Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor® (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

Economic impact of a rotavirus vaccine in Brazil

The study was done to evaluate the cost-effectiveness of a national rotavirus vaccination programme in Brazilian children from the healthcare system perspective. A hypothetical annual birth-cohort was followed for a five-year period. Published and national administrative data were incorporated into a model to quantify the consequences of vaccination versus no vaccination. Main outcome measures included the reduction in disease burden, lives saved, and disability-adjusted life-years (DALYs) averted. A rotavirus vaccination programme in Brazil would prevent an estimated 1,804 deaths associated with gastroenteritis due to rotavirus, 91,127 hospitalizations, and 550,198 outpatient visits. Vaccination is likely to reduce 76% of the overall healthcare burden of rotavirus-associated gastroenteritis in Brazil. At a vaccine price of US$ 7-8 per dose, the cost-effectiveness ratio would be US$ 643 per DALY averted. Rotavirus vaccination can reduce the burden of gastroenteritis due to rotavirus at a reasonable cost-effectiveness ratio.

Efficacy of sweet solutions for analgesia in infants between 1 and 12 months of age: a systematic review

Objective To compare the efficacy of oral sweet solutions to water or no treatment in infants aged 1-12 months during immunisation. Methods Randomised controlled trials (RCTs) were retrieved through internet searches or manual searches of reference lists. Search terms included newborn, infant, pain, sucrose and alternative names for sweet solutions. Summary estimates with 95% CIs were calculated and included relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, and weighted mean differences (WMD) for continuous outcomes. Where pooling of results was not possible, a narrative summary of study results is presented. Results Of the 695 studies identified, 14 RCTs with 1674 injections met the inclusion criteria. Sucrose or glucose, compared to water or no treatment decreased crying during or following immunisation in 13 of the 14 studies. Infants receiving 30% glucose (three trials, 243 infants) had a decreased RR in crying incidence following immunisation (typical RR 0.80, 95% CI 0.69 to 0.93; RD -0.17, 95% CI -0.29 to -0.05; NNTB 6, 95% CI 3 to 20). With sucrose or glucose, there was a 10% WMD reduction in proportion of crying time (95% CI - 18 to - 2) and a 12 s reduction in crying duration (95% CI - 23 to -0.7 s). An optimal dose of sucrose or glucose could not be ascertained due to the varied volumes and concentrations used. Conclusion Infants aged 1-12 months administered sucrose or glucose before immunisation had moderately reduced incidence and duration of crying. Healthcare professionals should consider using sucrose or glucose before and during immunisation.

Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A > G Variant Is Determinant of Increased Atorvastatin Response

Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot (R) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan (R) Real-time PCR. Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%: 1.3-8.0, p < 0.05). Conclusion: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.

Electrochemical Reduction Using Glassy Carbon Electrode in Aqueous Medium of a Potential Anti-Chagas Drug: NFOH

Nitrofurazone (NF) presents activity against Chagas' disease, yet it has a high toxicity. Its analog, hydroxymethylnitrofurazone (NFOH), is more potent against Trypanosoma cruzi and much less toxic than the parent drug, NF. The electrochemical reduction of NFOH in an aqueous medium using a glassy carbon electrode (GCE) is presented. By cyclic voltammetry in anacidic medium, one irreversible reduction peak related to hydroxylamine derivative formation was registered, being linearly pH dependent. However, from pH > 7, a reversible reduction peak at a more positive potential appears and corresponds to the formation of a nitro radical anion. The radical-anion kinetic stability was evaluated by Ip(a)/Ip(c) the current ratio of the R-NO(2)/R-NO(2)-redox couple. The nitro radical anion decays with a second-order rate constant (k(2)) of 6.07, 2.06, and 1.44(X 10(3)) L mol(-1) s(-1) corresponding to pH 8.29, 9.29, and 10.2, respectively, with a corresponding half-time life (t(1/2)) of 0.33, 0.97, and 1.4 s for each pH value. By polishing the GCE surface with diamond powder and comparing with the GCE surface polished with alumina, it is shown that the presence of alumina affects the lifetime of the nitro radical anion. (C) 2009 The Electrochemical Society. [DOI: 10.1149/1.3130082] All rights reserved.

Selectivity in reduction of natural furanoheliangolides with Stryker's reagent

Reduction of the natural sesquiterpene lactones furanoheliangolides with Stryker's reagent is an effective process for producing eremantholides through a biomimetic pathway. Other reduction products are also formed. Oxygenated functions at C-15 of the furanoheliangolide produce an increase in the velocities of the reactions and reduce the chemoselectivity of the reagent.

