34 research outputs found
Nonalcoholic steatohepatitis and hepatocellular carcinoma: Brazilian survey
OBJECTIVE: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time. METHODS: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>;20 g/day) and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseasesâ 2011 guidelines. RESULTS: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, SĂŁo Paulo, ParanĂĄ and Rio Grande do Sul). The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3), in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, â„3 nodules. CONCLUSIONS: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in patients with and without cirrhosis in Brazil. In this survey, hepatocellular carcinoma was observed in elevated numbers of patients with steatohepatitis without cirrhosis
Another Reason for Using Caffeine in Dermocosmetics: Sunscreen Adjuvant
The excessive exposure to ultraviolet (UV) radiation is the main cause of skin cancer, the most commonly diagnosed cancer in the world. In this context, the development of innovative and more effective sunscreens, with bioactive compounds like caffeine, displaying antioxidant and anticancer potential, is required. This research work assessed in vitro and in vivo the efficacy and safety of topical sunscreen formulations containing caffeine as an adjuvant of the UV filters. Sunscreens were prepared with 2.5% w/w caffeine or in the absence of this compound. In order to evaluate the safety of these formulations, stratum corneum hydration, skin barrier and colorimetry were assessed in vivo in healthy subjects before and after skin treatment with the samples. The efficacy of the sunscreens was assessed in vitro, using PMMA plates and a spectrophotometer equipped with an integrating sphere; and in vivo by the determination of the sun protection factor (SPF). None of the formulations caused erythema or impaired the skin barrier function. The in vitro functional characterization showed higher SPF values for the caffeine formulation. The in vivo studies also confirmed the higher SPF value of the formulation combining caffeine with the filters, compared to the caffeine-free sample. This improvement contributed to an increase of, approximately, 25% in the in vivo anti-UVB protection. In conclusion, caffeine was well tolerated by the skin and increased the photoprotective activity, being a new alternative adjuvant in sunscreens formulation
Planejamento, sĂntese e avaliação biolĂłgica de novos derivados da oxamniquina
A esquistossomĂase constituĂ grave problema de ordem sĂłcio-econĂŽmica e de saĂșde pĂșblica, principalmente nas regiĂ”es tropicais e subtropicais do mundo. Estima-se a existĂȘncia de 200 milhĂ”es de pessoas infectadas, estando 600 milhĂ”es em risco de contrair a doença. Ă causada por trematĂłdeos do gĂȘnero Schistosoma sendo a espĂ©cie S. mansoni a Ășnica encontrada no Brasil. Fatores como o aparecimento de cepas resistentes e efeitos adversos causados por fĂĄrmacos sĂŁo relevantes para agravar o controle da doença. A oxamniquina Ă© agente esquistossomicida bastante utilizado na terapĂȘutica brasileira contra S. mansoni. Embora seja relativamente bem tolerada, alguns efeitos adversos ao nĂvel de sistema nervoso central, como convulsĂ”es e alucinaçÔes, tĂȘm sido relatados. PropĂ”e-se o mĂ©todo de latenciação da oxamniquina, utilizando-se poliacriloil e polimetacriloil derivados como transportadores e aminoĂĄcidos (ĂĄcido aminocaprĂłico, ĂĄcido gama-aminobutĂrico e glicina) como unidades espaçantes, com o intuito de se obterem prĂł-fĂĄrmacos polimĂ©ricos, permitindo prolongamento de ação e redução dos efeitos adversos. Resultados mostram a formação dos monĂŽmeros acrĂlico e metacrĂlico, sendo que ambos foram amplamente caracterizados. O copolĂmero, ĂĄcido poli(metacrĂlico-co-metacrilato de oxamniquina), foi caracterizado por espectrofotometria no infravermelho e anĂĄlise tĂ©rmica e difração por raios-X. O polĂmero e copolĂmero, derivados do monĂŽmero acrĂlico, nĂŁo foram obtidos. Os derivados acriloilamĂdicos e metacriloilamĂdicos dos aminoĂĄcidos foram obtidos com grau de pureza satisfatĂłrio, mas os derivados ligados Ă oxamniquina nĂŁo foram obtidos atĂ© o momento. A modelagem molecular elucidou os problemas relativos Ă oxamniquina e obtenção de derivados. Um derivado cĂclico da oxamniquina foi obtido por mecanismo inĂ©dito e que ainda estĂĄ sob estudo. O grau de substituição do poli mero foi determinado a fim de se verificar a dose efetiva. A atividade biolĂłgica dos derivados acrĂlico, metacrĂlico e copolimĂ©rico foi avaliada pelo mĂ©todo do oograma quantitativo e pela perfusĂŁo de veias mesentĂ©ricas. Resultados mostraram atividade para os monĂŽmeros acrĂlico e metacrĂlico quando se utilizou metade da dose usual de oxamniquina. O copolĂmero nĂŁo apresentou atividade no perĂodo avaliado provavelmente em virtude de