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1.
MedUNAB ; 25(2): 279-289, 2022/08/01.
Article in Spanish | LILACS | ID: biblio-1395815

ABSTRACT

Introducción. La Organización Mundial de la Salud (OMS) estima que más del 40% de las mujeres embarazadas a nivel mundial tienen anemia, y la mitad de estas padecen deficiencia de hierro. La prevalencia en América Latina es del 40% y en Colombia del 44.7%. Fisiológicamente en el embarazo se produce una mal llamada "anemia dilucional", existen condiciones en la embarazada que la predisponen a tener una anemia patológica. Esta última es causada principalmente por un déficit de hierro, de allí la importancia de diagnosticar a tiempo esta entidad e iniciar el manejo. La administración de hierro es la base del tratamiento de la anemia por deficiencia de hierro. Puede ser administrado por vía oral, la cual es la preferida en la mayoría de las pacientes; sin embargo, cuando este no es posible administrarlo, es esencial recurrir al hierro parenteral. No obstante, el hierro parenteral es poco usado como primera línea en el manejo de la anemia gestacional. El presente artículo tiene como objetivo realizar una revisión que permita identificar la terapia con hierro parenteral como una alternativa eficaz de manejo para la anemia gestacional, teniendo en cuenta las características farmacológicas, la administración y el uso entre las diferentes moléculas disponibles en Colombia. Metodología. Corresponde a un estudio de revisión de literatura en bases de datos y bibliotecas electrónicas, los criterios que se tuvieron en cuenta fueron textos publicados entre 1996 y 2020, en español e inglés. Se obtuvo un resultado de 95 artículos, de los cuales se seleccionaron 49. Las palabras clave para su búsqueda fueron fisiología, hierro parenteral, anemia gestacional, déficit de hierro, complicaciones del embarazo, compuestos de hierro, farmacocinética, diagnóstico y tratamiento. División de temas tratados. Fisiología; ayudas diagnósticas; características farmacológicas del hierro parenteral; ventajas, indicaciones y contraindicaciones del hierro parenteral; efectos secundarios y forma de aplicación. Conclusiones. El hierro parenteral es un tratamiento seguro y eficaz para manejar la anemia en el embarazo, se debe tener en cuenta las indicaciones y la farmacología de las moléculas para elegir la más adecuada. Además, repone más rápidamente las reservas de hierro y los niveles de hemoglobina.


Introduction. The World Health Organization (WHO) estimates that more than 40% of pregnant women worldwide have anemia, and that half of them suffer from iron deficiency. The prevalence of this in Latin America is 40%, and in Colombia, 44.7%. Physiologically, a problem called "dilutional anemia" occurs during pregnancy. There are conditions in pregnant women that predispose them to suffering from pathological anemia. The latter is mainly caused by iron deficiency, hence the importance of diagnosing this entity on time and starting treatment. Iron administration is the basis of treatment of anemia caused by iron deficiency. It can be administered orally, which is the preferred option in the majority of patients. However, when this is not possible, parenteral iron must be used. However, parenteral iron is rarely used as the first line of treatment of gestational anemia. The objective of this article is to carry out a review that allows for the identification of therapy with parenteral iron as an efficient alternative for the treatment for gestational anemia, considering the pharmacological characteristics, administration, and use among the different molecules available in Colombia. Methodology. We carried out a search in databases and electronic libraries. The criteria considered were texts published between 1996 and 2020 in Spanish and English. 95 articles were obtained, of which 49 were selected. The keywords for their search were physiology, parenteral iron, gestational anemia, iron deficit, pregnancy complications, iron compounds, pharmacokinetics, diagnosis, and treatment. Division of Covered Topics. Physiology; diagnostic aids; pharmacological characteristics of parenteral iron; advantages, indications, and contraindications of parenteral iron; secondary effects and application method. Conclusions. Parenteral iron is a safe and efficient treatment to handle anemia during pregnancy. The indications and pharmacology of the molecules must be considered to choose the most appropriate option. In addition, it replaces iron reserves and hemoglobin levels more quickly.


Introdução. A Organização Mundial de Saúde (OMS) estima que mais de 40% das mulheres grávidas em todo o mundo são anêmicas, e metade delas sofre de deficiência de ferro. A prevalência na América Latina é de 40% e na Colômbia de 44.7%. Fisiologicamente na gravidez ocorre a chamada "anemia dilucional", e existem condições na gestante que a predispõem a ter uma anemia patológica. Esta última é causada principalmente por deficiência de ferro, daí a importância de diagnosticar esta entidade a tempo e iniciar o manejo. A administração de ferro é a base do tratamento da anemia por deficiência de ferro. Pode ser administrado por via oral, o que é preferido pela maioria das pacientes; porém, quando não for possível administrá-lo dessa forma, é imprescindível recorrer ao ferro parenteral. No entanto, o ferro parenteral é raramente usado como primeira linha no manejo da anemia gestacional. O objetivo deste artigo é realizar uma revisão que permita identificar a terapia com ferro parenteral como uma alternativa eficaz de tratamento da anemia gestacional, levando em consideração as características farmacológicas, administração e uso entre as diferentes moléculas disponíveis na Colômbia. Metodologia. Foi realizada uma busca em bases de dados e bibliotecas eletrônicas, os critérios levados em consideração foram textos publicados entre 1996 e 2020, em espanhol e inglês. Foi obtido um total de 95 artigos, dos quais 49 foram selecionados. As palavras-chave para a busca foram fisiologia, ferro parenteral, anemia gestacional, deficiência de ferro, complicações na gravidez, compostos de ferro, farmacocinética, diagnóstico e tratamento. Divisão dos temas abordados. Fisiologia; auxiliares de diagnóstico; características farmacológicas do ferro parenteral; vantagens, indicações e contraindicações do ferro parenteral; efeitos colaterais e método de aplicação. Conclusões. O ferro parenteral é um tratamento seguro e eficaz para o manejo da anemia na gravidez, as indicações e farmacologia das moléculas devem ser levadas em consideração a fim de escolher a mais adequada. Além disso, reabastece mais rapidamente as reservas de ferro e os níveis de hemoglobina.


Subject(s)
Maternal Nutritional Physiological Phenomena , Anemia , Pregnancy Complications , Pharmacokinetics , Iron Compounds , Iron Deficiencies
2.
Vitae (Medellín) ; 29(1): 1-8, 2022-01-09. Ilustraciones
Article in English | LILACS, COLNAL | ID: biblio-1363721

ABSTRACT

Background: In developing countries, particularly in Iraq, the use of generic medicines has been increasing in recent years, primarily as a cost-saving measure in healthcare provision. In the Iraqi market, famotidine tablets are available from different pharmaceutical companies. As a result, regular pre-marketing quality testing is required to check the quality and identify which product might safely substitute the innovator product in the event of the innovator brand's unavailability or high cost. Objective: various quality control tests have been conducted to determine the Pharmaceutical Equivalence of the different generic and brands of Famotidine film-coated tablets marketed in Iraq. Materials and Methods: Four different samples of the most commonly available Famotidine 20 mg tablets in the Iraqi market were tested for drug contents, friability, and hardness. Additionally, the in-vitro drug release and kinetics were evaluated. Results: slight differences in the products' content were found; however, they were within the acceptable requirement of British Pharmacopeia (BP) and The United States Pharmacopoeia (USP) 30, NF 25. Similarly, the friability and hardness were within the excellent range according to the B.P. and USP. The results of our study indicated that the tested brand (Famodin) and the three generic products (Famosam, Ulceran, and Famodar) of Famotidine tablets have a unique pattern of in-vitro release profiles. However, all the tested brands and generic pills complied with the USP specifications for the immediate release dosage forms except for Famosam. Release kinetic for the four tested products indicates first-order kinetic models. Conclusion: The findings revealed that nearly all of the tested Famotidine tablet brands and generics met the pharmacopeial requirements for oral tablets. As a result, if acquiring the innovative brand of famotidine tablets is difficult to obtain, healthcare providers may be advised to use the tested products instead


Antecedentes: En los países en vías de desarrollo, especialmente en Irak, el uso de medicamentos genéricos ha aumentado en los últimos años, principalmente como medida de ahorro en la prestación de servicios sanitarios. En el mercado iraquí, los comprimidos de famotidina están disponibles en diferentes empresas farmacéuticas. Por ello, es necesario realizar periódicamente pruebas de calidad previas a la comercialización para comprobar la calidad e identificar qué producto podría sustituir con seguridad al producto innovador en caso de que éste no esté disponible o tenga un coste elevado. Objetivo: se han realizado varias pruebas de control de calidad para determinar la Equivalencia Farmacéutica de los diferentes genéricos y marcas de Famotidina comprimidos recubiertos con película comercializados en Irak. Materiales y métodos: Se analizaron cuatro muestras diferentes de los comprimidos de 20 mg de Famotidina más comunes en el mercado iraquí para determinar el contenido de fármaco, la friabilidad y la dureza. Además, se evaluó la liberación in-vitro del fármaco y su cinética. Resultados: Se encontraron ligeras diferencias en el contenido de los productos; sin embargo, estaban dentro de los requisitos aceptables de B.P. y de la Farmacopea de Estados Unidos (USP) 30, NF 25. Así mismo, la friabilidad y la dureza estaban dentro del rango excelente según la B.P. y la USP. Los resultados de nuestro estudio indicaron que la marca probada (Famodin) y los tres productos genéricos (Famosam, Ulceran y Famodar) de comprimidos de famotidina tienen un patrón único de perfiles de liberación in-vitro. Sin embargo, todas las marcas y los comprimidos genéricos probados cumplieron con las especificaciones de la USP para las formas farmacéuticas de liberación inmediata, excepto Famosam. La cinética de liberación de los cuatro productos probados indica modelos cinéticos de primer orden. Conclusiones: Los resultados revelaron que casi todas las marcas y genéricos de comprimidos de Famotidina probados cumplían los requisitos farmacopeicos para los comprimidos orales. En consecuencia, si resulta difícil adquirir la marca innovadora de comprimidos de famotidina, se puede aconsejar a los profesionales sanitarios que utilicen los productos probados en su lugar


