Anxiolytic-like effect of noradrenaline microinjection into the dorsal periaqueductal gray of rats

The brain noradrenergic system has been implicated in the expression of defensive behaviors elicited by acute stress. The dorsal periaqueductal gray area (dPAG) is a key structure involved in the behavioral and cardiovascular responses elicited by fear and anxiety situations. Although there are noradrenergic terminals in the dPAG, few studies have investigated the role of noradrenaline (NA) in the dPAG on anxiety modulation. The aim of this study was to evaluate the effect of NA microinjection into the dPAG of rats subjected to two animal models of anxiety, the elevated plus-maze and the Vogel conflict test. Male Wistar rats implanted with a guide cannula aimed at the dPAG received microinjections of NA (3, 15, or 45 nmol/0.05 mu l) or artificial cerebral spinal fluid into the dPAG immediately before being exposed to the elevated plus-maze or the Vogel conflict test. NA increased the exploration of the open arms and the number of enclosed arm entries in the elevated plus-maze. The increase in open arm exploration remained significant after being subjected to an analysis of covariance using the latter variable as covariate. Moreover, the NA microinjection into the dPAG did not increase general exploratory activity of animals subjected to the open-field test, indicating that the increase in open arm exploration cannot be attributed to a nonspecific increase in exploratory activity. In the Vogel test, the NA microinjection into the dPAG increased the number of punished licks without changing the number of nonpunished licks or interfering with the tail-flick test. The results, therefore, indicate that the NA microinjection into the dPAG produces anxiolytic-like effects, suggesting its possible involvement in the anxiety modulation. Behavioural Pharmacology 20:252-259 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Adjunctive benefits of systemic etoricoxib in non-surgical treatment of aggressive periodontitis: Short-term evaluation

Background: This pilot study assessed the effect of short-duration treatment with etoricoxib as adjuvant therapy to scaling and root planing (SRP) on the clinical and radiographic parameters and prostaglandin E-2 (PGE(2)) levels in aggressive periodontitis. Methods: Subjects were randomly allocated to test or control treatment (n = 10 in each group) and submitted to SRP and treatment with etoricoxib, 120 mg/day, or placebo for 7 days. Probing depth, clinical attachment level (CAL), gingival recession, visible plaque index, bleeding on probing, linear distance (LD) from the cemento-enamel junction to the alveolar crest, and analysis of the gray levels were recorded before and 1 month after the therapies. The prostaglandin E-2 (PGE(2)) level in the gingival crevicular fluid (GCF) was measured by radioimmunoassay at the beginning of the study and 7 and 30 days after treatment. Results: No significant difference in the clinical parameters was observed between the groups at the end of the experimental period, although both groups presented significant improvement in all variables examined. There was a decrease in CAL from 5.54 +/- 0.47 mm to 3.59 +/- 0.53 mm in the test group and from 5.92 +/- 1.10 mmto 3.69 +/- 0.80 mm in the control group. A significant reduction in PGE(2) was found after 7 days of treatment. LD differed between the groups. Conclusion: Etoricoxib did not promote additional improvement in the clinical parameters; however, it produced an initial reduction in the PGE(2) levels in the GCF, which could be related to the discrete improvement in the bone condition.

Physical Properties of an Acrylic Resin after Incorporation of an Antimicrobial Monomer

Purpose: This study evaluated the effect of the incorporation of the antimicrobial monomer methacryloyloxyundecylpyridinium bromide (MUPB) on the hardness, roughness, flexural strength, and color stability of a denture base material. Materials and Methods: Ninety-six disk-shaped (14-mm diameter x 4-mm thick) and 30 rectangular (65 x 10 x 3.3 mm(3)) heat-polymerized acrylic resin specimens were divided into three groups according to the concentration of MUPB (w/w): (A) 0%, (B) 0.3%, (C) 0.6%. Hardness was assessed by a hardness tester equipped with a Vickers diamond penetrator. Flexural strength and surface roughness were tested on a universal testing machine and a surface roughness tester, respectively. Color alterations (Delta E) were measured by a portable spectrophotometer after 12 and 36 days of immersion in water, coffee, or wine. Variables were analyzed by ANOVA/Tukey HSD test (alpha = 0.05). Results: The following mean results (+/-SD) were obtained for hardness (A: 15.6 +/- 0.6, B: 14.6 +/- 1.7, C: 14.8 +/- 0.8 VHN; ANOVA: p = 0.061), flexural strength (A: 111 +/- 17, B: 105 +/- 12, C: 88 +/- 12 MPa; ANOVA: p = 0.008), and roughness (A: 0.20 +/- 0.11, B: 0.20 +/- 0.11, C: 0.24 +/- 0.08 mu m; ANOVA: p = 0.829). Color changes of immersed specimens were significantly influenced by solutions and time (A: 9.1 +/- 3.1, B: 14.8 +/- 7.5, C: 13.3 +/- 6.1 Delta E; ANOVA: p < 0.05). Conclusions: The incorporation of MUPB affects the mechanical properties of a denture base acrylic resin; however, the only significant change was observed for flexural strength and may not be critical. Color changes were slightly higher when resin containing MUPB was immersed in wine for a prolonged time; however, the difference has debatable clinical relevance.

