Platforms for the identification of GPCR targets, and of orthosteric and allosteric modulators

Areas covered in this review: The review provides a summary of old and new approaches for GPCR target identification and for the screening of molecules acting on GPCR targets. The new findings in the field are presented as well as an opinion about how these developments may help GPCR drug discovery. Importance in the field: GPCRs have been the most useful family of proteins in terms of targets for drug discovery. The expectations for GPCR target identification and discovery of new drugs acting on 'old' or 'new' GPCR targets are very high. Given the fact that the pace at which new 'GPCR drugs' appear in the market is decreasing and since the new developments in the field are not being translated into drug discovery there is a need to review the field from a critical perspective. Take home message: To overcome the limitation of the old approaches used in GPCR target identification and drugs discovery new approaches are required. In particular successful approaches in GPCR drug discovery should take into account that the real GPCR targets for a given disease are not GPCR monomers but GPCR heteromers. What the reader will gain: The reader will gain an overview of the strategies currently used and their pros and cons. The reader will also understand that new strategies may help in accelerating the access of GPCR into the market, and also notice that successful strategies should take advantage of the new findings in the field of GPCRs.     

Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer

Aliment Pharmacol Ther 2011; 34: 888–900

Summary

Background Determining the risk of rebleeding after endoscopic therapy for peptic ulcer bleeding (PUB) may be useful for establishing additional haemostatic measures in very high‐risk patients. Aim To identify predictors of rebleeding after endoscopic therapy. Methods Bibliographic database searches were performed to identify studies assessing rebleeding after endoscopic therapy for PUB. All searches and data abstraction were performed in duplicate. A parameter was considered to be an independent predictor of rebleeding when it was detected as prognostic by multivariate analyses in ≥2 studies. Pooled odds ratios (pOR) were calculated for prognostic variables. Results Fourteen studies met the prespecified inclusion criteria. Pre‐endoscopic predictors of rebleeding were: (i) Haemodynamic instability: significant in 9 of 13 studies evaluating the variable (pOR: 3.30, 95% CI: 2.57–4.24); (ii) Haemoglobin value: significant in 2 of 10 (pOR: 1.73, 95% CI: 1.14–2.62) and (iii) Transfusion: significant in two of six (pOR not calculable). Endoscopic predictors of rebleeding were: (i) Active bleeding: significant in 6 of 12 studies (pOR: 1.70, 95% CI: 1.31–2.22); (ii) Large ulcer size: significant in 8 of 12 studies (pOR: 2.81, 95% CI: 1.98–4.00); (iii) Posterior duodenal ulcer location: significant in four of eight studies (pOR: 3.83, 95% CI: 1.38–10.66) and (iv) High lesser gastric curvature ulcer location: significant in three of eight studies (pOR: 2.86; 95% CI: 1.69–4.86). Conclusions Major predictors for rebleeding in patients receiving endoscopic therapy are haemodynamic instability, active bleeding at endoscopy, large ulcer size, ulcer location, haemoglobin value and the need for transfusion. These risk factors may be useful for guiding clinical management in patients with PUB.     

Density of striatal D2 receptors in untreated first-episode psychosis: An I-IBZM SPECT study

There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n = 37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F = 10.2, p < 0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p = 0.006), and between schizophrenia and control groups (p < 0.001) but no differences between non-schizophrenia and control groups (p = 0.9). The logistic regression model showed that D2R binding (p = 0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p = 0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R² = 0.59; X² = 11.08, p = 0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.     

Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function.     

Comorbilidad de la depresión mayor con otros trastornos mentales comunes en pacientes de atención primaria

IntroductionPsychiatric comorbidity affects the impact, the prognosis and the management of depression.AimsTo determine the prevalence of other common mental disorders in patients with major depression and to analyse their associated comorbidities.DesignTwo-stage cross-sectional study: a) screening (Zung's Self-Rating Depression Scale); b) a standardised psychiatric interview.SettingsTen health centres in the province of Tarragona.PatientsA total of 906 consecutive patients were screened. In the second stage, the 209 patients who gave a positive result and 97 patients who gave a negative result (1/7 at random) were evaluated.AnalysisThe statistical analysis used weights that took into account the two-stage sampling. The frequency with which dysthymia, generalised anxiety disorder, panic disorder and somatisation disorder presented concomitantly with major depression was determined. The characteristics of the depressed patients were compared for different degrees of comorbidity.ResultsIn 45.7% (95% CI, 32.8–59.2) of patients with major depression there was one other coexisting mental disorder, in 19.9% (95% CI, 13.7–27.9) two more mental disorders and in 8.3% (95% CI, 4.5–14.8) three more mental disorders. Generalised anxiety disorder was present in 55.2% of depressed patients (95% CI, 41.6–68), panic disorder in 33.8% (95% CI, 21.1–47.1), dysthymia in 15.7% (95% CI, 10.3–23.4) and somatisation disorder in 6.6% (95% CI, 3.3-12.8). In the groups of patients with comorbidity, the depression was more severe and had a greater functional impact. There were no differences in the clinical management variables.ConclusionsPsychiatric comorbidity of depression is common in primary care. Most depressed patients suffer from other disorders, often anxiety.     

Efficacy of chlorhexidine,dexpanthenol, allantoin and chitosan gel in comparison with bicarbonate oral rinse in controlling post-interventional inflammation,pain and cicatrization in subjects undergoing dental surgery

Introduction:

Reducing post-interventional inflammation and pain in odontostomatological surgery procedures, such as tooth extractions, implants or oral biopsies is a relevant clinical goal. Chlorhexidine oral rinse is commonly used with this aim. Recently a new product containing chlorhexidine, dexpanthenol, allantoin and chitosan (Bexident Post [BP]) in a gel formulation has been developed. We evaluated the efficacy of BP in controlling postsurgical inflammation and pain and in promoting cicatrization in subjects undergoing molar extractions.

Subjects and methods:

We conducted a prospective sequential cross-over, randomized controlled study in patients undergoing surgical removal of at least two impacted mandibular third molars (teeth numbers 38 and 48) (numbers 17 and 32 in the Universal Tooth Numbering System), in two separate sessions, to determine the effect of BP in comparison with bicarbonate (BC) oral rinse (one spoonful in 200?ml of water), both used three times daily. Each subject utilized both products in a randomized sequential manner after each tooth extraction. Primary outcomes of the study were post-procedure pain and inflammation. Secondary outcomes were analgesic pill rescue use (metamizole 1 cap every 8 hours if needed) and an assessor-blinded evaluation of cicatrization with a semi-quantitative scale (good, satisfactory and insufficient). Post-procedure pain was assessed 6 hours after tooth extraction and for seven consecutive days by means of a 10?cm visual analogue scale (VAS) (from 0: no pain to 10: extreme pain). The extent of inflammation was evaluated through metric measurements of facial perimeter using standardized anatomical reference points.

Results:

A total of 47 patients (22 men and 25 women; mean age 34 years) were enrolled with a total of 94 molars extracted. Nineteen subjects applied BC as the first sequential treatment and 28 BP as the first. Before surgery no mean differences in the two treatments in inflammation measurements were observed. After surgery mean VAS pain score was similar between the two treatments in the first 6 hours (VAS score?=?6.5). A marked progressive reduction in pain intensity with the use of BP was observed throughout the treatment period in comparison with BC (7 day mean scores 3.7 vs. 5.3; p?=?0.0001). BP was superior to BC in reducing inflammation with ?50% of the inflammation-related measurement (6?mm vs. 12?mm; p?=?0.0001). Analgesic pill consumption was lower with BP in comparison with BC (13 pills vs. 24; p?p?=?0.0001). No serious side effects were reported with either treatment regimen.

Conclusion:

In this trial BP performed better than BC in controlling pain and inflammation in subjects undergoing dental surgery, reducing the consumption of analgesics and favoring better cicatrization.     

Occupation and gastric cancer in Spain

The association between occupational exposure and stomach cancer was investigated in a multicenter case-referent study conducted in Spain on 354 histologically confirmed cases and 354 hospital referents, matched by age, gender, and residence. An increased risk of gastric cancer was found for coal mining workers [odds ratio (OR) 11.8], but the number of workers was small, and therefore the 95% confidence interval (95% CI) was wide (95% CI 1.36-103). An increased risk was observed for wood and furniture workers (OR 1.76), construction workers (OR 1.68), and glass and ceramic workers (OR 2.18), but none of these risks were statistically significant. According to an occupation-exposure linkage system an increased risk was found for occupations associated with exposure to silica and mineral dust (OR 1.80, 95% CI 0.90-3.59). All of the OR estimates were adjusted for the confounding factors socioprofessional status and dietary habits. The possibility of a causal association between stomach cancer and coal and mineral dust is supported by the results.     

Structure-dependent efficacy of infectious bursal disease virus (IBDV) recombinant vaccines

The immunogenicity and protective capability of several baculovirus-expressed infectious bursal disease virus (IBDV)-derived assemblies as VP2 capsids, VPX tubules and polyprotein (PP)-derived mixed structures, were tested. Four-week-old chickens were immunised subcutaneously with one dose of each particulate antigen. VP2 icosahedral capsids induced the highest neutralising response, followed by PP-derived structures and then VPX tubules. All vaccinated animals were protected when challenged with a very virulent IBDV (vvIBDV) isolate, however the degree of protection is directly correlated with the levels of neutralising antibodies. VP2 capsids elicited stronger protective immunity than tubular structures and 3 micrograms of them were sufficient to confer a total protection comparable to that induced by an inactivated vaccine. Therefore, VP2 capsids represent a suitable candidate recombinant vaccine instead of virus-like particles (VLPs) for IBDV infections. Our results also provide clear evidence that the recombinant IBDV-derived antigens are structure-dependent in order to be efficient as vaccine components.