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BACKGROUND: This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). METHODS: A prospective cohort study was conducted on people with HIV (PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB+RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma HIV-1 viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. RESULTS: Among 173 patients with a median (IQR) follow-up of 11.1(7.1-13.2) months and 789 pre-dose measurements, 38.7% experienced VL≥20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in two cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis [AHR: 1.49 per log10 VL, 95% CI: 1.04-2.12, P =.027], detectable viremia on oral ART [AHR: 2.45, 95% CI: 1.29-4.65, P =.006], and the level of viral suppression at transition [AHR: 0.38, 95% CI: 0.19-0.75, P =.004]. We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. CONCLUSION: Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB+RPV LA was linked to pre-existing factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

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Interest in plant compounds has increased, given recent evidence regarding their role in human health due to their pleiotropic effects. For example, plant bioactive compounds present in food products, including polyphenols, are associated with preventive effects in various diseases, such as cancer or inflammation. Breast and colorectal cancers are among the most commonly diagnosed cancers globally. Although appreciable advances have been made in treatments, new therapeutic approaches are still needed. Thus, in this study, up to 28 olive leaf extracts were obtained during different seasons and using different drying temperatures. The influence of these conditions on total polyphenolic content (measured using Folin-Ciocalteu assays), antioxidant activity (using Trolox Equivalent Antioxidant Capacity and Ferric Reducing Ability of Plasma assays) and antiproliferative capacity (using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assays) was tested in breast and colorectal cancer cells. Increased phenolic composition and antioxidant and antiproliferative capacity are noted in the extracts obtained from leaves harvested in autumn, followed by summer, spring and winter. Regarding drying conditions, although there is not a general trend, conditions using the highest temperatures lead to the optimal phenolic content and antioxidant and antiproliferative activities in most cases. These results confirm previously published studies and provide evidence in support of the influence of both harvesting and drying conditions on the biological activity of olive leaf extracts.

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Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes-mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR's enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.

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It is estimated that over 60% of the approved drugs and new drug developments for cancer and infectious diseases are from natural origin. The use of natural compounds as a potential source of antitumor agents has been deeply studied in many cancer models, both in vitro and in vivo. Most of the Western medicine studies are based on the use of highly selective pure compounds with strong specificity for their targets such as colchicine or taxol. Nevertheless, approximately 60% of fairly specific drugs in their initial research fail because of toxicity or ineffectiveness in late-stage preclinical studies. Moreover, cancer is a multifaceted disease that in most cases deserves a polypharmacological therapeutic approach. Complex plant-derived mixtures such as natural extracts are difficult to characterize and hardly exhibit high pharmacological potency. However, in some cases, these may provide an advantage due to their multitargeted mode of action and potential synergistic behavior. The polypharmacology approach appears to be a plausible explanation for the multigargeted mechanism of complex natural extracts on different proteins within the same signalling pathway and in several biochemical pathways at once. This review focuses on the different aspects of natural extracts in the context of anticancer activity drug development, with special attention to synergy studies and xenohormesis.

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Breast cancer is one of the most common neoplasms worldwide, and in spite of clinical and pharmacological advances, it is still a clinical problem, causing morbidity and mortality. On the one hand, breast cancer shares with other neoplasms some molecular signatures such as an imbalanced redox state, cell cycle alterations, increased proliferation and an inflammatory status. On the other hand, breast cancer shows differential molecular subtypes that determine its prognosis and treatment. These are characterized mainly by hormone receptors especially estrogen receptors (ERs) and epidermal growth factor receptor 2 (HER2). Tumors with none of these receptors are classified as triple negative breast cancer (TNBC) and are associated with a worse prognosis. The success of treatments partially depends on their specificity and the adequate molecular classification of tumors. New advances in anticancer drug discovery using natural compounds have been made in the last few decades, and polyphenols have emerged as promising molecules. They may act on various molecular targets because of their promiscuous behavior, presenting several physiological effects, some of which confer antitumor activity. This review analyzes the accumulated evidence of the antitumor effects of plant polyphenols on breast cancer, with special attention to their activity on ERs and HER2 targets and also covering different aspects such as redox balance, uncontrolled proliferation and chronic inflammation.