Subject(s)
Humans , Pharmaceutical Preparations , Pharmacokinetics , Drugs, Generic
3.
São Paulo; s.n; s.n; 2022. 63 p. tab, tab.
Thesis in Portuguese | LILACS | ID: biblio-1396298

ABSTRACT

Introdução: Meropenem (MER) e Piperacilina/Tazobactana (PTZ) são agentes antimicrobianos largamente prescritos para pacientes grandes queimados internados em Unidade de Terapia Intensiva (UTI) com infecções nosocomiais causadas por Gram-negativos sensíveis CIM 2 mg/L, Enterobacteriaceae, EB e Non-enterobacteriaceae, NEB. A síndrome da resposta inflamatória sistêmica (SRIS) que ocorre durante o choque séptico no grande queimado pode causar alteração na farmacocinética do paciente em terapia intensiva, de modo que a dose recomendada pode não atingir o alvo desejado contra Gram-negativos de sensibilidade intermediária CIM >2 mg/L. Objetivo: Investigar a efetividade dos beta-lactâmicos piperacilina e meropenem na infusão estendida comparada à infusão intermitente recomendada, para os pacientes sépticos grandes queimados através da abordagem farmacocinética-farmacodinâmica (PK/PD). Ética, casuística e procedimentos: Autor e co-autores declararam não haver conflito de interesse. O protocolo foi aprovado, registro CAAE 07525118.3.0000.0068. No presente protocolo de estudo investigaram-se 36 pacientes sépticos grandes queimados, ambos os gêneros (12F/24M) em terapia intensiva do choque séptico com piperacilina-tazobactana 4,5g q6h ou meropenem 1g q8h. Os pacientes incluídos foram estratificados em dois grupos com base na administração através da infusão intermitente, 0,5 h (G1) ou da infusão estendida, 3 h (G2), ambos com 16 pacientes cada. Duas amostras sanguíneas (1,5mL/cada) foram coletadas no estado de equilíbrio (Steady State), 3ª e 5ª hora do início da infusão. Os níveis séricos de PTZ e MER foram mensurados através de cromatografia líquida, e a farmacocinética (PK) dos dois grupos de pacientes foi comparada aos dados reportados em voluntários sadios. A abordagem PK/PD foi aplicada para avaliação da cobertura do antimicrobiano a partir da estimativa do índice de predição de efetividade (% fΔT>CIM) e da probabilidade de alcançar o alvo terapêutico (PTA) com base no alvo PK/PD recomendado, 100%fΔT>CIM. Resultados e discussão: As características de admissão dos pacientes G1/G2 foram expressas através de mediana e interquartil: Clcr 115 (90-148) / 127 (90-170) ml/min; 30 (24-31) / 27 (24- 33,5) anos, 70 (61-75) / 71 (65-75) kg, 30 (20-42) / 33,9 (18-38,4)% área total de superfície queimada, SAPS3 53 (45-57) / 48 (37,8-59,5). Na admissão dos pacientes na UTI registrou-se G1/G2: trauma térmico (17/16), trauma elétrico (1/2), lesão inalatória (11/11), ventilação mecânica (16/9) e vasopressores foram necessários em 15/8 pacientes, G1/G2. Ocorreram diferentes alterações na farmacocinética dos dois beta-lactâmicos após a infusão estendida versus a infusão intermitente quando comparadas com dados relatados em voluntários sadios. Evidenciou-se prolongamento da meia vida decorrente do aumento do volume de distribuição. Estes resultados impactaram diferentemente a cobertura. O monitoramento de biomarcadores inflamatórios expressos em medianas (G1/G2) evidenciou aumento do PCR: 232/183mg/L e leucocitose (leucócitos 11/14 mil cel/mm3, neutrófilos 9/10 mil cel/mm3) na fase precoce do choque séptico. Relativamente à microbiologia dos isolados, a erradicação dos patógenos ocorreu para todos os pacientes após a infusão estendida contra Gram-negativos sensíveis (CIM: 2 mg/L), e de sensibilidade intermediária (CIM 4mg/L) como a K. pneumoniae e P. aeruginosa, enquanto a infusão intermitente garantiu erradicação de patógenos apenas até CIM 2 mg/L. Conclusão: Evidenciou-se a superioridade da infusão estendida frente à infusão intermitente na cobertura dos dois antimicrobianos, no alvo terapêutico considerado 100%fΔT>CIM. Registraram-se alterações na farmacocinética destes agentes nos pacientes frente aos dados reportados para voluntários sadios. Diferença significativa entre grupos (G1/G2) foi encontrada com relação meia vida biológica, e ao volume de distribuição tanto pata a piperacilina quanto para o meropenem


Background: Meropenem (MER) and Piperacillin/Tazobactam (PTZ), antimicrobial betalactam agents are widely prescribed to burn patients from the Intensive Care Unit (ICU) with nosocomial infections caused by Gram-negative strains. Change in the pharmacokinetics of critically ill patient occurs during the systemic inflammatory response syndrome (SIRS) at the course of septic shock. Then, the recommended dose administered by intermittent infusion, 0.5 hr cannot reach the target against gram-negative strains MIC > 2 mg/L. Subject: To investigate drug effectiveness of the beta-lactams piperacilin and meropenem in extended infusion compared to the recommended intermittent infusion in critically ill septic burn patients using pharmacokinetic-pharmacodynamic (PK/PD) approach. Ethics, Casuistry and Methods: All authors declared there is no conflict of interests. Ethical approval CAAE, register 07525118.3.0000.0068. It was investigated in the study protocol 36 septic burn patients of both genders (12M / 24F), undergoing antimicrobial therapy with PTZ 4.5 g q6h or MER 1g q8h. Based on the chosen antimicrobial therapy and drug infusion prescribed by the physician, patients were stratified in groups with intermittent 0.5h infusion (G1) or with the extended 3h infusion (G2), both groups with 16 patients each. Two blood samples were collected at the steady state (1.5mL / each), at the 3rd and 5th hrs of starting the infusion. Serum levels were measured by liquid chromatography. Pharmacokinetics (PK) of MER or PTZ was compared to data reported in healthy volunteers for both groups of patients. PK/PD approach was applied to estimate the drug effectiveness index (fΔT> MIC) and to assess the probability of target attained (PTA) based on the recommended PK/PD target, 100% fΔT> MIC. Results and discussion: Characteristics of patients admission G1/G2 were: Clcr 115(90- 148)/127(90-170) ml/min; 30(24-31)/27(24-34) yrs, 70(61-75)/71(65-75) kg, 30(20- 42)/33.9(18-38.4)% total burn surface area, SAPS3 53(45-57)/48(37.8-59.5), medians (interquartile): thermal trauma occurred (17/16), electric trauma (1/2), inhalation injury (11/11), mechanical ventilation (9/16) and vasopressors required in 15/8 patients. It was demonstrated that different PK changes occurred for both beta-lactam agents after the extended or intermittent infusion by comparison with data reported in healthy volunteers. PK changes were related to the prolongation of biological half-life and increases on volume of distribution with impact on pharmacodynamics. On the other hand, meropenem total body clearance reduced by 50% at the earlier period of septic shock could be explained by the reduction of MER-transporters expression in the tubular renal secretion, once only patients with renal function preserved were included in the study protocol. Inflammatory biomarkers increased at the earlier period of septic shock: C-rp 232/183mg/L; leukocytes 11/14*103cel/mm3, neutrophils 9/10*103cel/mm3, medians, G1/G2. Clinical and microbiological cure was obtained for all patients of G1 against MIC < 2mg/L after intermittent 0.5 h infusion; while PK/PD target was attained for G2 patients undergoing antimicrobial therapy with MER or PTZ by extended infusion against gram negative strains K. pneumoniae, P. aeruginosa up to MIC 4mg L. Conclusion: Superiority of the extended infusion over intermitent infusion was obtained for the two antimicrobials was evidenced, in the therapeutic target considered 100%fΔT>CIM. Changes in the pharmacokinetics of these agents were recorded in patients compared to data reported for healthy volunteers. A significant difference between groups (G1/G2) was found in relation to biological half-life and volume of distribution for both piperacillin and meropenem


Subject(s)
Piperacillin/analysis , Burns/diagnosis , Meropenem/analysis , Patients/classification , Shock, Septic/complications , Pharmacokinetics , Pharmaceutical Preparations , Cross Infection/complications , Chromatography, Liquid/methods , Critical Illness/classification , Systemic Inflammatory Response Syndrome/diagnosis , Pharmacologic Actions , Enterobacteriaceae , Dosage , Intensive Care Units/classification , Anti-Infective Agents/analysis
4.
Vitae (Medellín) ; 28(3): 1-14, 2021-08-11. Ilustraciones
Article in English | LILACS, COLNAL | ID: biblio-1363261

ABSTRACT

Background: Milk-derived biopeptides have reported in vitro dipeptidyl-peptidase IV (DPP-IV) inhibition, suggesting a glycemic-regulatory effect in Type 2 Diabetes Mellitus (T2DM). Nonetheless, the therapeutic application of these nutraceuticals is limited by the scarcity of knowledge regarding their pharmacokinetic profile. Objective: This study aimed to characterize and assess the pharmacokinetics of milk-derived biopeptides. Through an in silico comparative analysis with gliptins, we expected to identify enhanced properties in food-hydrolysates and suitable DPP-IV inhibiting peptides as candidates for T2DM therapy. Methods: A comparison between gliptins and biopeptides was conducted based on in silico evaluation of drug-likeness, physicochemical properties, pharmacokinetics, and synthetic accessibility. Suitable target proteins for gastrointestinal-absorbable biopeptides were determined as well. Data collection was performed on SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes, and BIOPEP-UWM platforms. Statistical analysis was carried out using a one-way ANOVA test. Results: Drug-likeness compliance showed no significant difference between gliptins and biopeptides (p>0.05) in three out of nine assessed rules, though gastrointestinal-absorbable biopeptides exhibited no significant difference with gliptins in five drug-likeness guidelines. The physicochemical evaluation revealed a significant difference (p<0.05) between both groups, with peptides exhibiting enhanced solubility, flexibility, and polarity. Nine out of thirty-six assessed biopeptides reported being likely gastrointestinal-absorbable molecules, from which six displayed ≥30% predicted bioavailability, two reported CYP450 interactions, and all were determined to be blood confined. Biopeptides showed a slightly lower clearance than gliptins yet counteracted by a significantly lower half-life. Moreover, synthetic accessibility scores indicated higher synthetic ease for biopeptides. In addition, absorbable bioactive peptides reported a considerable binding affinity to DPP-IV and Calpain-I. Conclusions: Compared to gliptins, gastrointestinal-absorbable biopeptides exhibit superior physicochemical properties (higher solubility, flexibility, and polarity), lesser CYP450 interactions, higher synthetic ease, and some reported an important affinity for DPP-IV and Calpain-I. Only a small fraction of milk-derived biopeptides are suitable drug-like compounds and feasible candidates for T2DM therapy; yet, testing their therapeutic potency remains subject to further studies


