Avaliação in silico da atividade ansiolítica de compostos do extrato de camomila (Matricaria recutita) nos receptores GABAa humanos / In silico evaluation of the anxiolytic activity of compounds from chamomile (Matricaria recutita) extract in human GABAa receptors

Objetivo: Avaliar a possível atividade ansiolítica de compostos presentes no extrato padronizado de camomila por meio da interação com o receptor GABAa, como também analisar parâmetros farmacocinéticos das moléculas escolhidas por meio de ferramentas computacionais. Método: Simulação da interação proteína-ligante da apigenina, alfa-bisabolol e camazuleno, por meio de docagem molecular com o receptor GABAa, comparadas com diazepam. Por fim, os parâmetros farmacocinéticos dos três compostos foram calculados, usando a ferramenta on line SwissADME. Resultados: Alfa-bisabolol e camazuleno adequaram-se aos parâmetros farmacocinéticos favoráveis, enquanto a apigenina e o diazepam não atenderam ao perfil de ideal de biodisponibilidade. No estudo docking, as energias de ligação obtidas foram de -5-1 (a-bisabolol), -7,0 (camazuleno), -7,5 (diazepam), e -8.3 kcal/mol (apigenina); também foram observadas ligações do tipo hidrofóbicas, de Van der Waals e interações eletrostáticas. Conclusão: Os parâmetros analisados sugerem a atividade ansiolítica das moléculas estudas. Ademais, mais pesquisas in vivo devem ser realizadas a fim de elucidar os resultados e seus mecanismos e possíveis limitações em humanos.

Objective: To evaluate the possible anxiolytic activity of compounds present in standardized chamomile extract through interaction with the GABAa receptor and to analyze pharmacokinetic parameters of the chosen molecules through computational tools. Methods: Simulation of the protein-ligand interaction of apigenin, alpha-bisabolol, and camazulene by molecular docking with the GABAa receptor compared with diazepam. Finally, the pharmacokinetic parameters of the compounds were calculated using the SwissADME online tool. Results: Alpha-bisabolol and camazulene fit the favorable pharmacokinetic parameters, while apigenin and diazepam did not meet the ideal bioavailability profile. In the docking study. The binding energies obtained were -5-1 ( a-bisabolol), -7.0 (camazulene), -7.5 (diazepam), and -8.3 kcal/mol (apigenin). Hydrophobic bonds, Van der Waals and electrostatic interactions were observed. Conclusion: The parameters analyzed suggest an anxiolytic activity of the molecules studied. Also, more in vivo research to elucidate the results and their human and possible resources used in humans

Elaboration of guideline for monitoring in relative bioavailability / pharmaceutical bioequivalence study by the sponsor / Elaboração de diretriz para monitoramento em biodisponibilidade relativa / estudo de bioequivalência farmacêutica pelo patrocinador / Elaboración de la directriz para el seguimiento en la biodisponibilidad relativa / estudio de bioequivalencia farmacéutica por parte del promotor

For registration of generic and similar drugs, it is necessary to carry out pharmaceutical equivalence (PE) tests and pharmaceutical bioequivalence (PB). To carry out these tests, duly qualified research centers are contracted, which need to be monitored by the sponsor who is legally responsible for the activities. To this end, it is the recommendation of the Document of the Americas, periodic monitoring to verify compliance with quality requirements, Standard Operating Procedures, Good Clinical Practices (GCP), Good Laboratory Practices (GLP), of the applicable regulatory framework, as well as of compliance with the study protocol. Thus, monitoring is a methodical and documented process to evaluate the degree of adhesion of the center to the planned design for the evaluation of the formulations. To this end, the implementation of a standardized and easily completed guideline is a very important tool to guarantee a consistent evaluation and maintain the organizational memory of the evaluated items by monitors designated by the sponsor, contributing to the constant improvement of the contracted centers and supporting traceability of the studies. This work provided a systemic view of the evidence process related mainly to pharmaceutical bioequivalence, with the monitoring guideline summarizing the items of greatest relevance to be verified.

Para registro de medicamentos genéricos e similares, é necessária a realização de testes de equivalência farmacêutica (EF) e bioequivalência farmacêutica (BF). Para a realização desses testes, são contratados centros de pesquisa devidamente habilitados, que precisam ser monitorados pelo patrocinador legalmente responsável pelas atividades. Há também a recomendação do Documento das Américas de realizar monitoramentos periódicos para verificar o cumprimento dos requisitos de qualidade, Procedimentos Operacionais Padrão, Boas Práticas Clínicas (BPC), Boas Práticas de Laboratório (BPL), de marco regulatório aplicável, bem como de cumprimento do protocolo do estudo. Assim, o monitoramento é um processo metódico e documentado para avaliar o grau de adesão do centro ao desenho planejado para a avaliação das formulações. Para tanto, a implantação de uma diretriz padronizada e de fácil preenchimento é uma ferramenta muito importante para garantir uma avaliação consistente e manter a memória organizacional dos itens avaliados por monitores designados pelo patrocinador, contribuindo para a melhoria constante dos centros contratados e apoiando rastreabilidade dos estudos. Este artigo forneceu uma visão sistêmica do processo de evidência relacionado principalmente à bioequivalência farmacêutica, com a diretriz de monitoramento resumindo os itens de maior relevância a serem verificados.

