochloride (10 μg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 μg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 μg), ondansetron (10 μg), mecamylamine (50 μg), antalarmin (24 μg), aSVG30 (12 μg), and SSR149415 (50 μg).

2021-05-01·Neuroscience Bulletin2区 · 医学

Paraventricular Nucleus P2X7 Receptors Aggravate Acute Myocardial Infarction Injury via ROS-Induced Vasopressin-V1b Activation in Rats

2区 · 医学

Article

作者: Feng, Yi ; Ooi, Kokwin ; Zhu, Danian ; Xia, Chunmei ; Sun, Yinggang ; Cheng, Wenjing ; Wu, Qin

AbstractThe present study was designed to investigate the mechanisms by which P2X7 receptors (P2X7Rs) mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleus (PVN) of the hypothalamus of rats with acute myocardial ischemia (AMI). The left anterior descending branch of the coronary artery was ligated to induce AMI in rats. The rats were pretreated with BBG (brilliant blue G, a P2X7R antagonist), nelivaptan (a vasopressin V1b receptor antagonist), or diphenyleneiodonium (DPI) [an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor]. Hemodynamic parameters of the heart were monitored. Myocardial injury and cardiomyocyte apoptosis were assessed. In the PVN of AMI rats, P2X7R mediated microglial activation, while reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) were higher than in the sham group. Intraperitoneal injection of BBG effectively reduced ROS production and vasopressin expression in the PVN of AMI rats. Moreover, both BBG and DPI pretreatment effectively reduced sympathetic hyperactivity and ameliorated AMI injury, as represented by reduced inflammation and apoptosis of cardiomyocytes. Furthermore, microinjection of nelivaptan into the PVN improved cardiac function and reduced the norepinephrine (AE) levels in AMI rats. Collectively, the results suggest that, within the PVN of AMI rats, P2X7R upregulation mediates microglial activation and the overproduction of ROS, which in turn activates vasopressinergic neuron-V1b receptors and sympathetic hyperactivity, hence aggravating myocardial injury in the AMI setting.

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