Antecedentes: Los biopéptidos derivados de la leche han mostrado inhibir la dipeptidil-peptidasa IV (DPP-IV) en ensayos in vitro, lo que sugiere una regulación de la glicemia en la Diabetes Mellitus Tipo 2 (DM2). Sin embargo, su uso terapéutico está limitado por el escaso conocimiento de sus propiedades farmacológicas. Objetivo: Caracterizar y evaluar el perfil farmacocinético de los biopéptidos derivados de la leche. Por medio de un análisis comparativo in silico, se buscó identificar propiedades de carácter superior a las gliptinas en los biopéptidos inhibidores de DPP-IV, así como posibles candidatos a agentes terapéuticos en la DMT2. Métodos: Se llevó a cabo una comparación entre las Gliptinas y los biopéptidos basada en la evaluación in silicode las características "d r ug - li ke", propiedades fisicoquímicas, farmacocinética y accesibilidad sintética. Adicionalmente, se determinaron posibles proteínas diana para los biopéptidos de alta probabilidad de absorción gastrointestinal. Los datos se obtuvieron en SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes y BIOPEP-UWM. El análisis estadístico se basó en un análisis de varianza (one-way ANOVA test). Resultados: El cumplimiento de las reglas de "drug-likeness" no mostró diferencias significativas entre las gliptinas y los biopéptidos (p>0.05) en tres de las nueve normas evaluadas, empero, los biopéptidos absorbibles no mostraron diferencias significativas con las gliptinas en cinco de estas. La evaluación fisicoquímica reveló una diferencia significativa (p>0.05) entre ambos grupos y una mayor solubilidad, flexibilidad y polaridad para los biopéptidos. Nueve de los treinta y seis biopéptidos estudiados reportaron alta probabilidad de absorción gastrointestinal, de los cuales seis presentaron una biodisponibilidad predicha ≥30%, dos reportaron interacciones con el CYP450, y todos mostraron permanecer confinados en sangre. Los biopéptidos mostraron una tasa de aclaramiento inferior a las gliptinas, sin embargo, contrarrestado por una vida-media significativamente menor. Los valores de accesibilidad sintética indicaron una mayor facilidad de síntesis para los biopéptidos. Por último, los biopéptidos absorbibles mostraron una considerable afinidad por la DPP-IV y la Calpaína-I. Conclusiones: Frente a las gliptinas, los biopéptidos absorbibles presentan: propiedades fisicoquímicas superiores (mayor solubilidad, flexibilidad y polaridad), menores interacciones con el CYP450, mayor facilidad de síntesis y algunos una importante afinidad por la DPP-IV y la Calpaína-I. Una mínima fracción de biopéptidos derivados de la leche son candidatos viables para la terapia de DM2; sin embargo, la determinación de su efectividad terapéutica permanece sujeta a futuros estudios


Subject(s)
Humans , Pharmacokinetics , Peptides , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors
5.
Rev. cuba. endocrinol ; 32(2): e277, 2021. tab, graf
Article in Spanish | LILACS, CUMED | ID: biblio-1347402

ABSTRACT

Introducción: La aplicación de actividades fijas en el tratamiento del hipertiroidismo con I131 (yoduro de sodio, conocido también como radioyodo), es el método más usado en nuestro país, a pesar de la individualidad morfo-funcional que caracteriza esta afección. Sin embargo, no existe aún, un consenso internacional sobre la dosis más conveniente para cada caso, y por ende, los resultados no siempre son los deseados. Objetivo: Evaluar la aplicabilidad de varios métodos de cálculo de dosis paciente-específica para el tratamiento de hipertiroidismo con yoduro de sodio. Métodos: Se realizó un análisis de los resultados de varios métodos de cálculo de dosis recomendados internacionalmente a partir de la actividad fija prescrita en 10 pacientes, con el empleo de tecnologías y herramientas ya desarrolladas y disponibles en el país. Se evaluó la variabilidad inter-especialista y su impacto en la dosis planificada para el tratamiento. Resultados: El uso de la información incompleta de la biodistribución y farmacocinética del paciente produjo diferencias entre -42 por ciento y 37 por ciento de las dosis para el mismo paciente. El resultado de la comparación del método de cálculo recomendado por la Sociedad Europea de Medicina Nuclear, manejando la masa por gammagrafía-2D / 3D y por ultrasonido, arrojó diferencias no significativas entre sí. La variabilidad inter-especialista de las actividades prescrita mostró diferencias significativas, que arrojan sobre el mismo paciente, discrepancias entre 44Gy y 243Gy de las dosis terapéuticas a recibir, situación que puede comprometer el éxito del tratamiento y producir efectos secundarios no deseados. Conclusiones: Las técnicas dosimétricas paciente-específicas se pueden implementar satisfactoriamente en nuestro país. Las diferencias numéricas encontradas, especialmente la variabilidad inter-especialista, demuestran la no estandarización terapéutica, lo que apoya el uso de la farmacocinética paciente-específica pre terapéutica y la masa por gammagrafía-3D para planificar el tratamiento siempre que sean posible(AU)


Introduction: Despite of its typical morpho-functional individuality, fixed activities remain as the most used method in Cuba for hyperthyroidism treatment with I (sodium iodide, also known as radioiodine). However, there is not yet an international consensus on the most convenient doses for each case, so, the results are not always the desired ones. Objective: To evaluate the applicability of various patient-specific dose calculation methods for the treatment of hyperthyroidism with sodium iodide. Methods: It was carried out an analysis in 10 patients of the results of some methods for dose calculation from the prescribed fixed activity recommended internationally, with the use of technologies and tools already developed and available in the country. The inter-specialist variability and its impact in the planned dose for the treatment were assessed. Results: The use of uncompleted biodistribution and pharmacokinetics information of the patient showed differences between -42 percent and 37 percent in the doses for the same patient. The outcome of the comparison of the calculation method recommended by the European Society of Nuclear Medicine managing the mass by 3D/2D gammagraphy and ultrasound, presented no significant discrepancies among them. The inter-specialist variability of prescribed activity was statistically significant, and it can produce in the same patient differences between 44Gy and 243Gy of the therapeutic doses, which could affect the treatment success and lead to unnecessary side effects. Conclusions: The patient´s personalized calculation methods can be satisfactorily applied in Cuba. The numeric differences found, especially inter-specialist variability, show the lack of therapeutic standardization, which supports the use of pre-therapeutic patient-specific pharmacokinetics and the mass by 3D-gammagraphy to plan the treatment when possible(AU)


Subject(s)
Humans , Male , Female , Adult , Sodium Iodide/therapeutic use , Pharmacokinetics , Hypothyroidism/therapy , Nuclear Medicine/methods , Reference Standards
6.
Rev. bras. ciênc. vet ; 28(2): 75-80, abr./jun. 2021. il.
Article in Portuguese | LILACS, VETINDEX | ID: biblio-1367182

ABSTRACT

O objetivo deste trabalho foi avaliar a eficácia do florfenicol na dose usualmente empregada em equinos de 22 mg/kg pelas vias intravenosa, intramuscular e oral para o tratamento de adenite equina por Streptococcus equi. subsp. equi, usando a modelagem farmacocinética/farmacodinâmica (PK/PD ­ Pharmacokinetic/Pharmacodynamic) e a simulação de Monte Carlo. Foi realizada uma simulação de Monte Carlo a partir dos parâmetros PK, logo depois, efetuou-se a modelagem PK/PD para determinar as taxas de eficácia do antimicrobiano para o tratamento dessa infecção bacteriana, de acordo com o valor da concentração inibitória mínima (CIM), em um intervalo de CIM de 0,125 ­ 4 µg/mL. Pela via intravenosa, a probabilidade de erradicação bacteriana foi de 100% para CIM até 0,5 µg/mL e efeito bacteriostático com probabilidades de 99% e 80% para CIMs de 2 e 4 µg/mL, respectivamente. Já pelas vias intramuscular e oral a probabilidade de se atingir o índice de erradicação bacteriológica foi de 100% para CIM de até 0,5 µg/mL, contudo, atinge valores de 80% e 81%, respectivamente, para CIM de 1 µg/mL considerando o efeito bactericida (p<0,01). Portanto, através desse estudo é evidenciado a eficácia do florfenicol até a CIM de 0,5 µg/mL para as três vias de administração citadas, entretanto, para CIMs superiores a esse valor, é imprescindível o ajuste da dose farmacológica, evitando falhas na terapêutica e possível resistência microbiana.


The objective of this study was to evaluate the efficacy of florfenicol at the dose usually used in horses of 22 mg/kg by intravenous, intramuscular and oral routes for the treatment of equine adenitis caused by Streptococcus equi. subsp. equi, using Pharmacokinetic/Pharmacodynamic (PK/PD) modeling and Monte Carlo simulation. A Monte Carlo simulation was performed from the PK parameters, then PK/PD modeling was performed to determine the antimicrobial efficacy rates for the treatment of this bacterial infection, according to the minimum inhibitory concentration (MIC) value, in a MIC range of 0.125 - 4 µg/mL. Intravenously, the probability of bacterial eradication was 100% for MICs up to 0.5 µg/mL, and the bacteriostatic effect was 99% and 80% for MICs of 2 and 4 µg/mL, respectively. However, for the intramuscular and oral routes, the probability of reaching the bacteriologic eradication index was 100% for MICs of up to 0.5 µg/mL, however, it reaches values of 80% and 81%, respectively, for MICs of 1 µg/mL considering the bactericidal effect (p<0.01). Therefore, through this study the efficacy of florfenicol is evidenced up to the MIC of 0.5 µg/mL for the three routes of administration cited, however, for MICs higher than this value, it is essential to adjust the pharmacological dose, avoiding failures in therapy and possible microbial resistance.


