Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor

Background

Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2α by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models.

Methods

We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition.

Results

By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19–21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the β-agonist ritodrine.

Conclusion

The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.

     

Gut–liver axis: The impact of gut microbiota on non alcoholic fatty liver disease

AimTo examine the impact of gut microbiota on non alcoholic fatty liver disease (NAFLD) pathogenesis.Data synthesisEmerging evidence suggests a strong interaction between gut microbiota and liver. Receiving approximately 70% of its blood supply from the intestine, the liver represents the first line of defence against gut-derived antigens. Intestinal bacteria play a key role in the maintenance of gut–liver axis health. Disturbances in the homeostasis between bacteria- and host-derived signals at the epithelial level lead to a break in intestinal barrier function and may foster “bacterial translocation”, defined as the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or other extraintestinal organs and sites. While the full repertoire of gut-derived microbial products that reach the liver in health and disease has yet to be explored, the levels of bacterial lipopolysaccharide, a component of the outer membrane of Gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver diseases. Derangement of the gut flora, particularly small intestinal bacterial overgrowth, occurs in a large percentage (20–75%) of patients with chronic liver disease. In addition, evidence implicating the gut–liver axis in the pathogenesis of metabolic liver disorders has accumulated over the past ten years.ConclusionsComplex metabolic diseases are the product of multiple perturbations under the influence of triggering factors such as gut microbiota and diet, thus, modulation of the gut microbiota may represent a new way to treat or prevent NAFLD.     

Effects of inhalational anaesthetics in experimental allergic asthma

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty‐six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro‐inflammatory (tumour necrosis factor‐α), pro‐fibrogenic (transforming growth factor‐β) and pro‐angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid‐2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor‐α, transforming growth factor‐β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid‐2‐related factor 2 expression. Sevoflurane down‐regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant–antioxidant imbalance, improving lung function in this model of asthma.     

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

Irritable bowel syndrome(IBS)is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role.The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors,interacting with peripheral/central neuroendocrine and immune changes,may induce symptoms of IBS,modulate symptom severity,influence illness experience and quality of life,and affect outcome.The present review focuses on the role of negative affects,including depression,anxiety,and anger,on pathogenesis and clinical expression of IBS.The potential role of the autonomic nervous system,stress-hormone system,and immune system in the pathophysiology of both negative affects and IBS are taken into account.Psychiatric comorbidity and subclinical variations in levels of depression,anxiety,and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS,such as sensorimotor functions,gut microbiota,inflammation/immunity,and symptom reporting.     

Sativex-induced neurobehavioral effects: causal or concausal? A practical advice!

Nabiximols (Sativex) is an oromucosal spray, containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), used as treatment for unresponsive spasticity in multiple sclerosis (MS) patients. Sativex is thought to not affect cognition or induce any psychiatric problem at the doses generally used. Nonetheless, it is known that the concomitant use of more than one muscle-relaxant drugs can result in additive neuropsychiatric effects. Herein we describe a case of a woman affected by MS and treated with baclofen and methylprednisolone, who developed important behavioral changes, including suicidal ideation, after 4 weeks of Sativex administration. We are not completely able to state if Sativex alone was responsible for our patient’s psychiatric symptoms, in reason of the concomitant use of the other drugs.In conclusion, physicians should pay more attention when prescribing drugs to MS patients affected by spasticity, including Sativex, since neurobehavioral side effects may emerge especially in predisposed individuals.     

Treatment of Helicobacter pylori infection: A clinical practice update

Background

Helicobacter pylori infection is still frequent in the community and all infected subjects should be offered an eradication therapy. Nowadays physicians have to face the challenge of antibiotic resistance in treating Helicobacter pylori‐infected individuals.

Aim

This review provides an overview of current international guidelines and reports recent evidence from systematic reviews and clinical trials on the treatment of Helicobacter pylori infection and should help physicians to better treat their patients.

Results

General rules to optimize the management of Helicobacter pylori infection include: (i) considering previous patient's exposure to antibiotics; (ii) using high dose of proton‐pump inhibitors; and (iii) avoiding repeating the same regimen, if it has already failure. Bismuth quadruple therapy and concomitant therapy are the best first‐line empirical treatments in areas with high clarithromycin resistance and in individuals with previous use of macrolides; otherwise, the 14‐day clarithromycin‐containing triple therapy is a valid regimen. The sequential therapy is no longer a suggested treatment by international guidelines.

Conclusions

Current international guidelines are consistent in defining treatment strategies for Helicobacter pylori infection. The use of national registries to monitor the efficacy and tolerability of different regimens in the real world of clinical practice is now needed.     

Association between vitamin D deficiency and serum Homocysteine levels and its relationship with coronary artery disease

Journal of Thrombosis and Thrombolysis - Homocysteine (Hcy) elevation and vitamin D deficiency have emerged as potential markers of coronary artery disease (CAD). However, even tough...     

The Tridimensional Personality Questionnaire in Males at High and Low Risk for Alcoholism

Cloninger has proposed a tridimensional model as the basis for the classification of personality variants and has developed the Tridimensional Personality Questionnaire (TPQ) as an empirical test of this model. In this study, the TPQ was administered to two groups of young men. One group was comprised of nonalcoholic sons of male alcoholics; the other group consisted of nonalcoholic men with no family history of alcoholism. Since the sons of male alcoholics are considered to be at greater risk to develop alcoholism than the sons of nonalcoholics, it was hypothesized that the two groups would demonstrate differences with regard to one or more personality variants as measured by the TPQ. No statistically significant differences in the three TPQ-subscale scores of the two groups were found.