Hemoglobin-degrading, aspartic proteases of blood-feeding parasites - Substrate specificity revealed by homology models

Blood-feeding parasites, including schistosomes, hookworms, and malaria parasites, employ aspartic proteases to make initial or early cleavages in ingested host hemoglobin. To better understand the substrate affinity of these aspartic proteases, sequences were aligned with and/or three-dimensional, molecular models were constructed of the cathepsin D-like aspartic proteases of schistosomes and hookworms and of plasmepsins of Plasmodium falciparum and Plasmodium vivax, using the structure of human cathepsin D bound to the inhibitor pepstatin as the template. The catalytic subsites S5 through S4' were determined for the modeled parasite proteases. Subsequently, the crystal structure of mouse renin complexed with the nonapeptidyl inhibitor t-butyl-CO-His-Pro-Phe-His-Leu [CHOHCH2]Leu-Tyr-Tyr-Ser-NH2 (CH-66) was used to build homology models of the hemoglobin-degrading peptidases docked with a series of octapeptide substrates. The modeled octapeptides included representative sites in hemoglobin known to be cleaved by both Schistosoma japonicum cathepsin D and human cathepsin D, as well as sites cleaved by one but not the other of these enzymes. The peptidase-octapeptide substrate models revealed that differences in cleavage sites were generally attributable to the influence of a single amino acid change among the P5 to P4' residues that would either enhance or diminish the enzymatic affinity. The difference in cleavage sites appeared to be more profound than might be expected from sequence differences in the enzymes and hemoglobins. The findings support the notion that selective inhibitors of the hemoglobin-degrading peptidases of blood-feeding parasites at large could be developed as novel anti-parasitic agents.

A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties

Two peptides, textilinins 1 and 2, isolated from the venom of the Australian common brown snake, Pseudonaja textilis textilis, are effective in preventing blood loss. To further investigate the potential of textilinins as anti-haemorrhagic agents, we cloned cDNAs encoding these proteins. The isolated full-length cDNA (430 bp in size) was shown to code for a 59 amino acid protein, corresponding in size to the native peptide, plus an additional 24 amino acid propeptide. Six such cDNAs were identified, differing in nucleotide sequence in the coding region but with an identical propeptide. All six sequences predicted peptides containing six conserved cysteines common to Kunitz-type serine protease inhibitors. When expressed as glutathione S-transferase (GST) fusion proteins and released by cleavage with thrombin, only those peptides corresponding to textilinin 1 and 2 were active in inhibiting plasmin with K-i values similar to those of their native counterparts and in binding to plasmin less tightly than aprotinin by two orders of magnitude. Similarly, in the mouse tail vein blood loss model only recombinant textilinin 1 and 2 were effective in reducing blood loss. These recombinant textilinins have potential as therapeutic agents for reducing blood loss in humans, obviating the need for reliance on aprotinin, a bovine product with possible risk of transmissible disease, and compromising the fibrinolytic system in a less irreversible manner.

