Pharmacokinetics of Antiretroviral Drugs in Older People Living with HIV: A Systematic Review.

BACKGROUND AND OBJECTIVE: The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the pharmacokinetics of drugs and, as a consequence, increase the risk of drug interactions and toxicity that may impact treatment. The aim of this study was to carry out a systematic review of the literature on the effect of aging on ARV pharmacokinetics. METHODS: Searches were performed in the BVS, EMBASE and PUBMED databases until November 2022. All studies available in English, Spanish and Portuguese investigating the pharmacokinetics of ARV approved by the US Food and Drug Administration (FDA) from 2005 to 2020 were selected. Peer-reviewed publications were included if they met all criteria: adults (≥ 18 years of age) living with or without HIV; report any pharmacokinetic parameter or plasma concentration of at least one of the following ARVs: tenofovir alafenamide fumarate (TAF); doravirine (DOR), rilpivirine (RIL) and etravirine (ETR); darunavir (DRV), tipranavir (TPV) and fostemsavir (FTR); dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC) and elvitegravir (EVG); maraviroc (MVC); ibalizumab (IBA); cobicistat (COBI). Pharmacokinetic parameters were reported stratified per age group: young adults (aged 18-49 years) or older (age ≥ 50 years) and all studies were evaluated for quality. The review protocol was registered in the PROSPERO database (registration number CRD42021236432). RESULTS: Among 97 studies included, 20 reported pharmacokinetic evaluation in older individuals (age ≥ 50 years). Twenty five percent of the articles were phase I randomized clinical trials with HIV-negative participants and non-compartmental pharmacokinetic analysis presenting the parameters area under the curve (AUC) and peak drug concentration (Cmax). Seven age-stratified studies evaluated BIC, ETR, DRV, DTG, DOR and RAL. We found publications with discordant results for ETR and DTG pharmacokinetics in different age groups. DRV exposure was highly variable but modestly increased in aging PLWHIV. In contrast, no influence of age on BIC, DOR and RAL exposure was observed. A variability in pharmacokinetic parameters could be observed for the other ARVs (TAF and MVC) in different age groups. CONCLUSION: Exposure to DRV increases modestly with age, while exposure to BIC, DOR and RAL appears to be unaffected by age. As the available evidence to confirm a potential effect of aging on ARV pharmacokinetics is limited, further studies are necessary.

Development and validation of liquid chromatography-tandem mass spectrometry method to quantify dasatinib in plasma and its application to a pharmacokinetic study

Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.

Pretreatment and non-specific binding in ultrafiltration device: Impact on protease inhibitor quantification.

INTRODUCTION: Ultrafiltration (UF) is used to separate unbound drugs; however, non-specific binding (NSB) may be a limiting factor of this technique. Pretreatment of UF devices has been suggested to reduce NSB. Therefore, the pretreatment methodologies for UF devices were evaluated in order to test their effectiveness in reducing NSB of protease inhibitors (PIs). METHODOLOGY: Two PIs (lopinavir-LPV and ritonavir-RTV) were tested. UF devices were pretreated with ultrapure water, Tween-20 or Tween-80. To evaluate the NSB, after UF devices being pretreated, ultrafiltrate solutions containing the analytes at two concentrations (low and high) were used. Samples were quantified by LC-MS/MS. RESULTS: UF devices pretreated with Tween-5% had the lowest NSB for both analytes. NSB values varied between 7 and 11% at low concentration 16-34% at high LPV concentration, respectively. For RTV, NSB was approximately 6% for low concentration and 18% for high concentration. Failure to completely remove Tween in UF devices could results in an overestimation of NSB. CONCLUSION: Pretreatment of UF device with Tween and subsequent removal proved to be effective in reducing NSB of PI.

Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer.

Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N = 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 - 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HRadjusted = 1.82; 95% CI = 1.16 - 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 - 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 - 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 - 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.