The inducing NO-vasodilation by chemical reduction of coordinated nitrite ion in cis-[Ru(NO(2))L(bpy)(2)](+) complex

The synthesis of [Ru(NO(2)) L(bpy)(2)](+) (bpy = 2,2'-bipyridine and L = pyridine (py) and pyrazine (pz)) can be accomplished by addition of [Ru(NO) L(bpy) 2](PF(6))(3) to aqueous solutions of physiological pH. The electrochemical processes of [Ru(NO2) L(bpy) 2]+ in aqueous solution were studied by cyclic voltammetry and differential pulse voltammetry. The anodic scan shows a peak around 1.00 V vs. Ag/AgCl attributed to the oxidation process centered on the metal ion. However, in the cathodic scan a second peak around-0.60 V vs. Ag/AgCl was observed and attributed to the reduction process centered on the nitrite ligand. The controlled reduction potential electrolysis at-0.80 V vs. Ag/AgCl shows NO release characteristics as judged by NO measurement with a NO-sensor. This assumption was confirmed by ESI/MS(+) and spectroelectrochemical experiment where cis-[Ru(bpy)(2)L(H(2)O)](2+) was obtained as a product of the reduction of cis-[Ru(II)(NO(2)) L(bpy)(2)](+). The vasorelaxation observed in denuded aortic rings pre-contracted with 0.1 mu mol L(-1) phenylephrine responded with relaxation in the presence of cis-[RuII(NO2) L(bpy) 2]+. The potential of rat aorta cells to metabolize cis-[RuII(NO(2)) L(bpy)(2)](+) was also followed by confocal analysis. The obtained results suggest that NO release happens by reduction of cis-[RuII(NO(2)) L(bpy)(2)](+) inside the cell. The maximum vasorelaxation was achieved with 1 x 10(-5) mol L(-1) of cis-[RuII(NO(2)) L(bpy)(2)](+) complex.

Protection against tuberculosis by a single intranasal administration of DNA-hsp65 vaccine complexed with cationic liposomes

Background: The greatest challenges in vaccine development include optimization of DNA vaccines for use in humans, creation of effective single-dose vaccines, development of delivery systems that do not involve live viruses, and the identification of effective new adjuvants. Herein, we describe a novel, simple technique for efficiently vaccinating mice against tuberculosis (TB). Our technique consists of a single-dose, genetic vaccine formulation of DNA-hsp65 complexed with cationic liposomes and administered intranasally. Results: We developed a novel and non-toxic formulation of cationic liposomes, in which the DNA-hsp65 vaccine was entrapped (ENTR-hsp65) or complexed (COMP-hsp65), and used to immunize mice by intramuscular or intranasal routes. Although both liposome formulations induced a typical Th1 pattern of immune response, the intramuscular route of delivery did not reduce the number of bacilli. However, a single intranasal immunization with COMP-hsp65, carrying as few as 25 mu g of plasmid DNA, leads to a remarkable reduction of the amount of bacilli in lungs. These effects were accompanied by increasing levels of IFN-gamma and lung parenchyma preservation, results similar to those found in mice vaccinated intramuscularly four times with naked DNA-hsp65 (total of 400 mu g). Conclusion: Our objective was to overcome the significant obstacles currently facing DNA vaccine development. Our results in the mouse TB model showed that a single intranasal dose of COMP-hsp65 elicited a cellular immune response that was as strong as that induced by four intramuscular doses of naked-DNA. This formulation allowed a 16-fold reduction in the amount of DNA administered. Moreover, we demonstrated that this vaccine is safe, biocompatible, stable, and easily manufactured at a low cost. We believe that this strategy can be applied to human vaccines to TB in a single dose or in prime-boost protocols, leading to a tremendous impact on the control of this infectious disease.

Antidepressant activity evaluation of Hypericum brasiliense standardized extract

Hypericum brasiliense (Hypericaceae) is a Brazilian traditional plant used as an excitant, antispasmodic and antiofidic agent in the South and Southeastern areas. Pharmacological studies were performed to evaluate antidepressant effects of standard extract of H. brasiliense (SEHB) alone or combined with fluoxetine (10 mg/kg i. p.), GBR-12909 (10 mg/kg ip) or Trans-2-phenylcyclopropylamine (5 mg/kg ip) using forced swimming test (FST), open field test (OFT) and rota rod assays. In the FST, SEHB reduced in a dose-dependent manner the immobility time, and has shown antagonistic effect when administrated with fluoxetine. In the OFT, SEHB has caused marginal effect of the evaluated parameters (ambulation and rearing), but when associated with fluoxetine or trans-2-phenylcyclopropylamine, the reduction of the parameters was noticed. On rota rod test, SEHB did not produce significant alteration. Based on results we suggest that SEHB has an antidepressant activity.