Evaluation of cyclooxygenase 2 inhibitor use in patients admitted to a large teaching hospital

Background: The heavy usage of coxibs in Australia far outstrips the predicted usage that was based on the treatment of patients with risk factors for upper gastro-intestinal adverse events from conventional anti--inflammatory agents. This raises questions regarding the appropriateness of prescribing. Aims: To determine: (i) the relationship between prescriptions for cyclooxygenase 2 (COX-2) inhibitors and objective evidence of inflammatory arthritis, (ii) prior experience with paracetamol and/or conventional non-steroidal anti-inflammatory drugs (NSAIDs), and (iii) contraindications to the use of NSAIDs. Methods: Drug utilization evaluation and rheumato-logical assessment was conducted on 70 consecutive patients admitted on COX-2 inhibitors to a 480-bed metropolitan hospital. The main outcome measures were: the indication for COX-2 inhibitor; objective -evidence of inflammatory arthritis; previous trial of -paracetamol or conventional NSAIDs; and patient -satisfaction. Results: Only 11 patients (16%) had symptoms or signs of an inflammatory arthropathy, and met Pharmaceut-ical Benefits Schedule criteria for prescribing a COX-2 inhibitor. Fifty-nine patients (84%) had chronic osteo-arthritis, degenerative spinal disease, injury or malignancy, without overt active inflammation. Fourteen patients (20%) had trialled regular paracetamol prior to using any NSAID treatment. Conventional NSAIDs had been previously used by 51 patients (73%). Eleven patients (16%) reported previous adverse gastrointestinal effects from conventional NSAIDs. On the basis of significant renal impairment (creatinine clearance 5/10). Conclusions: Drug utilization data indicate that COX-2 inhibitors are frequently used first line for degenerative osteoarthritis in the absence of overt inflammation, without prior adequate trial of paracetamol and with disregard for the cautions and contraindications of these agents. These findings may explain the unprecedented Pharmaceutical Benefits Schedule expenditure on COX-2 inhibitors in Australia.

A new strategy for the synthesis of 3-cinnamoyl-2-styrylchromones and their transformation into new xanthenodiones derivatives

23rd ISHC Congress will be held in Glasgow, Scotland from July 31 August 4, 2011.

Central obesity and dietary intake in HIV/AIDS patients

OBJECTIVE: To assess the association between dietary intake and central obesity among people living with HIV/AIDS and receiving highly active antiretroviral therapy. METHODS: A cross-sectional study was conducted involving 223 adult individuals in the city of São Paulo city in 2002. The study population was classified according to central obesity, defined as waist-to-hip ratio >0.95 for men and >0.85 for women. The dietary variables studied were energy consumption (in calories and calories/kilo of body weight), macronutrients (in grams and % of energy intake), total fiber (grams) and fruit and vegetables intake (grams). The potential confounders examined were sex, skin color, age, schooling, income, body mass index, physical activity, smoking habits, peripheral CD4+ T lymphocyte count and length of protease inhibitor use. The multiple logistic regression model was performed in order to evaluate the association between central obesity and dietary intake. RESULTS: The prevalence of central obesity was 45.7% and it was associated with greater consumption of lipids: for every increase of 10g of lipid intake the odds of central obesity increased 1.28 times. Carbohydrate consumption showed negative association (OR=0.93) with central obesity after adjustment for control variables. CONCLUSIONS: The results suggest that the amount of carbohydrates and lipids in the diet, regardless of total energy intake, may modify the chance of developing central obesity in the studied population. Nutritional interventions may be beneficial for preventing central obesity among HIV/AIDS patients.

Metabolic changes associated with antiretroviral therapy in HIV-positive patients

OBJECTIVE: To evaluate metabolic changes associated with highly active antiretroviral therapy (HAART) in HIV-positive patients, and to identify risk factors associated. METHODS: Retrospective study that included 110 HIV-positive patients who where on HAART in the city of Porto Alegre (Southern Brazil) between January 2003 and March 2004. Data on demographic variables, cigarette smoking, diabetes mellitus, cholesterol and triglyceride levels, stage of HIV infection, antiretroviral therapy and HCV coinfection were collected. General linear models procedure for repeated measures was used to test the interaction between HAART and HCV coinfection or protease inhibitor treatment. RESULTS: Total cholesterol, triglycerides, and glucose levels significantly increased after receiving HAART (p<0.001 for all variables), but no interaction with protease inhibitors was seen for total cholesterol, glucose and triglyceride levels (interaction treatment*protease inhibitors p=0.741, p=0.784, and p=0.081, respectively). An association between total cholesterol levels and HCV coinfection was found both at baseline and follow-up (effect of HCV coinfection, p=0.011). Glucose levels were increased by HAART (treatment effect, p=0.036), but the effect was associated to HCV coinfection (treatment*HCV effect, p=0.018). Gender, smoking habit, intravenous drug use and age were not significantly associated with cholesterol, triglyceride and glucose changes. CONCLUSIONS: HCV-infected patients at baseline were significantly less likely to develop hypercholesterolemia. The results provide further evidence of the role of HAART for the development of metabolic disturbances.