Caracterização do perfil de dano oxidativo em carcinoma mamário e avaliação de associação com parâmetroshistopatológicos / Profile characterization of oxidative damage in breast carcinoma and evaluation of association with histopathological parameters

O carcinoma mamário é uma doença complexa que engloba diversas alterações genéticas e bioquímicas, além de mudanças no microambiente tumoral, tais como o estresse oxidativo,que pode ocasionar danos estruturais em lipídios, proteínas, bem como no DNA nuclear. O presente estudo teve por objetivo caracterizar o perfil oxidativo de neoplasias mamárias,comparando o perfil de expressão de produtos dos processos de peroxidação lipídica, nitração proteica e oxidação de DNA em função de parâmetros histopatológicos com valor prognóstico quanto à evolução clínica do câncer de mama. (...) Contudo, quando o tamanho tumoral foi analisado separadamente entre tumores Triplo-Negativos ou entre os demais subtipos (Luminal A/B eHER2-like), não se observou efeito significativo sobre a expressão de 8-OHdG. Em conclusão, os dados indicam que alguns tumores Triplo-Negativos são mais resistentes a danos oxidativos sobre DNA, independentemente de grau ou tamanho tumoral, o que pode contribuir para o perfil de maior agressividade deste subtipo tumoral...

Breast cancer is a complex disease that involves multiple genetic and biochemical alterationsand changes in the tumor microenvironment, such as oxidative stress, which can lead tostructural damages to lipids, proteins and nuclear DNA. The present work aimed tocharacterize the oxidative profile of mammary tumors, comparing the products of profileexpression of lipid peroxidation processes, protein nitration and DNA oxidation according tohistopathological parameters with prognostic value as to clinical evolution of breast cancer. (...) However, when the tumor size was analyzed separately from Triple-Negativetumors or among the other subtypes (luminal A / B and HER2-like), there was no significanteffect on the expression of 8-OHdG. In conclusion, the data indicate that some triple-negativetumors are more resistant to oxidative damage over the DNA, regardless of tumor grade orsize, which may contribute to the more aggressive subtype of the tumor...

A relação psicologia comunitária e behaviorismo: das críticas às propostas de diálogo / The relation community psychology and behaviorism: from critique to dialogue / La relación entre psicología comunitaria y conductismo: de las críticas hacia el diálogo

O presente trabalho analisa diferentes relações entre intervenção comunitária e Behaviorismo, problematizando a tese de que há um antagonismo entre ambos, e discute as possibilidades de um diálogo crítico entre Behaviorismo e Psicologia Comunitária. Para tanto, foi realizada uma análise bibliográfica, em que foram considerados três tipos de estudos: críticas dirigidas ao conservadorismo de teses behavioristas; reflexões behavioristas sobre intervenções comunitárias; relatos de trabalhos comunitários guiados por um referencial behaviorista. Na análise problematiza-se a relação Psicologia Comunitária e Behaviorismo destacando diferenças e aproximações entre os dois campos por meio de uma comparação entre as ideias de autores behavioristas e os pressupostos defendidos na Psicologia Comunitária. As principais divergências relacionam-se com os temas sobre a participação comunitária e a relação colaborativa nas experiências comunitárias. Os pontos de convergência são identificados nos textos centrados em reflexões teóricas sobre colaboração, participação e o contexto da intervenção. (AU)

In this paper we analyze different relations between community intervention and Behaviorism questioning the thesis that there is an antagonistic relation between the latter and concerns with social transformation. Thus, this paper analyzes the possibilities for a dialogue between Behaviorism and Community Psychology. For this purpose, three types of papers were analyzed: criticisms of the conservatism of Behaviorism, reflections on community interventions from a behaviorist standpoint, reports of community interventions guided by Behaviorism. The relation Community Psychology–Behaviorism is discussed highlighting differences and similarities between the two fields. The main differences are related to the issues of participation and collaboration in the analyzed interventions. As for convergences, the theoretical discussions regarding the need of collaboration and participation and a concern with interventions beyond the immediate context are highlighted. (AU)