Clinical outcomes of long-acting injectable risperidone in patients with schizophrenia: six-month follow-up from the Electronic Schizophrenia Treatment Adherence Registry in Latin America

Background: Risperidone long-acting injection (RLAI) has been shown to be efficacious, improve compliance, and increase long-term retention rate on therapy. The aim of this work was to determine the effect of RLAI on clinical outcome and hospitalization rate in patients with schizophrenia or schizoaffective disorder enrolled in the electronic Schizophrenia Treatment Adherence Registry in Latin America. Methods: Data were collected at baseline, retrospectively for the 12 months prior to baseline, and prospectively every three months for 24 months. Hospitalization prior to therapy was assessed by a retrospective chart review. Efficacy and functioning were evaluated using Clinical Global Impression of Illness Severity (CGI-S), Personal and Social Performance (PSP), and Global Assessment of Functioning (GAF) scores. Relapse and treatment were also registered. Results: Patients were recruited in Mexico (n = 53), Brazil (n = 11), and Colombia (n = 15). Sixty-five percent (n = 52) were male, and mean age was 32.9 years. Patients were classified as having schizophrenia (n = 73) or schizoaffective disorder (n = 6). The mean dose of RLAI at six months was 34.1 mg (standard deviation = 10.2 mg). The percentage of hospitalized patients before treatment was 28.2% and 5.1% at six months after initiating RLAI (P < 0.001). Significant changes were registered on CGI-S, GAF, and PSP scores. Conclusions: RLAI was associated with an improvement in clinical symptoms and functioning, and a greater reduction in hospitalization.

Infliximab Induces Increase in Triglyceride Levels in Psoriatic Arthritis Patients

Objectives. To evaluate lipid profile changes after anti-TNF therapy in patients with psoriatic arthritis (PsA). Methods. Fifteen PsA patients (eight polyarticular, four oligoarticular, two axial, and one mutilating) under infliximab were included. None had dyslipoproteinemia or previous statin use. Total cholesterol (TC) and its fractions, inflammatory markers, and prednisone use were evaluated. Results. The comparisons of lipid levels between baseline and after three months (3M) of anti-TNF therapy showed that there was a significant increase in mean triglycerides (117.8 +/- 49.7 versus 140.1 +/- 64.1 mg/dL, P = 0.028) and VLDL-c (23.6 +/- 10.5 versus 28.4 +/- 13.7 mg/dL, P = 0.019) levels. In contrast, there were no differences in the mean TC (P = 0.28), LDL-c (P = 0.42), and HDL-c (P = 0.26) levels. Analysis of the frequencies of each lipid alteration at baseline and at 3M were alike (P > 0.05). Positive correlations were found between VLDL-c and CRP (r = 0.647, P = 0.009) and between triglycerides and CRP (r = 0.604, P = 0.017) levels at 3M. ESR reduction was observed after 3M (P = 0.04). Mean prednisone dose remained stable at beginning and at 3M (P = 0.37). Conclusion. This study demonstrated that anti-TNF may increase TG and VLDL-c levels in PsA patients after three months.

A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel/Prednisolone in Patients with Hormone-Refractory Prostate Cancer

Vandetanib (ZACTIMA(TM)) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection signaling. This randomized (1: 1), double-blind study evaluated vandetanib (100mg/day) or placebo in combination with docetaxel (D; 75mg/m(2) every 3 weeks) and prednisolone (P; 2 x 5 mg/day) in 86 patients with metastatic hormone-refractory prostate cancer (mHRPC). The primary assessment was prostate-specific antigen (PSA) response (confirmed reduction of >= 50% from baseline) and a greater number of patients showed a PSA response with placebo + DP (67%) versus vandetanib + DP (40%); hazard ratio = 2.23 (one-sided 80% confidence limit = 2.90; one-sided p = 0.99). More patients experienced progression events (disease progression or death from any cause) with vandetanib + DP (65%) versus placebo + DP (60%); hazard ratio = 1.13 (one-sided 80% confidence limit = 1.44; one-sided p = 0.67). The overall incidence of adverse events was similar in both groups, although more patients experienced adverse events, leading to permanent discontinuation with vandetanib + DP (28%) versus placebo + DP (12%). However, the safety and tolerability profile for vandetanib was similar to that previously reported; adverse events that occurred more frequently in the vandetanib + DP arm were hypertension (14% vs. 2%), erythematous rash (14% vs. 2%), and exfoliative rash (12% vs. 2%). In this study of patients with mHRPC, vandetanib + DP did not demonstrate any efficacy benefit, compared with placebo + DP.