Para el registro de medicamentos genéricos y similares, es necesario realizar pruebas de equivalencia farmacéutica (EP) y de bioequivalencia farmacéutica (PB). Para llevar a cabo estas pruebas se contratan centros de investigación debidamente cualificados, que deben ser supervisados por el promotor, que es el responsable legal de las actividades. Para ello, es la recomendación del Documento de las Américas, el monitoreo periódico para verificar el cumplimiento de los requisitos de calidad, los Procedimientos Operativos Estándar, las Buenas Prácticas Clínicas (BPC), las Buenas Prácticas de Laboratorio (BPL), del marco regulatorio aplicable, así como del cumplimiento del protocolo del estudio. Así, la monitorización es un proceso metódico y documentado para evaluar el grado de adhesión del centro al diseño previsto para la evaluación de las formulaciones. Para ello, la implantación de una pauta estandarizada y de fácil cumplimentación es una herramienta muy importante para garantizar una evaluación consistente y mantener la memoria organizativa de los elementos evaluados por parte de los monitores designados por el promotor, contribuyendo a la mejora constante de los centros contratados y apoyando la trazabilidad de los estudios. Este trabajo proporcionó una visión sistémica del proceso de evidencia relacionado principalmente con la bioequivalencia farmacéutica, con la pauta de monitoreo que resume los ítems de mayor relevancia a ser verificados.

Biodisponibilidad de fósforo en alimentos y su efecto en la enfermedad renal crónica / Bioavailability of phosphorus in food and its effect in chronic kidney disease

Resumen Introducción: el objetivo del presente trabajo se centra en reconocer la importancia de las investigaciones que relacionan la biodisponibilidad de fósforo en diferentes grupos de alimentos de origen animal, vegetal e industrial y su efecto en la progresión de la enfermedad renal crónica (ERC). Metodología: la revisión se sustentó en la búsqueda literaria en páginas web como PUBMED, Redalyc, SciELO, SCIHUB y Google Academic. Se seleccionó cada estudio, descartando aquellos que no fueran cuantitativos u originales, estuvieran incompletos, sin metodología clara, realizados en mamíferos o si los resultados no se especificaban en porcentajes. La lectura puso especial énfasis en el índice de biodisponibilidad de fósforo derivado del consumo de distintos productos alimenticios. Se elaboraron tres matrices de acuerdo con el origen del comestible y la biodisponibilidad de fósforo que absorbe el organismo. Resultados: se encontró que los alimentos industrializados y los aditivos muestran una biodisponibilidad de fósforo del 90 % al 100 %, los de origen animal del 40 % al 80 % y los de origen vegetal del 30 %. Conclusiones: los aditivos de los alimentos industrializados promueven la hiperfosfatemia y, con ello, aceleran la progresión de la enfermedad renal crónica, a diferencia de los de origen animal y vegetal, menos perjudiciales para la salud. Esto da pauta a la formación del sector salud para ampliar su conocimiento sobre el tratamiento nutricional del paciente.

Abstract Introduction: to know the importance of the investigations that relate the bioavailability of phosphorus in different groups of foods of animal, vegetable and industrialized origin and its effect on the progression in patients with Chronic Kidney Disease (CKD). Methodology: the review is based on a literary search that was carried out on web pages such as: PUBMED, Redalyc, SciELO, SCIHUB and Google Academic. Each of the studies was selected discarding those that were not quantitative, original, complete, with clear methodology, carried out in mammals, and that in their results specified the bioavailability of phosphorus in percentages. All the studies were read, placing main emphasis and interest on the percentage of phosphorus bioavailability when consuming different food groups. Three matrices were made according to the origin of the food and the bioavailability of phosphorus that is absorbed in the body; grouping them into foods of animal, vegetable and industrialized origin and additives. Results: it was found that industrialized foods and additives show a phosphorus bioavailability of 90-100%, those of animal origin 40-80%, those of plant origin 30%. Conclusions: The additives used in industrialized foods promote hyperphosphatemia and thus accelerate the progression of chronic kidney disease, unlike foods of animal and vegetable origin that are less harmful to health. This guides the training of the health sector, expanding its knowledge in the nutritional treatment of the patient.

