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Hydroxymethylation is a simple chemical reaction, in which the introduction of the hydroxymethyl group can lead to physical-chemical property changes and offer several therapeutic advantages, contributing to the improved biological activity of drugs. There are many examples in the literature of the pharmaceutical, pharmacokinetic, and pharmacodynamic benefits, which the hydroxymethyl group can confer to drugs, prodrugs, drug metabolites, and other therapeutic compounds. It is worth noting that this group can enhance the drug's interaction with the active site, and it can be employed as an intermediary in synthesizing other therapeutic agents. In addition, the hydroxymethyl derivative can result in more active compounds than the parent drug as well as increase the water solubility of poorly soluble drugs. Taking this into consideration, this review aims to discuss different applications of hydroxymethyl derived from biological agents and its influence on the pharmacological effects of drugs, prodrugs, active metabolites, and compounds of natural origin. Finally, we report a successful compound synthesized by our research group and used for the treatment of neglected diseases, which is created from the hydroxymethylation of its parent drug.

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More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.

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BACKGROUND: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. OBJECTIVE: Current approaches to drug discovery for Chagas disease. METHOD: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. RESULTS: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. CONCLUSION: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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Hydroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug effective in vivo during acute infections, and it has less hepatotoxicity effect than the standard drug benznidazole (BZN) which has been used during short- and long-term treatment. In the present study, we induced the indeterminate form of Chagas disease in mice with a Y strain of Trypanosoma cruzi and analysed the histopathological data about the effects of NFOH and BZN on different tissues, including the heart, skeletal muscle, liver, kidney, colon, spleen and brain. After infection, BALB/c mice were treated with NFOH (150 mg/kg) and BZN (60 mg/kg) for 60 days and then submitted to immunosuppression using dexamethasone (5 mg/kg) for 14 days. Two trained analysts, as part of a blind evaluation, examined the results using serial sections of 3 mm diameter in two different moments. The results showed reactivation of the disease only in the infected nontreated group (POS). After treatment, amastigote nests were found in the heart, colon, liver and skeletal muscle in the POS group and in the heart and liver of the BZN group. Interestingly, amastigote nests were not found in the NFOH and NEG groups. The histopathological analysis showed fewer tissue lesions and parasite infiltrates in the NFOH group when compared with the BZN and POS groups. We have not observed any increase in the levels of hepatocellular injury biomarkers (AST/ALT) in the NFOH group. These in vivo studies show the potential for NFOH as an effective and safe compound useful as an anti-T. cruzi agent.

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ABSTRACT The present study aimed to investigate the anti-inflammatory activity of ethanolic extract from Casearia sylvestris Sw., Salicaceae, leaves and to identify the compounds responsible for this activity. The ethanolic extract from C. sylvestris leaves was fractionated by solid phase extraction and the chemical composition of extract and fractions were assessed by chromatographic techniques. Casearin-like clerodane diterpenes were quantified in ethanolic extract (27.4%, w/w) and in fraction 2 of solid phase extraction (50.6%, w/w). Carrageenan-induced paw edema and carrageenan-induced pleurisy assays (rats) were used to evaluate anti-inflammatory activity of ethanolic extract, its fractions and clerodane diterpenes from C. sylvestris - caseargrewiin F and casearin B. The ethanolic extract was tested in the rat paw edema model and the doses tested (10 and 100 mg/kg) had no effect. In the pleurisy model, the extract doses of 300 and 500 mg/kg showed inhibitory effect. The fraction 2 of solid phase extraction (10 mg/kg), caseargrewiin F and casearin B (0.5 mg/kg) showed a significant reduction (p < 0.05) of the carrageenan-induced paw edema in rats compared to indomethacin. Gastric ulcers were not observed in animals treated with samples from C. sylvestris. In conclusion, the ethanolic extract from C. sylvestris, its enriched fraction of clerodane diterpenes, casearin B and caseargrewiin F exhibited anti-inflammatory activity on in vivo models in rats. Casearin-like clerodane diterpenes may be considered active chemical markers for C. sylvestris leaves. On the other hand, these diterpenes are promising compounds in the development of new drugs with anti-inflammatory action without gastric side effects.

