ABSTRACT
The objective of this study was to evaluate the antiretroviral efficacy and safety of ritonavir (600 mg twice a day [b.i.d.])-saquinavir (400 mg b.i.d.) compared to ritonavir (600 mg b.i.d.) in patients pretreated and receiving continued treatment with two nucleoside analogs. The study was placebo controlled, randomized, and double blind. Inclusion criteria included protease inhibitor naive status and a viral load of >10,000 copies/ml. The main end point was viral load at week 24. Forty-seven patients were included (25 given ritonavir and 22 given ritonavir-saquinavir) and monitored until week 48. At inclusion, 23% had had at least one AIDS-defining event. Previous treatment durations (mean and standard deviation) were 42 +/- 25 and 37 +/- 23 months, viral loads were 4.75 +/- 0.62 and 4.76 +/- 0.50 log(10) copies/ml, and CD4 cell counts were 236 +/- 126 and 234 +/- 125/mm(3) in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 +/- 1.48 and 2.08 +/- 1.14 log(10) copies/ml (P = 0.04) and CD4 cell counts were 330 +/- 151 and 364 +/- 185/mm(3) (P = 0.49) in the ritonavir and ritonavir-saquinavir groups, respectively. Similar results were observed at week 48. Moreover, at week 48, 40 and 68% (P = 0.05) and 28 and 59% (P = 0.03) of patients achieved viral suppression at below 200 and 50 copies/ml in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, six patients in the ritonavir group but only one in the ritonavir-saquinavir group had key mutations conferring resistance to protease inhibitors. Clinical and biological tolerances were similar in both groups. In nucleoside analog-pretreated patients, ritonavir-saquinavir has higher antiretroviral efficacy than and is as well tolerated as ritonavir alone.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Ritonavir/therapeutic use , Saquinavir/therapeutic use , Adult , Anti-HIV Agents/adverse effects , Anti-HIV Agents/blood , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , HIV Infections/blood , HIV Infections/virology , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/blood , Humans , Liver Function Tests , Male , Ritonavir/adverse effects , Ritonavir/blood , Saquinavir/adverse effects , Saquinavir/blood , Viral LoadABSTRACT
A new coumarin identified as 5-hydroxy-6-methoxy-7-(3-methyl-but-2-enyloxy)-2H-1-benzopyran-2-one (isoobtusitin) was isolated from Psiadia dentata. This compound showed, in vitro, a moderate inhibitory activity against poliovirus and a very weak activity against (HIV), whereas it was inactive against (HSV1), (VSV), and murine tumoral cell lines (3LL, L1210).
Subject(s)
Coumarins/isolation & purification , Coumarins/pharmacology , Plants, Medicinal/chemistry , Animals , Anti-HIV Agents/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Plant Leaves/chemistry , Poliovirus/drug effects , Reunion , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Tumor Cells, CulturedABSTRACT
Oxidative stress and glutathione (GSH) deficit may play an important role in HIV infection pathogenesis, and oral administration of GSH-replenishing drugs such as N-acetylcysteine (NAC) and 2-oxothiazolidine-4(R)-carboxylic acid (OTC) may be associated with an increased survival rate of HIV-infected patients. Nevertheless, beneficial effects of these molecules are restricted in vivo by the high concentrations that are necessary to obtain biological effects, rapid extracellular metabolization, and low availability and plasma concentrations. We synthesized OTC derivatives that are more lipophilic than OTC and theoretically able to overcome these limitations and to generate, in addition to cysteine, other substrates of the gamma-glutamyl cycle. Their antiviral effects were investigated in human HIV-1/Ba-L-infected monocyte-derived macrophages. In our experimental conditions, OTC exhibited anti-HIV-1 effects and little cytotoxicity at high doses. None of the nine tested derivatives showed higher cytotoxicity than OTC, nor anti-HIV-1/Ba-L activity.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV-1/drug effects , Macrophages/drug effects , Monocytes/drug effects , Thiazoles/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Humans , Macrophages/virology , Monocytes/virology , Pyrrolidonecarboxylic Acid , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , ThiazolidinesABSTRACT
Interleukin 10 is a pleiotropic cytokine that is overexpressed in HIV-infected patients. Here, we investigated IL-10 expression in primary cultures of monocyte-derived macrophages (MDMs) in response to in vitro infection by HIV-1/Ba-L or two macrophage-tropic HIV-1 primary isolates. Whatever the multiplicity of infection used, and in spite of high replication levels and an increase in HIV-infected cell frequency, neither significant IL-10 secretion nor IL-10 mRNA overexpression was induced in HIV-1-infected MDMs. Moreover, identical results were obtained with HIV-1-infected 1-day monocytes. These results show that MDM infection by HIV is not sufficient by itself for inducing IL-10 synthesis.