The relationships among Flory-Huggins specific interaction parameters, maximum amorphous capacity, and solid-state interactions of spray dried amorphous drug dispersions with conventional and novel pharmaceutical polymers / Las relaciones entre los parámetros de interacción específicos de Flry-Huggins, la capacidad amorfa máxima y las interacciones en estado sólido de las dispersiones de fármacos amorfos secados por aspersión con polímeros farmacéuticos convencionales y nuevos

This study evaluated the specific interactions between drug and polymers in amorphous spray dried dispersions (SDDs). Four Biopharmaceutics Classification System (BCS) II class drugs were evaluated. Binary and ternary SDDs were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between drug and polymer were determined using theoretical calculations and DSC data. Analytical methods were used to evaluate solid and solution state interactions. Maximum amorphous content for each formulation was calculated using DSC. Flory-Huggins Specific Interaction Parameters were calculated. Negative specific parameters were associated with solid-state interactions and improved capacity of drug in the amorphous state. Ternary SDDs containing drug, polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary SDDs. Solution-state interactions observed in binary systems may be used in tertiary systems to improve the amorphous drug capacity and improved dissolution compared to the binary. The resultant tertiary systems are an improvement over binary drug polymer systems.

Este estudio evaluó las interacciones específicas entre el fármaco y los polímeros en dispersiones amorfas secadas por pulverización (SDD). Se evaluaron cuatro fármacos de clase II del Sistema de Clasificación Biofarmacéutica (BCS). Los SDD binarios y ternarios se fabricaron con polímeros convencionales y arabinogalactano. Los parámetros de interacción específicos entre el fármaco y el polímero se determinaron utilizando cálculos teóricos y datos de DSC. Se utilizaron métodos analíticos para evaluar las interacciones del estado sólido y de la solución. El contenido amorfo máximo para cada formulación se calculó usando DSC. Se calcularon los parámetros de interacción específicos de Flory-Huggins. Los parámetros específicos negativos se asociaron con interacciones en estado sólido y una capacidad mejorada del fármaco en el estado amorfo. Los SDD ternarios que contienen fármaco, polímero y arabinogalactano mostraron enlaces de hidrógeno similares a los observados con los SDD binarios. Las interacciones de estado de solución observadas en sistemas binarios pueden usarse en sistemas terciarios para mejorar la capacidad del fármaco amorfo y mejorar la disolución en comparación con el binario. Los sistemas terciarios resultantes son una mejora con respecto a los sistemas de polímeros de fármacos binarios.

Poloxamer-enhanced solubility of griseofulvin and its related antifungal activity against Trichophyton spp

Abstract Poorly water-soluble drugs, such as the antifungal drug griseofulvin (GF), exhibit limited bioavailability, despite their high membrane permeability. Several technological approaches have been proposed to enhance the water solubility and bioavailability of GF, including micellar solubilization. Poloxamers are amphiphilic block copolymers that increase drug solubility by forming micelles and supra-micellar structures via molecular self-association. In this regard, the aim of this study was to evaluate the water solubility increment of GF by poloxamer 407 (P407) and its effect on the antifungal activity against three Trichophyton mentagrophytes and two T. rubrum isolates. The GF water solubility profile with P407 revealed a non-linear behavior, well-fitted by the sigmoid model of Morgan-Mercer-Flodin. The polymer promoted an 8-fold increase in GF water solubility. Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and 2D nuclear magnetic resonance (NMR Roesy) spectroscopy suggested a GF-P407 interaction, which occurs in the GF cyclohexene ring. These results were supported by an increase in the water solubility of the GF impurities with the same molecular structure. The MIC values recorded for GF ranged from 0.0028 to 0.0172 mM, except for T. Mentagrophytes TME34. Notably, the micellar solubilization of GF did not increase its antifungal activity, which could be related to the high binding constant between GF and P407.

Bioavailability augmentation of silymarin using natural bioenhancers: An in vivo pharmacokinetic study

Abstract Pharmacokinetic studies were carried out in male and female rats to quantify silymarin as silybin (A+B) after the oral administration of various silymarin formulations combined with three bioenhancers, namely, lysergol, piperine, and fulvic acid, and compared with plain silymarin formulation (control). A non-compartmental analysis, model independent analysis, was utilized, and various pharmacokinetic parameters (C max, T max, and AUC 0-t) were calculated individually for each treatment group, and the values were expressed as mean ± SEM (n = 6). Plasma samples obtained from the rats were analyzed for the concentration of silymarin through a validated RP-HPLC method and on the basis of data generated from the pharmacokinetic studies. Results indicated that the bioenhancers augmented pharmacokinetic parameters and bioavailability increased 2.4-14.5-fold in all the formulations compared with the control. The current work envisages the development of an industrially viable product that can be further subjected to clinical trials and scientifically supports the development of silymarin as a contemporary therapeutic agent with enhanced bioavailability and medicinal values.

Pharmaceutical co-crystals of posaconazole for improvement of physicochemical properties

Abstract Posaconazole exerts an extended spectrum of antifungal activity against various strains of clinically relevant moulds and yeasts. In recent years, antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. After oral administration of posaconazole, absolute bioavailability has been estimated to range from 8% to 47%. Pharmaceutical co-crystallization is a promising approach for improving dissolution rate or manipulating other physical properties of API. The objective of this study is to improve the dissolution rate of posaconazole by co-crystallization. A 1:1 stoichiometric co-crystals of adipic acid were prepared by solvent assisted grinding method. The prepared co-crystals were subjected to solid-state characterization by FTIR, PXRD and DSC studies. The physicochemical properties of posaconazole and co-crystals were assessed in terms of melting point, flowability and dissolution rate. The results indicated improvement in flow property and dissolution rate. In vitro dissolution profile of co-crystals showed a significant increased dissolution of posaconazole from initial period in 0.1 N hydrochloric acid solution. The dissolution efficiency for posaconazole-adipic acid co-crystal was 61.65 % against posaconazole, 46.58 %. Thus, co-crystallization can be a promising approach to prepare posaconazole-adipic acid co-crystals with improved physicochemical properties.