Subject(s)
Animals , Horse Diseases/therapy , Lymphadenitis/veterinary , Anti-Bacterial Agents/therapeutic use , Pharmacokinetics , Monte Carlo Method
7.
São Paulo; s.n; s.n; 2021. 74 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-1378864

ABSTRACT

As infecções relacionadas à assistência à saúde (IRAS) podem ser causadas por bactérias, vírus e fungos, sendo de extrema importância para o sistema de tratamento e pacientes. Com o alarmante avanço no surgimento de bactérias resistentes, tem havido uma preocupação crescente com as IRAS de origem bacteriana. Nesse sentido, várias pesquisas buscam alternativas para os fármacos antimicrobianos convencionais, sendo que os peptídeos antimicrobianos (AMPs), como a lunatina-1, aparecem como moléculas promissoras. No entanto, os AMPs geralmente apresentam rápida degradação proteolítica no trato gastrointestinal e meia-vida curta na corrente sanguínea, principais fatores limitantes para sua aplicação no tratamento de IRAS. Entre as estratégias empregadas para superar esses inconvenientes, a PEGuilação apresenta-se como alternativa eficaz que aumenta o tempo de circulação in vivo dos AMPs, resultando na melhora farmacocinética e, em alguns casos, também farmacodinâmica. A PEGuilação consiste na ligação covalente de cadeias de polietileno glicol (PEG) ao peptídeo, que pode ser efetuada por meio de uma reação aleatória ou sítio-específica. Neste trabalho, desenvolveu-se uma PEGuilação sítio-específica no N-terminal da lunatina-1 empregando-se mPEG-NHS de 2 kDa em tampão fosfato 100 mM, visando o aumento da solibilidade deste peptídeo, bem como para avaliar sua ação antimicrobiana. Com relação à reação de PEGuilação, avaliou-se a influência da razão molar PEG:peptídeo (10:1 ou 15:1) a pH 8,5. Foi obtido um rendimento de PEGuilação de 92%, através da análise por RP-HPLC quantitativo. Quanto à purificação da lunatina-1 PEGuilada, foi empregada a técnica semi-preparativa de RP-HPLC utilizando a coluna C18. A caracterização da lunatina-1 PEGuilada, incluindo determinação do grau de PEGuilação, foi realizada por MALDI-TOF Autoflex Speed (Bruker), mostrando que a molécula foi monoPEGuilada na região N-terminal. A atividade antimicrobiana de lunatina-1 livre e bioconjugada frente a diferentes cepas bacterianas, sendo duas Gram-negativas (ATCC 25922 de Escherichia coli e ATCC 9027 de Pseudomonas aeruginosa) e uma Gram-positiva (CECT 239 de Staphylococcus aureus), foi estudada por determinação da concentração inibitória mínima (CIM) em microplaca, sendo que foram obtidos valores de CIM de 86 e 140 µM para o peptídeo liver e PEGuilado, respetivamente. O potencial hemolítico também foi estudado, sendo que a forma PEGuilada mostrou significativa redução da atividade hemolítica em comparação à forma livre. Em suma, a PEGuilação da lunatina-1, aumenta a sua solubilidade e reduz a atividade hemolítica. Porém, para viabilizar esta estratégia a PEGuilação deve ser reversível, pois a conjugação ao polímero reduz atividade antimicrobiana


Health care-related infections (HAIs) caused by bacteria, viruses and fungi are extremely important for patients and health systems. With the alarming advance in the emergence of resistant bacteria, a growing concern with HAIs of bacterial origin is observed. In this sense, several studies investigate alternatives to conventional antimicrobial drugs and antimicrobial peptides (AMPs), such as lunatin-1, appear as promising molecules. However, AMPs generally show rapid proteolytic degradation in the gastrointestinal tract and short half-life in the bloodstream, the main limiting factors for their therapeutic application to treat HAIs. Among the strategies used to overcome these drawbacks, PEGylation presents itself as an effective alternative that increases the in vivo circulation time of AMPs, resulting in improved pharmacokinetics and, in some cases, also pharmacodynamics. PEGylation consists on the covalent attachment of polyethylene glycol (PEG) chains to the peptide, which can be carried out by means of a random or site-specific reaction. In this work, a site-specific PEGylation was developed at the N-terminus of lunatin-1 using 2 kDa mPEG-NHS to increase the solubility of this peptide, as well as to evaluate its antimicrobial activity. Regarding the PEGylation reaction, the influence of the molar ratio PEG: peptide (10: 1 or 15: 1) at pH 8.5 was evaluated and a PEGylation yield of 92% was obtained, based on quantitative RP-HPLC analysis. As for the purification of PEGylated lunatin-1, semi-preparative RP-HPLC was used. The characterization of PEGylated lunatin-1, including determination of the degree of PEGylation, was performed by MALDI-TOF Autoflex Speed (Bruker), showing that the peptide was monoPEGylated in the N-terminal region. The antimicrobial activity of free and bioconjugated lunatin-1 against different bacterial strains, two Gram-negative (ATCC 25922 from Escherichia coli and ATCC 9027 from Pseudomonas aeruginosa), and one Gram positive (CECT 239 from Staphylococcus aureus), was studied by determining the minimum inhibitory concentration (MIC) in a microplate, resulting in MIC values of 86 and 140 µM for the free and PEGylated peptide, respectively. The hemolytic potential was also studied and the PEGylated form showed a significant reduction in hemolytic activity compared to the free form. In short, the PEGylation of lunatin-1 increases its solubility and reduces hemolytic activity. However, to make this strategy feasible, PEGylation must be reversible, since the conjugation to the polymer reduces antimicrobial activity


Subject(s)
Pharmacokinetics , Pharmaceutical Preparations/analysis , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Pharmacologic Actions , Infections/complications , Chromatography, High Pressure Liquid , Health Strategies , Delivery of Health Care/classification , Escherichia coli
8.
São Paulo; s.n; s.n; 2021. 110 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-1379145

ABSTRACT

Introdução: O Meropenem é um carbapenêmico de amplo espectro, prescrito na terapia do choque séptico nos pacientes graves adultos de UTI, com infecções graves causadas por patógenos Gram-negativos susceptíveis. Objetivo: Avaliar a efetividade do Meropenem em pacientes sépticos queimados, investigar a farmacocinética na fase precoce e na fase tardia durante o curso do choque séptico e o impacto no desfecho clínico. Ética, Casuística e Procedimentos: Aprovação ética, registro CAAE07525118.3.0000.0068; nenhum conflito de interesse declarado foi obtido dos autores. Após assinatura do TCLE pelo responsável legal, o paciente foi incluído no protocolo. Investigou-se a população de 15 pacientes sépticos grandes queimados, adultos de ambos os gêneros (10 M/ 5F) com função renal preservada (Clcr> 50 ml/min). As características demográficas da população de pacientes incluídos foram idade de 37(33 -41) anos, 71(59,5 - 80,0) kg e índice de massa corpórea de 24,3(20,6-24,7) kg/m2, medianas (interquartil). Registrou-se o escore SAPS*3 54(47-59) de admissão dos pacientes na UTI; a superfície corpórea total queimada foi de 33% (18,3-34,4), SCTQ medianas (interquartil). A lesão inalatória e o uso de vasopressores foram registrados em 12/15 pacientes após trauma térmico/ elétrico (10/5). Após intubação orotraqueal, a ventilação mecânica foi registrada em 13/15 pacientes. A terapia empírica do choque séptico com Meropenem no regime de 1g q8h, por infusão estendida de 3 horas, foi iniciada após a coleta das culturas. Realizou-se coleta seriada de amostras sanguíneas para dosagem sérica do antimicrobiano por cromatografia líquida. Aplicou-se o modelo aberto monocompartimental para estudo da farmacocinética e estimativa dos parâmetros, meia vida biológica, depuração total corporal e volume de distribuição. A abordagem farmacocinética-farmacodinâmica (PK-PD) foi baseada na dosagem sérica do Meropenem e na taxa de eliminação, para estimativa do índice de predição de efetividade (% ƒ Δ?T> CIM), considerando o novo alvo terapêutico de 100% ƒ Δ?T> CIM. Utilizou-se estatística não paramétrica pela aplicação do teste de Wilcoxon para dados pareados e testes de correlação linear. Resultados e Discussão: Registrou-se alteração dos parâmetros farmacocinéticos nos pacientes sépticos investigados frente aos dados reportados para voluntários sadios. Evidenciou-se redução na taxa de eliminação e da depuração total corporal; o prolongamento da meia vida biológica ocorreu pelo aumento do volume de distribuição. Estas alterações impactaram estendendo a cobertura do Meropenem, na fase precoce do choque séptico, contra os patógenos de susceptibilidade intermediária com CIM 4 mg/L. Conclusão: A cobertura do Meropenem foi garantida contra os patógenos isolados até CIM 2 mg/L para todos os pacientes. Adicionalmente, ocorreu a erradicação de patógenos de susceptibilidade intermediária CIM 4 mg/L, pela cobertura que foi atingida apenas na fase precoce do choque séptico. Então, a abordagem PK / PD contribui para a obtenção do resultado


