Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day

BACKGROUND: Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES: These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS: We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS: Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION: A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL.

Comparison of selective and non selective cyclo-oxygenase 2 inhibitors in experimental colitis exacerbation: role of leukotriene B4 and superoxide dismutase

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

Avaliação do potencial efeito cicatrizante gástrico e antiartrítico da mangiferina, uma xantona glicosilada da Mangifera indica

Rheumatoid arthritis (RA) is a chronic illness with great potential to cause comorbidities resulting from cumulative inflammatory activities, and it contributes with the increase of disabilities and death of patients. It affects 1 to 2% of world population and usually occurs between 30 and 50 years of age. Among existing therapeutic options for the disease non-steroidal anti-inflammatory drugs (NSAIDs) still play an important part in the treatment, being widely used by patients to relieve pain and stiffness. However, this class of drugs causes many adverse gastrointestinal effects, such as dyspepsia, heartburn, nausea and vomit, and its use is one of the most common causes of peptic ulcers. Mangiferin (a glicosilated xanthone extracted mainly from the bark of Mangifera indica L.) is the main compound of an aqueous extract made from the bark stem of the mango tree. Previous studies conducted by our research group prove the anti-inflammatory action of mangiferin on an animal model of periodontitis, and its gastroprotective action has been described before. Considering these informations this study evaluated mangiferin’s potential on the treatment of RA and on gastric ulcer healing in animal models, and analyzed toxicity parameters to assure efficacy and safety of the compound as potential new drug for the treatment of the disease. RA was induced in rats by subcutaneous injection of bovine collagen and Freund’s complete adjuvant. This method presented low incidence of RA in rats, but we were able to induce the disease in 60 to 70% of the animals. Due to the wide use of NSAIDs and its potential to cause peptic ulcers, we induced gastric ulcer on arthritic rats to analyze mangiferin’s gastric healing effect. After 14 days of treatment we noticed small increase of the lesion area of animals treated with mangiferin or ibuprofen, when compared to the animals... (Complete abstract click electronic access below)

Síntese e caracterização do complexo de lantânio (III) e indometacina no estado sólido

In this study, the drug indomethacin, a non-steroidal anti-inflammatory indoleacetic acid derivative and the complex of indomethacin and lanthanum (III) in solid form were synthesized and characterized by Thermogravimetry (TGA), Differential Thermal Analysis (DTA), Differential Scanning Calorimetry (DSC) and powder X-ray diffractometry (XRD), infrared vibrational spectroscopy by diffuse reflectance (FTIR) and complexometric titration with EDTA. With the TG curves it was possible to determine the stoichiometry of the complex as La(Ind)3·3.5H2O where Ind is the drug indomethacin. The result of thermal analyzes provided information on the thermal stability, enthalpy of dehydration and thermal behavior of the compounds. The infrared spectrum and with the aid of theoretical calculations suggests that the indomethacin is coordinated by the carboxylate group in the bidentate mode

Obtenção e caracterização de nanopartículas lipídicas sólidas como sistema de transporte para ibuprofeno

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Síntese e caracterização de complexos de lantanídeos pesados e ítrio(III) como o fármaco ibuprofeno no estado sólido

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Muscle lesion treatment in Brazilian soccer players: theory vs. practice

Background: In this study we evaluated the rehabilitation profile of Brazilian soccer players which underwent lower limb muscle lesions. Methods: This is a descriptive investigation. We evaluated 139 professional soccer players (1724 years old). We evaluated the following variables: muscle lesion diagnosis, symptoms, non steroidal anti-inflammatory used, physiotherapy treatment, which physiotherapy recourses was used if treated and train adaptation. Results: In great part of the athletes muscle lesion remained between 2 weeks and 1 month. Around 54% were diagnosed by a physician; the other part was diagnosed by a physical therapist. Non steroidal anti-inflammatory were prescribed by physicians in 42% of the cases; in 7% the physical therapist prescribed the medication while in 49% of the cases the masseur prescribed the drug. More than 1/4 of the athletes received physiotherapy treatement between 48 hours and 5 days. Isometric exercise therapy was applied in 15% of the cases. 63% were not accompanied by the physiotherapist on their return to the field. 48% received massages immediately after injury. Conclusion: We presented discrepancy between the recommended theory described by several researches and the practice. We indicate the necessity of recycling in a general context the rehabilitation of muscle injuries.

