The main focus of this study is exploring the effect and mechanism of two HIV‐protease inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO‐modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells. 相似文献
ObjectiveTo evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia).DesignCross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011.MethodsPatients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm3, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography.Results and discussionOverall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). No statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir.ConclusionIn summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. Prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068). 相似文献
Objectives: To assess safety and efficacy of a switch to unboosted atazanavir (ATV) among HIV-infected adults receiving ATV/ritonavir (r) and tenofovir disoproxil fumarate (TDF).
Methods: HIV-infected adults with viral load (VL) <40 copies/mL at screening and <150 copies/mL consistently for ≥3 months while receiving a regimen including ATV/r and TDF were randomized to continue ATV/r 300/100 mg daily (control) or change to ATV 400 mg daily (switch), while maintaining their TDF backbone. The primary outcome was proportion of subjects without treatment failure (regimen switch or VL > 200 copies/mL twice consecutively) at 48 weeks.
Results: Fifty participants (46 male, median age 47 years) were randomized, 25 to each arm. At week 48, treatment success occurred in 76% in the control arm and 92% in the switch arm (ITT, p = 0.25). ATV trough levels at week 9 were higher in controls (median 438 ng/mL) than in the switch arm (median 124 ng/mL) (p = 0.003), as was total bilirubin at week 48 (median 38 μmol/L and 28 μmol/L, respectively; p = 0.02). Estimated glomerular filtration rate (eGFR) decreased in the control arm (p = 0.007), but did not change in the switch arm. At week 48, eGFR was higher in the switch arm (median 96 mL/min) than in the control arm (median 85 mL/min) (p = 0.035), but the arms were similar with respect to fasting glucose, C-reactive protein, and lipid parameters.
Conclusions: Switching from ATV/r to unboosted ATV appears to be safe and effective in selected virologically suppressed patients receiving TDF-containing regimens, and may have favorable effects on bilirubin and renal function. 相似文献