Effects of high-dose creatine supplementation on kidney and liver responses in sedentary and exercised rats

This study evaluated the effects of high-dose of short-term creatine supplementation (5g.kg(-1). day(-1) to 1 week) and long-term creatine supplementation (1g.kg(-1). day(-1) to 4-8 weeks) on kidney and liver structure and function of sedentary and exercised Wistar rats ( Exercise sessions consisted of swimming at 80% of maximal work load supported during 5 days per week with daily sessions of 60 minutes throughout the duration of the supplementation). Seventy-two animals ( 245 +/- 5g) were divided into four groups (n = 18): control diet Sedentary ( SED), Creatine diet Sedentary (CRE), control diet Exercised (EXE), and Creatine diet Exercised (EXECRE). Histological and blood biochemical studies were performed after one, four, and eight weeks of creatine supplementation and exercise ( n = 6). No differences were found when comparing SED, EXE and EXECRE groups for kidney and liver structure and function at one, four and eight weeks. However, the CRE group showed higher levels of creatinine (1.1 +/- 0.2 vs. 0.4 +/- 0.1 mg.dl(-1); p < 0.05), and urea ( 37 +/- 3 vs. 19 +/- 1 mg. dl(-1); p < 0.05) when compared with all others groups at four and eight weeks. At eight weeks, the CRE group presented increased levels of ALT (41 +/- 7 vs. 23 +/- 7 U.L(-1); p < 0.05), AST (89 +/- 6 vs. 62 +/- 5 U. L(-1); p < 0.05), GGT (8.0 +/- 0.9 vs. 3.9 +/- 1.0 U. L(-1); p < 0.05), and AP (125 +/- 10 vs. 69 +/- 9 U. L(-1); p < 0.05) also when compared with all others groups. Moreover, the CRE group demonstrated some structural alterations indicating renal and hepatic damage at four and eight weeks, respectively. These results suggest that long-term creatine supplementation (up to 4-8 weeks) may adversely affect kidney and liver structure and function of sedentary but not of exercised rats.

Schistosomicidal Activity of the Essential Oil of Ageratum conyzoides L. (Asteraceae) against Adult Schistosoma mansoni Worms

The in vitro schistosomicidal effects of the essential oil of Ageratum conyzoides L. (Ac-EO) against adult worms of Schistosoma mansoni is reported in this paper. Concerning this activity, Ac-EO was considered to be active, but less effective than the positive control (praziquantel, PZQ) in terms of separation of coupled pairs, mortality, decrease in motor activity, and tegumental alterations. However, Ac-EO caused an interesting dose-dependent reduction in the number of eggs of S. mansoni. Precocene I (74.30%) and (E)-caryophyllene (14.23%) were identified as the two major constituents of Ac-EO. These compounds were tested individually and were found to be much less effective than Ac-EO and PZQ. A mixture of the two major compounds in a ratio similar to that found in the Ac-EO was also less effective than Ac-EO, thus revealing that there are no synergistic effects between these components. These results suggest that the essential oil of A. conyzoides is very promising for the development of new schistosomicidal agents.

Determination of Threshold Dose of Photodynamic Therapy to Measure Superficial Necrosis

Background Data: Photodynamic therapy (PDT) involves the photoinduction of cytotoxicity using a photosensitizer agent, a light source of the proper wavelength, and the presence of molecular oxygen. A model for tissue response to PDT based on the photodynamic threshold dose (Dth) has been widely used. In this model cells exposed to doses below Dth survive while at doses above the Dth necrosis takes place. Objective: This study evaluated the light Dth values by using two different methods of determination. One model concerns the depth of necrosis and the other the width of superficial necrosis. Materials and Methods: Using normal rat liver we investigated the depth and width of necrosis induced by PDT when a laser with a gaussian intensity profile is used. Different light doses, photosensitizers (Photogem, Photofrin, Photosan, Foscan, Photodithazine, and Radachlorin), and concentrations were employed. Each experiment was performed on five animals and the average and standard deviations were calculated. Results: A simple depth and width of necrosis model analysis allows us to determine the threshold dose by measuring both depth and surface data. Comparison shows that both measurements provide the same value within the degree of experimental error. Conclusion: This work demonstrates that by knowing the extent of the superficial necrotic area of a target tissue irradiated by a gaussian light beam, it is possible to estimate the threshold dose. This technique may find application where the determination of Dth must be done without cutting the tissue.