Saneamiento industrial: Biodisponibilidad de patógenos en superficies / Industrial sanitation: Bioavailability of pathogens on surfaces

En condiciones adecuadas como humedad, alcalinidad, o temperatura, determinados patógenos logran adherirse a las superficies y sobrevivir ciertos períodos fuera de un anfitrión, persistiendo en algunos casos a procesos deficientes de limpieza y desinfección, configurándose como un posible foco de transmisión. Por ello, el correcto saneamiento cumple un propósito vital en la protección de los trabajadores de la industria y otros sectores frente al riesgo de contaminación por contacto directo con las superficies contaminadas. La literatura científica muestra amplia evidencia de la supervivencia de patógenos sobre superficies que son habituales dentro de instalaciones industriales, como acero, aluminio, madera, plástico y vidrio. La supervivencia de microorganismos en las superficies puede configurarse como candidato a marcador de biodisponibilidad, que puede ser usado en la industria para establecer y auditar los planes de higienización y saneamiento industrial, permitiendo estudiar la eficacia de los compuestos usados en la desinfección, y variables como su concentración, temperatura, e intervalos de aplicación y remoción(AU)

Under suitable conditions such as humidity, alkalinity, or temperature, certain pathogens manage to adhere to surfaces and survive certain periods outside of a host, persisting in some cases to poor cleaning and disinfection processes, becoming a possible source of transmission. Therefore, proper sanitation serves a vital purpose in protecting workers in industry and other sectors from the risk of contamination by direct contact with contaminated surfaces. The scientific literature shows ample evidence of the survival of pathogens on surfaces that are common within industrial facilities, such as steel, aluminum, wood, plastic and glass. The survival of microorganisms on surfaces can be configured as a candidate for bioavailability marker, which can be used in the industry to establish and audit industrial sanitation and sanitation plans, allowing to study the efficacy of the compounds used in disinfection, and variables such as its concentration, temperature, and application and removal intervals(AU(

Fluoride bioavailability on demineralized enamel by commercial mouth rinses

Abstract The ability of mouth rinses, available in the international market, to form reaction products on demineralized enamel (bioavailability test) was evaluated in vitro. Nine mouth rinses purchased in Chile were evaluated; eight formulated with NaF (one containing 100 µg F/mL and seven containing 226) and one with Na2FPO3 (226 µg F/mL as ion F). Demineralized enamel slabs (n=15 per mouth rinse) were sectioned; one half was subjected to the assigned mouth rinse treatment for 10 min and the other half was used to obtain baseline data. Loosely bound and firmly bound fluoride formed on enamel were determined with an ion-specific electrode and the values were expressed in µg F/cm2. The concentration of fluoride and the pH of the mouth rinses were previously determined. Concentrations of loosely bound and firmly bound fluoride formed on enamel were independently analyzed by ANOVA and Tukey's test (α=5%). The loosely bound and firmly bound fluoride concentrations (µg F/cm2) formed ranged from 3.2 to 36.2 and 0.4 to 1.7, respectively. Loosely bound fluoride formed on enamel was significantly more effective in discriminating the effect of different commercial mouth rinses than firmly bound fluoride. Mouth rinses with 226 ppm F as NaF and low pH presented significantly greater bioavailability of fluoride on enamel than those with higher pH or lower NaF concentration. The mouth rinse with Na2FPO3 showed low reactivity. Although further studies are necessary, the findings showed that commercial fluoride-containing mouth rinses have important variations in enamel fluoride bioavailability, which may result in differences on anticaries efficacy.