Gamma-secretase modulators and inhibitors in Alzheimer's disease: influence of genetic background on efficacy and mechanism of action

According to the amyloid hypothesis, Alzheimer’s disease (AD) is caused by aberrant production or clearance of the amyloid-β (Aβ) peptides, and in particular of the longer more aggregation-prone Aβ42. The Aβ peptides are generated through successive proteolytic cleavage of the amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE) and γ-secretase. γ-secretase produces Aβ peptides with variable C-termini ranging from Aβ34 to Aβ48, presumably by sequential trimming of longer into shorter peptides. γ-secretase is a multiprotein complex consisting of at least four different proteins and the presenilin proteins (PS1 or PS2) contain the catalytic center of the complex. In 2001 several non-steroidal anti-inflammatory drugs were identified as the founding members of a new class of γ-secretase modulators (GSMs) that can selectively reduce production of Aβ42. Concomitantly, these GSMs increase Aβ38 production indicating closely coordinated generation of Aβ42 and Aβ38 and a potential precursor-product relationship between these peptides. GSMs seem to exert their activity by direct modulation of γ-secretase. Support for this hypothesis is drawn from the finding that some PS mutations associated with early-onset familial AD (FAD) can modulate the cellular response to GSMs and to γ-secretase inhibitors (GSIs), which inhibit production of all Aβ peptides and are known to directly interact with PS. A particularly interesting FAD PS mutation is PS1-ΔExon9, a complex deletion mutant that blocks endoproteolysis of PS1 and renders cells completely non-responsive to GSMs. Studies presented in this thesis show that the diminished response of PS1-ΔExon9 to GSMs is mainly caused by its lack of endoproteolytic cleavage. Furthermore, we were able to demonstrate that a reduced response to GSMs and GSIs is not limited to PS1-ΔExon9 but is a common effect of aggressive FAD-associated PS1 mutations. Surprisingly, we also found that while the Aβ42 response to GSMs is almost completely abolished by these PS1 mutations, the accompanying Aβ38 increase was indistinguishable to wild-type PS1. Finally, the reduced response to GSIs was confirmed in a mouse model with transgenic expression of an aggressive FAD-associated PS1 mutation as a highly potent GSI failed to reduce Aβ42 levels in brain of these mice. Taken together, our findings provide clear evidence for independent generation of Aβ42 and Aβ38 peptides, and argue that the sequential cleavage model might be an oversimplification of the molecular mechanism of γ-secretase. Most importantly, our results highlight the significance of genetic background in drug discovery efforts aimed at γ-secretase, and indicate that the use of cellular models with transgenic expression of FAD-associated PS mutations might confound studies of the potency and efficacy of GSMs and GSIs. Therefore, such models should be strictly avoided in the ongoing preclinical development of these promising and potentially disease-modifying therapeutics for AD.

Risk of serious NSAID-related gastrointestinal events during long-term exposure: a systematic review

