Tamoxifen favoured the rat sensorial cortex regeneration after a penetrating brain injury

Abstract

Background: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. Methods: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. Findings: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2 0%, 95% CI -0 7 to 4 7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0 08 vs 0 12 mg/dL; p<0 0001), significantly less proteinuria (median % change -3 vs 20; p<0 0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1 30 vs -2 86; p<0 0001) and hip (-0 66 vs -2 95; p<0 0001) at 48 weeks. Interpretation: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Funding: Gilead Sciences. " 2015 Elsevier Ltd.",,,,,,"10.1016/S0140-6736(15)60616-X",,,"http://hdl.handle.net/20.500.12104/44992","http://www.scopus.com/inward/record.url?eid=2-s2.0-84927586093&partnerID=40&md5=fdc5f0e69f8f03ab50642a6a5d057fab",,,,,,,,"The Lancet",,,,,,"Scopus",,,,,,,,,,,,"Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials",,"Article in Press" "46737","123456789/35008",,"Franco Rodríguez, N.E., Laboratorio de Neurofisiología, Edificio P, Tercer piso, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco CP 44340, Mexico; Dueñas Jiménez, J.M., Laboratorio de Neurofisiología, Edificio P, Tercer piso, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco CP 44340, Mexico; De la Torre Valdovinos, B., Laboratorio de Neurofisiología, Edificio P, Tercer piso, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco CP 44340, Mexico; López Ruiz, J.R., Laboratorio de Neurofisiología, Edificio P, Tercer piso, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco CP 44340, Mexico; Hernández Hernández, L., Laboratorio de Neurofisiología, Edificio P, Tercer piso, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco CP 44340, Mexico; Dueñas Jiménez, S.H., Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, Colonia Independencia, Guadalajara, Jalisco CP 44340, Mexico",,"Franco Rodriguez, N.E.

Duenas Jimenez, J.M.

De la Torre Valdovinos, B.

Lopez Ruiz, J.R.

Hernandez Hernandez, L.

Duenas Jimenez, S.H.",,"2013",,"A penetrating brain injury produces a glial scar formed by astrocytes, oligodendrocytes, microglia and NG2 cells. Glial scar is a barrier preventing the extent of damage but it has deleterious effects in the regeneration of the axons. Estradiol and tamoxifen reduce gliosis and have neuroprotective effects in the hippocampus and the spinal cord. We evaluated the proliferation of glia and the electrocorticogram in the sensorial cortex in a brain injury model. At seven days post-injury, estradiol, tamoxifen and estradiol plus tamoxifen reduced the number of resident and proliferative NG2 and reactive astrocyte vimentin+ cells. Estradiol and tamoxifen effects on NG2 cells could be produced by the classical oestrogen receptors found in these cells. The glial scar was also reduced by tamoxifen. At thirty days post-injury, the amount of resident and proliferative astrocytes increased significantly, except in the estradiol plus tamoxifen group, whilst the oligodendrocytes proliferation in the glial scar was reduced in treated animals. Tamoxifen promotes the survival of FOX-3+ neurons in the injured area and a recovery in the amplitude of electrocorticogram waves. At thirty days, estradiol did not favour the suvival of neurons but produced a greater number of reactive astrocytes. In contrast, the number of oligodendrocytes was reduced. Tamoxifen could favour brain repair promoting neuron survival and adjusting glial cell number. It seems to recover adequate neural communication. " 2013 Elsevier Inc..