Long-term health benefits of appetite suppressants remain unproven

Because of the increasing prevalence of obesity, prevention and treatment of overweight has become a major public health concern. In addition to diet and exercise, drugs are needed for patients who failed to lose weight with behavioral treatment. The current article aimed to summarize recent concerns on the safety and efficacy of appetite suppressants. Several appetite suppressants have been banned for safety reasons. In 2010, sibutramine was withdrawn from the market because a long-term study showed it increased the risks of cardiovascular events. So far no study with a sufficiently large sample size has demonstrated that appetite suppressants can reduce morbidity and mortality associated with overweight. The withdrawal of sibutramine highlights that guidelines for the evaluation of weight control drugs must be more stringent, and studies on their long-term health benefits are needed prior to their marketing.

Direct treatment costs of HIV/AIDS in Portugal

OBJECTIVE To analyze the direct medical costs of HIV/AIDS in Portugal from the perspective of the National Health Service. METHODS A retrospective analysis of medical records was conducted for 150 patients from five specialized centers in Portugal in 2008. Data on utilization of medical resources during 12 months and patients&#8217; characteristics were collected. A unit cost was applied to each care component using official sources and accounting data from National Health Service hospitals. RESULTS The average cost of treatment was 14,277 &#8364;/patient/year. The main cost-driver was antiretroviral treatment (&#8364; 9,598), followed by hospitalization costs (&#8364; 1,323). Treatment costs increased with the severity of disease from &#8364; 11,901 (> 500 CD4 cells/&#181;l) to &#8364; 23,351 (CD4 count &#8804; 50 cells/ &#181;l). Cost progression was mainly due to the increase in hospitalization costs, while antiretroviral treatment costs remained stable over disease stages. CONCLUSIONS The high burden related to antiretroviral treatment is counterbalanced by relatively low hospitalization costs, which, however, increase with severity of disease. The relatively modest progression of total costs highlights that alternative public health strategies that do not affect transmission of disease may only have a limited impact on expenditure, since treatment costs are largely dominated by constant antiretroviral treatment costs.

Strategies for price reduction of HIV medicines under a monopoly situation in Brazil

ABSTRACT OBJECTIVE To analyze Government strategies for reducing prices of antiretroviral medicines for HIV in Brazil. METHODS Analysis of Ministry of Health purchases of antiretroviral medicines, from 2005 to 2013. Expenditures and costs of the treatment per year were analyzed and compared to international prices of atazanavir. Price reductions were estimated based on the terms of a voluntary license of patent rights and technology transfer in the Partnership for Productive Development Agreement for atazanavir. RESULTS Atazanavir, a patented medicine, represented a significant share of the expenditures on antiretrovirals purchased from the private sector. Prices in Brazil were higher than international references, and no evidence was found of a relationship between purchase volume and price paid by the Ministry of Health. Concerning the latest strategy to reduce prices, involving local production of the 200 mg capsule, the price reduction was greater than the estimated reduction. As for the 300 mg capsule, the amounts paid in the first two years after the Partnership for Productive Development Agreement were close to the estimated values. Prices in nominal values for both dosage forms remained virtually constant between 2011 (the signature of the Partnership for Productive Development Agreement), 2012 and 2013 (after the establishment of the Partnership). CONCLUSIONS Price reduction of medicines is complex in limited-competition environments. The use of a Partnership for Productive Development Agreement as a strategy to increase the capacity of local production and to reduce prices raises issues regarding its effectiveness in reducing prices and to overcome patent barriers. Investments in research and development that can stimulate technological accumulation should be considered by the Government to strengthen its bargaining power to negotiate medicines prices under a monopoly situation.