problemas relacionados Ă liberação do fĂĄrmaco a partir da matriz polimĂ©rica.Schistosomiasis, a tropical disease that affects humans for millions of years, is among the parasitic great incidence illness in subdeveloped countries. Even after all advances gotten in the treatment and prevention, the disease still has significative numbers of prevalence and morbity. The disease is directly associated with low acquisitive power, the Jack of information and bad sanitary and habitat conditions. The trematodes of Schistosoma gender are considered the disease causing agents, and the most important species that affect humans are S. mansoni, S. mekongi e S. japonicum, S. haematobium e S. intercalatum: others species affect human less frequently. Oxamniquine is an schistosomicide agent wide/y used in brazilian therapeutics against S. mansoni, due to low cost and good efficacy. Although the drug is relatively we/1 tolerated, some adverse effects in the central nervous system, as convulsions and alucinations have been described. The latentiation method was proposed with the aim to achieve polymeric prodrugs, allowing prolonged action and reduction of adverse effects. Polyacryloil and polymethacryloil derivatives were choosed to be the carriers and aminoacids (aminocaproic acid, gama-aminobutyric acid and glycine) were used as spacer groups. The acrylic and methacrylic prodrugs were obtained and a complete characterization was performed. The copolymer, poly (methacrylic-co-oxamniquine methacrylate) acid, was characterized by infrared spectrometry, thermal analysis and X-ray difratometry. The polymer and copolymer of the acrylic prodrug were not obtained. Although the oxamniquine prodrugs were not obtained yet, the acrylamidics and methacrylamidc derivativas of aminoacids were achieved with high purity degree. The molecular modeling solved some problems related to the oxamniquine\'s spacial structure and the obtention of its derivatives. An oxamniquine\'s cyclic derivative was achived by an unpublished reaction and still remains under research. The substitution degree of the copolymer was determined to determine the efective dose. The biological activity of the acrylic, methacrylic prodrugs and copolymer was evaluated by the quantitative oogram method and mesenteric blood vessels perfusion. Results show activity for the prodrugs, but not for the polymeric prodrug
Perfil comparativo do custo do tratamento entre prĂł- fĂĄrmacos e os seus fĂĄrmacos precursores
A latenciação é uma importante ferramenta no processo
de desenvolvimento de fårmacos, pois através dela,
diversas barreiras biolĂłgicas que limitam o uso de
um agente terapĂȘutico podem ser superadas. Assim,
esta estratégia permite a reintrodução de substùncias
anteriormente descartadas por suas propriedades
indesejĂĄveis e o aprimoramento de novos fĂĄrmacos,
antes mesmo que sejam lançados na terapĂȘutica.
Embora a latenciação apresente vantagens clĂnicas,
nĂŁo existem estudos demonstrando a vantagem
econÎmica do uso de pró-fårmacos em relação à s
substĂąncias precursoras. Dessa forma, o objetivo do
presente trabalho foi elaborar um perfil comparativo
do custo do tratamento entre prĂł-fĂĄrmacos e seus
respectivos fĂĄrmacos precursores, disponĂveis no
mercado farmacĂȘutico brasileiro, visando demonstrar
a real importùncia da latenciação como ferramenta
norteadora para o desenvolvimento de fĂĄrmacos e,
principalmente, a viabilidade financeira do uso de
prĂł-fĂĄrmacos. Constatou-se que seis do total de prĂł-
fĂĄrmacos analisados apresentaram-se financeiramente
mais vantajosos que os seus precursores e, mesmo para
os prĂł-fĂĄrmacos que tiveram custo mais elevado, a
vantagem clĂnica alcançada justifica sua utilização
Peppers: A âHotâ Natural Source for Antitumor Compounds
Piper, Capsicum, and Pimenta are the main genera of peppers consumed worldwide. The traditional use of peppers by either ancient civilizations or modern societies has raised interest in their biological applications, including cytotoxic and antiproliferative effects. Cellular responses upon treatment with isolated pepper-derived compounds involve mechanisms of cell death, especially through proapoptotic stimuli in tumorigenic cells. In this review, we highlight naturally occurring secondary metabolites of peppers with cytotoxic effects on cancer cell lines. Available mechanisms of cell death, as well as the development of analogues, are also discussed
Analysis of the applicability and use of lipinski's rule for central nervous system drugs