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OBJECTIVE: To assess perinatal outcomes and intrauterine complications following fetal intervention for congenital heart disease (CHD). METHODS: A systematic review and meta-analysis were performed following an electronic search of PubMed and Scopus databases (last searched August 2015). Perinatal outcomes that were assessed included fetal death, live birth, preterm delivery < 37 weeks' gestation and neonatal death. Intrauterine complications that were assessed included bradycardia requiring treatment and hemopericardium requiring drainage. Estimated proportions were reported as mean (95% CI). Inconsistency was assessed using the I2 statistic. RESULTS: An electronic search identified 2279 records, of which 29 studies (11 retrospective cohort and 18 case reports) were considered eligible for analysis. Fetal death after treatment of CHD by aortic valvuloplasty was reported in three studies, with a rate of 31% (95% CI, 9-60%), after pulmonary valvuloplasty in one study, with a rate of 25% (95% CI, 10-49%), after septoplasty in one study, with a rate of 14% (95% CI, 6-28%) and after pericardiocentesis and/or pericardioamniotic shunt placement in 24 studies, with a rate of 29% (95% CI, 18-41%). Bradycardia requiring treatment was reported after aortic valvuloplasty in two studies, with a rate of 52% (95% CI, 16-87%), after pulmonary valvuloplasty in one study, with a rate of 44% (95% CI, 23-67%), and after septoplasty in one study, with a rate of 27% (95% CI, 15-43%). CONCLUSIONS: Current evidence on the effectiveness of prenatal intervention for CHD derives mostly from case reports and a few larger series; no study was randomized. Although the results of the meta-analysis are encouraging in terms of perinatal survival, they should be interpreted with caution when comparing with procedures performed after delivery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

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O Programa Nacional de Triagem Neonatal (PNTN) implantado no Brasil tem como objetivo, considerando cada fase de execução local, detectar doenças como fenilcetonúria, hipotereoidismo congênito, hemoglobinopatias e fibrose cística. O objetivo deste trabalho foi analisar, através de um estudo transversal e observacional, a prevalência das doenças detectadas pelo PNTN no município de Araraquara emitidas pela APAE de São Paulo no período compreendido entre abril e dezembro de 2009. Os resultados mostram que o município apresentou, no ano de 2009, prevalência de fenilcetonúria e hipotireoidismo congênito de 0,06% acima da média nacional, que é de 0,01% e 0,03%, respectivamente. Com relação às hemoglobinopatias, encontrou-se prevalência do traço para anemia falciforme de 2,15% abaixo da média nacional, que é de 2,6%. A prevalência do traço C no município foi de 0,57%, semelhante a valores nacionais disponíveis na literatura. FA BART´S confirmado apresentou valor de 0,13% abaixo da média de 0,38% da região do município de Araraquara. A realização do teste do pezinho e o aconselhamento aos cuidadores são fatores importantes para redução de morbidades relacionadas à evolução dessas doenças.

The National Neonatal Screening Program (NNSP) set up in all Brazil, aims, through planned phases of local implementation, to detect diseases such as phenylketonuria, congenital hypothyroidism, hemoglobinopathies and cystic fibrosis. The aim of this study was to assess, through a cross-sectional observational study, the prevalence of the diseases detected by the NNSP in the city of Araraquara, in records issued by the São Paulo APAE laboratory in the period between April and December 2009.The results show that Araraquara had a prevalence of phenylketonuria and congenital hypothyroidism 0.06% above the national averages of 0.01% and 0.03% respectively. With respect to hemoglobinopathies, the prevalence of sickle cell trait was 2.15% below the national average of 2.6%. The prevalence of Hb C in the city was 0.57%, similar to national values reported in the literature. Confirmed Hb Bart´s had a prevalence of 0.13% in Araraquara, below the average of 0.38% for the surrounding region. The neonatal screening by heel-prick test and counseling for caregivers are important factors in reducing morbidity related to the evolution of these diseases.

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Cetoconazol é um antifúngico sintético, derivado imidazólico de amplo espectro de ação, efetivo no tratamento de infecções superficiais e sistêmicas. Foram estudadas diferentes metodologias para análise do cetoconazol em especialidades farmacêuticas diversas usando espectrofotometria no ultravioleta, no infravermelho e análise térmica. Os resultados mostram que a espectrofotometria ultravioleta é um método rápido, prático e econômico e apontam que outros métodos como a espectrofotometria no infravermelho e análise térmica são uma alternativa à análise do cetoconazol em diferentes especialidades farmacêuticas.

Ketoconazole is a synthetic broad-spectrum oral and topical antifungal drug derived from imidazole, effective in the treatment of superficial mycoses and systemic infections. In this study we have tested several methods to analyze ketoconazole in various pharmaceutical products containing this drug, employing techniques such as UV and IR spectrophotometry and thermal analysis. The results showed that UV spectrophotometryis a fast, practical and economical method and indicated that other methods, such as IR spectrophotometry and thermal analysis, could be good alternative methods for ketoconazole analysis in certain pharmaceutical forms.

