Computer-aided Drug Design of Novel PLA(2) Inhibitor Candidates for Treatment of Snakebite

Phospholipases A(2) (PLA(2)) are enzymes commonly found in snake venoms from Viperidae and Elaphidae families, which are major components thereof. Many plants are used in traditional medicine its active agents against various effects induced by snakebite. This article presents the PLA(2) BthTX-I structure prediction based on homology modeling. In addition, we have performed virtual screening in a large database yielding a set of potential bioactive inhibitors. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. We have performed molecular interaction fields (MIFs) calculations with the phospholipase model. Results confirm the important role of Lys49 for binding ligands and suggest three additional residues as well. We have proposed a theoretically nontoxic, drug-like, and potential novel BthTX-I inhibitor. These calculations have been used to guide the design of novel phospholipase inhibitors as potential lead compounds that may be optimized for future treatment of snakebite victims as well as other human diseases in which PLA(2) enzymes are involved.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

alpha-Arylation and Alkynylation of Cyclic alpha-Iodoenones Using Palladium-Catalyzed Cross-Coupling Reactions with Trifluoroborate Salts

An expeditious synthesis of alpha-aryl- and alpha-alkynylcyclo-hexenones is described and illustrated by palladium-catalyzed cross-coupling reaction of cyclic alpha-iodoenones with potassium aryltrifluoroborate salts. This procedure offers easy access to alpha-arylated and alkynylated cyclohexenones functionalized with electrondonor and -acceptor substituents in good yields.

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound. (c) 2009 Elsevier B.V. All rights reserved.

Analysis of Liquid Crystalline Nanoparticles by Small Angle X-Ray Diffraction: Evaluation of Drug and Pharmaceutical Additives Influence on the Internal Structure

The goal of this work was to study the liquid crystalline structure of a nanodispersion delivery system intended to be used in photodynamic therapy after loading with photosensitizers (PSs) and additives such as preservatives and thickening polymers. Polarized light microscopy and light scattering were performed on a standard nanodispersion in order to determine the anisotropy of the liquid crystalline structure and the mean diameter of the nanoparticles, respectively. Small angle X-ray diffraction (SAXRD) was used to verify the influence of drug loading and additives on the liquid crystalline structure of the nanodispersions. The samples, before and after the addition of PSs and additives, were stable over 90 days, as verified by dynamic light scattering. SAXRD revealed that despite the alteration observed in some of the samples analyzed in the presence of photosensitizing drugs and additives, the hexagonal phase still remained in the crystalline phase. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100: 2849-2857, 2011

Cyclic Guanosine Monophosphate Signaling Cascade Mediates Pigment Aggregation in Freshwater Shrimp Chromatophores

The cell signaling cascades that mediate pigment movements in crustacean chromatophores are not yet well established, although Ca(2+) and cyclic nucleotide second messengers are involved. Here, we examine the participation of cyclic guanosine monophosphate (cGMP) in pigment aggregation triggered by red pigment concentrating hormone (RPCH) in the red ovarian chromatophores of freshwater shrimp. In Ca(2+)-containing (5.5 mmol l(-1)) saline, 10 mu mol l(-1) dibutyryl cGMP alone produced complete pigment aggregation with the same time course (approximate to 20 min) and peak velocity (approximate to 17 mu m/min) as 10(-8) mol l(-1) RPCH; however, in Ca(2+)-free saline (9 X 10(-11) mol l(-1) Ca(2+)), db-cGMP was without effect. The soluble guanylyl cyclase (GC-S) activators sodium nitroprusside (SNP, 0.5 mu mol l(-1)) and 3-morpholinosydnonimine (SIN-1, 100 mu mol l(-1)) induced moderate aggregation by themselves (approximate to 35%-40%) but did not affect RPCH-triggered aggregation. The GC-S inhibitors zinc protoporphyrin IX (ZnPP-XI, 30 mu mol l(-1)) and 6-anilino-5,8-quinolinedione (LY83583, 10 mu mol l(-1)) partially inhibited RPCH-triggered aggregation by approximate to 35%. Escherichia coli heat-stable enterotoxin (STa, 1 mu mol l(-1)), a membrane-receptor guanylyl cyclase stimulator, did not induce or affect RPCH-triggered aggregation. We propose that the binding of RPCH to an unknown membrane-receptor type activates a Ca(2+)-dependent signaling cascade coupled via cytosolic guanylyl cyclase and cGMP to protein kinase G-phosphorylated proteins that regulate aggregation-associated, cytoskeletal molecular motor activity. This is a further example of a cGMP signaling cascade mediating the effect of a crustacean X-organ neurosecretory peptide.

Recognition of cyclic, acyclic, exocyclic, and spiro Acetals via structurally diagnostic ion/molecule reactions with the (CH3)(2)N-C+=O acylium ion

Reactions of the model acylium ion (CH3)(2)N-C+=O with acyclic, exocyclic, and Spiro acetals of the general formula (RO)-O-1-(CRR4)-R-3-OR2-upole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [(RO-)-O-1 and (RO-)-O-2] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R-3 or R-4 substituents and (b) OH- abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.