Background: Meropenem is a carbapenêmic, agent largely prescribed to septic patients in the Intensive Care Units with severe infections caused by Gram-negative susceptible strains. Objective: To evaluate Meropenem effectiveness in ICU septic burn patients and to investigate pharmacokinetic changes that could impact the desired outcome by eradication of Gram-negative strains of intermediate susceptibility. Ethics, Casuistry and Methods: Ethical approval register CAEE 07525118.3.0000.0068was obtained; no conflicts of interest to declare were obtained from all authors. Fifteen burn adult patients of both genders (10 M/ 5F) with preserved renal function (Clcr> 50 ml/min) were investigated after TCLE signed. Demographic characteristics of patients included were: 37(33 -41) years, 71(59.5- 80.0) kg, 24.3 (20.6-24.7) kg/m2 body mass index, medians (quartiles). ICU patients admission was based on SAPS*3 score of 54(47-59), 33% (18.3-34.4) TBSA medians (quartiles). Inhalation injury and vasopressors requirements were in 12/15 patients after fire/electricity (10/5, proportion). Mechanical ventilation was necessary in 13/15 patients. Antimicrobial therapy of septic shock with meropenem 1g q8h 3 hours infusion started, after cultures collection. A serial of blood samples was collected from the central catheter after a minimum of 48 hours of Meropenem therapy for drug serum measurements by liquid chromatography. One compartment open model was applied to estimate PK data related to the elimination rate constant, biological half-life, total body clearance and volume of distribution PK/PD approach was based on serum trough levels and elimination rate constant to estimate the predictive index of drug effectiveness (% fΔT>CIM), based on the new PK/PD target 100% fΔT>CIM. Non parametric statistics was applied, Wilcoxon test for paired data and linear correlations. Results: Pharmacokinetic changes occurred in septic burn patients investigated by comparison with results reported in healthy volunteers as follows by the reduction on elimination rate constant and also on total body clearance, in spite of preserved renal function for all patients included. In addition, a prolongation of biological half-life occurred as a consequence of increases on volume of distribution. Pharmacodynamics was impacted by PK changes only at the earlier period of septic shock, once pathogens isolated of intermediate susceptibility up to MIC 4 mg/L were eradicated. Conclusion: Meropenem effectiveness was guaranteed against Gram-negative up to MIC 2 mg/L strains isolated for all patients. In addition, eradication of pathogens of intermediate susceptibility MIC 4 mg/L strains occurred only at the earlier period of septic shock. Then, PK/PD approach contributes to desired outcome achievement


Subject(s)
Humans , Male , Female , Adult , Patients , Wounds and Injuries/drug therapy , Burns/pathology , Pharmacokinetics , Meropenem/analysis , Shock, Septic/complications , Pharmaceutical Preparations/administration & dosage , Inhalation , Chromatography, Liquid/methods , Pharmacologic Actions , Intensive Care Units/classification
9.
São Paulo; s.n; s.n; 2021. 127 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-1396077

ABSTRACT

A inibição de alvos específicos como metaloproteinase de matriz (MMP) e histona desacetilase (HDAC) é amplamente estudada para impedir o progresso do câncer. Foi estabelecido que a inibição concomitante de MMP e HDAC é eficaz no combate de tumores sólidos e hematológicos. Ambos os alvos possuem um íon Zn2+ em seu sítio ativo, fundamental para a atividade destas enzimas. A alta afinidade dos inibidores conhecidos de MMP e de HDAC é conferida, principalmente, por um potente grupo ligante de zinco (ZBG). O ácido hidroxâmico é o ZBG mais potente conhecido atualmente, entretanto, este apresenta instabilidade farmacocinética, levando a ineficácia e genotoxicidade em testes clínicos. Frente a este contexto, o presente trabalho teve como objetivo o planejamento, síntese, modelagem molecular e avaliação biológica de novos inibidores duais MMP/HDAC não-hidroxamatos. Os compostos foram planejados utilizando estratégias de hibridação molecular, a partir de arcabouços provenientes inibidores de HDAC e MMP, gerando compostos arilsulfonamídicos com variações no tipo de ZBG inserido e na sua respectiva posição relativa na estrutura geral. Foram sintetizados sete análogos, em duas a três etapas reacionais, utilizando métodos de sulfonilação e acoplamento com agentes condensantes, partindo dos ésteres para e meta aminobenzoicos. Os rendimentos globais variaram de 25% a 55% e os produtos obtidos foram caracterizados por RMN 1H e 13C, LC/MS, CLAE e ponto de fusão. Os compostos tiveram sua atividade citotóxica avaliada em células HOG (oligodendroma) e T98G (glioblastoma), dentre os quais o 6a, que possui o ZBG 2-amino anilida, foi o mais promissor, apresentando atividade nas duas linhagens na casa de nM. Ensaios de coordenação com Fe2+ comprovaram a capacidade quelante dos análogos contendo ácido hidroxâmico e dos demais compostos citotóxicos, 4a e 4b (ZBG-2, salicilal-hidrazona), o que não foi observado para o composto 6a. Os estudos de ancoramento molecular permitiram sugerir um modo de interação para todos os ZBG propostos frente aos respectivos alvos (HDAC e MMP), sendo observado que o ZBG 4 (2-amino anilida) faria a interação de modo monodentado com a HDAC, enquanto não seria possível o encaixe no sítio catalítico da MMP. Conclui-se, portanto, que o planejamento proposto permitiu a obtenção de compostos promissores como antitumorais, e que a substituição do ácido hidroxâmico por outros ZBG fornece moléculas ativas frente a células tumorais. Entretanto, a avaliação biológica frente à MMP e HDAC é necessária para confirmar o mecanismo de ação proposto


Inhibition of specific targets such as matrix metalloproteinase (MMP) and histone deacetylase (HDAC) is extensively studied regarding arrest cancer growth. Particularly, concomitant inhibition of MMP and HDAC is effective against solid and hematologic tumors. Both targets have an ion Zn2+ at their catalytic site, which is essential for respective enzymatic activity. High affinity of known MMP and HDAC inhibitors is mainly provided by a potent zinc binding group (ZBG). Hydroxamic acid is the most potent ZBG currently known; however, it presents low pharmacokinetics stability, which results in its ineffectiveness and genotoxicity along clinical trial. So, the aim of this work comprised the design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors. Compounds were designed by molecular hybridation, employing scaffolds from HDAC and MMP inhibitors, which provided arylsulfonamides with variation about the ZBG type and its respective relative position in the general structure. Seven compounds were synthesized, in two to three reaction steps, through methods that comprise sulfonilation and coupling with condensing agents, using para and meta-aminobenzoic esters as starting material. Compounds showed global yields around 25-55 % and were characterized by 1H and 13C NMR, LC/MS, HPLC and melting point. Compounds were evaluated about their cytotoxicity against HOG (oligodendroma) and T98G (glioblastoma) cells, which 6a, with ZBG 2-aminobenzamide, was the most promising molecules, presenting activity against both cell lines at nM range. Coordination assays with Fe2+ proved the chelating capacity of hydroxamate analogues as well as the cytotoxic compounds, 4a and 4b (ZBG-2, salicylal-hydrazone), which was not observed about 6a. Molecular docking allowed to suggest an interaction model for all proposed ZBG with the respective targets (MMP and HDAC), showing that (ZBG-4) 2-aminobenzamide interacts with HDAC by monodentate way, but does not docks at MMP catalytic site. We conclude that the proposed design allowed obtaining promising compounds as antitumors agents, and the replacement of hydroxamic acid by other ZBG provide active molecules against tumor cells. However, biological evaluation against MMP and HDAC is necessary to confirm the proposed action mechanism


Subject(s)
Pharmacokinetics , Genotoxicity , Planning , Chromatography, High Pressure Liquid/methods , Quality Indicators, Health Care/classification , Histone Deacetylase Inhibitors/adverse effects , Matrix Metalloproteinase Inhibitors/adverse effects , Carbon-13 Magnetic Resonance Spectroscopy , Proton Magnetic Resonance Spectroscopy/methods , Neoplasms/pathology
10.
Rev. cuba. invest. bioméd ; 40(supl.1): e678, 2021. tab, graf
Article in Spanish | LILACS, CUMED | ID: biblio-1289466

ABSTRACT

Introducción: Los hongos comestibles, en particular Pleurotus ostreatus, representan una importante fuente de metabolitos bioactivos con propiedades inmunomoduladoras, antioxidantes y antiinflamatorias. Trabajos recientes han demostrado que extractos y compuestos purificados a partir de esta seta, entre ellos, la fracción rica en fenoles, inhiben el factor nuclear kappa B(NF-κB), la cicloxigenasa (COX) y modulan cascadas de señalización relacionadas con el balance redox. De acuerdo con estos antecedentes, dichos compuestos podrían actuar, además, como inhibidores de la enzima 5- lipoxigenasa (5-LOX). Objetivo: Evaluar el efecto in silico de trece compuestos fenólicos presentes en la especie Pleurotus ostreatus sobre la enzima 5-LOX, al utilizar como compuesto de referencia la mangiferina. Métodos: El acoplamiento se llevó a cabo a través del programa AutoDock 4.2 (http://autodock.scripps.edu) y la estructura de 5 LOX se obtuvo con la base de datos de proteínas, PDB (www.wwpdb.org). Se estimaron la energía libre (ΔG), la constante de disociación (Ki) y la eficiencia de ligando (LE). Se obtuvieron los parámetros de similitud a un fármaco y los relacionados con la absorción, distribución, metabolismo, excreción y toxicidad (ADME/T) de los mejores modelos de acoplamiento. Resultados: Los mejores indicadores de ΔG y Ki, correspondieron a los ácidos homogentísico, clorogénico y gentísico, con valores de ΔG (-11,81; -12,28 y -11,67 kcal/moL) y Ki (2,19 10-9; 9,99 10-10, 2,79 10-9 M), respectivamente. La eficiencia de ligando alcanzó valores adecuados para estos tres compuestos fenólicos. El modelo de acoplamiento del ácido homogentísico mostró los mejores resultados en cuanto a la similitud a un fármaco y pruebas ADME/T. Conclusiones: El estudio in silico reveló las potencialidades de la fracción rica en fenoles de P. ostreatus, y en particular, del ácido homogentísico como inhibidor de la enzima 5 -LOX, y justifica el desarrollo de ensayos confirmativos in vitro/ in vivo que corroboren sus efectos antioxidantes y antinflamatorios(AU)


