Isolation and HPLC Quantitative Analysis of Antioxidant Flavonoids from Alternanthera tenella Colla

Phytochemical analysis of the antioxidant ethanolic extract of Alternanthera tenella Colla led to the isolation of six flavonoids, acacetin 8

Relative Contributions of Active Mediated Transport and Passive Diffusion of Fluoroquinolones with Various Lipophilicities in a Calu-3 Lung Epithelial Cell Model▿

The transport characteristics of six fluoroquinolones (FQs) with various lipophilicities were compared in a Calu-3 cell model. For each FQ, an active polarized transport was observed in the direction of the apical side. However, the apparent permeability of FQs resulted from active transport and passive diffusion that were highly variable between compounds and mainly governed by lipophilicity. Therefore, active transport was predominant for compounds with relatively low lipophilicity but minor for FQs with higher lipophilicity

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model▿

Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent Pmax = 13.6 × 10−6 cm·s−1; apparent Km = 147 μM), suggesting saturated transport at concentrations higher than 350 μg/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This P-glycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators

Interchangeability among carbamazepine formulations: the impact over epilepsy patients

The treatment of epilepsy is complex and a matter of concern is the interchangeability among different formulations available for antiepileptic drugs. To evaluate the effects of interchangeability among carbamazepine formulations on patients with epilepsy. This is a prospective cohort study that included adult outpatients diagnosed with epilepsy and under pharmacological treatment with carbamazepine. Before switching the brand/manufacturer, the “Interchangeable Pharmaceutical Product in the Treatment of Epilepsies” questionnaire was applied. The questionnaires “Adverse Events Profile” and Quality of Life in Epilepsy-31, so as the plasma carbamazepine concentrations, were evaluated before and after the brand/ manufacturer switch. Physical-chemical tests aiming to assess tablets quality were performed in accordance with the Brazilian Pharmacopoeia 5th edition. The study population was composed by 14 patients (mean age: 44.6 years), with 10 of females. From those interviewed, 10 had no knowledge about the three antiepileptic drugs formulations available. The frequency of adverse event “problems with skin” incresead (p=0.023) and “upset stomach” decreased (p=0.041) after the changeover. The adverse events profile was associated with only two quality of life domains: “energy/fatigue” (p=0.048) and “total score” (p=0.018). Divergent results between generic and reference formulations were observed in purity-water test (reference: 1.96%, generic: 4.84%) and dissolution test, in which the generic formulation presented 66.27 to 85.77% of carbamazepine dissolved after the third level

El efecto de la división sobre la calidad y la liberación in vitro del clorhidrato de metformina de las tabletas de liberación prolongada (XR)

