indinavir

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 μM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected...

Insulin-dependent glucose influx in skeletal muscle and adipocytes is believed to rely largely on GLUT4, but this has not been confirmed directly. We assessed the relative functional contribution of GLUT4 in experimental models of skeletal muscle and adipocytes using the HIV-1 protease inhibitor indinavir. Indinavir (up to 100 micro mol/l) was added to the glucose transport solution after insulin stimulation of wild-type L6 muscle cells, L6 cells over-expressing either GLUT4myc or GLUT1myc, 3T3-L1 adipocytes, isolated mouse brown or white adipocytes, and isolated mouse muscle preparations. 100 micro mol/l indinavir inhibited 80% of both basal and insulin-stimulated 2-deoxyglucose uptake in L6GLUT4myc myotubes and myoblasts, but only 25% in L6GLUT1myc cells. Cell-surface density of glucose transporters was not affected. In isolated soleus and extensor digitorum longus muscles, primary white and brown adipocytes, insulin-stimulated glucose uptake was inhibited 70 to 80% by indinavir. ...

Since the appearance of resistance to antiretroviral treatment is unavoidable, the host cell's transcription factor NF-kappaB is a novel HIV target. The goal of this study was to characterize the effect of two immunomodulators, curcumin (Cur) and sulfasalazine (Sul), with a protease inhibitor, indinavir (IDV), on HIV-1 persistently infected CD4+ T-cells. Viral p24 antigen production, viral infectivity (tested on MAGI cells) and viral relative infectivity (viral infectivity/p24) were analysed. When used alone, both immunomodulators were able to reduce viral infectivity. When in combination, both 10 microM IDV plus 10 microM Cur and 10 microM IDV plus 250 microM Sul showed a significant reduction in viral infectivity and viral relative infectivity when compared to the reduction produced by IDV alone. Thus, the use of immunomodulators with IDV could help to reduce HIV-1 production in persistently infected cells.

Women with a singleton, uncomplicated pregnancy between 14 and 28 weeks of gestation according to menstrual and ultrasound dating were enrolled after signing institutional human subjects committee-approved informed consent statements. Exclusion criteria included prior ...

We examined the prevalence of cleavage site mutations, both within and outside the gag region, in 28 protease inhibitor (PI) cross-resistant patients treated with indinavir, ritonavir, and/or saquinavir compared to control patients treated with reverse transcriptase inhibitors. Three human immunodeficiency virus protease cleavage sites within gag (p2/NC, NC/p1, and NC/TFP) showed considerable in vivo evolution before and after therapy with indinavir, ritonavir, and/or saquinavir. Another gag cleavage site (p1/p6 gag ) showed a trend compared to matched controls. The other eight recognized cleavage sites showed relatively little difference between PI-resistant cases and controls. An A→V substitution at the P2 position of the NC/p1 and NC/TFP cleavage sites was the most common (29%) change selected by the PIs used in this study.

Resumen Objetivo: el incremento de la resistencia a antifúngicos en Candida spp. una levadura de carácter oportunista asociada a múltiples infecciones superficiales y sistémicas, plantea la necesidad de buscar diferentes estrategias para hallar nuevas opciones terapéuticas más selectivas y específicas. Una alternativa es el tamizaje basado en el acoplamiento virtual. En el presente trabajo, se analizaron 13418 compuestos con estructuras similares a compuestos reconocidos como inhibidores de la proteína SAP-2, seleccionada como diana antifúngica para el análisis virtual. Materiales y métodos: el estudio se realizó utilizando el programa SYBYL 8, al tiempo que se evaluó la afi-nidad de estas estructuras con los sitios activos de la enzima seleccionada mediante el programa FlexX integrado en SYBYL 8 y se realizó un consenso comparando los resultados con el programa Autodock Vina. Resultados: los resultados obtenidos mostraron una mayor afinidad por móleculas con estructura similar a los antirretro-virales, inhibidores de proteasas; amprenavir, saquinavir e indinavir. Conclusiones: los resultados obtenidos sugieren que estos lnhibidores de proteasas pueden ser propuestos como modelos para la búsqueda de nuevos antifúngicos que sean más selectivos contra Candida spp.

Vgamma2Vdelta2+ T cells play a role in antimicrobial responses. It is unknown whether adaptive Vgamma2Vdelta2+ T cell responses during active mycobacterial coinfection of human immunodeficiency virus-infected humans can be generated during effective antiretroviral treatment. Here, simian immunodeficiency virus (SIV)mac-infected macaques previously exposed to bacille Calmette-Guerin (BCG) were reinfected with BCG, were treated either with tenofovir or tenofovir plus indinavir, and were assessed for the development of Vgamma2Vdelta2+ T cell responses during active BCG coinfection. A restored capacity of Vgamma2Vdelta2+ T cells to undergo major expansions and pulmonary migration during active BCG coinfection was detected after simultaneous BCG reinfection and treatment with tenofovir of the SIVmac-infected macaques. Interestingly, a restored expansion of Vgamma2Vdelta2+ T cells in the SIVmac/BCG-coinfected macaques was detectable, even though antiretroviral treatment was initiated 1 month after BCG reinfection. Importantly, the restored expansion of Vgamma2Vdelta2+ T cells coincided with increases in numbers of purified protein derivative-specific interferon- gamma -producing CD4+ T cells and increases in the magnitude of their proliferative responses. In contrast, the SIVmac-infected control macaques exhibited diminished responses of Vgamma2Vdelta2+ T cells and mycobacterium-specific CD4+ T cells during active BCG coinfection. Our results suggest that the development of adaptive immune responses of phosphoantigen-specific Vgamma2Vdelta2+ T cells during active mycobacterium/HIV coinfection requires control of viral infection and immune competence of peptide-specific CD4+ T cells.

We evaluate by simulation three model-based methods to test the influence of a single nucleotide polymorphism on a pharmacokinetic parameter of a drug: analysis of variance (ANOVA) on the empirical Bayes estimates of the individual parameters, likelihood ratio ...

Objetivo. El incremento de la resistencia a antifúngicos en Candida spp. una levadura de carácter oportunista asociada a múltiples infecciones superficiales y sistémicas, plantea la necesidad de buscar diferentes estrategias para hallar nuevas opciones terapéuticas más selectivas y específicas. Una alternativa es el tamizaje basado en el acoplamiento virtual. En el presente trabajo, se analizaron 13418 compuestos con estructuras similares a  compuestos reconocidos como inhibidores de la proteína SAP-2, seleccionada como diana antifúngica para el análisis virtual. Materiales y método. El estudio se realizó utilizando el programa SYBYL 8, al tiempo que se evaluó  la afinidad de estas estructuras  con los sitios activos de  la enzima seleccionada mediante el programa FlexX integrado en SYBYL 8 y se realizó un consenso comparando  los resultados con el programa Autodock Vina. Resultados Los resultados obtenidos mostraron una mayor afinidad por móleculas con estructura similar  a los ant...