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Propolis is a natural product collected by honeybees and has a large range of pharmacological activity, including antimicrobial, antitumoral, antioxidant andanti-inflammatory. Its use as a popular medicine is increasing all over the world, creating a need for quality control of the commercial products. In this study the levels of calcium and magnesium in commercial hydroalcoholic propolis extracts from varios states of Brazil were determined by atomic absorption flame spectrophotometry and different values were obtained for northern and southern states. This study can beextended to the analysis of metals that are harmfulto health. The results showed that the calibration curves were linear over a wide concentration range (0.5-4.0 miug.mL-1 for calcium and 0.05-0.4 miug.mL-1 formagnesium) with good correlation coefficients (0.999 and 0.988, respectively). Good analytical recovery (94%) was obtained. The proposed method showed adequate precision and relative standard deviation lower than 2%. The method is accurate and precise as well as having advantages such as simplicity and speed.

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Durante o planejamento estrutural de novos fármacos, é possível prever a influência de grupamentos específicos na atividade farmacológica. Entre estes, encontra-se o grupo nitro, que possui potencial atividade antimicrobiana, estando presente em diversos fármacos como o metronidazol, nitrofural, furazolidona, oxamniquina, cloranfenicol, entre outros. Também, a introdução do grupo nitro na molécula pode alterar as propriedades físico-químicas e eletrônicas da substância, estando presente em fármacos de outras classes terapêuticas como anti-úlcera, ansiolítico, antiinflamatório. Entretanto, restrições têm sido apontadas para o planejamento de novos fármacos contendo este grupo, devido à toxicidade relacionada. Este estudo trata-se da revisão sobre a toxicidadede compostos nitrofurânicos, bem como os possíveis mecanismos e a utilização do método de latenciação na diminuição desta toxicidade.

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No fully effective treatment has been developed since the discovery of Chagas' disease by Carlos Chagas in 1909. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effectiveness in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Many natural and/or synthetic substances showing trypanocidal activity have been used, even though they are not likely to be turned into clinically approved drugs. Originally, drug screening was performed using natural products, with only limited knowledge of the molecular mechanism involved in the development of diseases. Trans-splicing, which is unusual RNA processing reaction and occurs in nematodes and trypanosomes, implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre-mRNA, giving origin to the mature mRNA. In the present study, permeable cells of T. cruzi epimastigote forms (Y, BOL and NCS strains) were treated to evaluate the interference of two drugs (hydroxymethylnitrofurazone - NFOH-121 and nitrofurazone) in the trans-splicing reaction using silver-stained PAGE analysis. Both drugs induced a significant reduction in RNA processing at concentrations from 5 to 12.5 microM. These data agreed with the biological findings, since the number of parasites decreased, especially with NFOH-121. This proposed methodology allows a rapid and cost-effective screening strategy for detecting drug interference in the trans-splicing mechanism of T. cruzi.

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No fully effective treatment has been developed since the discovery of Chagas' disease by Carlos Chagas in 1909. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effectiveness in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Many natural and/or synthetic substances showing trypanocidal activity have been used, even though they are not likely to be turned into clinically approved drugs. Originally, drug screening was performed using natural products, with only limited knowledge of the molecular mechanism involved in the development of diseases. Trans-splicing, which is unusual RNA processing reaction and occurs in nematodes and trypanosomes, implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre-mRNA, giving origin to the mature mRNA. In the present study, permeable cells of T. cruzi epimastigote forms (Y, BOL and NCS strains) were treated to evaluate the interference of two drugs (hydroxymethylnitrofurazone - NFOH-121 and nitrofurazone) in the trans-splicing reaction using silver-stained PAGE analysis. Both drugs induced a significant reduction in RNA processing at concentrations from 5 to 12.5 æM. These data agreed with the biological findings, since the number of parasites decreased, especially with NFOH-121. This proposed methodology allows a rapid and cost-effective screening strategy for detecting drug interference in the trans-splicing mechanism of T. cruzi.

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Os fármacos antiinflamatórios são sabidamente os mais comercializados em todo o mundo, e apesar disto apresentam sérios efeitos colaterais, sobretudo no que se refere ao trato gastrintestinal. A descoberta de novos protótipos com atividade e segurança terapêutica melhoradas continua sendo uma busca constante. Com o adventoda química computacional torna-se mais fácil o estudo teórico do comportamento fisiológico de uma nova substância bem como a compreensão do possível mecanismo de ação destas novas moléculas. Assim, através de modelos matemáticos de moléculas e receptores estudou-se neste trabalho o composto I (1-(2,6- diclorofenil)indolin-2-ona) quanto à sua possibilidade deinibir seletivamente a isoforma COX-2 da enzima prostaglandina endoperóxido sintase (PGHS), e também as melhores posições para a introdução de grupamentos químicos e modificações moleculares.

