Prodrugs for the treatment of neglected diseases

Recently, World Health Organization ( WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [ 3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas' disease ( American trypanosomiasis), sleeping sickness ( African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

Canine trypanosomiasis: etiology of infection and implications for public health

Canine trypanosomiasis, caused by protozoans of the genus Trypanosoma, is divided into two primary types: the American form (Chagas disease), due to Trypanosoma cruzi infection, and the African form (sleeping sickness or surra), provoked by Trypanosoma evansi. This disease was originally enzootic and affected only wild animals, including mammals and birds, which served as reservoirs. Later, it spread to domestic animals such as horses, cattle and dogs. The disease became a zoonosis when contact between rural inhabitants and natural Trypanosoma foci occurred, due to ecological imbalances and increasing migration. Dogs are significantly involved in this context, because they are the main domestic animals and participate in the transmission and maintenance cycles of these parasites. This article reports etiological, epidemiological and public health aspects of canine trypanosomiasis, and the most important peculiarities of this zoonosis in dogs.

Conformational analyses and docking studies of a series of 5-nitrofuran- and 5-nitrothiophen-semicarbazone derivatives in three possible binding sites of trypanothione and glutathione reductases

To explore three possible binding sites of trypanothione and glutathione reductase, namely, the active, the dimer interface and the coenzyme NADPH binding site, a series of eight compounds, nitrofurans and nitrothiophenes derivatives, were docked, using their crystallographic and modeled conformations. Docking results showed that, for both families and both enzymes, compounds are more likely to bind in the interface site, even though there is some probability of binding in the active site. These studies are in agreement with experimental data, which suggest that these class of compounds can act either as uncompetitive or mixed type inhibitors, and also with the finding that there is an alpha-helix which connects the active with the interface site, thus allowing charge transference between them. (c) 2005 Elsevier B.V. All rights reserved.

The lipid composition of a cell membrane modulates the interaction of an antiparasitic peptide at the air-water interface

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

Reação de trans-splicing in vitro utilizando extrato nuclear livre de células e sequencia parcial de alfa tubulina de Trypanosoma cruzi

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação do potencial tripanocida dos óleos essenciais de Melampodium divaricatum e Hedychium coronarium e dos extratos de Polygonum ferrugineum em cepas de Trypanosoma brucei

Pós-graduação em Biotecnologia - IQ

Avaliação do potencial tripanocida de diaminas, diaminas de ferroceno e derivados de 1,4-naftoquinonas em cepas de Trypanosoma brucei

Pós-graduação em Biotecnologia - IQ

Padronização da reação de trans-splicing in vitro em tripanosomas utilizando a técnica de RT-PCR

Pós-graduação em Biotecnologia - IQ

Synthesis and tripanocidal activity of ferrocenyl and benzyl diamines against Trypanosoma brucei and Trypanosoma cruzi

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

Temporal Analysis of Lipopolysaccharide-Induced Sickness Behavior in Virgin and Lactating Female Rats

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

Participation of α2 -adrenoceptors in sodium appetite inhibition during sickness behaviour following administration of lipopolysaccharide

Sickness behaviour, a syndrome characterized by a general reduction in animal activity, is part of the active-phase response to fight infection. Lipopolysaccharide (LPS), an effective endotoxin to model sickness behaviour, reduces thirst and sodium excretion, and increases neurohypophysial secretion. Here we review the effects of LPS on thirst and sodium appetite. Altered renal function and hydromineral fluid intake in response to LPS occur in the context of behavioural reorganization, which manifests itself as part of the syndrome. Recent data show that, in addition to its classical effect on thirst, non-septic doses of LPS injected intraperitoneally produce a preferential inhibition of intracellular thirst versus extracellular thirst. Moreover, LPS also reduced hypertonic NaCl intake in sodium-depleted rats that entered a sodium appetite test. Antagonism of α2 -adrenoceptors abolished the effect of LPS on sodium appetite. LPS and cytokine transduction potentially recruit brain noradrenaline and α2 -adrenoceptors to control sodium appetite and sickness behaviour.

Cellular and molecular characterization of an embryonic cell line (BME26) from the tick Rhipicephalus (Boophilus) microplus

The cellular and molecular characteristics of a cell line (BME26) derived from embryos of the cattle tick Rhipicephalus (Boophilus) microplus were studied. The cells contained glycogen inclusions, numerous mitochondria, and vesicles with heterogeneous electron densities dispersed throughout the cytoplasm. Vesicles contained lipids and sequestered palladium meso-porphyrin (Pd-mP) and rhodamine-hemoglobin, suggesting their involvement in the autophagic and endocytic pathways. The cells phagocytosed yeast and expressed genes encoding the antimicrobial peptides (microplusin and defensin). A cDNA library was made and 898 unique mRNA sequences were obtained. Among them, 556 sequences were not significantly similar to any sequence found in public databases. Annotation using Gene Ontology revealed transcripts related to several different functional classes. We identified transcripts involved in immune response such as ferritin, serine proteases, protease inhibitors,. antimicrobial peptides, heat shock protein, glutathione S-transferase, peroxidase, and NADPH oxidase. BME26 cells transfected with a plasmid carrying a red fluorescent protein reporter gene (DsRed2) transiently expressed DsRed2 for up to 5 weeks. We conclude that BME26 can be used to experimentally analyze diverse biological processes that occur in R. (B.) microplus such as the innate immune response to tick-borne pathogens. (C) 2008 Elsevier Ltd. All rights reserved.

Ascorbic acid supplementation has a cytoprotective effect on secondary biliary cirrhosis: experimental study in young rats

Objective: To test whether ascorbic acid supplementation has any cytoprotective effect on a model of secondary biliary cirrhosis in young rats.Methods: We studied 40 Wistar rats weaned at the 21st postnatal day. Each group of 10 was subjected to one of the following four treatments, until 49th postnatal day, when they suffered euthanasia: 1) LC-double ligature and resection of the common bile duct and daily administration of ascorbic acid [100 mg/g of body weight (bw)]; 2) LA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw); 3) SC-sham operation and daily administration of ascorbic acid (100 mg/g bw); 4) SA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw). The rats were weighed daily. on the 27th day after the operation they received an intra-peritoneal injection of 1.5 mg/g bw of sodium pentobarbital, and the pentobarbital sleeping time was measured. Blood was collected for serum alanine aminotransferase and aspartate aminotransferase activity measurements, serum albumin and globulin concentrations, and the liver was assessed for liver water and fat content. Data were submitted to two-way ANOVA and paired comparisons between groups were tested using the SNK method. Significance level was set at 0.05.Results: Ascorbic acid supplementation attenuated the effects of cholestasis: decreased the pentobarbital sleeping time, serum globulin, and the liver fat content.Conclusions: Our results corroborate the hypothesis that ascorbic acid supplementation has a cytoprotective effect in secondary biliary cirrhosis.

Qualidade de vida em urticária crônica: inquérito em ambulatório público universitário, Botucatu (Brasil)

OBJETIVO: Avaliar o impacto da urticária crônica na qualidade de vida dos pacientes de ambulatório universitário a partir do questionário DLQI (Dermatology Life Quality Index). MÉTODOS: Inquérito sobre o impacto na qualidade de vida infligido pela urticária crônica a partir do questionário DLQI validado para a língua portuguesa. Pacientes foram entrevistados durante suas consultas em ambulatório especializado, entre maio de 2009 e maio de 2010, em serviço público brasileiro (Botucatu-SP). Os escores do DLQI foram analisados segundo subgrupos: idade, gênero, escolaridade, tempo de doença e presença de angioedema. RESULTADOS: Foram entrevistados 100 pacientes com urticária crônica. Predominou o gênero feminino (86%), a idade média foi de 41,8 anos, duração média da doença foi de seis anos e angioedema ocorreu em 82% dos pacientes. O escore médio do DLQI foi de 13,5, caracterizando grave impacto à qualidade de vida, superior a hanseníase, psoríase, eczema atópico e carcinoma basocelular. Presença de angioedema se associou a maiores escores: 14,5 x 9,9 (p < 0,01). Pacientes do gênero feminino referiram maior impacto quanto ao vestuário, já o gênero masculino referiu quanto ao tratamento, trabalho e estudo (p < 0,05). CONCLUSÃO: Urticária crônica inflige grave comprometimento da qualidade de vida nos pacientes avaliados em serviço universitário brasileiro, especialmente nos portadores de angioedema.

Identificação de indivíduos vulneráveis no entorno de um hospital universitário: conectando vulnerabilidade, solidariedade e saúde

No entorno de um hospital universitário do interior do estado de São Paulo há pessoas dormindo, se alimentando ou descansando nos gramados e arredores, permanecendo nestes locais durante horas. Este estudo objetivou identificar e caracterizar indivíduos vulneráveis em área externa deste hospital, oferecendo ajuda. A coleta dos dados foi realizada no período de novembro de 2007 a outubro de 2008, semanalmente, em dias e horários sorteados. Identificaram-se pessoas que permaneciam nesses locais, sendo entrevistados 52 sujeitos. Esses indivíduos são, predominantemente, do sexo feminino (67,3%), brancos (51,9%), casados (59,6%), com escolaridade de até quatro anos de estudo (44,2%) e sem profissão definida (84,6%). A maioria aguardava o horário do ônibus da prefeitura de seu município de origem; o tempo médio de espera foi de aproximadamente 90 minutos e grande parte dos sujeitos apresentou necessidades durante os períodos de espera. Foi oferecida ajuda a 15 pessoas que referiram necessidades no momento da entrevista. Concluiu-se que esses indivíduos se encontram em situação de vulnerabilidade individual, social e programática, destacando-se a vulnerabilidade sócio-econômica, apresentam capacidade de autodeterminação reduzida, submetendo-se a condições desfavoráveis por dependerem dos serviços públicos.