Safety and efficacy of fenproporex for obesity treatment: a systematic review

ABSTRACT OBJECTIVE To evaluate clinical evidence on the safety and efficacy of fenproporex for treating obesity. METHODS MEDLINE, LILACS and Cochrane Controlled Trials Register were searched as well as references cited by articles and relevant documents. Two authors independently assessed the studies for inclusion and regarding risk of bias, collected data, and accuracy. Eligible studies were all those placebo-controlled that provided data on the efficacy and safety of Fenproporex to treat obesity. RESULTS Only four controlled studies met the inclusion criteria. One randomized, placebo-controlled trial on Fenproporex was found on electronic databases. Three placebo-controlled studies (in non-indexed journals) were identified by hand-searching. Patients with cardiovascular and other comorbidities were excluded in all studies. Trials lasted from 40 to 364 days and doses ranged from 20 to 33.6 mg/d. All controlled studies found that weight loss among Fenproporex-treated patients was greater than that produced by the placebo, but drug effect was modest. Fenproporex produced additional weight reductions of 4.7 kg (one year), 3.8 kg (six months) and 1.55 kg (two months) in average, in relation to diet and exercise only (three trials). Insomnia, irritability, and anxiety were the most frequently reported side effects in the four studies. CONCLUSIONS There is a paucity of randomized, placebo-controlled trials on Fenproporex and those identified here present major methodological flaws. These studies suggest that Fenproporex is modestly effective in promoting weight loss. Nonetheless, they failed to provide evidence that it reduces obesity-associated morbidity and mortality. Data from these studies are insufficient to determine the risk-benefit profile of Fenproporex. Abuse potential and amphetamine-like adverse effects are causes for concern.

"In-vitro" corrosion behaviour of the magnesium alloy with Al and Zn (AZ31) protected with a biodegradable polycaprolactone coating loaded with hydroxyapatite and cephalexin

Mg alloys are very susceptible to corrosion in physiological media. This behaviour limits its widespread use in biomedical applications as bioresorbable implants, but it can be controlled by applying protective coatings. On one hand, coatings must delay and control the degradation process of the bare alloy and, on the other hand, they must be functional and biocompatible. In this study a biocompatible polycaprolactone (PCL) coating was functionalised with nano hydroxyapatite (HA) particles for enhanced biocompatibility and with an antibiotic, cephalexin, for anti-bacterial purposes and applied on the AZ31 alloy. The chemical composition and the surface morphology of the coated samples, before and after the corrosion tests, were studied by scanning electron microscopy (SEM) coupled with energy dispersive x-ray analysis (EDX) and Raman. The results showed that the presence of additives induced the formation of agglomerates and defects in the coating that resulted in the formation of pores during immersion in Hanks' solution. The corrosion resistance of the coated samples was studied in Hank's solution by electrochemical impedance spectroscopy (EIS). The results evidenced that all the coatings can provide corrosion protection of the bare alloy. However, in the presence of the additives, corrosion protection decreased. The wetting behaviour of the coating was evaluated by the static contact angle method and it was found that the presence of both hydroxyapatite and cephalexin increased the hydrophilic behaviour of the surface. The results showed that it is possible to tailor a composite coating that can store an antibiotic and nano hydroxyapatite particles, while allowing to control the in-vitro corrosion degradation of the bioresorbable Mg alloy AZ31. (C) 2015 Elsevier Ltd. All rights reserved.

Etiology and severity of community acquired pneumonia in children from Uruguay: a 4-year study

The 4-year study (1987-1990) covered the major clinical-epidemiological characteristics of pneumonia in children as diagnosed at the emergency service of the Children's Hospital, as well as etiologies, and factors involved in the most severe cases. Etiology was determined in 47.7% of the 541 pneumonia cases, involving 283 pathogens of which 38.6% were viruses and 12.6% bacteria. Viral and mixed etiologies were more frequent in children under 12 months of age. Bacteria predominated in ages between 6 and 23 months. Among the viruses, respiratory syncytial virus predominated (66%). The bacterial pneumonias accounted for 12.2% of the recognized etiologies. The most important bacterial agents were S. pneumoniae (64%) and H. influenzae (19%). H. influenzae and mixed infections had a relevant participation during the 1988 season, pointing to annual variations in the relative participation of pathogens and its possible implication in severity of diseases. Correlation of severity and increased percentage of etiological diagnosis was assessed: patients with respiratory rates over 70 rpm, or pleural effusion and/or extensive pulmonary parenchyma compromise yielded higher positive laboratory results. Various individual and family risk factors were recognized when comparing pneumonia children with healthy controls.