Disease relevance of nelfinavir

• Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team [1].
• We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations [1].
• Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight [2].
• Therefore, we examined this with the hypoxia marker EF5 and found that nelfinavir leads to increased oxygenation within tumor xenografts [3].
• Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts [4].
• These results support the clinical investigation of nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas [5].

Psychiatry related information on nelfinavir

• Insufficient concentrations of protease inhibitors such as nelfinavir may reduce the effectiveness of HIV dementia treatment [6].
• Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex [7].

High impact information on nelfinavir

• RESULTS: At week 16 and at weeks 40 and 48, the proportions of patients in whom a plasma HIV-1 RNA level of less than 500 copies per milliliter was achieved were, respectively, 81 percent and 74 percent in the nelfinavir-plus-efavirenz group, 69 percent and 60 percent in the efavirenz group, and 64 percent and 35 percent in the nelfinavir group [8].
• In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis [9].
• We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene [10].
• We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia [11].
• RESULTS: Nelfinavir, ritonavir and saquinavir inhibited adipogenesis and up-regulated the expression of TNF-alpha and IL-6, but this effect was not seen with indinavir, zidovudine and stavudine [12].

Chemical compound and disease context of nelfinavir

• The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function [13].
• STUDY DESIGN AND METHODS: The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment [14].
• In addition, in vivo, doses of amprenavir or nelfinavir comparable with the therapeutic levels achieved in HIV patients were sufficient to down-regulate phosphorylation of Akt in SQ20B and T24 xenografts [15].
• METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir [16].
• Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1) [17].

Biological context of nelfinavir

• Pharmacokinetics of nelfinavir in children: influencing factors and dose implications [2].
• OBJECTIVES: The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir [14].
• Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy [18].
• We have assessed metabolic and immunological effects of a nelfinavir-containing regimen in healthy HIV-1-uninfected individuals receiving post-exposure prophylaxis [19].
• Instead, Nfv inhibits mitochondrial transmembrane potential loss (Delta psi(m)) and the subsequent release of apoptotic mediators [20].

Anatomical context of nelfinavir

• Expression of diacylglycerol transferase, a marker of adipocyte differentiation, decreased in hMSCs treated with NFV [21].
• When considered together, these results suggest that nelfinavir may promote adipose tissue atrophy by compromising adipocyte viability and preventing replacement of lost adipocytes by inhibiting preadipocyte differentiation [22].
• In human mesenchymal stem cells (hMSCs), the PIs LPV and NFV decreased osteoblast alkaline phosphatase enzyme activity and gene expression significantly (p < 0.05) [21].
• Osteoclast activity, measured using a rat neonatal calvaria assay, increased in the presence of nelfinavir (NFV; 47.2%, p = 0.001), indinavir (34.6%, p = 0.001), saquinavir (24.3%, p = 0.001), or ritonavir (18%, p < 0.01) [21].
• CONCLUSIONS: We show in an adipose cell line that IDV and NFV induced alterations at the nuclear level by promoting defects in lamin A/C maturation, organization and stability [23].

Associations of nelfinavir with other chemical compounds

• Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir [24].
• CONCLUSIONS: These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response [25].
• The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively [26].
• The parameters AUC0-12, C0, Cmax and Tmax were compared for nelfinavir with and without tenofovir by calculating geometric mean ratios (GMRs) of the pharmacokinetic parameters with associated 95% confidence intervals (95% CIs) [27].
• Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation, and nelfinavir extracted from cells in the presence of 60% methanol and evaporated to dryness [28].

Gene context of nelfinavir

• However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-zeta (PKC-zeta) to plasma membrane fractions of nelfinavir-treated adipocytes [29].
• BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A [30].
• We found that ritonavir, saquinavir, and nelfinavir were effective inhibitors of wild-type BCRP (482R) with IC50 values of 19.5 +/- 0.8 microM, 19.5 +/- 7.6 microM, and 12.5 +/- 4.1 microM, respectively [31].
• Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control [32].
• We examined the effects of two human immunodeficiency virus protease inhibitors, nelfinavir and amprenavir, which inhibit Akt signaling, on VEGF and HIF-1alpha expression and on angiogenesis [33].

Analytical, diagnostic and therapeutic context of nelfinavir

• The salvage therapy included nelfinavir as new PI in all cases [34].
• Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children [2].
• METHODS: HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study [2].
• We conducted a cohort study of 63 extensively antiretroviral pretreated patients who initiated nelfinavir as part of salvage therapy, to determine predictors of virological response [35].
• Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered [2].

References