Disease relevance of SAQUINAVIR

• This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of activation markers in serum more than did treatment with zidovudine and either saquinavir or zalcitabine [1].
• Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir [2].
• Safety and activity of saquinavir in HIV infection [3].
• CONCLUSION: Saquinavir is a potent antiviral agent that has a favorable toxicity profile at high doses [4].
• Saquinavir-induced hypoglycemia in type 2 diabetes [5].

Psychiatry related information on SAQUINAVIR

• Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18) [6].
• Although alcohol consumption is a factor in which the bioavailability of saquinavir (SQV) are retarded, the cause for this phenomenon remains to be uncertain [7].

High impact information on SAQUINAVIR

• The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively [8].
• We evaluated saquinavir, an orally active, selective inhibitor of HIV proteinase, in a randomised, double-blind, dose-ranging study in 49 zidovudine-naive HIV-positive patients with few or no symptoms and CD4 cell counts of 500 or less [3].
• The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients [4].
• The relative bioavailability of FCT SOV versus HC SQV was calculated as the ratio of the respective estimated mean saquinavir AUC0-alpha and Cmax [9].
• Saquinavir 500 mg film-coated tablets demonstrate bioequivalence to saquinavir 200 mg hard capsules when boosted with twice-daily ritonavir in healthy volunteers [9].

Chemical compound and disease context of SAQUINAVIR

• RESULTS: At baseline, the median CD4 cell counts were 126 (range: 0-942) (nelfinavir/nevirapine) and 150 (0-642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3-6.4) in both groups [10].
• Patients failing saquinavir therapy require an early change to indinavir before HIV-1 viral load reaches high levels [11].
• Long-term efficacy and safety of twice-daily saquinavir soft gelatin capsules (SGC), with or without nelfinavir, and three times daily saquinavir-SGC, in triple combination therapy for HIV infection: 100-week follow-up [12].
• Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3 [13].
• METHODS: One-hundred-and-sixty HIV-1 infected protease inhibitor- and stavudine-naive patients participating in a trial of ritonavir/saquinavir versus ritonavir/saquinavir/ stavudine completed an adherence questionnaire and a symptom checklist at weeks 12, 24, 36 and 48 [14].

Biological context of SAQUINAVIR

• Pharmacokinetics of once-daily saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen [15].
• The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells [16].
• There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml) [17].
• In these patients, there was no evidence of mutations suggestive of drug resistance, and plasma saquinavir levels were within the expected range [18].
• HIV phenotype switching during antiretroviral therapy: emergence of saquinavir-resistant strains with less cytopathogenicity [19].

Anatomical context of SAQUINAVIR

• The study of the human immunodeficiency virus protease inhibitor saquinavir with Caco-2 cells and phospholipid membranes reveals that the compound interacts with the lipidic bilayer of model membranes with a simple hyperbolic binding profile but with Caco-2 cells in a cooperative way involving membrane receptors [20].
• Effects of the membrane dipole potential on the interaction of saquinavir with phospholipid membranes and plasma membrane receptors of Caco-2 cells [20].
• Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine [21].
• Using a protocol in which a specific HIV protease inhibitor, Saquinavir, was continuously present in the culture medium during selection, we could generate stable cell lines inducibly expressing high amounts of subviral particles [22].
• P-gp is known to limit the bioavailability, brain, testis, and fetal penetration of its substrates, so effective inhibition of P-gp by ritonavir in vivo might open up pharmacological sanctuary sites for saquinavir, with the potential of beneficial effects on therapy, but also of increased toxicity [23].

Associations of SAQUINAVIR with other chemical compounds

• In the group receiving 600 mg of saquinavir plus zidovudine, the median change in CD4 cell count remained high for the 16-week period (median change of 48 cells/mm3 at week 2 and 61 cells/mm3 at week 16) [24].
• Pharmacokinetics of lower doses of saquinavir soft-gel caps (800 and 1200 mg twice daily) boosted with itraconazole in HIV-1-positive patients [25].
• Sulfanitran also stimulated MRP2 activity in cells, i.e. the transport of saquinavir through monolayers of Madin-Darby canine kidney II cells [26].
• The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20-5.03; versus IDV) [27].
• RESULTS: For all PI, the transepithelial permeability ratio (basolateral-to-apical transport divided by apical-to-basolateral transport) was significantly greater in MDR1(1199A) cells than MDR1wt cells: amprenavir (1.7-fold), indinavir (1.8-fold), lopinavir (1.5-fold), ritonavir (2.8-fold), and saquinavir (2.1-fold) [28].

Gene context of SAQUINAVIR

• METHODS: Twenty healthy subjects received a single oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor) [29].
• Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7-54.6 L/h] and 19.3 L/h [95% CI, 11.2-27.4 L/h], respectively; P = .03) [29].
• Functionally, although these correlates had no impact on HIV-1 production from either X4- or R5-tropic virus, expression correlated significantly with the activity of the HIV-1 protease inhibitor (PI) saquinavir for both P-gp (rho = 0.75; P = 0.0019) and CXCR4 (rho = 0.71; P = 0.0041) [30].
• Collectively, the cytotoxicity and transport results provide direct evidence that saquinavir is transported by MRP1 and MRP2 [31].
• Many drugs including saquinavir are substrates of both PGP and CYP3A [32].

Analytical, diagnostic and therapeutic context of SAQUINAVIR

• Because saquinavir induced apoptosis in human cancer cells, HIV-I protease inhibitors might become a new class of cytotoxic drugs, alone or in combination with radiation or chemotherapy [16].
• METHODS: A total of 26 patients enrolled in the nelfinavir clinical trials AG506 and AG511 at our two sites who failed (two consecutive HIV viral loads > 5000 copies/ml; branched DNA assay) were switched to a combination of stavudine 40 mg twice daily, lamivudine 150 mg twice daily, ritonavir 400 mg twice daily and saquinavir 400 mg twice daily [33].
• CONCLUSIONS: HAART is associated with a favorable virological response if started when the baseline HIV-1 RNA level is low, if at least 2 new nucleoside retrotranscriptase inhibitors are added, and if standard doses of saquinavir hard gel capsule are avoided as a single protease inhibitor [34].
• Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay [35].
• Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens [36].

References