RESUMO
Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent. However, poor and highly variable bioavailability are limiting factors for its use in systemic illnesses. The present study aimed to develop two parenteral formulations of albendazole and to compare its pharmacokinetic profile with the conventional oral administration. Parenteral formulations were developed using two different approaches: a phosphonooxymethylated prodrug and cosolvents. For the albendazole prodrug, once synthetized, its solubility and hydrolysis with alkaline phosphatase were evaluated. A factorial design of experiments was used for the cosolvent formulation. Stability and hemolytic activity were assessed. A pharmacokinetic study was performed on New Zealand rabbits. Both formulations were administered intravenously, and the prodrug was also administered intramuscularly. Results were compared with those obtained after the oral administration of albendazole. A 20,000-fold and 6000-fold increase in albendazole solubility was found with the prodrug and cosolvent formulations, respectively. Both parenteral formulations displayed higher albendazole plasma concentrations for the first 2 h compared with oral administration, even when the oral dose was doubled. The absolute bioavailability of oral albendazole was 15.5% while for the intramuscular administration of the prodrug was 102.6%. Both parenteral formulations showed a significant decrease in the formation of albendazole sulfoxide (ANOVA p<0.05) and allowed greater exposure to albendazole. Albendazole cosolvent parenteral formulation could be a promising option in systemic illnesses considering its ease of preparation and superb pharmacokinetic performance.
Assuntos
Anti-Helmínticos , Antineoplásicos , Pró-Fármacos , Animais , Coelhos , Albendazol , Pró-Fármacos/farmacocinética , Disponibilidade Biológica , Administração OralRESUMO
Abstract Albendazole is an anthelmintic drug commonly used in parenchymal neurocysticercosis and cystic echinococcosis. The aim of this study was to explore whether disparities in the dissolution profiles of albendazole products lead to significant differences in pharmacokinetic parameters. Three generic products and the innovator were evaluated in vitro. Quality control tests were performed, and dissolution profiles were obtained according to the Mexican Pharmacopeia. Although all products passed the quality control tests, none of the generic products complied with the similarity factor (f 2). The product with the lowest f 2 value in respect to the reference was chosen for in vivo evaluation. The study was carried out in 12 healthy volunteers who received 400 mg of the generic or reference product according to a crossover design. No significant differences were found in Cmax and AUC for albendazole and its main metabolite, albendazole sulfoxide, between products. Two absorption peaks were observed in the pharmacokinetic profile, and a population (22%) with different absorption rates and delay time for the the second peak was found. Based on the results, due to the high variability in the absorption process the differences observed in vitro could not be observed in vivo.
Assuntos
Humanos , Masculino , Feminino , Técnicas In Vitro/métodos , Farmacocinética , Albendazol/análise , Dissolução , Controle de Qualidade , Preparações Farmacêuticas/administração & dosagem , Neurocisticercose/patologiaRESUMO
Microalgae have demonstrated a large potential in biotechnology as a source of various macromolecules (proteins, carbohydrates, and lipids) and high-added value products (pigments, poly-unsaturated fatty acids, peptides, exo-polysaccharides, etc.). The production of biomass at a large scale becomes more economically feasible when it is part of a biorefinery designed within the circular economy concept. Thus, the aim of this critical review is to highlight and discuss challenges and future trends related to the multi-product microalgae-based biorefineries, including both phototrophic and mixotrophic cultures treating wastewater and the recovery of biomass as a source of valuable macromolecules and high-added and low-value products (biofertilizers and biostimulants). The therapeutic properties of some microalgae-bioactive compounds are also discussed. Novel trends such as the screening of species for antimicrobial compounds, the production of bioplastics using wastewater, the circular economy strategy, and the need for more Life Cycle Assessment studies (LCA) are suggested as some of the future research lines.
RESUMO
G protein-activated inward-rectifying potassium (K+ ) channels (Kir3/GIRK) participate in cell excitability. The GIRK5 channel is present in Xenopus laevis oocytes. In an attempt to investigate the physiological role of GIRK5, we identified a noncanonical di-arginine endoplasmic reticulum (ER) retention motif (KRXY). This retention motif is located at the N-terminal region of GIRK5, coded by two small exons found only in X. laevis and X. tropicalis. These novel exons are expressed through use of an alternative transcription start site. Mutations in the sequence KRXY produced functional channels and induced progesterone-independent oocyte meiotic progression. The chimeric proteins enhanced green fluorescent protein (EGFP)-GIRK5-WT and the EGFP-GIRK5K13AR14A double mutant, were localized to the ER and the plasma membrane of the vegetal pole of the oocyte, respectively. Silencing of GIRK5 or blocking of this channel by external barium prevented progesterone-induced meiotic progression. The endogenous level of GIRK5 protein decreased through oocyte stages in prophase I augmenting by progesterone. In conclusion, we have identified a unique mechanism by which the expression pattern of a K+ channel evolved to control Xenopus oocyte maturation.
Assuntos
Motivos de Aminoácidos , Sequência de Aminoácidos , Retículo Endoplasmático/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/química , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Oócitos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteínas de Xenopus/química , Proteínas de Xenopus/metabolismo , Animais , Sequência Conservada , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Humanos , Oócitos/efeitos dos fármacos , Filogenia , Ligação Proteica , Proteínas de Xenopus/genética , Xenopus laevisRESUMO
Although mebendazole (MBZ) has demonstrated antitumor activity in glioblastoma models, the drug has low aqueous solubility and therefore is poorly absorbed. Considering that other strategies are needed to improve its bioavailability, the current study was aimed to develop and evaluate novel microemulsions of MBZ (MBZ-NaH ME) for intranasal administration. MBZ raw materials were characterized by FTIR, DSC, and XDP. Subsequently, the raw material that contained mainly polymorph C was selected to prepare microemulsions. Two different oleic acid (OA) systems were selected. Formulation A was composed of OA and docosahexaenoic acid (3:1% w/w), while formulation B was composed of OA and Labrafil M2125 (1:1% w/w). Sodium hyaluronate (NaH) at 0.1% was selected as a mucoadhesive agent. MBZ MEs showed a particle size of 209 nm and 145 nm, respectively, and the pH was suitable for nasal formulations (4.5-6.5). Formulation B, which showed the best solubility and rheological behavior, was selected for intranasal evaluation. The nasal toxicity study revealed no damage in the epithelium. Furthermore, formulation B improved significantly the median survival time in the orthotopic C6 rat model compared to the control group. Moreover, NIRF signal intensity revealed a decrease in tumor growth in the treated group with MBZ-MaH ME, which was confirmed by histologic examinations. Results suggest that the intranasal administration of mebendazole-loaded microemulsion might be appropriated for glioblastoma treatment. Graphical abstract.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Emulsões/química , Glioblastoma/tratamento farmacológico , Mebendazol/administração & dosagem , Administração Intranasal , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Masculino , Mebendazol/farmacocinética , Mebendazol/uso terapêutico , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Água/químicaRESUMO
Foreign modelling agent reactions (FMAR) are the result of the injection of unapproved high-viscosity fluids with the purpose of cosmetic body modelling. Its consequences lead to ulceration, disfigurement and even death, and it has reached epidemic proportions in several regions of the world. We describe a series of patients treated for FMARs in a specialised wound care centre and a thorough review of the literature. A retrospective chart review was performed from January 1999 to September 2015 of patients who had been injected with non-medical foreign agents and who developed cutaneous ulceration needing treatment at the dermatology wound care centre. This study involved 23 patients whose ages ranged from 22 to 67 years with higher proportion of women and homosexual men. The most commonly injected sites were the buttocks (38·5%), legs (18%), thighs (15·4%) and breasts (11·8%). Mineral oil (39%) and other unknown substances (30·4%) were the most commonly injected. The latency period ranged from 1 week to 17 years. Complications included several skin changes such as sclerosis and ulceration as well as systemic complications. FMAR is a severe syndrome that may lead to deadly complications, and is still very common in Latin America.
Assuntos
Cosméticos/efeitos adversos , Corpos Estranhos/imunologia , Reação a Corpo Estranho/complicações , Óleo Mineral/efeitos adversos , Úlcera Cutânea/etiologia , Úlcera Cutânea/terapia , Adulto , Idoso , Mama/fisiopatologia , Nádegas/fisiopatologia , Cosméticos/administração & dosagem , Feminino , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Óleo Mineral/administração & dosagem , Estudos Retrospectivos , Pele/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: To determine the factors prognostics of early mortality in the malignant billary estenosis after the endoscopic derivation. BACKGROUND DATA: The surgical, percutaneous or endoscopic derivation is the alternative of palliative treatment in the biliary obstruction unresectable. The factors prognostic the early mortality after surgical derivation are: hemoglobin < 10 g/dL, serum bilirubin > 10 mg/dL and serum albumin < 2.5 g/dL; for the percutaneous derivation they are the sanguineous urea more of 4.3 mmol/L and hemoglobin < 10.9 g/dL; whereas in the single endoscopic derivation type 3 of Bismuth and the infectious complications after the endoscopic colangiography and the absence of the clinical success were factors prognoses of early mortality. METHODS: Descriptive and retrospective analysis of 97 cases with malignant biliary obstruction. The factors were evaluated prognoses of early mortality. Univariated and bivaried analysis and of survival by the method of Kaplan-Meier was made curved. RESULTS: 97 cases were included that presented/displayed unresectable disease and had a biochemical control subsequent to the drainage. They were 58 women and 39 men. More frequent symptoms: ictericia, pain and prurito. 61 cases of distal obstruction and 36 with proximal obstruction. Twenty deaths (25.9%) happened within the 30 later days to the treatment. The bilirubin > 14 mg/dL and the proximal location were like predicting of early mortality. CONCLUSIONS: The obstruction biliary more frequent is located in choledocho distal and is of pancreatic origin. The main factors associated to early mortality are: the bilirubin > of 14 mg/dL and the proximal location reason why is important the suitable selection of patient candidates to endoscopic derivation. The survival is better in the distal obstruction.
Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Colestase Extra-Hepática/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/diagnóstico , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Análise Química do Sangue , Colangiografia , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/cirurgia , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Prognóstico , Estudos Retrospectivos , Stents , Análise de SobrevidaRESUMO
Introducción: Con el objetivo de mejorar la calidad de la atención hospitalaria de los niños que ingresan por infección respiratoria aguda baja al Centro Hospitalario Pereira Rossell, se aplicó entre mayo y setiembre de 1999 una estrategia que se denominó Plan de Invierno. Objetivo: Evaluar el impacto que tuvo esta estrategia en el gasto en antibióticos (ATB), broncodilatadores (?2 agonistas) y corticoides en el Hospital Pediátrico. Metodología: Se compararon las unidades consumidas y el gasto (en pesos uruguayos) en ATB, ?2 agonistas y corticoides en el período enero-setiembre 1998 versus enero-setiembre 1999. Los datos fueron obtenidos del programa de uso de medicamentos de la farmacia clínica del hospital. Resultados: El gasto, entre enero y setiembre de 1999, fue menor que en el mismo período de 1998 (28,6% versus 37,6%). El gasto en ATB y corticoides disminuyó en los servicios de pediatría general (PG) y unidad de cuidados intensivos pediátricos (UCIN). El gasto en ?2 disminuyó sólo en UCIN. El gasto por día cama ocupado (DCO) en ATB disminuyó en PG y aumentó en UCIN. Conclusión: Es posible que el cumplimiento de las pautas terapéuticas recomendadas y la mejoría en la calidad de los diagnósticos realizados durante la aplicación de esta estrategia asistencial hayan contribuido a un menor gasto en ATB, ?2 y corticoides en los niños con infección respiratoria aguda baja (IRAB) que ingresaron al hospital.
Summary Introduction: A strategy called Plan de Invierno was developed between May and September of 1999 in order to improve the attention at the Centro Hospitalario Pereira Rossell on children affected by low respiratory tract infections. Objective: To evaluate the impact of this strategy on the spending related to the purchase of antibiotics (ATB), bronchodilators (2agonists) and corticosteroids in the Paediatric Hospital. Methods: Numbers of consumed units and money spent on ATB, (2agonistas) and corticosteroids were compared during the periods of January to September of 1998 and January to September of 1999. Data were obtained from the hospital clinical pharmacy. Results: During the period January - September of 1999, the spending was lower than during the period January - September 1998 (28.6% and 37.6% respectively). Spending on ATB and corticosteroids diminished in the general paediatric service (GP) and in the intensive paediatric care unit (UCIN). Spending related to ?2 agonists diminished only at the UCIN. Bed/day spending (DCO) on ATB decreased at the GP but was increased at the UCIN. Conclusions: Following of the recommended therapeutic guidelines and the improvement of quality of diagnoses performed during the period of this assistance strategy probably contributed to reduce ATB, ?2 agonists, and expenses.
Résumé Introduction: Afin d'améliorer la qualité de l'assistance hospitalière des enfants qui sont admis au Centre Hospitalier Pereira Rossell avec infection respiratoire aigüe, on met en marche une stratégie appelée Plan d'Hiver entre mai et septembre 1999. But: Evaluer l'impact que cette stratégie a eu dans le frais d'antibiotiques(ATB),broncho-dilatateurs(?2 agonistes) et corticoïdes à l'Hôpital Pédiatrique. Méthodologie: On compare les unités consommées et les frais (en monnaie uruguayenne)de ATB, ?2 agonistes et de corticoïdes pendant la période janvier-septembre 1998 versus janvier-septembre 1999. Les données ont été tirées du programme de la pharmacie clinique de l'hôpital. Résultats: Les frais ont été moins grands en 1999 qu'en 1998 (28,6% versus 37,6%). Les frais de ATB et de corti-coïdes ont diminué dans les services de pédiatrie générale (PG) et UCIN. Conclusion: Il est possible que le respect des lignes thérapeutiques recommandées et l'amélioration de la qualité des diagnostics réalisés pendant l'application de cette stratégie d'assistance, aient contribué à diminuer les frais de ATB, ?2 et de corticoïdes chez les enfants avec IRAB admis à l'hôpital.