PHBHV/PCL microspheres as biodegradable drug delivery systems (DDS) for photodynamic therapy (PDT)

Unloaded microspheres were prepared from polyhydroxybutyrate-co-valerate (PHBHV) and poly(epsilon-caprolactone) (PCL) polymers using the emulsification-solvent evaporation method (EE). The study was conducted to determine the ideal polymeric composition and ideal molecular weight for the microspheres preparation to be used as a Drug Delivery System (DDS) for cancer therapy. In this work, NzPC, a new photosensitizer, has been investigated when incorporated into microspheres of PHBHV/PCL evaluating its application for Photodynamic Therapy (PDT) of neoplastic tissue. The biodegradation studies were conducted to analyze the effects of the incorporation of the NzPC and also to determine the release profiles in vitro condition. We also evaluated the dark toxicity and the photobiological effect of the PHBHV-PCL microspheres in cutaneous melanoma cell line (B-16-A1) used as a biological neoplastic medium.

Randomized Evaluation of Two Drug-Eluting Stents With Identical Metallic Platform and Biodegradable Polymer But Different Agents (Paclitaxel or Sirolimus) Compared Against Bare Stents: 1-Year Results of the PAINT Trial

Objectives: We tested two novel drug-eluting stents (DES), covered with a biodegradable-polymer carrier and releasing paclitaxel or sirolimus, which were compared against a bare metal stent (primary objective). The DES differed by the drug, but were identical otherwise, allowing to compare the anti-restenosis effects of sirolimus versus paclitaxel (secondary objective). Background: The efficacy of novel DES with biodegradable polymers should be tested in the context of randomized trials, even when using drugs known to be effective, such as sirolimus and paclitaxel. Methods: Overall, 274 patients with de novo coronary lesions in native vessels scheduled for stent implantation were randomly assigned (2:21 ratio) for the paclitaxel (n = 111), sirolimus (n = 106), or bare metal stent (n = 57) groups. Angiographic follow-up was obtained at 9 months and major cardiac adverse events up to 12 months. Results: Both paclitaxel and sirolimus stents reduced the 9-month in-stent late loss (0.54-0.44 mm, 0.32-0.43 mm, vs. 0.90-0.45 mm respectively), and 1-year risk of target vessel revascularization and combined major adverse cardiac events (P < 0.05 for both, in all comparisons), compared with controls. Sirolimus stents had lower late loss than paclitaxel stents (P < 0.01), but similar 1-year clinical outcomes. There were no differences in the risk of death, infarction, or stent thrombosis among the study groups. Conclusion: Both novel DES were effective in reducing neointimal hyperplasia and 1-year re-intervention, compared to bare metal stents. Our findings also suggest that sirolimus is more effective than paclitaxel in reducing angiographic neointima, although this effect was not associated with better clinical outcomes. (C) 2009 Wiley-Liss, Inc.

Psychosocial pathways to inconsistent condom use among male sex workers: personality, drug misuse and criminality

Background: This research compared street male sex workers in Santo Andre, Brazil, that reported consistent condom use with those that revealed inconsistent condom use with their clients, concerning personality aspects, impulsiveness, alcohol and drug consumption, depressive symptoms, sociodemographic data and criminal involvement. Methods: Eighty-six male sex workers were evaluated in face-to-face interviews at their place of work. A `snowball` sampling procedure was used to access this hard-to-reach population. Findings: Male sex workers with inconsistent condom use showed greater involvement with criminal activities, higher reward dependence level and more frequent self-report of being HIV-positive. Conclusions: Conceptualisation of male sex workers` psychological characteristics may be required where HIV risk is not only attributed to sex work per se, but to other aspects such as personality-related factors and negative identity.

Cost analysis of drug therapy in rheumatoid arthritis

With the aim to compare the cost of treatment for rheumatoid arthritis therapy with desease-modifying antirheumatic drugs (DMARDS) for a 48-month period, were studied five different treatment stage based on clinical protocols recommended by the Brazilian Society of Rheumatology, and then five therapy cycles. The analytical model based on the Markov Analysis, considered chaces for the patient continue in some stages or change between them according with a positive effect on outcomes. Only direct costs were comprised in the analyzed data, like drugs, materials and tests used for monitoring these patients. The results of the model show that the stage in with metotrexato drug is used like monotherapy was cost-effective (R$ 113,900,00 for patient during 48 months), followed by refractory patient (R$ 1,554,483,43), those that use therapy triplicate followed by infleximable drug (R$ 1, 701, 286.76), the metotrexato intolearant patient (R$ 2,629,919,14), and final the result from that use metotrexato and infliximable in the beginning (R$ 9,292,879,31). The sensitivity analysis confirm this results, when alternate the efficacy of metotrexato and infliximabe.

