Computational analysis and physico-chemical characterization of an inclusion compound between praziquantel and methyl-beta-cyclodextrin for use as an alternative in the treatment of schistosomiasis

Schistosomiasis is still an endemic disease in many regions, with 250 million people infected with Schistosoma and about 500,000 deaths per year. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, however it is classified as Class II in the Biopharmaceutics Classification System, as its low solubility hinders its performance in biological systems. The use of cyclodextrins is a useful tool to increase the solubility and bioavailability of drugs. The aim of this work was to prepare an inclusion compound of PZQ and methyl-beta-cyclodextrin (MeCD), perform its physico-chemical characterization, and explore its in vitro cytotoxicity. SEM showed a change of the morphological characteristics of PZQ:MeCD crystals, and IR data supported this finding, with changes after interaction with MeCD including effects on the C-H of the aromatic ring, observed at 758 cm(-1). Differential scanning calorimetry measurements revealed that complexation occurred in a 1:1 molar ratio, as evidenced by the lack of a PZQ transition temperature after inclusion into the MeCD cavity. In solution, the PZQ UV spectrum profile in the presence of MeCD was comparable to the PZQ spectrum in a hydrophobic solvent. Phase solubility diagrams showed that there was a 5.5-fold increase in PZQ solubility, and were indicative of a type A(L) isotherm, that was used to determine an association constant (K(a)) of 140.8 M(-1). No cytotoxicity of the PZQ:MeCD inclusion compound was observed in tests using 3T3 cells. The results suggest that the association of PZQ with MeCD could be a good alternative for the treatment of schistosomiasis.

Genetic differences between strains of Biomphalaria glabrata (Planorbidae) that are susceptible and unsusceptible to schistosomiasis

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

Development of praziquantel-loaded PLGA nanoparticles and evaluation of intestinal permeation by the everted gut Sac model

Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticles made of poly(D,L-lactide-co-glycolide) acid with controlled size were designed as drug carriers. Praziquantel, a hydrophobic drug, was entrapped into the polymeric nanoparticles with 30% (w/w) of theoretical loading. The nanoparticles size was approximately of 350 nm with 66% of encapsulation efficiency. The everted gut sac model shows to be efficient to evaluate the drug permeation through the intestinal membrane. The results show that free praziquantel presents 4-fold times more permeation than praziquantel-loaded PLGA nanoparticles and physical mixture. For this drug, in special, this result can be interesting, since the nanoparticulate system can behave as a drug reservoir and/or to have a more localized effect in intestinal membrane for a prolonged period of time, since great amounts of parasites can be usually found in the mesenteric veins.

PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution

Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticulate drug carriers made of poly(D,L-lactide-co-glycolide) acid with controlled size were designed. Praziquantel, a hydrophobic molecule, was entrapped into the nanoparticles with theoretical loading varying from 10 to 30% (w/w). This investigates the effects of some process variables on the size distribution of nanoparticles prepared by emulsion-solvent evaporation method. The results show that sonication time, PLGA and drug amounts, PVA concentration, ratio between aqueous and organic phases, and the method of solvent evaporation have a significant influence on size distribution of the nanoparticles. (C) 2004 Elsevier B.V. All rights reserved.

Improvement of antischistosomal activity of praziquantel by incorporation into phosphatidylcholine-containing liposomes

Praziquantel (PZQ) is effective against all known species of Schistosomes that infect humans. The failure of mass treatment of schistosomiasis has been attributed to the fact that therapy is not sufficiently long-lasting. This effect may be due to the low bioavailability of PZQ that has a low hydrosolubility and fast metabolism. Liposomes have been used to prolong drug levels. reduce the side effects, direct drugs to specific sites and increase bioavailability after administration. The aim of this work was to study the effect of phosphatidylcholine (PC)-containing liposomes to vehiculate PZQ to improve the treatment of schistosomiasis. The in vitro Study was carried out using Schistosoma mansoni parasites recovered by perfusion from the hepatic portal system of infected mice. Suspensions of liposomes with PZQ and free PZQ were administered p.o. in mice after 14 days of infection. The effect of both preparations in vitro on S. mansoni culture was similar. In the in vivo test, PZQ-liposomes caused a decrease in amounts of eggs and parasites. Liposomes improve the antischistosomal activity of praziquantel. This can be used as a starting point to investigate alternative administration routes or dosage forms and to examine the mechanism of intestinal absorption of PRZ © 2005 Elsevier B.V. All rights reserved.

Bothrops moojeni myotoxin-II, a Lys49-phospholipase A(2) homologue: An example of function versatility of snake venom proteins

MjTX-II, a myotoxic phospholipase A(2) (PLA(2)) homologue from Bothrops moojeni venom, was functionally and structurally characterized. The MjTX-II characterization included: (i) functional characterization (antitumoral, antimicrobial and antiparasitic effects); (ii) effects of structural modifications by 4-bromophenacyl bromide (BPB), cyanogen bromide (CNBr), acetic anhydride and 2-nitrobenzenesulphonyl fluoride (NBSF); (iii) enzymatic characterization: inhibition by low molecular weight heparin and EDTA; and (iv) molecular characterization: cDNA sequence and molecular structure prediction. The results demonstrated that MjTX-II displayed antimicrobial activity by growth inhibition against Escherichia coli and Candida albicans, antitumoral activity against Erlich ascitic tumor (EAT), human breast adenocarcinoma (SK-BR-3) and human T leukemia cells (JURKAT) and antiparasitic effects against Schistosoma mansoni and Leishmania spp., which makes MjTX-II a promising molecular model for future therapeutic applications, as well as other multifunctional homologous Lys49-PLA(2)S or even derived peptides. This work provides useful insights into the structural determinants of the action of Lys49-PLA2 homologues and, together with additional strategies, supports the concept of the presence of others bioactive sites distinct from the catalytic site in snake venom myotoxic PLA(2)s. (c) 2005 Elsevier B.V. All rights reserved.

Sex Determination and Female Reproductive Development in the GenuSchistosoma: A Review

Os parasitas do gênero Schistosoma situam-se entre os primeiros metazoários que desenvolveram sexos separados, determinado cromossomicamente no ovo fertilizado. Apesar da ocorrência de cromossomos sexuais específicos, as fêmeas de Schistosoma não atingem a maturidade somática e sexual sem a presença dos machos. Na verdade, um dos aspectos mais controversos e, ao mesmo tempo, mais fascinantes, envolvendo o desenvolvimento sexual das fêmeas está em se desvendar a natureza do estímulo que controla e mantém tal processo. Muito embora a natureza do estímulo (físico ou químico) seja motivo de controvérsia, concordam os mais diferentes autores que o acasalamento é um requisito indispensável para que ocorra a maturação e migração das fêmeas para o sítio definitivo de permanência no sistema vascular do hospedeiro vertebrado. Admite-se, ainda, que o estímulo não é espécie-específico e, em alguns casos, nem mesmo gênero-específico. Não obstante a existência de um número considerável de artigos dedicados ao tema, não há um consenso sobre o processo (ou processos) que controla(m) o encontro de machos e fêmeas no sistema circulatório do hospedeiro vertebrado, bem como está por ser determinada a natureza do estímulo, oriundo dos machos, que controla e mantém o desenvolvimento somático e sexual das fêmeas. Ao longo dos anos os machos de Schistosoma têm sido considerados, por vezes pejorativamente, os irmãos, os músculos ou o fígado das fêmeas. em síntese, resta saber se a natureza do estímulo responsável pelo desenvolvimento das fêmas envolve a transferência de hormônios, nutrientes, a mera estimulação tátil ou a combinação de dois ou mais desses fatores

A LINE2 repetitive DNA sequence from the cichlid fish, Oreochromis niloticus: sequence analysis and chromosomal distribution

We report the cloning and characterization of a long interspersed nucleotide element (LINE) fi-om a cichlid fish, Oreochromis niloticus, and show the distribution of this element, called CiLINE2 for cichlid LINE2, in the chromosomes of this species. The identification of an open reading frame in CiLINE2 with amino acid sequence similarity to reverse transcriptases encoded by LINE-like elements in Caenorhabditis elegans, Platemys spixii, Schistosoma mansoni, Gallus gallus (CRI), Drosophila melanogaster (I factor), and Homo sapiens (LINE2), as well as the structure of the element, suggest it is a member of this family of non-long terminal repeat-containing retrotransposons. Search of a DNA sequence database identified sequences similar to CiLINE2 in four other fish species (Haplotaxodon microlepis, Oreochromis mossambicus, Pseudotropheus zebra, and Fugu rubripes). Southern blot hybridization experiments revealed the presence of sequences similar to CiLINE2 in all Tilapiini species analyzed from the genera Oreochromis, Tilapia, and Sarotherodon, and gave an estimated copy number of about 5500 for the haploid genome of O. niloticus. Fluorescent in situ hybridization showed that CiLINE2 sequences were organized in small clusters dispersed over all chromosomes of O. niloticus, with a higher concentration near chromosome ends. Furthermore the long arm of chromosome 1 was strikingly enriched with this sequence. The distribution of LINE2-related elements might underlie the difference in chromosome banding patterns observed between cold-blooded vertebrates and mammals.

Síntese e atividade biológica do derivado 6-formil-oxamniquina

Schistosomiasis, an important disease in Brazil, is caused by a trematode of the genus Schistosoma, reaching millions of person in one of the most endemic region of this disease in the whole globe. The main goal of this work was to syntetize the 6-formyl- oxamniquine derivative and evaluate its biological activity. The 6-formyl-oxamniquine derivative was obtained by the oxidation of oxamniquine with MnO 2, applying CH 2Cl 2 as solvent at room temperature for 24 hours. The obtaintion of 6-formyl-oxamniquine derivative compound was confirmed by IR spectroscopy and 13C NMR and 1H NMR, presenting similar activity when compared to the commercial oxamniquine (Mansil®).

Desenvolvimento de hidrogéis de dextrano contendo praziquantel

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Desenvolvimento e caracterização de carreadores lipídicos nanoestruturados contendo praziquantel

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estudo sobre o uso do pentacloreto de nióbio em reações multicomponentes para síntese de derivados de 4-ARIL-3,4-DI-Hidrocumarinas

Pós-graduação em Ciência e Tecnologia de Materiais - FC

Desenvolvimento de nanopartículas lipídicas sólidas contendo praziquantel

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Desenvolvimento de blendas de dextranos de pesos moleculares 70 e 148 KDA para a obtenção de hidrogéis contendo praziquantel

Pós-graduação em Ciências Farmacêuticas - FCFAR

In Vitro Antiparasitic Activity and Chemical Composition of the Essential Oil Obtained from the Fruits of Piper cubeba

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)