Introduction: Edible mushrooms, Pleurotus ostreatus in particular, are an important source of bioactive metabolites with immunomodulatory, antioxidant and anti-inflammatory properties. Recent studies have shown that extracts and compounds purified from this mushroom, among them the phenol-rich fraction, inhibit nuclear factor kappa B (NF-κB), cyclooxygenase (COX), and modulate signaling cascades related to redox balance. According to these antecedents, such compounds could also act as inhibitors of the enzyme 5-lipoxygenase (5-LOX). Objective: Evaluate the in silico effect of 13 phenolic compounds present in the species Pleurotus ostreatus on the enzyme 5-LOX using mangiferin as reference compound. Methods: Docking was carried out with the software AutoDock 4.2 (http://autodock.scripps.edu) and the 5-LOX structure was obtained with the protein database PDB (www.wwpdb.org). Estimation was performed of free energy (ΔG), dissociation constant (Kd) and ligand efficiency (LE). Drug-likeness parameters were obtained, as well as those related to absorption, distribution, metabolism, excretion and toxicity (ADMET) of the best docking models. Results: The best ΔG and Kd indicators were homogentisic, chlorogenic and gentisic acids, with ΔG and Kd values of -11.81, -12.28, -11.67 kcal/mol, and 2.19 10-9, 9.99 10-10, 2.79 10-9 M, respectively. Ligand efficiency achieved adequate values for these three phenolic compounds. The docking model for homogentisic acid showed the best results in terms of drug likeness and ADMET tests. Conclusions: The in silico study revealed the potential of the phenol-rich fraction of P. ostreatus, homogentisic acid in particular, as an enzyme 5-LOX inhibitor, and justifies the development of confirmatory in vitro / in vivo assays to corroborate its antioxidant and anti-inflammatory effects(AU)


Subject(s)
Humans , Male , Female , Arachidonate 5-Lipoxygenase , Pharmacokinetics , Reference Standards
11.
Article in English | AIM | ID: biblio-1342017

ABSTRACT

Lipophilicity is an important physicochemical parameter of biological relevance; although its in- vivo predictive capability is dependent on accuracy and reliability of platforms used for its determination. This work examines biomimetic attribute of isocratic chromatographic hydrophobicity index (ICHI), experimental logarithm of octanol ­ water partition coefficient (LogP) and some computed lipophilicity indices for eight (8) selected antipsychotic agents and their predictive capability in drug discovery. The retention behavior of 5 first-generation and 3 second-generation antipsychotics was determined on reversed-phase chromatographic platform using methanol-phosphate buffer (pH 6.8) mobile phase. The retardation factor obtained was transformed to Rm, and plotted against volume fraction of organic modifier in the mobile phase to generate linear graph whose x- intercept is ICHI. Experimental LogP values were curled from literature while computed LogP were obtained using respective software. The experimentally determined LogPoctanol/water and ICHI were first correlated with index of brain permeability (BBB); before all lipophilicity indices were comparatively evaluated and correlated with in-vivo-normalized pharmacokinetic parameters curled from literature. ICHI gave better correlation with BBB index (r = 0.976) compared to Log Poctanol/water (r = 0.557). Comparative lipophilicity evaluation shows clustered pattern for second generation antipsychotics compared to first generation. In vivo correlation was poorer for the 8 drugs (r < 0.7), better with subset of phenothiazine homologues (r = 0.51 to 0.97). The ALogP, LogPoctanol/water, cLogP and ICHI gave highest correlation with the pharmacokinetic parameters. The biomimetic attributes of ICHI is better than for LogPoctanol/water in predicting brain permeability, but lower for in-vivo pharmacokinetic prediction.


Subject(s)
Humans , Biomimetics , Hydrophobic and Hydrophilic Interactions , Permeability , Antipsychotic Agents , Pharmacokinetics
12.
Rev. chil. pediatr ; 91(5): 828-837, oct. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1144283

ABSTRACT

La metodología estadística Bayesiana permite, si se conoce la probabilidad poblacional de que un suceso ocurra, modificar su valor cuando se dispone de nueva información individual. Aunque las metodologías Bayesiana y frecuentista (clásica) tienen idénticos campos de aplicación, la primera se aplica cada vez más en investigación científica y análisis de big data. En la farmacoterapia moderna, la farmacocinética clínica ha sido responsable de la expansión de la monitorización, facilitada por desarrollos técnico-analíticos y matemático-estadísticos. La farmacocinética poblacional ha permitido identificar y cuantificar las características fisiopatológicas y de tratamiento en una población de pacientes determinada, en particular en pediatría y neonatología, y otros grupos vulnerables, explicando la variabilidad farmacocinética interindividual. Asimismo, la estimación Bayesiana resulta importante como herramienta estadística aplicada en programas informáticos de optimización farmacoterapéutica cuando la monitorización farmacológica se basa en la interpretación farmacocinética clínica. Aunque con ventajas y limitaciones, la optimización farmacoterapéutica basada en la estimación Bayesiana es cada vez más usada en la actualidad, siendo el método de referencia. Esto es particularmente conveniente para la práctica clínica de rutina debido al limitado número de muestras requeridas por parte del paciente, y a la flexibilidad en cuanto a los tiempos de muestreo de sangre para cuantificación de fármacos. Así, la aplicación de los principios Bayesianos a la práctica de la farmacocinética clínica resulta en la mejora de la atención farmacoterapéutica.


If one knows the probability of an event occurring in a population, Bayesian statistics allows mo difying its value when there is new individual information available. Although the Bayesian and frequentist (classical) methodologies have identical fields of application, the first one is increasin gly applied in scientific research and big data analysis. In modern pharmacotherapy, clinical phar macokinetics has been used for the expansion of monitoring, facilitated by technical-analytical and mathematical-statistical developments. Population pharmacokinetics has allowed the identification and quantification of pathophysiological and treatment characteristics in a specific patient popu lation, especially in the pediatric and neonatal population and other vulnerable groups, explaining interindividual variability. Likewise, Bayesian estimation is important as a statistical tool applied in pharmacotherapy optimization software when pharmacological monitoring is based on clinical phar macokinetic interpretation. With its advantages and despite its limitations, pharmacotherapeutic op timization based on Bayesian estimation is increasingly used, becoming the reference method today. This characteristic is particularly convenient for routine clinical practice due to the limited number of samples required from the patient and the flexibility it shows regarding blood sampling times for drug quantification. Therefore, the application of Bayesian principles to the practice of clinical phar macokinetics has led to the improvement of pharmacotherapeutic care.


Subject(s)
Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Pharmacology, Clinical/methods , Research Design , Pharmacokinetics , Data Interpretation, Statistical , Models, Statistical , Bayes Theorem , Pharmacology, Clinical/statistics & numerical data , Drug Monitoring/methods , Drug Monitoring/statistics & numerical data
13.
Rev. MVZ Córdoba ; 25(1): 24-33, ene.-abr. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1279651

ABSTRACT

RESUMEN Objetivo. Comparar las concentraciones plasmáticas y tisulares de florfenicol (FFC) y su metabolito florfenicol amina (FFC-a) entre ovinos y conejos, posterior a la administración intramuscular de 20 mg/kg de FFC. Materiales y métodos. Cinco ovinos Suffolk Down y seis conejos Neozelandés fueron utilizados en el estudio. Se colectaron muestras de sangre, previo a la administración de FFC, y a las 0.25, 0.5, 1, 1.5, 2, 3 y 4 horas posteriores al tratamiento. A las 4 horas posteriores al tratamiento, a los animales se les aplicó la eutanasia. Las concentraciones plasmáticas y tisulares de FFC y FFC-a fueron determinadas mediante HPLC. Resultados. Las concentraciones plasmáticas máximas, tasa de absorción, vida media de absorción, tasa de distribución y área bajo la curva de FFC, fueron significativamente mayores en conejos respecto a los ovinos. Asimismo, para FFC-a, las concentraciones plasmáticas máximas y área bajo la curva de concentraciones plasmáticas en el tiempo fueron significativamente mayores en conejos respecto a los ovinos. La proporción de metabolito fue mayor en conejos (12.7±3.07%) en comparación con ovinos (3.99±0.87%) (p<0.05), al igual que las concentraciones tisulares de FFC y FFC-a. Conclusiones. Se observaron diferencias significativas en la farmacocinética y concentraciones tisulares de FFC y FFC-a entre estas dos especies. La mayor concentración de FFC-a en conejos indica un mayor nivel de metabolismo de FFC, respecto a los ovinos. Esto es importante de considerar al momento de establecer dosificaciones y frecuencia de administración de FFC en conejos.


ABSTRACT Objective. The aim of this study was to compare tissue and plasma concentrations of florfenicol (FFC) and its metabolite florfenicol amine (FFC-a) between sheep and rabbits, after intramuscular administration of 20 mg FFC/kg. Materials and methods. Five Suffolk Down sheep and six New Zealand rabbits were used in this study. Blood samples were collected before FFC administration and at 0.25, 0.5, 1, 1.5, 2, 3 and 4 hours after treatment. At 4 hours after treatment, euthanasia was applied to animals. Plasma and tissue concentrations of FFC and FFC-a were determined by HPLC. Results. For FFC, maximum plasma concentrations, absorption rate, absorption half-life, distribution rate, and area under the plasma concentration-time curve were all found to be significantly higher in rabbits than in sheep. Similarly, for FFC-a, significantly higher maximum plasma concentrations and area under the concentration-time curve were observed in rabbits as compared to sheep. The metabolite ratio was higher in rabbits (12.7±3.07%) compared to sheep (3.99±0.87%) (p<0.05), as were the tissue concentrations of FFC and FFC-a. Conclusions. Significant differences in the pharmacokinetics and tissue concentrations of FFC, and its metabolite FFC-a, were observed between these two animal species. The higher concentrations of FFC-a in rabbits indicate a greater level of FFC metabolism as compared to sheep. This should be considered when establishing dosage and frequency of FFC administration for rabbits.