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Microondas são utilizadas na síntese orgânica desde 1986, e mostra-se vantajosa em diversos aspectos como possibilidade de maiores rendimentos, maior seletividade e menor decomposição térmica. A ftalimida e derivados, constituem-se em uma importante classe de compostos utilizados na química orgânica sintética, e do ponto de vista da Química Farmacêutica e Medicinal, é considerada um importante bióforo constituindo subunidade estrutural de caráter farmacofórico para uma série de compostos com diferentes atividades farmacológicas, entre elas, a anemia falciforme. O objetivo deste trabalho foi desenvolver metodologia alternativa na síntese de derivados ftalimídicos explorando a condensação de anidrido ftálico com aminas funcionalizadas sob radiação de microondas doméstico. Os resultados mostraram que os compostos ftalímidicos sintetizados podem ser obtidos em menores tempos reacionais (5-10 minutos) e maiores rendimentos(60-89%) quando comparados ao aquecimento convencional (refluxo), demonstrando o potencial da utilização do microondas na obtenção destas moléculas...

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A utilização de produtos naturais na medicina popular é milenar e persiste até os dias atuais. Entretanto, a idéia de que estes produtos são isentos de toxicidade torna o uso de medicamentos fitoterápicos cada vez maior e indiscriminado. Este trabalho trata de uma revisão sobre as interações que podem ocorrer com a utilização concomitante de Hypericum perforatum L. (erva de são joão) e Piper methysticum F. (kava-kava) com fármacos, podendo levar a sérios efeitos tóxicos, incluindo a fatalidade.

Natural products in popular medicine have been used for hundreds of years and persists nowadays. However, the idea that these products are exempted of toxicity turns the use of herbs to be larger and indiscriminate. This work is a review of interactions that can happen with concomitant use of Hypericum perforatum L. (St. John's wort) and Piper methysticum F. (kava-kava) with medicines that can result in serious toxicological effects including fate.

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Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.

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For the restoration of thumb opposition many types of tendon transfer techniques have been described. The flexor digitorum superficialis (FDS) of the ring finger is commonly selected as a motor. On occasion, however, the quality of the flexor muscles of the fingers or wrist is not good enough for tendon transfer and another available muscle must be selected. In this situation, we have preferred to use an extensor carpi radialis longus (ECRL) or brevis (ECRB) transfer to restore opposition of the thumb. Follow-up examination, at an average 5 years and 10 months after operation, showed that the results of ten of 11 transfers were excellent and the other was good.

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American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million people in Latin America. Currently, therapy is unsatisfactory and only two drugs are available. Primaquine, an antimalarial drug, has trypanocidal activity. Dipeptide derivatives of primaquine, Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ, were synthesized. The choice of the peptides was based on the primary specificity of cruzipain, the major cysteine proteinase from T cruzi. The prodrugs obtained were tested on the LLC-MK2 cell culture infected with trypomastigotes forms of T. cruzi. Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ were active in all stages.

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Sixty-four neonates, with gestational age ranging from 27 1/2 to 40 weeks, postnatal age from 1 to 15 days, and birth weight from 800 to 3400 gm, were given netilmicin 2.5 mg/kg intramuscularly two or three times per day according to postnatal age, for 5 to 14 days. Serum concentrations were measured before and 1 hour after a dose at least twice during treatment. The serum washout profile of the drug was observed in 22 neonates after discontinuation of therapy. Renal function was studied in 37 infants by measuring serum creatinine concentrations and in 27 by urinary excretion of N-acetyl-glucosaminidase during and up to 15 days after therapy. Behavioral and impedance audiometry, and in infants failing those, auditory brainstem evoked response tests, were performed between 6 and 12 months of age. In 23.5% of the neonates, trough serum levels were greater than 3 micrograms/ml. The serum washout followed a multiexponential decay, accounting for distributional, rapid (initial), and slow (tissue) elimination phases. Linear regression analysis performed between each kinetic parameter and gestational age or birth weight showed that initial elimination half-life, steady-state volume of distribution, and total body clearance were significantly correlated with both variables. Netilmicin did not cause detectable renal or auditory damage.

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