Objective: Exposure to non-steroidal anti-inflammatory drugs (NSAIDs) is associated wit increased risk of serious gastrointestinal (GI) events compared with non-exposure. We investigated whether that risk is sustained over time. Data sources: Cochrane Controlled Trials Register (to 2002); MEDLINE, EMBASE, Derwent Drug File and Current Contents (1999-2002); manual searching of reviews (1999-2002). Study selection: From 479 search results reviewed and 221 articles retrieved, seven studies of patients exposed to prescription non-selective NSAIDs for more than 6 months and reporting time-dependent serious GI event rates were selected for quantitative data synthesis. These were stratified into two groups by study design. Data extraction: Incidence of GI events and number of patients at specific time points were extracted. Data synthesis: Meta-regression analyses were performed. Change in risk was evaluated by testing whether the slope of the regression line declined over time. Four randomised controlled trials (RCTs) provided evaluable data from five NSAID arms (aspirin, naproxen, two ibuprofen arms, and diclofenac). When the RCT data were combined, a small significant decline in annualised risk was seen: -0.005% (95% Cl, -0.008% to -0.001%) per month. Sensitivity analyses were conducted because there was disparity within the RCT data. The pooled estimate from three cohort studies showed no significant decline in annualised risk over periods up to 2 years: -0.003% (95% Cl, -0.008% to 0.003%) per month. Conclusions: Small decreases in risk over time were observed; these were of negligible clinical importance. For patients who need long-term (> 6 months) treatment, precautionary measures should be considered to reduce the net probability of serious GI events over the anticipated treatment duration. The effect of intermittent versus regular daily therapy on long-term risk needs further investigation.

Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Ionic and neutral hydrogels for dermal and ophthalmic applications

This thesis is concerned with the use of ionic and neutral hydrogels in dermal and ocular applications with particular reference to controlled release applications. The work consists of three interconnected themes.The first area of study is the use of skin adhesive bioelectrode hydrogels as ground plate electrodes for ophthalmic iontophoresis applications. The work provides a basis of understanding the relative contributions made by ionic monomers (such as sodium s-(acrylamide)-2-methyl propane sulphonate and acrylic acid-bis-(3-sulfopropyl-ester, potassium salt) and neutral monomers (such as acryloymorpholine, N,N-dimethylacrylamide and N-vinyl pyrrolidone) to adhesion, rheology and impedance of bioelectrode gels. The general advantage of neutral monomers, which have been used to successfully replace ionic monomers, is that they enable more effective control of independent anion and cation species (for example potassium chloride and sodium chloride) unlike ionic monomers where polymerisation produces an immobile polyanion thus limiting cation mobility. Secondly, release from a completely neutral hydrogel under the influence of mechanical shaking was studied for the case of crosslinked polyvinyl alcohol (PVA) containing low concentration of linear soluble PVA in a contact lens application. The soluble PVA was observed to be eluting by reptation from the lens matrix due to the mechanical action of the eyelid. This process was studied in an in vitro model, which in this research was used as a basis for developing a lens made with enhanced release polymer. The third area of work is related to the factors that control drug release (in particular non-steroidal anti-inflammatory drugs) from a hydrogel matrix. This links both electrotherapy applications, such as transcutaneous electrical nerve stimulation, in which the passive diffusion from the gel could be used in conjunction with enhanced transmission across the dermal surface with passive diffusion from a contact lens matrix and the development of therapeutic contact lenses.

High permeability of the anionic form restricts accumulation of indomethacin by cultured gastric surface epithelial cells exposed to low apical pH

The 'ion-trapping' hypothesis suggests that the intracellular concentration of acidic non-steroidal anti-inflammatory drugs in gastric epithelial cells could be much higher than in the gastric lumen, and that such accumulation could contribute to their gastrotoxicity. Our aim was to examine the effect of the pH of the apical medium on the apical to basal transfer of the acidic drug indomethacin (pK a 4.5) across a gastric mucous epithelial cell monolayer, and to determine whether indomethacin accumulated in cells exposed to a low apical pH. Guinea-pig gastric mucous epithelial cells were grown on porous membrane culture inserts (Transwells®) for 72 h. Transfer and accumulation of [ 14C] indomethacin were assessed by scintillation counting. Transfer of [ 3H]mannitol and measurement of trans-epithelial electrical resistance were used to assess integrity of the monolayer. Distribution of [ 14C] urea was used to estimate the intracellular volume of the monolayer. The monolayer was not disrupted by exposure of the apical face to media of pH ≥ 3, or by indomethacin. Transfer of indomethacin (12 μM) to the basal medium increased with decreasing apical medium pH. The apparent permeability of the undissociated acid was estimated to be five times that of the anion. The intracellular concentration of indomethacin was respectively 5.3, 4.1 and 4.3 times that in the apical medium at pH 5.5, 4.5 and 3.0. In conclusion, this study represents the first direct demonstration that indomethacin accumulates in gastric epithelial cells exposed to low apical pH. However, accumulation of indomethacin was moderate and the predictions of the ion-trapping hypothesis were not met, probably due to the substantial permeability of anionic indomethacin across membranes. © 2006 Elsevier B.V. All rights reserved.

Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo

Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.

Beers versus STOPP criteria in polyharmacy community-dwelling older patients

Objective: To assess potentially inappropriate prescribing (PIP) using Beers (2012 version) and STOPP (2008 version) criteria in polypharmacy, community-dwelling, older patients. Methods: From the information collected in the invoicing data of the prescriptions and the electronic medical records, a sample was selected of 223 ≥ 65-year-old patients who were taking simultaneously 10 or more drugs per day. Beers and STOPP criteria were separately applied, and the results obtained with the two methods were compared. Results: A total of 141 (63.2%) patients presented at least one Beers criterion. The two most frequently observed Beers criteria independent of diagnosis were the use of benzodiazepines and the use of non-COX-2-selective non-steroidal anti-inflammatory drugs. With regard to Beers criteria considering diagnosis, the most frequent were the use of anticholinergic drugs in patients with lower urinary tract symptoms or benign prostatic hyperplasia, and the use of benzodiazepines, antipsychotics, Zolpidem or H2-antihistamines, in patients with dementia or cognitive impairment. A total of 165 (73.9%) patients had at least one PIP according to the STOPP criteria. Duplicate drug classes and long-term use of long-acting benzodiazepines were the two most frequent STOPP criteria. Discussion: Our study identified a high frequency of PIP in poly-medicated community-dwelling older patients. Simultaneous application of Beers and STOPP criteria represents a useful tool to improve prescribing in this population group.

A systematic review of axillary web syndrome (AWS)

Introduction Axillary web syndrome (AWS) can result in early post-operative and long-term difficulties following lymphadenectomy for cancer and should be recognised by clinicians. This systematic review was conducted to synthesise information on AWS clinical presentation and diagnosis, frequency, natural progression, grading, pathoaetiology, risk factors, symptoms, interventions and outcomes. Methods Electronic searches were conducted using Cochrane, Pubmed, MEDLINE, CINAHL, EMBASE, AMED, PEDro and Google Scholar until June 2013. The methodological quality of included studies was determined using the Downs and Black checklist. Narrative synthesis of results was undertaken. Results Thirty-seven studies with methodological quality scores ranging from 11 to 26 on a 28-point scale were included. AWS diagnosis relies on inspection and palpation; grading has not been validated. AWS frequency was reported in up to 85.4 % of patients. Biopsies identified venous and lymphatic pathoaetiology with five studies suggesting lymphatic involvement. Twenty-one studies reported AWS occurrence within eight post-operative weeks, but late occurrence of greater than 3 months is possible. Pain was commonly reported with shoulder abduction more restricted than flexion. AWS symptoms usually resolve within 3 months but may persist. Risk factors may include extensiveness of surgery, younger age, lower body mass index, ethnicity and healing complications. Low-quality studies suggest that conservative approaches including analgesics, non-steroidal anti-inflammatory drugs and/or physiotherapy may be safe and effective for early symptom reduction. Conclusions AWS appears common. Current evidence for the treatment of AWS is insufficient to provide clear guidance for clinical practice. Implications for Cancer Survivors Cancer survivors should be informed about AWS. Further investigation is needed into pathoaetiology, long-term outcomes and to determine effective treatment using standardised outcomes.