Resumo Os enxaguatórios bucais comerciais fluoretados diferem na concentração e tipo de sal de fluoreto, no pH e têm alguns ingredientes que podem interferir na reatividade do fluoreto com o esmalte desmineralizado. A capacidade de enxaguatórios bucais comerciais de formar produtos de reação em esmalte desmineralizado (teste de biodisponibilidade) foi avaliada in vitro. Nove enxaguatórios bucais adquiridos no Chile foram avaliados, oito formulados com NaF (um contendo 100 µg F/mL e sete contendo 226) e um com Na2FPO3 (226 µg F/mL como íon F). Os blocos de esmalte desmineralizados (n=15 por grupo) foram seccionados, uma metade foi submetida ao tratamento com o enxaguatório designado por 10 min e a outra metade foi usada para dados baseline. Fluoreto fracamente e firmemente ligados formados no esmalte foram determinados com um eletrodo íon-específico e os valores foram expressos em µg F /cm2. A concentração de fluoreto e o pH dos enxaguatórios foi previamente determinada. As concentrações de fluoreto tipo fluoreto fracamente ligado e fortemente ligado formadas no esmalte foram analisadas independentemente por ANOVA e teste de Tukey (α=5%). As concentrações de fluoreto fracamente ligado e fortemente ligado formados variaram de 3,2 a 36,2 e 0,4 a 1,7, respectivamente. O fluoreto fracamente ligado formado no esmalte foi significativamente mais eficaz para discriminar o efeito dos diferentes enxaguatórios bucais comerciais do que o fluoreto firmemente ligado. Enxaguatórios bucais com 226 ppm F na forma de NaF e baixo pH apresentaram significativamente maior biodisponibilidade de fluoreto no esmalte do que aqueles com maior pH ou menor concentração de NaF. O enxaguatório com Na2FPO3 apresentou reatividade muito baixa. Embora mais estudos sejam necessários, os resultados mostraram que os enxaguatórios bucais comerciais contendo fluoreto apresentam variações importantes na biodisponibilidade do fluoreto, o que poderia resultar em diferenças na eficácia anticárie.

Eficiencia del tratamiento de casos nuevos de tuberculosis sensible en Chile / Treatment efficiency in new cases of susceptible tuberculosis in Chile

Resumen La terapia de la tuberculosis con el esquema primario recomendado por la OMS no logra la curación de todos los casos a nivel mundial, pero en general alcanza un éxito de curación de al menos el 85% de los casos en el año 2018. El mismo año en Chile la eficiencia del tratamiento es solo de 76%, principalmente por la alta proporción de muertes y pérdida de seguimiento durante la terapia. Datos preliminares muestran que la cohorte ingresada en 2019 tuvo un éxito de tratamiento cercano a 74%. En Chile los fracasos de tratamiento son infrecuentes, debido principalmente a la vigilancia nacional de la susceptibilidad a fármacos. Para reducir la letalidad es necesario reforzar las estrategias para el diagnóstico precoz de la tuberculosis, mediante nuevos algoritmos que incorporen la biología molecular y la radiología en casos sospechosos de esta enfermedad, fomentar el adecuado manejo de las comorbilidades, establecer una adecuada red de apoyo social y disponer de centros de hospitalización cuando se requieren. Además, se debe fortalecer la adherencia a la terapia de los pacientes con estrategias de incentivo y facilitación de la asistencia.

Tuberculosis therapy with the primary regimen recommended by the World Health Organization does not cure all cases globally, but it reached success in at least 85% of cases in the year 2018. The same year in Chile, treatment efficiency is achieved in only 76%, mainly due to the high proportion of deaths and loss of follow-up during therapy. Preliminary data show that in the 2019 cohort the success was achieved only in about 74% of new cases. Treatment failures in Chile are rare due to national surveillance of drug susceptibility. To reduce fatality, it is necessary to reinforce the strategies for early diagnosis of tuberculosis through new algorithms. Such strategies should include molecular biology and radiology in suspected TB cases, to promote proper management of comorbidities, establish an adequate social support network and have centers available for prolonged hospitalization when needed. In addition, patient's adherence to therapy should be strengthened with strategies that encourage and facilitate attendance.

Fluoride bioavailability on demineralized enamel by commercial mouthrinses

Abstract The ability of mouthrinses, available in the international market, to form reaction products on demineralized enamel (bioavailability test) was evaluated in vitro. Nine mouthrinses purchased in Chile were evaluated; eight formulated with NaF (one containing 100 µg F/mL and seven containing 226) and one with Na2FPO3 (226 µg F/mL as ion FPO3 ). Demineralized enamel slabs (n=15 per mouthrinse) were sectioned; one half was subjected to the assigned mouthrinse treatment for 10 min and the other half was used to obtain baseline data. Loosely bound and firmly bound fluoride formed on enamel were determined with an ion-specific electrode and the values were expressed in µg F/cm2. The concentration of fluoride and the pH of the mouthrinses were previously determined. Concentrations of loosely bound and firmly bound fluoride formed on enamel were independently analyzed by ANOVA and Tukey's test (α=5%). The loosely bound and firmly bound fluoride concentrations formed ranged from 3.2 to 36.2 and 0.4 to 1.7, respectively. Loosely bound fluoride formed on enamel was significantly more effective in discriminating the effect of different commercial mouthrinses than firmly bound fluoride. Mouthrinses with 226 ppm F as NaF and low pH presented significantly greater bioavailability of fluoride on enamel than those with higher pH or lower NaF concentration. The mouthrinse with Na2FPO3 showed low reactivity. Although further studies are necessary, the findings showed that commercial fluoride-containing mouthrinses have important variations in enamel fluoride bioavailability, which may result in differences on anticaries efficacy.