Outcomes and safety of drug provocation tests

Drug provocation tests (DPTs) are considered the gold standard for identifying adverse drug reactions (ADRs). The aim of this study was to analyze DPT results and discuss severe systemic reactions associated with them. This was a retrospective analysis of 500 patients with ADRs who sought treatment and were submitted to DPTs when indicated between 2006 and 2010. We performed DPTs according to the European Network for Drug Allergy recommendations. Single-blind, placebo-controlled DPTs were performed with antibiotics, local anesthetics, and nonsteroidal anti-inflammatory drugs, as well as with other drugs. Patient characteristics, DPT results, and reactions were analyzed. The sample comprised 198 patients (80.8% of whom were female patients) submitted to 243 DPTs. Ages ranged from 9 to 84 years (mean, 39.9 years). The 243 DPTs were performed with local anesthetics (n = 93), antibiotics (n = 19), acetaminophen (n = 44), benzydamine (n = 33), COX-2 inhibitors (n = 26), dipyrone (n = 7), aspirin (n = 4), or other drugs (n = 17). The results of 4 tests (1.6%) were inconclusive, whereas those of 10 (4.1%) revealed positive reactions to antibiotics (2/19), COX-2 inhibitors (2/26), acetaminophen (3/44), and local anesthetics (3/93). Two severe reactions were observed: cephalexin-induced anaphylactic shock and bupivacaine-induced anaphylaxis without shock. Four patients (2.0%) reacted to the placebo before administration of the drug. Drug provocation tests are safe for use in clinical practice but they should be placebo-controlled and should be performed under the supervision of an allergist. To confirm a presumptive diagnosis and to manage allergies appropriately, it is crucial to perform DPTs. (Allergy Asthma Proc 32:301-306, 2011; doi: 10.2500/aap.2011.32.3450)

Antiretroviral Drug Resistance in a Respondent-Driven Sample of HIV-Infected Men Who Have Sex With Men in Brazil

Background: There are few studies on HIV subtypes and primary and secondary antiretroviral drug resistance (ADR) in community-recruited samples in Brazil. We analyzed HIV clade diversity and prevalence of mutations associated with ADR in men who have sex with men in all five regions of Brazil. Methods: Using respondent-driven sampling, we recruited 3515 men who have sex with men in nine cities: 299 (9.5%) were HIV-positive; 143 subjects had adequate genotyping and epidemiologic data. Forty-four (30.8%) subjects were antiretroviral therapy-experienced (AE) and 99 (69.2%) antiretroviral therapy-naive (AN). We sequenced the reverse transcriptase and protease regions of the virus and analyzed them for drug resistant mutations using World Health Organization guidelines. Results: The most common subtypes were B (81.8%), C (7.7%), and recombinant forms (6.9%). The overall prevalence of primary ADR resistance was 21.4% (i.e. among the AN) and secondary ADR was 35.8% (i.e. among the AE). The prevalence of resistance to protease inhibitors was 3.9% (AN) and 4.4% (AE); to nucleoside reverse transcriptase inhibitors 15.0% (AN) and 31.0% (AE) and to nonnucleoside reverse transcriptase inhibitors 5.5% (AN) and 13.2% (AE). The most common resistance mutation for nucleoside reverse transcriptase inhibitors was 184V (17 cases) and for nonnucleoside reverse transcriptase inhibitors 103N (16 cases). Conclusions: Our data suggest a high level of both primary and secondary ADR in men who have sex with men in Brazil. Additional studies are needed to identify the correlates and causes of antiretroviral therapy resistance to limit the development of resistance among those in care and the transmission of resistant strains in the wider epidemic.

Alcohol and drug consumption among sexual offenders

Purpose: To evaluate the role of alcohol and drug consumption between sexual offenders against boys and girls. Method: It was an observational, retrospective and cross-sectional study carried out by the Ambulatory for the treatment of sexual disorders of ABC Medical College, Santo Andre, Sao Paulo, Brazil (ABSex). The sample comprised 104 convicts, over 18 years old, sentenced only for sexual crimes against children (below 11 years old). Alcohol and drug consumption, sexual abuse history, sexual impulsivity, and risk of recidivism were evaluated. Results: The sexual offenders against boys showed higher alcohol consumption problems than sexual offenders against girls (chi(2) = 19.76, 1 d.f., p < 0.01). The severity of alcohol consumption was also significantly higher in the sexual offenders against non-related boys than in the sexual offenders against non-related girls (p = 0.037, ANOVA). After adjustment for other variables, such as monthly income before the penalty and alcohol consumption at the moment of the crime, the alcohol consumption severity in sexual offenders against boys was significantly higher than in sexual offenders against girls (OR = 1.05, CI 1.01-1.08, p < 0.01). Conclusions: Alcohol use or abuse is associated with the perpetration of sexual aggression. The role of alcohol consumption seems to be greater in sexual offenders against boys than in girls and this can contribute to criminal recidivism. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Drug consumption among sexual offenders against females

This article aims to evaluate the role of drug consumption among sexual offenders against females. Three groups of participants (N = 133) comprising sexual offenders against girls, pubertal females, and women were examined with reference to history of drug and/or alcohol use, impulsivity level, sexual addiction, and recidivism risk. Sexual offenders against women were found to have significantly more difficulties with drug use, higher impulsivity level, and to be younger than the sexual offenders against girls and pubertal females. The combination of drug consumption and higher level of impulsivity may contribute to sexual aggression against adult females.