Este trabajo analiza diferencias entre la Psicología Comunitaria y el Conductismo con el fin de problematizar la tesis de que existe un antagonismo entre el último y las preocupaciones con la transformación social. Este análisis sirve a una reflexión sobre las posibilidades de diálogo entre el Conductismo y la Psicología Comunitaria. Se analizaron tres tipos de trabajos: críticas hacia el conservadurismo del Conductismo, teorías sobre intervenciones en comunidad desde el Conductismo; informes de intervenciones comunitarias guiadas por el Conductismo. Se analizan las relaciones Psicología Comunitaria–Conductismo destacando las diferenciasy aproximaciones entre los dos campos. Las diferencias subrayadas son la falta de participación y colaboración en las intervenciones conductistas. Las convergencias son caracterizadas por discusiones teóricas sobre colaboración, participación y la preocupación con intervenciones más allá del contexto inmediato. (AU)

A relação Psicologia Comunitária e Behaviorismo: das críticas às propostas de diálogo / The Relation Community Psychology and Behaviorism: From Critique to Dialogue / La Relación entre Psicología Comunitaria y Conductismo: de las Críticas hacia el Diálogo

O presente trabalho analisa diferentes relações entre intervençãocomunitária e Behaviorismo, problematizando a tese de que há umantagonismo entre ambos, e discute as possibilidades de um diálogo críticoentre Behaviorismo e Psicologia Comunitária. Para tanto, foi realizadauma análise bibliográfica, em que foram considerados três tipos de estudos: críticas dirigidas ao conservadorismo de teses behavioristas; reflexões behavioristas sobre intervenções comunitárias; relatos de trabalhos comunitários guiados por um referencial behaviorista. Na análise problematiza-se a relação Psicologia Comunitária e Behaviorismo destacando diferenças e aproximações entre os dois campos por meio de uma comparação entre as ideias de autores behavioristas e os pressupostos defendidos na Psicologia Comunitária. As principais divergências relacionamse com os temas sobre a participação comunitária e a relação colaborativa nas experiências comunitárias. Os pontos de convergência são identificados nos textos centrados em reflexões teóricas sobre colaboração, participação e o contexto da intervenção...

In this paper we analyze different relations between community intervention and Behaviorism questioning the thesis that there is an antagonistic relation between the latter and concerns with social transformation. Thus, this paper analyzes the possibilities for a dialogue between Behaviorism and Community Psychology. For this purpose, three types of papers were analyzed: criticisms of the conservatism of Behaviorism, reflections on community interventions from a behaviorist standpoint, reports of community interventions guided by Behaviorism. The relation Community Psychology–Behaviorism is discussed highlighting differences and similarities between the two fields. The main differences are related to the issues of participation and collaboration in the analyzed interventions. As for convergences, the theoretical discussions regarding the need of collaboration and participation and a concern with interventions beyond the immediate context are highlighted...

Este trabajo analiza diferencias entre la Psicología Comunitaria y el Conductismo con el fin de problematizar la tesis de que existe un antagonismo entre el último y las preocupaciones con la transformación social. Este análisis sirve a una reflexión sobre las posibilidades de diálogo entre el Conductismo y la Psicología Comunitaria. Se analizaron tres tipos de trabajos: críticas hacia el conservadurismo del Conductismo, teorías sobre intervenciones en comunidad desde el Conductismo; informes de intervenciones comunitarias guiadas por el Conductismo. Se analizan las relaciones Psicología Comunitaria–Conductismo destacando las diferenciasy aproximaciones entre los dos campos. Las diferencias subrayadas son la falta de participación y colaboración en las intervenciones conductistas. Las convergencias son caracterizadas por discusiones teóricas sobre colaboración, participación y la preocupación con intervenciones más allá del contexto inmediato...