Resumo Os enxaguatórios bucais comerciais fluoretados diferem na concentração e tipo de sal de fluoreto, no pH e têm alguns ingredientes que podem interferir na reatividade do fluoreto com o esmalte desmineralizado. A capacidade de enxaguatórios bucais comerciais de formar produtos de reação em esmalte desmineralizado (teste de biodisponibilidade) foi avaliada in vitro. Nove enxaguatórios bucais adquiridos no Chile foram avaliados, oito formulados com NaF (um contendo 100 µg F/mL e sete contendo 226) e um com Na2FPO3 (226 µg F/mL como íon F). Os blocos de esmalte desmineralizados (n=15 por grupo) foram seccionados, uma metade foi submetida ao tratamento com o enxaguatório designado por 10 min e a outra metade foi usada para dados baseline. Fluoreto fracamente e firmemente ligados formados no esmalte foram determinados com um eletrodo íonespecífico e os valores foram expressos em µg F /cm2. A concentração de fluoreto e o pH dos enxaguatórios foi previamente determinada. As concentrações de fluoreto tipo fluoreto fracamente ligado e fortemente ligado formadas no esmalte foram analisadas independentemente por ANOVA e teste de Tukey (α=5%). As concentrações de fluoreto fracamente ligado e fortemente ligado formados variaram de 3,2 a 36,2 e 0,4 a 1,7, respectivamente. O fluoreto fracamente ligado formado no esmalte foi significativamente mais eficaz para discriminar o efeito dos diferentes enxaguatórios bucais comerciais do que o fluoreto firmemente ligado. Enxaguatórios bucais com 226 ppm F na forma de NaF e baixo pH apresentaram significativamente maior biodisponibilidade de fluoreto no esmalte do que aqueles com maior pH ou menor concentração de NaF. O enxaguatório com Na2FPO3 apresentou reatividade muito baixa. Embora mais estudos sejam necessários, os resultados mostraram que os enxaguatórios bucais comerciais contendo fluoreto apresentam variações importantes na biodisponibilidade do fluoreto, o que poderia resultar em diferenças na eficácia anticárie

Effects of HPMCAS MF on absorption of silybin from supersaturable self-nanoemulsifying drug delivery system / 中国中药杂志

To evaluate the effects of Hydroxypropyl methylcellulose acetate succinate(HPMCAS MF) on absorption of silybin(SLB) from supersaturable self-nanoemulsifying drug delivery system which was pre-prepared at the early stage experiment. The cell toxicity of self-emulsifying preparation was evaluated by the MTT method, and the in vitro membrane permeability and absorption promoting effect of the self-emulsifying preparation were evaluated by establishing a Caco-2 cell monolayer model. The in vivo and in vitro supersaturation correlation was evaluated via the blood concentration of SLB. The results of MTT showed that the concentration of the preparation below 2 mg·mL~(-1)(C_(SLB) 100 μg·mL~(-1)) was not toxic to Caco-2 cells, and the addition of polymer had no significant effect on Caco-2 cells viability. As compared with the solution group, the transport results showed that the P_(app)(AP→BL) of the self-emulsifying preparation had a very significant increase; the transport rate of silybin can be reduced by polymer in 0-30 min; however, there was no difference in supersaturated transport between supersaturated SLB self-nanoemulsion drug delivery system(SLB-SSNEDDS) and SLB self-nanoemulsion drug delivery system(SLB-SNEDDS) within 2 hours. As compared with SLB suspension, pharmacokinetic parameters showed that the blood concentration of both SLB-SNEDDS and SLB-SSNEDDS groups were significantly increased, and C_(max) was 5.25 times and 9.69 times respectively of that in SLB suspension group, with a relative bioavailability of 578.45% and 1 139.44% respectively. C_(max) and relative bioavailability of SLB-SSNEDDS were 1.85 times and 197% of those of SLB-SNEDDS, respectively. Therefore, on the one hand, SSNEDDS can increase the solubility of SLB in gastrointestinal tract by maintaining stability of SLB supersaturation state; on the other hand, the osmotic transport process of SLB was regulated through the composition of its preparations, and both of them could jointly promote the transport and absorption of SLB to improve the oral bioavailability of SLB.

Enzymatic synthesis of acylated quercetin 3-O-glycosides: a review / 生物工程学报

Quercetin 3-O-glycosides (Q3Gs) are important members of quercetin glycosides with excellent pharmacological activities such as anti-oxidation, anti-inflammation, anti-cancer and anti-virus. Two representatives of Q3Gs, rutin and troxerutin, have been developed into clinical drugs, demonstrating Q3Gs have become one of the important sources of innovative drugs. However, the applications of Q3Gs in food and pharmaceutical industries are hampered by its poor bioavailability. Of the known means, selective acylation modification of Q3Gs through enzymatic catalysis to obtain Q3G esters is one of the effective ways to improve its bioavailability. Herein, the enzyme-mediated acylation of Q3Gs were reviewed in details, focusing on the four tool enzymes (acyltransferases, lipases, proteases and esterases) and the whole-cell mediated biotransformation, as well as the effect of acylations on the biological activities of Q3Gs. Furthermore, the highly efficient synthesis and diversification of acylated site for Q3G esters were also discussed. Taken together, this review provides a new perspective for further structural modifications of Q3Gs towards drug development.