Subject(s)
Animals , Rabbits , Rabbits , Sheep , Anti-Bacterial Agents , Pharmacokinetics , Chromatography , Metabolism
14.
Braz. J. Pharm. Sci. (Online) ; 56: e17420, 2020. tab, graf
Article in English | LILACS | ID: biblio-1142490

ABSTRACT

Dengue fever has emerged as a big threat to human health since the last decade owing to high morbidity with considerable mortalities. The proposed study aims at the in silico investigation of the inhibitory action against DENV4-NS1 of phytochemicals from two local medicinal plants of Pakistan. Non-Structural Protein 1 of Dengue Virus 4 (DENV4-NS1) is known to be involved in the replication and maturation of viron in the host cells. A total of 129 phytochemicals (50 from Tanacetum parthenium and 79 from Silybum marianum) were selected for this study. The tertiary structure of DENV4-NS1 was predicted based on homology modelling using Modeller 9.18 and the structural stability was evaluated using molecular dynamics simulations. Absorption, distribution, metabolism, excretion and toxicity (ADMET) along with the drug-likeness was also predicted for these phytochemicals using SwissADME and PreADMET servers. The results of ADMET and drug-likeness predictions exhibited that 54 phytochemicals i.e. 25 from Tanacetum parthenium and 29 from Silybum marianum showed effective druglikeness. These phytochemicals were docked against DENV4-NS1 using AutoDock Vina and 18 most suitable phytochemicals with binding affinities ≤ -6.0 kcal/mol were selected as potential inhibitors for DENV4-NS1. Proposed study also exploits the novel inhibitory action of Jaceidin, Centaureidin, Artecanin, Secotanaparthenolide, Artematin, Schizolaenone B, Isopomiferin, 6, 8-Diprenyleriodictyol, and Anthraxin against dengue virus. It is concluded that the screened 18 phytochemicals have strong inhibition potential against Dengue Virus 4.


Subject(s)
Computer Simulation , Proteins/classification , Dengue , Dengue Virus , Phytochemicals/analysis , Plants, Medicinal/metabolism , Pharmacokinetics , Tanacetum parthenium/adverse effects , Molecular Dynamics Simulation
15.
Article in Chinese | WPRIM | ID: wpr-828521

ABSTRACT

OBJECTIVE@#To study the plasma concentration and pharmacokinetics of 3, 29-Dibenzoyl Karounitriol (3, 29-DK) from sustained- release pellets and extracts of Trichosanthes at different time points in rats using high-performance liquid chromatography- tandem mass spectrometry (LC-MS/MS).@*METHODS@#Healthy male SD rats were given a single gavage of Trichosanthes sustained-release pellets or Trichosanthes extract, and orbital blood samples were taken at different time points within 48 h after drug administration in the pellet group and within 5 h in Trichosanthes extract group for determination of the plasma concentrations of 3, 29-DK using LC-MS/MS. The standard curve of 3, 29-DK content was established, and the specificity, minimum detection limit, precision and accuracy, extraction recovery, stability and matrix effect of LC-MS/MS analysis were assessed. The mean plasms levels of 3, 29-DK at different time points after the drug administration were determined and its pharmacokinetic parameters were calculated using Das 2.0 software.@*RESULTS@#LC-MS/MS analysis showed a good linearity of 3, 29-DK concentration within the range of 0.5-32 ng/mL, and the results of methodological validation confirmed the validity of this method for biological sample determination. Trichosanthes sustained-release pellets and Trichosanthes extract showed significant differences in their AUC, AUC, MRT, MRT, t and T of 3, 29-DK after administration in rats ( < 0.05).@*CONCLUSIONS@#Trichosanthes sustained-release pellets are capable of sustained-release of 3, 29-DK in rats, and thus provides a basis for the study of new dosage forms of Trichosanthes.


Subject(s)
Animals , Area Under Curve , Benzoates , Pharmacokinetics , Chromatography, Liquid , Delayed-Action Preparations , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Tandem Mass Spectrometry , Trichosanthes , Chemistry
16.
Chinese Journal of Biotechnology ; (12): 750-762, 2020.
Article in Chinese | WPRIM | ID: wpr-826901

ABSTRACT

PEGylation is considered one of the most successful techniques to improve the characteristics of protein drugs including to increase the circulating half-life of proteins in blood and to decrease their immunogenicity and antigenicity. One known PEG modification method is to attach PEG to the free amino group, typically at lysine residues or at the N-terminal amino acid with no selectivity, resulting in a heterogeneous product mixture. This lack of selectivity can present problems when a therapeutic PEGylated protein is being developed, because predictability of activity and manufacturing reproducibility are needed for regulatory approval. Enzymatic PEGylation of proteins is one route to overcome this limitation. Transglutaminases (TGase) are enzyme candidates for site-specific PEGylation. We use human interferon alpha 2a (IFN α2a) as a test case, and predict that the potential modification residues are Gln101 by computational approach as it contains 12 potential PEGylation sites. IFN α2a was PEGylated by Y shaped PEG40k-NH2 mediated by microbial transglutaminase. Our results show that the microbial transglutaminase mediated PEGylation of IFN α2a was site-specific only at the site of Gln101 in IFN α2a, yielding the single mono-conjugate PEG-Gln101-IFN α2a with a mass of 59 374.66 Da. Circular dichroism studies showed that PEG-Gln101-IFN α2a preserved the same secondary structures as native IFN α2a. As expected, the bioactivity and pharmacokinetic profile in rats of PEG-Gln101-IFN α2a revealed a significant improvement to unmodified IFN α2a, and better than PEGASYS.


Subject(s)
Animals , Antiviral Agents , Humans , Interferon alpha-2 , Metabolism , Interferon-alpha , Pharmacokinetics , Polyethylene Glycols , Pharmacokinetics , Protein Structure, Secondary , Rats , Recombinant Proteins , Pharmacokinetics , Pharmacology , Reproducibility of Results , Transglutaminases , Metabolism
17.
Actual. SIDA. infectol ; 27(100): 52-60, 20190000. graf, tab
Article in Spanish | LILACS, BINACIS | ID: biblio-1354093

ABSTRACT

Introducción: Los pacientes críticamente enfermos presentan cambios fisiopatológicos que alteran las concentraciones de antibióticos betalactámicos. El objetivo fue determinar si las dosis de uso habitual en pacientes críticos alcanzan las concentraciones asociadas con mayor actividad y establecer las variables de PK/PD que se asocian con concentraciones subóptimas de antibiótico.Métodos: Estudio prospectivo realizado en una terapia intensiva de adultos en un periodo de 13 meses. Se incluyeron pacientes que recibieron cefazolina, ceftriaxona, ceftazidima o meropenem. Se realizó dosaje de concentración de antibiótico en plasma en el 50% del intervalo de dosis. Se calculó la concentración de antibiótico libre y se comparó con el objetivo 50% fT>CIM y el objetivo 50% fT>CIM x 4 para los microorganismos susceptibles definidos, según criterios del CLSI. Se comparó el grupo de pacientes que cumplió el objetivo 50% fT>CIM x 4 con el que no, en términos de variables de PK/PD.Resultados: Se incluyeron 29 determinaciones y 55 comparaciones. En el 92,7% de los casos se alcanzó el objetivo 50% fT>CIM y en el 61,8% el objetivo 50% fT>CIM x 4. En el peor escenario, es decir considerando el germen susceptible con CIM más alta, solo el 48,3% de los pacientes cumplieron el objetivo 50% fT>CIM x 4. Los pacientes que no llegaron al objetivo 50% fT>CIM x 4 tuvieron mayor RESUMENARTÍCULO ORIGINALaclaramiento renal que los que sí lo hicieron (160 vs 108,5 ml/min/1,73m2, p= 0,01). Conclusiones: un gran porcentaje de pacientes críticos que recibe betalactámicos no alcanza las metas de PK/PD recomendadas en la actualidad


Introduction: critically ill patients have physiopathological changes that upset the concentrations of beta-lactam antibiotics. The aim was to determine if the doses of usual use in critically ill patients reach the concentrations associated with maximal activity and to establish the variables of PK/PD that are associated with suboptimal concentrations of antibiotic. Methods: prospective study conducted in an intensive therapy of adults in a period of 13 months. Patients who received cefazolin, ceftriaxone, ceftazidime or meropenem were included. Dosage of antibiotic concentration in plasma was performed at 50% of the dose interval. The concentration of free antibiotic was calculated and compared with the objective 50% fT>MIC and the objective 50% fT>MIC x 4 for susceptible microorganisms, according to CLSI criteria. The group of patients who met the 50% objective fT>MIC x 4 was compared with the one who did not, in terms of PK/PD variables. Results: 29 determinations and 55 comparisons were included. The objective 50% fT>MIC was reached in 92.7% of the cases and the target 50% fT>MIC x 4 was achieved in 61.8%. In the worst scenario, that is, considering the germ susceptible with MIC higher, only 48.3% of patients met the objective 50% fT>MIC x 4. Patients who did not reach the goal 50% fT>MIC x 4 had greater renal clearance than those who reached the goal (160 vs 108.5 ml/min/1.73m2, p=0.01). Conclusions: a large percentage of critically ill patients receiving beta-lactams do not reach the PK/PD goals recommended nowadays


Subject(s)
Humans , Aged , Aged, 80 and over , Pharmacokinetics , Data Collection , Prospective Studies , Critical Illness , Pharmacologic Actions , Critical Care , beta-Lactams/administration & dosage , beta-Lactams/adverse effects , Antimicrobial Stewardship
18.
Vaccimonitor (La Habana, Print) ; 28(1)ene.-abr. 2019. tab, graf
Article in English | LILACS, CUMED | ID: biblio-1094620

ABSTRACT

The African most prevalent tropical disease after malaria is schistosomiasis and this disease in the developing countries is a massive socio-economic and public health burden. The disease also caused over 200,000 deaths. The development and design of new and novel antischistosomal drugs is now very important, as there are no vaccines currently and there is only one drug at the moment for the treatment of schistosomiasis. In this article, 6-gingerol was docked against the Schistosoma mansoni phosphofructokinase and the docking result was compared to those obtained from the docking of its modified analogues against the same enzyme. The chemical structure of 6-gingerol was obtained from the PubChem database while the modified analogues were designed using the ChemAxon software. The molecular docking procedure was carried out with the aid of the AutoDock Vina software while polar interactions which were eventually used in predicting the amino acid residues at the Schistosoma mansoni phosphofructokinase active site were visualized using the Pymol software. The Schistosoma mansoni phosphofructokinase 3D crystallized structure was modeled using the Swiss Model server. The molecular docking result showed that the modifications made on 6-gingerol had a positive effect on the binding energy of the compound to the enzyme active site as an appreciable increase was observed. 6-Gingerol and its modified analogues also violated none of the Lipinski's rule with suggests that the experimental compounds are drug-like. The C2H5 analogue of 6 gingerol was selected as the ideal therapeutic agent based on the pharmacokinetics study and the exhibited binding energy(AU)


