In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs / Modelo de correlación farmacocinético in vitro-in vivo para el aseguramiento de la calidad de medicamentos antirretrovirales

Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/ effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.

Introducción: Los modelos de correlación In vitro-in vivo (IVIVC) son parte integral del proceso de investigación y desarrollo de fármacos. La capacidad de predecir con exactitud el perfil in vivo a partir de las observaciones in vitro tiene diversas aplicaciones durante el desarrollo exitoso de una formulación. Objetivo: Desarrollar un modelo integral para predecir la absorción in vivo de fármacos antirretrovirales con base en estudios de permeabilidad, solubilidad in vitro e in vivo y demostrar su correlación con la farmacocinética en humanos. Métodos: Se desarrollaron y validaron las técnicas bioanalíticas para valorar las propiedades biofarmacéuticas de Estavudina, Lamivudina y Zidovudina. Se evaluó las cineticas de disolución, la permeabilidad en monocapas celulares Caco-2 y la farmacocinética de absorción in vivo en conejos y voluntarios sanos. Resultados: Los valores de AUC acumulados en el sistema de células Caco-2, en la disolución y en el modelo animal, fueron correlacionados con los valores de AUC acumulados en el humano. Con lo anterior se demostró una relación directamente proporcional entre los resultados in vitro con respecto a los obtenidos en la fase de absorción tanto en el humano como en el modelo animal. Conclusiones: Los métodos analíticos y procedimientos aplicados en la IVIVC demostraron las correspondencias directas entre sí, con altos niveles de correlación. Se proponen estos modelos IVIVC como métodos alternativos costo/efectivos para la valoración de las propiedades biofarmacéuticas que determinan la biodisponibilidad, en el desarrollo de productos, en el aseguramiento de la calidad y como pruebas de bioequivalencia en los programas de farmacovigilancia.

Sleep Respiratory Disorders and Clinical Profile in Patients with Type 2 Diabetes Mellitus

Introduction Sleep respiratory disorders (SRDs) are often found in patients with type 2 diabetes mellitus (T2DM). Objective The aim was to establish the prevalence of risk to develop an SRD using the Clinical Berlin Questionnaire (CBQ) and Epworth Sleepiness Scale (ESS) in patients with T2DM and verifying the correlation of anthropometric measurements and life quality (LQ) with ESS. Methods A descriptive and analytical study of a case series evaluating 208 patients with T2DM, submitted to clinical and biochemical evaluation and implementation of CBQ, ESS, and WHOQOL-bref to evaluate LQ. Results Mean age was 60.8 8.8 years, and 65.4% were women. Most diabetics were overweight (36.1%), and 29.8% were class I obese. One-third had positive risk signals for a SRD, with 87.0 and 34.1% having high risk in CBQ and sleep disorders in ESS, respectively. There was a significant difference in the general LQ between the low- and high-risk groups in the CBQ. Conclusion In this scenario, it is noteworthy that the active search for sleep disorders must start from simple methods, such as application of protocols. .

Reversed phase HPLC determination of zidovudine in rat plasma and its pharmacokinetics after a single intranasal dose administration

The development and validation of a simple and accurate method based on HPLC with ultraviolet detection for the quantification of zidovudine in rat plasma and its application to a pharmacokinetic study following a single intranasal dose zidovudine is described. Zidovudine was extracted from the plasma using a single-step deproteinization. Chromatographic separation of zidovudine from interfering components was achieved with a C-18 reverse phase column, a mobile phase consisting of a mixture of sodium acetate buffer (55mM) with pH adjusted to 7.0 and acetonitrile (91:9 v/v) and UV detection set at 265 nm. The method was linear from 100 to 10000 ng.mL"¹ (r² > 0.9995), and zidovudine had a mean recovery from plasma of 92.8 percent. The coefficient of variation of inter-day and intra-day quality control samples was less than 15 percent. After a single intranasal dose of zidovudine administered to rats, pharmacokinetic parameters (AUC0 24, Cmax, t , t1/2) were determined. The proposed method was found to be simple, specific, accurate, and precise and could be applied to the quantitative analysis of clinical pharmacokinetic studies of zidovudine in rats.

Consideraciones generales sobre el uso de agentes antimicrobianos en pacientes hepáticos / General remarks: antimicrobial agents use in hepatic patients

El hígado juega un papel fundamental en el metabolismo de las drogas, incluyendo los antimicrobianos. En los pacientes con enfermedad hepática, se deben monitorizar cuidadosamente los efectos adversos y toxicidad de estos medicamentos. En este artículo se analizan los aspectos del metabolismo de los antimicrobianos, particularmente relacionados a los cambios farmacocinéticos en los pacientes hepáticos. Además, se dan algunas recomendaciones prácticas sobre su uso en estos pacientes

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.

Resistencia del virus de inmunodeficiencia humano (VIH) a zidovudina (AZT): análisis genotípico en cepas aisladas de pacientes chilenos / Resistance of human immunodeficiency virus (VIH) to zidovudine: genotypic analysis in strains isolated from chilean patients

Background: Resistance of HIV to AZT is the result of mutations in the pol gene that codifies the enzyme reverse transcriptase. Aim: To asses the resistance to antiretroviral drugs in Chhilean patients infected with HIV. Material and methods: The presence of mutations was searched in 22 patients infected with HIV. The emergence or persistence of these mutations was studiend in sequential samples of 19 patients. The presence of the mutation that confers resistance to didanosine (ddi) was studied in those subjects exposed to the drug. Polymerase chain reaction techniques were used to analyze mutations in codons 41, 70 and 215 of the pol gene (resistance to AZT) and the mutation in codon 71 (resistance to DDI). Results: On admission, none of the patients without previous exposure to AZT had drug resistance mutations. Seven of 12 patients (58.3 percent) that had received AZT had mutations in codon 215. In two, they were associated to a mutation in codon 41 and in two, to a mutation in codon 70. After a mean follow up of 14 months, 13 of 15 patients (86 percent) that received AZT had viral strains genotypically resistant to the drug. In nine of these, the resistance was associated with disease progression. None of the 10 patients that received DDI had the mutation in codon 74 that confers resistance to the drug. However, in one of these patients, that never receided AZT, virus with a mutation in codon 215 was detected. Conclusions: A high percentage of patients that have received monotheraphy with AZT have genotypic resistance to the drug. This resistance is associated with clinical and immunological derangement in 70 percent of these subjects

AZT: farmacologia, benefícios e aplicaçÆes clínicas / AZT: pharmacology, general considerations and clinical effects

Este trabalho consiste numa revisåo dos principais tópicos referentes ao uso do AZT, como histórico, consideraçÆes gerais, mecanismo de açåo, farmacocinética, uso terapêutico e efeitos clínicos, reaçÆes adversas e interaçÆes medicamentosas. Pretender uma introduçåo para a descriçåo de nossa experiência com a droga, através de dois grupos de pacientes, 40 no total, a ser publicada num futuro próximo

Infección por virus de la inmunodeficiencia humana: actualidades en el tratamiento / H.I.V. infections: Current treatment concepts

Ante el aumento progresivo de nuevos casos del síndrome de inmunodeficiencia adquirida (SIDA) en México, presentamos esta revisión de los medicamentos y sustancias que actualmente se encuentran en diversas fases de investigación clínica para el tratamiento de esta infección que, sin duda, es la pandemia más importante de la segunda mitad del siglo veinte. También revisamos las indicaciones en los pacientes con SIDA. Asimismo, se incluyen los medicamentos adyuvantes en el tratamiento de las complicaciones de la infección, su uso y efectos adversos, así como sus interacciones medicamentosas