A systematic review of pharmacological activities, toxicological mechanisms and pharmacokinetic studies on Aconitum alkaloids / 中国天然药物

The tubers and roots of Aconitum (Ranunculaceae) are widely used as heart medicine or analgesic agents for the treatment of coronary heart disease, chronic heart failure, rheumatoid arthritis and neuropathic pain since ancient times. As a type of natural products mainly extracted from Aconitum plants, Aconitum alkaloids have complex chemical structures and exert remarkable biological activity, which are mainly responsible for significant effects of Aconitum plants. The present review is to summarize the progress of the pharmacological, toxicological, and pharmacokinetic studies of Aconitum alkaloids, so as to provide evidence for better clinical application. Research data concerning pharmacological, toxicological and pharmacokinetic studies of Aconitum alkaloids were collected from different scientific databases (PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science) using the phrase Aconitum alkaloids, as well as generic synonyms. Aconitum alkaloids are both bioactive compounds and toxic ingredients in Aconitum plants. They produce a wide range of pharmacological activities, including protecting the cardiovascular system, nervous system, and immune system and anti-cancer effects. Notably, Aconitum alkaloids also exert strong cardiac toxicity, neurotoxicity and liver toxicity, which are supported by clinical studies. Finally, pharmacokinetic studies indicated that cytochrome P450 proteins (CYPs) and efflux transporters (ETs) are closely related to the low bioavailability of Aconitum alkaloids and play an important role in their metabolism and detoxification in vivo.

Research progress on rutin derivatives / 中国中药杂志

Compounds derived from natural products present satisfactory efficacy in disease prevention and treatment. The use of chemical substances in plants to promote healthhas increasingly attracted people's attention. Rutin, a typical flavonoid, is mainly found in various vegetables, fruits and Chinese herbal medicines. As a natural antioxidant, it features many pharmacological activities, such as anti-inflammation, anti-virus, anti-tumor, and prevention and treatment of cardiovascular and cerebrovascular diseases. However, the low bioavailability and poor water solubility limit its clinical application. In view of this, its structure is optimized and modified to afford rutin derivatives with good solubility, high bioavailability, stable metabolism and small toxic side effects. So far, a large number of rutin ethers, esters, and complexes have been synthesized and undergone activity testing. This paper reviews the structural modification of rutin in recent years, and the obtained derivatives have excellent properties and significant biological activity.

Research progress on therapeutic potential of quercetin / 中国中药杂志

Quercetin is a naturally occurring phytochemical with good bioactivity, which mainly exists in the form of glycoside in vegetables, fruits, tea, and wine and exhibits beneficial health effects. Quercetin is a dietary polyphenol that exerts the protective effects through diet or use as a food supplement. Compared with chemical agents, quercetin is widely available and safe. Quercetin has been extensively studied for its anti-diabetic, anti-hypertensive, anti-Alzheimer's disease, anti-arthritic, anti-influenza virus, anti-microbial infection, anti-aging, autophagy-regulating, and cardiovascular protective effects. Studies on its activities against different can-cer cell lines have also been reported recently. However, the poor water solubility, rapid in vivo metabolism, and short half-life of quercetin have led to its low bioavailability, thus limiting its application in the field of medicine. Quercetin nanoparticles and nanoparticle drug delivery system have been effectively utilized for enhancing its bioavailability. This paper reviewed the therapeutic potential of quercetin from both preclinical and clinical aspects and proposed solutions to improve its bioavailability, so as to provide a reference for the therapeutic application of natural compounds in the field of medicine.

An attempt to enhance solubility of metoclopramide base by Solid dispersion strategy and its application on development of Transdermal device

Chemotherapy induced nausea and vomiting (CINV) is an issue, which usually occurs in cancer patient. Despite high bioavailability of oral and intravenous administration, these have some drawbacks. The oral route causes hepatic first pass metabolism and intravenous route is invasive in nature. Hence, antiemetic drug by means of transdermal route is necessary to administer in such cases. The aim of the present investigation is to develop suitable Transdermal Therapeutic System (TTS) with an objective to enhance solubility and skin permeability properties of metoclopramide base. Preformulation study begins with an approach to enhance solubility of 40 metoclopramide base by solid dispersion technique. transdermal films were prepared with 41 the solid dispersion as well as with pure drug. Phase solubility study at various temperatures reveals binding constants (Ka, 95-350 M-1 for PVP K30; 56-81 M-1 for HPßCD). Spontaneity of solubilization was justified by AL type linear profiles. The films showed satisfactory diffusion (%), permeation rate and flux after 8 h study. The transdermal patches as prepared were analyzed under FTIR, DSC and SEM. Both solubility and permeability rate in this investigation have been enhanced. So, it can be affirmed that this route would effectively enhance bioavailability