El clorhidrato de metformina (MetCl) se utiliza en todo el mundo para el tratamiento de la diabetes mellitus tipo 2. Aunque se comercializan tabletas de liberación prolongada (XR) que contienen 500 mg, 850 mg y 1000 mg de MetCl, no es raro dividir la tableta cuando la forma de dosificación de la concentración requerida no está disponible comercialmente. El objetivo del trabajo fue evaluar los efectos de la división en el rendimiento in vitro de tabletas XR que contienen MetCl. Realizamos ensayos de control de calidad y estudios comparativos de perfil de disolución entre varios medicamentos que contienen 500 mg y 1000 mg de MetCl, comercializados en Brasil y Argentina. Las tabletas que contenían 1000 mg de MetCl se dividieron a la mitad (muestras de prueba) y se compararon con tabletas enteras de productos que contenían 500 mg de MetCl (muestras de referencia). Las tabletas partidas a la mitad eran más frágiles y presentaban menor uniformidad de masa y unidad de dosificación en comparación con las enteras. Sin embargo, el parámetro de arranque F2 demostró que la división de las tabletas de MetCl XR no tuvo un impacto significativo en los perfiles de liberación de fármacos in vitro en comparación con las tabletas completas. Además, ni el mecanismo de liberación del fármaco ni la cinética de liberación se vieron afectados significativamente. Las tabletas XR que contienen 1000 mg de clorhidrato de metformina podrían ser elegibles para la división, sin embargo, los fabricantes deber proporcionar surcos apropiados en las superficies de las tabletas para que la división sea adecuada y más segura para los pacientes.O cloridrato de metformina (MetCl) é usado mundialmente no tratamento do diabetes mellitus tipo 2. Embora os comprimidos de liberação prolongada (XR) contendo 500 mg, 850 mg e 1000 mg de MetCl sejam comercializados, não é incomum dividir o comprimido quando a dosagem necessária não está disponível comercialmente. O objetivo do trabalho foi avaliar os efeitos da divisão no desempenho in vitro de comprimidos XR contendo MetCl. Realizamos ensaios de controle de qualidade e estudos de perfil de dissolução comparativos entre diversos medicamentos contendo 500 mg e 1000 mg de MetCl, comercializados no Brasil e na Argentina. Comprimidos contendo 1000 mg de MetCl foram divididos pela metade (amostras de teste) e comparados com comprimidos inteiros de produtos contendo 500 mg de MetCl (amostras de referência). Os comprimidos reduzidos ao meio são mais frágeis e apresentam menor uniformidade de massa e unidade de dosagem em relação aos inteiros. No entanto, foi evidenciado pelo parâmetro de F2 bootstrapping que a divisão dos comprimidos de MetCl XR não afetou significativamente os perfis de liberação do fármaco in vitro em comparação com os comprimidos inteiros. Além disso, nem o mecanismo de liberação do fármaco nem a cinética de liberação foram significativamente afetados. Os comprimidos XR contendo 1000 mg de cloridrato de metformina podem ser elegíveis para divisão, no entanto, os fabricantes devem fornecer sulcos adequadas nas superfícies dos comprimidos para tornar a divisão adequada e mais segura para os pacientes.Metformin hydrochloride (MetCl) is used worldwide in the treatment of type-2 diabetes mellitus. Although extendedrelease (XR) tablets containing 500 mg, 850 mg, and 1000 mg of MetCl are marketed, it is not uncommon to split the tablet when the dosage form of the required strength is not available commercially. The aim of work was to evaluate the effects of splitting on the in vitro performance of XR tablets containing MetCl. We performed quality control assays and comparative dissolution profile studies among several medicines containing 500 mg and 1000 mg of MetCl, marketed in Brazil and Argentina. Tablets containing 1000 mg of MetCl were halved (test samples) and compared with whole tablets of products containing 500 mg of MetCl (reference samples). The halved tablets were more fragile and presented lower uniformity of mass and dosage unit as compared to the whole ones. However, it was evidenced by the F2 bootstrapping parameter that splitting MetCl XR tablets did not significantly impact the in vitro drug release profiles as compared to the whole tablets. In addition, nor the drug release mechanism neither the release kinetics were significantly affected. The XR tablets containing 1000 mg of metformin hydrochloride might be eligible for division, however, manufacturers could provide appropriate scores in the tablets surfaces to make the splitting proper and safer for the patients.Fil: Santos, Luiz Gustavo Fonseca. Universidade Federal de São João del-Rei; BrasilFil: Segall, Adriana Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Han, Yong Ki. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; ArgentinaFil: Kizelman, Maria Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; ArgentinaFil: Ferreira, Maira Peres. Universidade de Sao Paulo; BrasilFil: Silva, Amanda Cristina Funari. Universidade de Sao Paulo; BrasilFil: Martins, Frederico Severino. Universidade de Sao Paulo; BrasilFil: Castro, Whocely Victor de. Universidade Federal de São João del-Rei; BrasilFil: Freitas, Osvaldo de. Universidade de Sao Paulo; BrasilFil: Couto, Rene Oliveira do. Universidade Federal de São João del-Rei; Brasi

Characterization, in vitro dissolution, and pharmacokinetics of different batches of efavirenz raw materials

International audienceObjective To perform the solid-state characterization and the in vitro-in vivo correlation (IVIVC) of three batches of efavirenz (EFV) active pharmaceutical ingredients. Significance EFV is an effective anti-HIV drug. Due to the poor aqueous solubility, the rate and extent of EFV absorption deeply depend on its dissolution characteristics. Methods Thermal analyses, x-ray diffraction, and particle size distribution were performed. The saturation solubility and dissolution profiles were assessed in 0.5% (w/v) sodium lauryl sulfate (SLS), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) using a flow-through cell. Each batch was orally administered to Wistar rats and the pharmacokinetic parameters were correlated with those obtained from in vitro dissolution. Results All batches of EFV consisted polymorph I. EFV-A presented the lowest particle size distribution [d(v,0.5) = 197.8 mu m; d(v,0.9) = 444.6 mu m] followed by EFV-B [d(v,0.5) = 223.9 mu m; d(v,0.9) = 481.1 mu m], and EFV-C [d(v,0.5) = 240.8 mu m; d(v,0.9) = 497.3 mu m]. The saturated solubility in FaSSIF was 36% and 40% of that in FeSSIF and SLS, respectively. EFV-A presented the fastest rate and largest extension of dissolution than EFV-B and C (79.15%, 69.93% and 54.22%, respectively, as well as the highest maximum plasma concentration. Levels B, C, and multiple-C of IVIVC models were achieved. Conclusion The FaSSIF medium discriminated the dissolution profiles of EFV APIs. Small differences in particle size distribution had a significant impact on the biopharmaceutical parameters of EFV, suggesting that strict control of such parameter is an important aspect during API development and drug formulation

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle : mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to?lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7??M, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50?mg/kg. In silico and UV?vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound