The chemical composition and pharmacological activities of geopropolis produced by Melipona fasciculata Smith in northeast Brazil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Conjunctival inflammation in patients under topical glaucoma treatment with indication to surgery

PURPOSE: To compare the frequency of conjunctival HLA-DR expression (a surrogate marker for inflammation) in eyes treated with topical prostaglandin analogues versus eyes treated with other topical antiglaucomatous drugs. METHODS: Patients diagnosed with primary open-angle glaucoma presenting indication for trabeculectomy were divided in groups according to the use or not of prostaglandin analogues. All subjects were treated with the maximum tolerated dose of antiglaucomatous drugs until the date of the surgery. At the beginning of the surgical procedure, a 5 x 5 mm biopsy of the bulbar conjunctiva was collected, incubated with monoclonal anti-HLA-DR antibody and processed for histological analysis. RESULTS: Of the 31 eyes included (31 patients), 25 were under topical prostaglandin analogues (Group 1) and six under other topical pharmacological agents (Group 2). Fourteen eyes of Group 1 (56%) and three of Group 2 (50 %) were positive for the inflammatory marker HLA-DR (P=1.0). The percentage of stained cells ranged from 15.49 to 48.09% (median: 27.61) in Group 1, and from 18.35 to 28 (median: 20.71) in Group 2, with no differences statistically significant (p=0.33). CONCLUSION: The use of prostaglandin analogues did not increase conjunctival expression of HLA-DR compared to other topical antiglaucomatous agents.

Role of Two Clusters of Male Alcoholics in Treatment Retention

Aims: This study aimed to classify alcohol-dependent outpatients on the basis of clinical factors and to verify if the resulting types show different treatment retention. Methods: The sample comprised 332 alcoholics that were enrolled in three different pharmacological trials carried out at Sao Paulo University, Brazil. Based on four clinical factors problem drinking onset age, familial alcoholism, alcohol dependence severity, and depression - K-means cluster analysis was performed by using the average silhouette width to determine the number of clusters. A direct logistic regression was performed to analyze the influence of clusters, medication groups, and Alcoholics Anonymous ( AA) attendance in treatment retention. Results: Two clusters were delineated. The cluster characterized by earlier onset age, more familial alcoholism, higher alcoholism severity, and less depression symptoms showed a higher chance of discontinuing the treatment, independently of medications used and AA attendance. Participation in AA was significantly related to treatment retention. Discussion: Health services should broaden the scope of services offered to meet heterogeneous needs of clients, and identify treatment practices and therapists which improve retention. Information about patients' characteristics linked to dropout should be used to make treatment programs more responsive and attractive, combining pharmacological agents with more intensive and diversified psychosocial interventions. Copyright (C) 2012 S. Karger AG, Basel

Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression

Background: Abnormal regulation of glycogen synthase kinase 3-beta (GSK3B) activity has been implicated in the pathophysiology of mood disorders. Many pharmacological agents, including antidepressants, can modulate GSK3B. The aim of the present study was to investigate the effect of short-and long-term sertraline treatment on the expression and phosphorylation of GSK3B in platelets of patients with late-life major depression. Methods: Thirty-nine unmedicated elderly adults with major depressive disorder (MOD) were initially included in this study. The comparison group comprised 18 age-matched, healthy individuals. The expression of total and Ser-9 phosphorylated GSK3B (pGSK3B) was determined by Enzyme Immunometric Assay (EIA) in platelets of patients and controls at baseline, and after 3 and 12 months of sertraline treatments for patients only. During this period, patients were continuously treated with therapeutic doses of sertraline. GSK3B activity was indirectly estimated by calculating the proportion of inactive (phosphorylated) forms (pGSK3B) in relation to the total expression of the enzyme (i.e.. GSK3B ratio). Results: Depressed patients had significantly higher levels of pGSK3B as compared to controls (p < 0.001). Within the MDD group, after 3 months of sertraline treatment no significant changes were observed in GSK3B expression and phosphorylation state, as compared to baseline levels. However, after 12 months of treatment we found a significant increase in the expression of total GSK3B (p = 0.05), in the absence of any significant changes in pGSK3B (p = 0.12), leading to a significant reduction in GSK3B ratio (p = 0.001). Conclusions: Our findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline, along with an increment in the proportion of active forms of the enzyme. This is compatible with an increase in overall GSK3B activity, which may have been induced by the long-term treatment of late-life depression with sertraline. (C) 2012 Elsevier Ltd. All rights reserved.