Effects of vitamin D-induced supernatant of placental explants from preeclamptic women on oxidative stress and nitric oxide bioavailability in human umbilical vein endothelial cells

The study evaluated the effect of the supernatant of placental explants from preeclamptic (PE) and normotensive (NT) pregnant women after tissue treatment with or without vitamin D (VD) on oxidative stress and nitric oxide (NO) bioavailability in human umbilical vein endothelial cells (HUVEC). Placental explants were prepared from eight NT and eight PE women, and supernatants were obtained after incubation with or without hydrogen peroxide (H2O2) and/or VD. HUVEC were cultured for 24 h with supernatants, and the following parameters were analyzed in HUVEC cultures: NO, nitrate (NO3-), and nitrite (NO2-) levels, lipid peroxidation, and intracellular reactive oxygen species (ROS). Results showed that the production of NO3-, NO2-, malondialdehyde (MDA), and ROS were significantly higher in HUVEC treated with explant supernatant from PE compared to NT pregnant women, while the supernatant of PE explants treated with VD led to a decrease in these parameters. A significantly high production of NO was detected in HUVEC cultured with control supernatant of NT group, and in cultures treated with supernatant of PE explants treated with VD. Taken together, these results demonstrated that cultures of placental explants from PE women with VD treatment generated a supernatant that decreased oxidative stress and increased the bioavailability of NO in endothelial cells.

Fluoride Concentration in SDF Commercial Products and Their Bioavailability with Demineralized Dentine

Abstract The aim of this in vitro study was to determine the fluoride concentration in silver diamine fluoride (SDF) products and their bioavailability with demineralized dentine. The products evaluated (expected fluoride concentrations) were: I: Saforide 38% (45,283 ppm F); II: Advantage Arrest 38.3 to 43.2% (45,283 to 51,013 ppm F); III: Ancárie 12% (14,100 ppm F); IV: Ancárie 30% (35,400 ppm F), V: Cariestop 12% (14,100 ppm F) and VI: Cariestop 30% (35,400 ppm F). The fluoride concentration was evaluated using an ion-specific electrode (ISE) by direct technique, which was confirmed after microdiffusion. The pH of the products was determined with a pH test strip. For the bioavailability test, demineralized dentine slabs were treated with one of the products for 1 min. Loosely (CaF2-like) and firmly-bound fluoride (FAp) were determined. The fluoride concentration found in the products (mean±SD; ppm F) by the ISE direct technique was: I:53,491±554; II:57,249±1,851; III:4,814±268; IV:5,726±43; V:10,145±468; VI:11,858±575; these values were confirmed after microdiffusion (t-test; p>0.05) and disagree with the declared by the manufacturers. The pH of Ancárie 12 and 30% was 6.0 and 4.5, respectively, in disagreement with the alkaline pH expected for SDF solution and found in the other products evaluated. There was no correlation between either CaF2-like (r=0.221; p=0.337) or FAp (r=-0.144; p=0.830) formed in demineralized dentine and fluoride concentration found in the products. The problems of pH and fluoride concentration found in available professional commercial SDF products suggest that they are not under sanitary surveillance.

Resumo O objetivo deste estudo in vitro foi determinar a concentração de fluoreto nos produtos de diamino fluoreto de prata (DFP) e sua biodisponibilidade com dentina desmineralizada. Os produtos avaliados (concentrações esperadas de flúor) foram: I: Saforide 38% (45.283 ppm F); II: Advantage Arrest 38,3 a 43,2% (45.283 a 51.013 ppm F); III: Ancárie 12% (14.100 ppm F); IV: Ancárie 30% (35.400 ppm F), V: Cariestop 12% (14.100 ppm F) e VI: Cariestop 30% (35.400 ppm F). A concentração de fluoreto foi avaliada utilizando um eletrodo íon-específico (EIE) por técnica direta, que foi confirmada após microdifusão. O pH dos produtos foi determinado com uma tira de teste de pH. Para o teste de biodisponibilidade, blocos de dentina desmineralizada foram tratados com um dos produtos por 1 min. Fluoreto fracamente (tipo CaF2) e firmemente ligado (FAp) foram determinados. A concentração de fluoreto encontrada nos produtos (média±DP; ppm F) pela técnica direta com EIE foi: I: 53.491±554; II: 57.249±1.851; III: 4.814±268; IV: 5.726±43; V: 10.145±468; VI: 11.858±575; esses valores foram confirmados após microdifusão (teste t; p>0,05) e discordam dos declarados pelos fabricantes. O pH do Ancárie 12 e 30% foi de 6,0 e 4,5, respectivamente, em desacordo com o pH alcalino esperado para a solução de DFP e encontrado nos demais produtos avaliados. Não houve correlação entre CaF2 (r=0,221; p=0,337) ou FAp (r=-0,144; p=0,830) formados na dentina desmineralizada e concentração de fluoreto encontrada nos produtos. Os problemas de pH e concentração de fluoreto encontrados nos produtos comerciais profissionais disponíveis de DFP sugerem que eles não estão sob vigilância sanitária.