La enfermedad tropical con más prevalencia en África después de la malaria es la esquistosomiasis; en los países en vías de desarrollo constituye una carga socio-económica y de salud pública enorme. La enfermedad ha ocasionado más de 200.000 muertes anuales. El desarrollo y diseño de nuevas y novedosas drogas antiesquistosomales es muy importante, ya que actualmente no existe vacuna disponible y solo hay una sola droga licenciada para su tratamiento. En esta investigación, el compuesto 6-gingerol se acopló a la enzima fosfofructoquinasa de Schistosoma mansoni y se comparó con los resultados obtenidos a partir de las interacciones de sus análogos modificados a la misma enzima. La estructura química del 6-gingerol se obtuvo de la base de datos PubChem, mientras que los análogos modificados se diseñaron utilizando el software ChemAxon. El procedimiento de acoplamiento molecular se llevó a cabo con la ayuda del software AutoDockVina, mientras las interacciones polares eventualmente utilizadas para predecir los residuos de aminoácidos en el sitio activo de la enzima fosfofructoquinasa de Schistosoma mansoni se visualizaron empleando el software Pymol. La estructura cristalizada tridimensional de la enzima fosfofructoquinasa de Schistosoma mansoni se modeló utilizando el programa Swiss Model. Se demostró que las modificaciones realizadas en el 6-gingerol tuvieron un efecto positivo en la energía de unión del compuesto al sitio activo de la enzima, tras observarse un aumento apreciable de dicha energía. El compuesto 6-Gingerol y sus análogos modificados tampoco violaron ninguna de las reglas de Lipinski, lo que sugiere que estos compuestos experimentales tienen propiedades similares a los medicamentos. El análogo C2H5 de 6-gingerol se seleccionó como el agente terapéutico ideal, basados en el estudio de farmacocinética y la energía de enlace demostrada(AU)


Subject(s)
Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/epidemiology , Pharmacokinetics , Phosphofructokinases/therapeutic use , Africa
19.
São Paulo; s.n; s.n; 2019. graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-1015315

ABSTRACT

O meropenem é um carbapenêmico de amplo espectro e alta potência, largamente prescrito para tratamento de infecções graves causadas por bactérias sensíveis gram-negativas em pacientes críticos internados em Unidades de Terapia Intensiva. O objetivo do presente estudo foi avaliar a efetividade do antimicrobiano em pacientes grandes queimados, recebendo a dose recomendada 1 g q8h através da infusão intermitente de 0,5 hora que ocorreu até 2014 (grupo 1) comparada a infusão estendida de 3 horas que ocorreu após esse período (grupo 2). Investigaram-se 25 pacientes sépticos de ambos os sexos (6F/19M), 26 (21-34) anos, medianas (interquartil), 70 (60-75) kg, superfície corporal total queimada (SCTQ) 35 (16-42)%, SAPS 3: 55 (45-59) e Clcr 129 (95-152) ml/min que foram distribuídos em dois grupos. Registrou-se trauma térmico pelo fogo em 19/25 e trauma elétrico no restante dos pacientes (6/25), lesão inalatória (17/25), intubação orotraqueal e a necessidade de vasopressores em 18/25 pacientes. Duas amostras de sangue foram coletadas (3ª e 5ª horas) para dosagem sérica do meropenem por cromatografia líquida no período precoce do choque séptico. A farmacocinética foi investigada pela aplicação do modelo aberto de um compartimento e a abordagem PK/PD foi realizada com base no novo índice recomendado 100%fΔT>CIM. Evidenciou-se aumento do PCR 224 (179-286) versus 300 (264-339) mg/L, p=0,0411 e neutrofilia: 12 (8-17) versus 8 (2-15) células/mm3, p=0,1404, respectivamente nos grupos de infusão estendida versus infusão intermitente. Os níveis séricos obtidos mostraram diferença significativa entre grupos (p<0,0001) tanto para o pico 21 (21-22) mg/L versus 44 (42-45) mg/L, como para o vale 7,8 (7,3-9,5) mg/L versus 3,0 (2,6-3,7) mg/L. A farmacocinética mostrou-se alterada nos dois grupos frente aos dados de referência reportados em voluntários sadios. Significativa alteração ocorreu em diferentes proporções pela comparação entre os grupos relativamente à constante de eliminação 0,190 (0,157-0,211) versus 0,349 (0,334-0,382) h-1; meia-vida biológica 3,6 (3,3-4,4) versus 2,0 (1,8-2,1) h; depuração total corporal 8,6 (8,2-8,9) versus 5,3 (5,2-5,4) L/h; volume de distribuição 41,8 (39,9-44,5) versus 15,4 (14,1-16,2) L (p<0,0001). A infecção de ferida foi a mais prevalente nos dois grupos com 47% versus 38% dos isolados, sendo a Klebsiella pneumoniae, a principal enterobactéria. A abordagem PK/PD para patógenos CIM 1 a 4 mg/L mostrou cobertura até CIM 4 mg/L para a infusão estendida e até CIM 2 mg/L para infusão intermitente. Em conclusão, demonstrou-se a superioridade da infusão estendida decorrente de alterações na farmacocinética do meropenem em pacientes grandes queimados. O aumento do volume de distribuição contribuiu para o prolongamento da meia-vida e dos altos níveis de vale registrados, o justifica o impacto na cobertura antimicrobiana após infusão estendida e controle das infecções com cura desses pacientes


Meropenem is a broad-spectrum agent widely prescribed for the treatment of septic shock caused by gram-negative susceptible strains in critically ill patients from the Intensive Care Units. Subject of the present study was to evaluate the drug effectiveness in critically ill septic burn patients in SIRS at the early period of septic shock receiving the recommended dose of Meropenem 1 g q8h by intermittent 0.5 hour infusion or the extended 3 hour infusion. Twenty-five septic patients were: (6F/19M), 26 (21-34) years, medians (quartiles), 70 (60-75) kg, total burn body surface (SCTQ) 35 (16-42) %, SAPS 3: 55 (45-59) and Clcr 129 (95-152) ml/min. Thermal trauma was registered in 19/25 and electrical trauma in the remaining patients (6/25), inhalation injury (17/25), orotracheal intubation and vasopressor requirement in 18/25 patients. Patients were distributed in two groups on the basis of the duration of drug infusion that occurred for the patients of group 1 (1g q8h 0.5 hr) until 2014, December in the hospital. In addition, the extended 3 hours infusion occurred after that period for patients enrolled afterwards (group 2). Pharmacokinetics was investigated after blood sampling at the third (3rd) hour and the fifth (5th) hour of starting the meropenem infusion. Serum drug measurement was done by liquid chromatography. A one compartment open model was applied and kinetic parameters were estimated. PK/PD approach based on the new recommended index of drug effectiveness 100% fΔT>MIC was performed, on the basis on PK parameters and the minimum inhibitory concentration, PD parameter. It was demonstrated a significant difference between groups (p <0.0001) related to the trough levels 7.8 (7.3-9.5) mg/L versus 3.0 (2.6-3.7) mg/L, respectively after extended infusion or intermittent infusion. Concerning the pharmacokinetics, it was shown profound changes on meropenem kinetic parameters in both groups of burn patients by comparison with the reference data reported in healthy volunteers. In addition, it is important to highlight that significant changes occurred also by comparison of PK data between groups of patients related to the parameters: elimination constant 0.190 (0.157-0.211) versus 0.349 (0.334-0.382) h-1; biological half-life 3.6 (3.3-4.4) versus 2.0 (1.8-2.1) hr; total body clearance 8.6 (8.2-8.9) versus 5.3 (5.2-5.4) L/hr; volume of distribution 41.8 (39.9-44.5) versus 15.4 (14.1-16.2) L. Concerning the inflammatory biomarker an increase of C-reactive protein was registered in both groups of septic patients in SIRS: 224 versus 300 mg/L, p = 0.0411, after the extended infusion versus intermittent infusion, respectively. Wound and bone were the most prevalent sites of infection in those patients of both groups. It was shown in the isolates the prevalence of Gram-negative strains 54/83 (65%) that were distributed in Enterobacteriaceae, K. pneumoniae 7/30 (23%), and Non-Enterobacteriaceae, P. aeruginosa 13/54 (24%) followed by Acinetobacter baumannii 11/54 (20%). Drug effectiveness against susceptible strains was demonstrated by PK/PD approach up to 4 mg/L over 2 mg/L, after the extended infusion or after intermittent infusion, respectively. In conclusion, the superiority of the extended infusion in septic burn patients at the earlier period of septic shock was demonstrated, once considerable increases on volume of distribution impacted the drug effectiveness of these patients. Cure was obtained by meropenem monotherapy in 22/25 patients; only three patients (3/25) received meropenem - colistine combined therapy due to Acinetobacter baumannii isolated


Subject(s)
Humans , Male , Female , Adult , Shock, Septic/classification , Wounds and Injuries/drug therapy , Burns/drug therapy , Meropenem/analysis , Pharmacokinetics , Pharmacologic Actions
20.
Braz. J. Pharm. Sci. (Online) ; 55: e17536, 2019. tab, graf
Article in English | LILACS | ID: biblio-1055294

ABSTRACT

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 µm. The encapsulation efficiency and drug loading yield of TDF-PLGA-MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF-PLGA-MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 µm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF-PLGA-MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung ​​were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy.


Subject(s)
Pharmacokinetics , Tadalafil/adverse effects , Pulmonary Arterial Hypertension/drug therapy , Microspheres , Patients/classification , Solubility/drug effects , In Vitro Techniques/instrumentation , Pharmaceutical Preparations/administration & dosage , Drug Therapy , Lung
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