Psychosocial and clinical predictors of retention in outpatient alcoholism treatment

Objective: One of the factors associated with low rates of compliance in the treatment for alcoholism seems to be the intensity of craving for alcohol. This study aimed to evaluate the associations between alcohol craving and biopsychosocial addiction model-related variables and to verify whether these variables could predict treatment retention. Methods: The sample consisted of 257 male alcoholics who were enrolled in two different pharmacological trials conducted at the Universidade de Sao Paulo in Brazil. Based on four factors measured at baseline - biological (age, race, and family alcoholism), psychiatric (depression symptoms), social (financial and marital status), and addiction (craving intensity, severity of alcohol dependence, smoking status, drinking history, preferential beverage, daily intake of alcohol before treatment) - direct logistic regression was performed to analyze these factors' influence on treatment retention after controlling for medication groups and AA attendance. Results: Increasing age, participation in Alcoholics Anonymous groups, and beer preference among drinkers were independently associated with higher treatment retention. Conversely, higher scores for depression increased dropout rates. Conclusion: Health services should identify the treatment practices and therapists that improve retention. Information about patients' characteristics linked to dropouts should be studied to render treatment programs more responsive and attractive, combining pharmacological agents with more intensive and diversified psychosocial interventions.

Behavioral characterization of the alarm reaction and anxiolytic-like effect of acute treatment with fluoxetine in piaucu fish

In Ostariophysan fish, the detection of the alarm substance liberated into the water as a consequence of an attack by a predator elicits an alarm reaction or anti-predatory behavior. In this study, experiments were performed to: (i) describe and quantitatively characterize the behavioral and ventilatory responses in piaucu fish (Leporinus macrocephalus), individually and as part of a school, to conspecific alarm substance (CAS) and; (ii) test the effect of acute fluoxetine treatment on alarm reaction. Histological analysis revealed the presence of club cells in the intermediate and superficial layers of the epidermis. The predominant behavioral response to CAS was freezing for fish held individually, characterized by the cessation of the swimming activity as the animal settles to a bottom corner of the aquarium. Fish exposed to CAS showed decrease in the mean ventilatory frequency (approximately 13%) relative to control. In schools, CAS elicited a biphasic response that was characterized by erratic movements followed by increased school cohesion and immobility, reflected as an increased school cohesion (65.5% vs. -5.8% for controls) and in the number of animals near the bottom of the aquarium (42.0% vs. 6.5% for controls). Animals treated with single i.p. injections of fluoxetine (10 mu g/g b.w.) did not exhibit alarm behavior following CAS stimulation. These results show that an alarm pheromone system is present in piaucu fish, evidenced by the presence of epidermal club cells and an alarm reaction induced by CAS and consequently of a chemosensory system to transmit the appropriate information to neural structures responsible for initiating anti-predator behavioral responses. In addition, fluoxetine treatment caused an anxiolytic-like effect following CAS exposure. Thus, the alarm reaction in piaucu can be a useful model for neuroethological and pharmacological studies of anxiety-related states. (C) 2011 Elsevier Inc. All rights reserved.

Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats

Objective: To investigate, in male Wistar rats, the effects of long-term moderate red wine (RW) consumption (equivalent to similar to 0.15 mg% resveratrol RS), or RS in low (L, 0.15 mg%) or high (H, 400 mg%) doses in chow. Background: Both RW and RS exhibit cardioprotection. RS extends lifespan in obese rats. It is unclear whether RW consumption or low-dose RS delay vascular aging and prolong life span in the absence of overt risk factors. Methods: Endpoints were aerobic performance, exercise capacity, aging biomarkers (p53,p16,p21, telomere length and telomerase activity in aortic homogenates), vascular reactivity. Data were compared with controls (C) given regular chow. Results: Expressions of p53 decreased similar to 50% similar to with RW and LRS (p < 0.05 vs. C), p16 by similar to 29% with RW (p < 0.05 vs. C) and p21 was unaltered. RW and LRS increased telomere length >6.5-fold vs. C, and telomerase activity increased with LRS and HRS. All treatments increased aerobic capacity (C 32.5 +/- 1.2, RW 38.7 + 1.7, LRS 38.5 + 1.6, HRS 38.3 + 1.8 mlO2 min(-1) kg(-1)), and RW or LRS also improved time of exercise tolerance vs. C (p < 0.05). Endothelium-dependent relaxation improved with all treatments vs. C. Life span, however, was unaltered with each treatment vs. C = 673 +/- 30 days, p = NS. Conclusions: RW and LRS can preserve vascular function indexes in normal rats, although not extending life span. These effects were translated into better aerobic performance and exercise capacity. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors

p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Several p38 MAPK inhibitors have been developed as drug candidates to treatment of autoimmune disorders, such as rheumatoid arthritis. In this paper we reported the docking, synthesis and pharmacological activity of novel urea-derivatives (4a-e) designed as p38 MAPK inhibitors. These derivatives presented good theoretical affinity to the target p38 MAPK, standing out compound 4e (LASSBio-998), which showed a better score value compared to the prototype GK-00687. This compound was able to reduce in vitro TNF-alpha production and was orally active in a hypernociceptive murine model sensible to p38 MAPK inhibitors. Otherwise, compound 4e presented a dose-dependent analgesic effect in a model of antigen (mBSA)-induced arthritis and anti-inflammatory profile in carrageenan induced paw edema, indicating its potential as a new antiarthritis prototype. (c) 2012 Elsevier Masson SAS. All rights reserved.

Influence of genetic variants and post transcriptional factors on imatinib transporters as determinants of the pharmacological response

Introduction – Although imatinib (IM) is a recognized gold standard in chronic myeloid leukemia (CML) therapy, resistance has emerged in a significant proportion of patients. Aim – The aim of this study was: (1) to investigate the role of genetic variants in genes encoding for IM transporters, as candidate of IM responsiveness and (2) to test the influence of miRNAs on IM response, focusing on efflux transporters. Methods – As a first step, a panel of polymorphisms (SNPs) was genotyped in a subgroup population of 189 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial. The association with cytogenetic response and molecular response (MR) was assessed for each SNP. As a second step, an in vitro IM-resistant model (K-562 CML cell line) was established. miRNAs profiles were analyzed using Taqman arrays and in silico search was performed for miRNAs deregulated after IM treatment. mRNA and protein expression were quantified using TaqMan realtime PCR and Western blotting, respectively. Results – (1) Among Caucasian patients, ABCB1 rs60023214 significantly correlated with complete MR (P = 0.005). Concerning SNPs combination in IM uptake transporters, the associations with treatment outcomes were statistically significant for both major and complete MR (P = 0.005 and P = 0.01, respectively). (2) ABCB1 protein was not expressed under any conditions of treatment, differently from ABCG2. Two deregulated miRNAs, namely miR-212 and miR-328, were identified to be inversely correlated with ABCG2 (r2= 0.57; p=0.03 and r2=0.47; p=0.06, respectively). Experiments of loss and gain of function confirmed the functional influence of these miRNAs on ABCG2. Conclusion – The multiple candidate gene approach identified single and combination of SNPs that can be proposed as predictor of IM response. The in vitro study suggested that IM resistance could be mediated by miRNA-dependent mechanism. Further studies are needed to validate these preliminary findings.

Pharmacological Rescue of Dendritic Pathology in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS) is a genetic pathology characterized by brain hypotrophy and severe cognitive disability. Although defective neurogenesis is an important determinant of cognitive impairment, a severe dendritic pathology appears to be an equally important factor. It is well established that serotonin plays a pivotal role both on neurogenesis and dendritic maturation. Since the serotonergic system is profoundly altered in the DS brain, we wondered whether defects in the hippocampal development can be rescued by treatment with fluoxetine, a selective serotonin reuptake inhibitor and a widely used antidepressant drug. A previous study of our group showed that fluoxetine fully restores neurogenesis in the Ts65Dn mouse model of DS and that this effect is accompanied by a recovery of memory functions. The goal of the current study was to establish whether fluoxetine also restores dendritic development and maturation. In mice aged 45 days, treated with fluoxetine in the postnatal period P3-P15, we examined the dendritic arbor of newborn and mature granule cells of the dentate gyrus (DG). The granule cells of trisomic mice had a severely hypotrophic dendritic arbor, fewer spines and a reduced innervation than euploid mice. Treatment with fluoxetine fully restored all these defects. Moreover the impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons was fully normalized in treated trisomic mice, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The widespread beneficial effects of fluoxetine on the hippocampal formation suggest that early treatment with fluoxetine can be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. These findings may open the way for future clinical trials in children and adolescents with DS.

Insulin-like growth factor-I treatment in primary growth hormone insensitivity: effect of recombinant human IGF-I (rhIGF-I) and rhIGF-I/rhIGF-binding protein-3 complex

Growth hormone insensitivity syndrome (GHIS) is a rare cause of growth retardation characterized by high serum GH levels, and low serum insulin-like growth factor I (IGF-I) levels associated with a genetic defect of the GH receptor (GHR) as well post-GHR signaling pathway. Based on clinical, as well as biochemical characteristics, GHIS can be genetically classified as classical/Laron's syndrome and nonclassical/atypical GHIS. Recombinant human IGF-I (rhIGF-I) treatment is effective in promoting growth in subjects who have GHIS. Further, pharmacological studies of a IGF-I compound containing a 1:1 molar complex of rhIGF-I and rhIGF-binding protein-3 (BP-3) demonstrated that the complex was effective in increasing levels of circulating total and free IGF-I and that the administration in patients with GHIS should be safe, well-tolerated and more effective than rhIGF-I on its own.

Targeting siglecs--a novel pharmacological strategy for immuno- and glycotherapy

The immune system must be tightly held in check to avoid bystander tissue damage as well as autoreactivity caused by overwhelming immune reactions. A novel family of immunoregulatory, carbohydrate-binding receptors, the Siglecs (sialic acid binding immunoglobulin-like lectins), has received particular attention in light of their capacity to mediate cell death, anti-proliferative effects and to regulate a variety of cellular activities. Siglec receptors are mainly expressed on leukocytes in a cell type-specific and differentiation-dependent manner. Siglecs might potentially be exploited as targets of novel immune- and glycotherapeutics for cell-directed therapies in autoimmune and allergic diseases, as well as in haematologic malignancies. Here we present novel insights on structural and functional characteristics, expression patterns and evolutionary aspects of Siglecs and their ligands. Pharmacological strategies using Siglec agonistic cross-linking therapeutics, such as monoclonal or engineered antibodies, intravenous immunoglobulin (IVIG), or glycomimetics are discussed. Modulation of immune responses by targeting Siglecs using agonistic or antagonistic therapeutics may have important clinical implications and may pave the way for novel pharmacological avenues for the treatment of autoimmune and allergic diseases or for tumor immunotherapy.

[Surgical treatment options in end-stage heart failure]

Despite significant improvements in pharmacological therapy heart failure is still one of the leading causes for death in the Western World. The gold standard treatment of end-stage heart failure remains cardiac transplantation, but there is a great excess of eligible candidates compared with the low number of suitable donor organs. The variety of surgical organ preserving treatment strategies has significantly increased during the last 20 years, intenting either to delay or even to prevent the need for cardiac transplantation. An individually tailored surgical concept should be considered as an alternative in any heart failure patient who has reached the limits of pharmacologic therapy. This article gives an overview about current and potential future therapeutic options in end-stage heart failure.

Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE)

Despite a broad and efficient pharmacological antihypertensive armamentarium, blood pressure (BP) control is suboptimal and heterogeneous throughout Europe. Recent representative data from Switzerland are limited. The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerland in accordance with current guidelines. The influence of risk factors, target organ damage and medication on BP levels and control was also evaluated.

Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review

OBJECTIVE: To review the efficacy of pharmacological prevention of serious reactions to iodinated contrast media. DESIGN: Systematic review. DATA SOURCES: Systematic search (multiple databases, bibliographies, all languages, to October 2005) for randomised comparisons of pretreatment with placebo or no treatment (control) in patients receiving iodinated contrast media. Review methods Trial quality was assessed by all investigators. Information on trial design, population, interventions, and outcomes was abstracted by one investigator and cross checked by the others. Data were combined by using Peto odds ratios with 95% confidence intervals. RESULTS: Nine trials (1975-96, 10 011 adults) tested H1 antihistamines, corticosteroids, and an H1-H2 combination. No trial included exclusively patients with a history of allergic reactions. Many outcomes were not allergy related, and only a few were potentially life threatening. No reports on death, cardiopulmonary resuscitation, irreversible neurological deficit, or prolonged hospital stays were found. In two trials, 3/778 (0.4%) patients who received oral methylprednisolone 2x32 mg or intravenous prednisolone 250 mg had laryngeal oedema compared with 11/769 (1.4%) controls (odds ratio 0.31, 95% confidence interval 0.11 to 0.88). In two trials, 7/3093 (0.2%) patients who received oral methylprednisolone 2x32 mg had a composite outcome (including shock, bronchospasm, and laryngospasm) compared with 20/2178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60). In one trial, 1/196 (0.5%) patients who received intravenous clemastine 0.03 mg/kg and cimetidine 2-5 mg/kg had angio-oedema compared with 8/194 (4.1%) controls (odds ratio 0.20, 0.05 to 0.76). CONCLUSIONS: Life threatening anaphylactic reactions due to iodinated contrast media are rare. In unselected patients, the usefulness of premedication is doubtful, as a large number of patients need to receive premedication to prevent one potentially serious reaction. Data supporting the use of premedication in patients with a history of allergic reactions are lacking. Physicians who are dealing with these patients should not rely on the efficacy of premedication.