Complexes between methyltestosterone and ß-cyclodextrin for application in aquaculture production.

The inclusion complexes between 17-α-methyltestosterone (MT) and ß-cyclodextrin (bCD) were prepared and characterized in dissolution and solid phase. The complex promoted a sixfold increment in solubility of the hormone. It has a limited solubility and stoichiometry of 2:1 (bCD:MT) determined by DSC, NMR and solubility experiments, the association constant Ka=2846Lmol-1 and complex fraction of 76% (assessed by DOSY-NMR, in (1:3) DMSO/D2O). The association constant obtained in water by the solubility isotherms is 7540Lmol-1. 2D-ROESY experiments indicate the intermolecular orientation (complete inclusion of the hormone in the cavity). Simulations by molecular dynamics agreed with the formation of the inclusion complex 2:1. Release tests showed the slower release for the complexes, with 50% for lyophilization and 56% for malaxation. These results clearly demonstrate the complexation of MT in bCD, which formulations are promising for further applications involving this steroid in aquaculture, both for sexual reversal and in technologies of hormone in water sequestration.

Caracterização física e química das frações do fruto atemoia Gefner / Physical and chemical characterization of fractions of fruit atemoya Gefner

A atemoia é um fruto híbrido derivado do cruzamento entre a fruta-do-conde, mais conhecida como ata (Annona squamosa L.), com a cherimoia (Annona cherimola Mill.). Este trabalho foi realizado com o objetivo de caracterizar os constituintes químicos das frações casca, polpa e semente de atemoia Gefner. Os frutos adquiridos foram selecionados, pesados e medidos. Foram separados em casca, polpa, semente e eixo floral, que também foram pesados para determinar suas proporções. Para o restante dos frutos, foram separadas as frações em sete repetições de 13 frutos. Em seguida, as frações casca, polpa e sementes foram liofilizadas e armazenadas em freezer. Foi determinada a proporção das frações do fruto, a composição centesimal, o ácido ascórbico, os açúcares totais, os minerais e alguns compostos bioativos. A polpa representou cerca de 60% do peso do fruto, enquanto a casca 28,13% e as sementes 8,34%. O fruto apresentou, em média, 56 sementes, com diâmetro longitudinal de 10,79cm e diâmetro transversal de 26,64cm. Os maiores teores de proteína bruta, extrato etéreo e fibra alimentar foram encontrados nas sementes e casca. A casca se destacou nos teores de cinzas. A polpa apresentou os maiores teores de ácido ascórbico e açúcares totais em relação às outras frações. A ordem da composição de macronutrientes na casca, na polpa e nas sementes da atemoia foi K>P>Ca>Mg; para os micronutrientes na casca e nas sementes, foi Fe>Zn>Cu>Mn>S e, na polpa, foi Fe>Zn>Mn>Cu>S. A casca apresentou os níveis mais altos de inibidores de tripsina e atividade hemaglutinante. Os teores de compostos fenólicos foram relativamente baixos no fruto.

The atemoya is a hybrid fruit derived from the cross between the sugar apple (fruta-do-conde), better known as ata (Annona squamosa L.) with the cherimoya (Annona cherimola Mill.). The aim of this research was to characterize the chemical constituents of the fractions skin, pulp and seed of the hybrid fruit atemoya, variety Gefner. The fruits purchased and selected were weighed and measured. They were separated into skin, pulp, seed and floral axis which were also weighted to determine their proportions. For the rest of the fruits, the fractions were separated into 7 replicates of 13 fruits. Then, the fractions skin, pulp and seeds were freeze-dried and stored in freezer. The proportion of the fruit fractions, the centesimal composition, ascorbic acid, total sugars, minerals and some bioactive compounds were determined. The pulp represented about 60% of the fruit weight, while the skin 28.13% and the seeds 8.34%. The fruit presented on the average 56 seeds, with longitudinal diameter of 10.79 cm and transversal diameter of 26.64 cm. The largest contents of crude protein, ether extract and dietary fiber were found in both seeds and skin. The skin stood out in the ash contents. The pulp showed the highest contents of ascorbic acid and total sugars in relation to the other fractions. The order of the composition of macronutrients in the skin, pulp and seeds of the atemoya was K>P>Ca>Mg; for the skin and seed micronutrients were Fe>Zn>Cu>Mn>S and in the pulp were Fe>Zn>Mn>Cu>S. The skin presented the highest levels of trypsin inhibitors and hemagglutinating activity. The phenolic compounds were relatively low in the fruit.

Improvement of the oral praziquantel anthelmintic effect by cyclodextrin complexation.

Schistosomiasis is a parasitic disease which kills a half million people per year, all over the world. Praziquantel (PZQ) is the drug-of-choice for schistosomiasis because of its effectiveness, ease of administration, and low cost. However, poor solubility restricts its delivery, especially via the oral route. In this study, we describe beta-cyclodextrin (beta-CD) complexation as an alternative to improve the PZQ bioavailability. Physicochemical analysis were performed to characterize the inclusion complex formed between PZQ and beta-CD. Differential scanning calorimetry (DSC) thermograms and morphological analysis using scanning electronic microscopy (SEM) gave evidences of the complex formation. Diffusion NMR experiments allowed determination of the fraction of PZQ bound to beta-CD (37%) and the association constant (941 +/- 47 M(-1)). The in vivo evaluation of the complexation on the effect of PZQ was performed on mice infected with Schistosoma mansoni (BH strain); after 15 days of treatment with the PZQ:beta-CD complex the efficacy, evaluated by the number of remaining alive worms, was 99%, against 59% elicited by plain PZQ.

Formulações de anestésicos locais de liberação controlada: aplicações terapêuticas / Drug-delivery systems for local anesthetics: therapeutic applications

JUSTIFICATIVA E OBJETIVOS: O desenvolvimento de sistemas de liberação controlada tem sido alvo de pesquisas há pelo menos quatro décadas. Desde que foi sugerida sua aplicação na indústria farmacêutica, muitos resultados foram obtidos, especialmente na manipulação molecular de carreadores e no estudo de suas interações com as drogas encapsuladas. Esses novos carreadores têm a vantagem de contornar propriedades físico-químicas limitantes (como a solubilidade aquosa ou em membranas) das drogas encapsuladas, melhorando assim a farmacodinâmica (potencialização do efeito terapêutico), farmacocinética (controle da absorção e distribuição tecidual) e os efeitos toxicológicos (redução da toxicidade local e sistêmica) das mesmas. Entre os principais carreadores, destacam-se os lipossomas e as ciclodextrinas, que vêm trazendo inúmeras vantagens no desenvolvimento de formulações para liberação controlada de anestésicos locais. Este trabalho de revisão objetiva descrever a interação de anestésicos locais com lipossomas ou ciclodextrinas, o desenvolvimento das pesquisas básica e clínica nessa área, além da aplicabilidade terapêutica dessas formulações. CONTEUDO: Lipossomas têm a capacidade de veicular drogas em órgãos-alvo, disponibilizando apenas uma fração - liberação controlada - para o sítio de ação. Já as ciclodextrinas alteram a intensidade e a duração do efeitos das drogas através da baixa absorção sistêmica do complexo...

BACKGROUND AND OBJECTIVES: Many researchers in the last four decades have been devoted to the development of drug-delivery systems. Since its first application in the pharmaceutical industry, many results have been obtained especially in the molecular manipulation of carriers and their interaction with encapsulated drugs. These new carriers have the advantage of bypassing encapsulated drugs restraining physicochemical properties (such as water or membrane solubility), thus improving pharmacodynamics (therapeutic effect potentiation), pharmacokinetics (control of tissue absorption and distribution) and toxic effects (lower local and systemic toxicity). Liposomes and cyclodextrins are among the most important carriers which have shown to be quite advantageous in the development of drug-delivery systems for local anesthetics. This study aimed at reviewing the interaction of local anesthetics with liposomes and cyclodextrins, the development of basic and applied research on the field, in addition to therapeutic applicability of these formulations. CONTENTS: Liposomes have the ability to control drug delivery to target tissues, fractionating drug release in its site of action. Cyclodextrins, on the other hand, change intensity and duration of effects due to low systemic drug absorption...

JUSTIFICATIVA Y OBJETIVOS: El desenvolvimiento de sistemas de liberación controlada ha sido motivo de pesquisas desde cuatro décadas por lo menos. Desde que fue sugerida su aplicación en la industria farmacéutica, fueron obtenidos muchos resultados, especialmente en la manipulación molecular de carreadores y en el estudio de sus interacciones con las drogas encapsuladas. Esos nuevos carreadores tienen la ventaja de contornar propiedades físico-químicas limitantes (como la solubilidad acuosa o en membranas) de las drogas encapsuladas, mejorando asi la farmacodinámica (potencialización del efecto terapéutico), farmacocinética (control de la absorción y distribución de tejidos) y los efectos toxicológicos (reducción de la toxicidad local y sistémica) de las mismas. Entre los principales carreadores, se destacan los liposomas y las ciclodextrinas, que están trayendo innúmeras ventajas en el desarrollo de formulaciones para liberación controlada de anestésicos locales. Este trabajo de revisión, objetiva describir la interacción de anestésicos locales con liposomas o ciclodextrinas, el desarrollo de las pesquisas básica y clínica en esa área, además de la aplicabilidad terapéutica de esas formulaciones. CONTENIDO: Liposomas tienen la capacidad de transportar drogas en órganos-clave, disponibilizando apenas una fracción - liberación controlada - para el sitio de acción. Ya las ciclodextrinas alteran la intensidad y la duración de efectos de las drogas a través de la baja absorción sistémica del complejo...

Drug-delivery systems for local anesthetics: therapeutic applications.

BACKGROUND AND OBJECTIVES: Many researchers in the last four decades have been devoted to the development of drug-delivery systems. Since its first application in the pharmaceutical industry, many results have been obtained especially in the molecular manipulation of carriers and their interaction with encapsulated drugs. These new carriers have the advantage of bypassing encapsulated drugs restraining physicochemical properties (such as water or membrane solubility), thus improving pharmacodynamics (therapeutic effect potentiation), pharmacokinetics (control of tissue absorption and distribution) and toxic effects (lower local and systemic toxicity). Liposomes and cyclodextrins are among the most important carriers which have shown to be quite advantageous in the development of drug-delivery systems for local anesthetics. This study aimed at reviewing the interaction of local anesthetics with liposomes and cyclodextrins, the development of basic and applied research on the field, in addition to therapeutic applicability of these formulations. CONTENTS: Liposomes have the ability to control drug delivery to target tissues, fractionating drug release in its site of action. Cyclodextrins, on the other hand, change intensity and duration of effects due to low systemic drug absorption. Basic and clinical studies have pointed out that the administration of local anesthetics in liposome or cyclodextrin formulations induces slow release of the drugs, prolonging the anesthetic action and decreasing cardiac and nervous systems toxicity. CONCLUSIONS: Although studies are still in progress, drug-delivery systems are flagging a new direction for the development of safer and more effective local anesthetic formulations.

Spectroscopic evidence for a preferential location of lidocaine inside phospholipid bilayers.

We examined the effect of uncharged lidocaine on the structure and dynamics of egg phosphatidylcholine (EPC) membranes at pH 10.5 in order to assess the location of this local anesthetic in the bilayer. Changes in the organization of small unilamellar vesicles were monitored either by electron paramagnetic resonance (EPR)-in the spectra of doxyl derivatives of stearic acid methyl esters labeled at different positions in the acyl chain (5-, 7-, 12- and 16-MeSL)-or by fluorescence, with pyrene fatty-acid (4-, 6-, 10- and 16-Py) probes. The largest effects were observed with labels located at the upper positions of the fatty-acid acyl-chain. Dynamic information was obtained by 1H-NMR. Lidocaine protons presented shorter longitudinal relaxation times (T(1)) values due to their binding, and consequent immobilization to the membrane. In the presence of lidocaine the mobility of all glycerol protons of EPC decreased, while the choline protons revealed a higher degree of mobility, indicating a reduced participation in lipid-lipid interactions. Two-dimensional Nuclear Overhauser Effect experiments detected contacts between aromatic lidocaine protons and the phospholipid-choline methyl group. Fourier-transform infrared spectroscopy spectra revealed that lidocaine changes the access of water to the glycerol region of the bilayer. A "transient site" model for lidocaine preferential location in EPC bilayers is proposed. The model is based on the consideration that insertion of the bulky aromatic ring of the anesthetic into the glycerol backbone region causes a decrease in the mobility of that EPC region (T(1) data) and an increased mobility of the acyl chains (EPR and fluorescence data).