Lipinski`s Rule for central nervous system drugs (RoCNS), reported in 1999, predicts that poor absorption or permeation is more likely when there are more than three hydrogen bond donors (HBD), seven hydrogen bond acceptors (HBA), molecular weight (MW) is greater than 400 Da and CLog P is greater than five. The objective of this work was to evaluate the applicability of RoCNS for drugs approved from 1985 to 2014. Calculated physicochemical properties of central nervous system (CNS) drugs were compared to parameters established by the rule. From 1985 to 1999, 48 drugs were introduced for clinical therapy and 31% unsuited the RoCNS (among which six drugs did not fit within the determined CLog P, four the MW, four the HDA and two the HBD). From 2000 to 2014, 38 drugs were introduced and 32% violated RoCNS parameters (among which eight drugs did not fit within the determined MW, four the HBD, two the HBA and one the CLog P). These findings suggest that even though drugs introduced to the market after RoCNS publication showed a tendency to apply the rule, the application of the rule is similar for both periods. Examining the applicability of the RoCNS, it may serve as a guide for medicinal chemists designing future CNS-active small molecules13109991006CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTĂFICO E TECNOLĂGICO - CNPQCOORDENAĂĂO DE APERFEIĂOAMENTO DE PESSOAL DE NĂVEL SUPERIOR - CAPESFUNDAĂĂO DE AMPARO Ă PESQUISA DO ESTADO DE SĂO PAULO - FAPESPnĂŁo temnĂŁo tem2013/18160-
Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
Transient receptor potential vanilloid 6 (TRPV6) is a calcium channel implicated in multifactorial diseases and overexpressed in numerous cancers. We recently reported the phenyl-cyclohexyl-piperazine cis-22a as the first submicromolar TRPV6 inhibitor. This inhibitor showed a seven-fold selectivity against the closely related calcium channel TRPV5 and no activity on store-operated calcium channels (SOC), but very significant off-target effects and low microsomal stability. Here, we surveyed analogues incorporating structural features of the natural product capsaicin and identified 3OG, a new oxygenated analog with similar potency against TRPV6 (IC50 = 0.082 ± 0.004 ΌM) and ion channel selectivity, but with high microsomal stability and very low off-target effects. This natural product-inspired inhibitor does not exhibit any non-specific toxicity effects on various cell lines and is proposed as a new tool compound to test pharmacological inhibition of TRPV6 mediated calcium flux in disease models
N-[(1,3-Benzodioxol-5-yl)methyl]-4-methylbenzamide: an analogue of capsaicin
In the title compound, C16H15NO3, the five-membered 1,3-dioxole ring is in an envelope conformation with the methylene C atom as the flap atom [lying 0.202 (3) Å out of the plane formed by the other four atoms]. The benzene ring makes a dihedral angle of 84.65 (4)° with the best least-squares plane through the 1,3-benzodioxole fused-ring system, which substitutes the 2-methoxyphenol moiety in capsaicin. In the crystal, molecules are connected into a zigzag supramolecular chain along the c-axis direction by N—H...O hydrogen bonds. These chains are connected into a layer in the ac plane by C—H...π interactions
INTERAĂĂES FĂRMACO-RECEPTOR: APLICAĂĂES DE TĂCNICAS COMPUTACIONAIS EM AULA PRĂTICA SOBRE A EVOLUĂĂO DOS INIBIDORES DA ENZIMA CONVERSORA DE ANGIOTENSINA
Teaching classes and events regarding the molecular aspects of drug-receptor interactions is not an easy task. The ligand stereochemistry and the spatial arrangement of the macromolecular targets highly increase the complexity of the process. In this context, the use of alternative and more playful approaches could allow students to gain a more thorough understanding of this important topic in medicinal chemistry. Herein, we describe a practical teaching approach that uses computational strategies as a tool for drug-receptor interaction studies performed for angiotencsin converting enzyme inhibitors (ACEi). Firstly, the students learn how to find the crystallographic structure (enzyme-ligand complex). Then, they proceed to the treatment of crude crystallographic data. Thereafter, they learn how to analyze the positioning of the drug on the active site of the enzyme, looking for regions related to the molecular recognition. At the end of the study, students can summarize the molecular requirements for the interaction and the structure-activity relationships of the studied drugs
N-[(1,3-Benzodioxol-5-yl)methyl]benzenesulfonamide: an analogue of capsaicin
The title compound, C14H13NO4S, an analogue of capsaicin, differs from the latter by having a 1,3-benzodioxole ring rather than a 2-methoxyphenol moiety, and having a benzenesulfonamide group instead of an aliphatic amide chain. The five-membered ring is in an envelope conformation with the methylene C atom lying 0.221 (6) Å out of the plane formed by the other four atoms. The dihedral angle between the phenyl ring and the mean plane of the 1,3-benzodioxole fused-ring system is 84.65 (4)°. In the crystal, molecules aggregate into supramolecular layers in the ac plane through C—H...O, N—H...O and C—H...π interactions