piperidines and Dilatation--Pathologic

Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS.. To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not.. Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed.. Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus).. Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Anxiety; Arousal; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Emotions; Female; Humans; Irritable Bowel Syndrome; Middle Aged; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Pilot Projects; Piperidines; Receptors, Neurokinin-1; Stress, Psychological; Visceral Pain; Young Adult

The ventricle-brain ratio (VBR) of 42 chronic schizophrenic patients was compared with that of 42 age-matched medical controls. For the schizophrenics, the relationship of various clinical parameters to the VBR was assessed, and the outcome of 12 weeks of double-blind treatment with either risperidone or haloperidol. The results confirm that schizophrenic patients have slightly enlarged lateral ventricles compared with medical controls. Only for schizophrenics, an effect of age, but not of duration of illness, was noticed. This study does not support the validity of a clinical subdivision of chronic schizophrenic patients on the basis of the VBR. Neither negative, positive nor general psychopathological symptoms, as measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), were related to the VBR, nor were abnormal involuntary movements or extrapyramidal symptoms. No association between season of birth or a family history of major mental disorder and VBR could be demonstrated. Treatment response was predicted by the total PANSS score and the PANSS general psychopathology subscale score at baseline. There was a trend for patients with higher VBR to have a more or haloperidol). or haloperidol).

Topics: Adult; Aged; Antipsychotic Agents; Brain; Cerebral Ventricles; Chronic Disease; Dilatation, Pathologic; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Tomography, X-Ray Computed

Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel antidiabetic drug, has a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. However, the effect of DPP-4 inhibitor on aneurysm formation has not been investigated. We aimed to test the hypothesis that the DPP-4 inhibitor, alogliptin, attenuates vascular oxidative stress and thus inhibits abdominal aortic aneurysm (AAA) formation.. AAAs were created with intraluminal elastase and extraluminal calcium chloride in 36 male rats. Rats were divided into three groups: a low dose of alogliptin group (group LD; 1 mg/kg/d), a high-dose group (group HD; 3 mg/kg/d), and a control group (group C, water). Alogliptin was administered by gastric gavage once daily beginning 3 days before surgery. On day 7 after aneurysm preparation, reactive oxygen species (ROS) expression was semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Blood glucose concentrations were measured. Hematoxylin and eosin and elastica Van Gieson stainings were performed on day 28, and the AAA dilatation ratio was calculated.. On day 7 (six in each group), dihydroethidium staining of the aneurysm wall showed a reduced level of ROS expression (4.6 ± 0.6 in group C, 2.7 ± 0.3 in group LD, and 1.7 ± 0.5 in group HD; P < .0001) and showed fewer 8-OHdG-positive cells in alogliptin-treated samples (138.1 ± 7.4 cells in group C, 102.5 ± 4.5 cells in group LD, and 66.1 ± 4.5 cells in group HD; P < .0001) The treatment significantly reduced messenger RNA expression of matrix metalloproteinases (MMPs) in aneurysm walls (relative expression: MMP-2: 2.1 ± 0.4 in group C, 1.3 ± 0.3 in group LD, and 0.9 ± 0.2 in group HD; P < .001; MMP-9: 2.0 ± 0.5 in group C, 0.3 ± 0.3 in group LD, and 0.3 ± 0.2 in group HD; P < .001). On day 28 (six in each group), the aortic wall in groups LD and HD was less dilated (dilatation ratio: 199.2% ± 11.8% in group C, 159.6% ± 2.8% in group LD, and 147.1% ± 1.9% in group HD; P < .02 group C vs HD) and had higher elastin content than in group C. The difference in blood glucose levels among the three groups was not significant.. The DPP-4 inhibitor, alogliptin, attenuates aneurysm formation and expansion dose-dependently in a rat AAA model via an antioxidative action.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Blood Glucose; Calcium Chloride; Deoxyguanosine; Dilatation, Pathologic; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Time Factors; Uracil

Distension of the rat intestine causes a depressor response which is predictive of nociception. This study investigated the effects of previous infection with Nippostrongylus (N.) brasiliensis on the sensitivity to intestinal distension and the role of tachykinin NK2 receptors. The tachykinin NK2 receptor antagonist, SR48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloropheny l)butyl]benzamide) inhibited the nociceptive response (ED50 = 0.7 mg/kg) in control rats. In post-N. brasiliensis-infected rats sensitivity to intestinal distension was increased which was accompanied by an increase in the apparent potency value of SR48968 (ED50 = 0.1 mg/kg). The hypersensitivity was limited to areas of hypermastocytosis. It is concluded that the post-inflammatory changes that occur in post-infected rats increase visceral sensitivity and the apparent potency of tachykinin NK2 receptor antagonists.

Topics: Animals; Benzamides; Colon; Colonic Diseases; Dilatation, Pathologic; Intestinal Diseases, Parasitic; Jejunal Diseases; Jejunum; Male; Mast Cells; Nippostrongylus; Pain Measurement; Peroxidase; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Strongylida Infections