Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stavudine (2',3'-didehydro-3'deoxythymidine) is a pyrimidine analogue that may be of great value in combination antiretroviral therapy (ART) for treating patients infected with human immunodeficiency virus type 1 (HIV-1). We assessed potential neurotoxic side effects by comparing peripheral nerve function in patients receiving ART including stavudine (n = 107) with that of patients receiving ART with zidovudine (n = 103). A cross-sectional analysis of electroneurographic data revealed no significant differences. In a follow-up examination of 31 patients newly started on ART with stavudine we observed no significant effects of the drug on electrophysiological measures. At a daily dose of 1.0 mg/kg the incidence of peripheral nervous system disease in our patients was about 10%. Repeated follow-up analysis of 13 patients on stavudine showed a significant reduction in sural nerve amplitude. Quantitative sensory testing in 13 patients revealed no systematic effect of stavudine on small nerve fibers. Peripheral nerve function in HIV-1 seropositive patients on ART with stavudine did not differ significantly from that in patients on ART with zidovudine. Therefore stavudine at a daily dose of 1.0 mg/kg is an alternative for patients who do not tolerate, or who have become resistant to zidovudine and can be recommended as a first-line drug in combination ART.
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PMID:Stavudine and the peripheral nerve in HIV-1 infected patients. 1032 20

Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor superfamily with critical roles in T cell activation and death, B cell function, dendritic cell maturation and leucocyte traffic regulation. The aim of this study was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and Fas expression on freshly isolated peripheral blood T cells by three-colour flow cytometry and compare them with lymphoproliferative responses, peripheral blood cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially for 48 weeks. At baseline, patients exhibited significantly enhanced proportions and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load rebound during therapy in spite of increasing CD4 counts, the reduction of the levels of these costimulatory molecules was similarly maintained. Therapy induced a decrease in the over-expression of Fas, particularly in the CD4 subset where normal levels were reached at week 8. This reduction occurred in parallel with the major recovery of lymphoproliferative responses. Higher basal levels and lower reduction of Fas were associated with suboptimal suppression of viraemia. In conclusion, this previously undescribed increased expression of CD40L and OX40 may play a role in the HIV-associated pan-immune activation and represent a possible target for immunointervention, as suggested for several immunologically mediated diseases. Moreover, HAART induced an early correction of the over-expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the recovery of the cell traffic disturbances and in the T cell renewal capacity.
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PMID:Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery. 1033 23

A therapeutic dilemma arises once HIV-infected patients develop a break-through of HIV-replication under potent antiretroviral therapy. Therefore, we studied whether patients (n = 12) who failed double nucleoside reverse transcriptase (NRTI) plus indinavir or ritonavir triple therapy can be rescued when therapy is switched to double protease inhibitor (PI) treatment (nelfinavir and hard gel saquinavir) and stavudine. With the rescue regimen HIV-RNA levels initially dropped from 148,571 +/- 45,258 copies/ml to 9,310 +/- 6, 965 copies/ml at week 4 (p = 0.0117). However, virus load subsequently increased to almost baseline levels (131,230 +/- 37,743 copies/ml) at week 12. Likewise, CD4-cell counts could only be stabilized initially (baseline 267 +/- 51; week 4 296 +/- 65 cells/microl), but gradually declined thereafter (216 +/- 34 cells/microl week 12). Before therapy was switched, the viral protease gene from 5 analyzed patients showed 3-5 amino acid substitutions. Moreover, 4 of these patients had one amino acid substitution associated with resistance to nelfinavir. Our data suggest that HIV-infected patients resistant to indinavir or ritonavir and double NRTI combination therapy respond to double PI nelfinavir/saquinavir and D4T rescue therapy only initially but have no sustained benefit.
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PMID:Failure of double protease inhibitor therapy as a salvage therapy for HIV-infected patients resistant to conventional triple therapy. 1042 64

Synthesis and anti-HIV data for a bioconjugate molecule incorporating a HIV protease inhibitor (A74704) and a HIV RT inhibitor (d4T) are presented.
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PMID:Synthesis of a nucleoside bioconjugate system as a potential anti-HIV agent. 1043 75

Cytotoxic and antiretroviral activity of cycloSal-d4TMP derivatives were tested in a new AZT-resistant H9 cell subline (H9rAZT250). The results showed, that cycloSal-d4TMP derivatives overcame resistance of HIV-1 to d4T in H9rAZT250 cells, which exert decreased thymidine kinase (TK) gene expression.
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PMID:Effects of cycloSal-d4TMP derivatives in H9 cells with induced AZT resistance phenotype. 1043 12

The synthesis and anti-HIV activities of phenyl S-pivaloyl-2-thioethyl (tBuSATE) phosphotriesters of AZT and d4T are reported. These compounds show similar activity compared to bis(tBuSATE) phosphotriesters and appear to be able to deliver the corresponding 5'-mononucleotides inside the cells.
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PMID:New series of mixed pronucleotides. Synthesis and anti-HIV activities of mononucleoside phenyl SATE phosphotriesters. 1043 35

Novel series of [ddN]-(CH2)n-[TSAO-T] heterodimers have been prepared and tested for their anti-HIV-1 and HIV-2 activity. The most active compound of this series was the [d4T]-(CH2)3-[TSAO-T] heterodimer (EC50 = 0.018 +/- 0.03 microM).
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PMID:Novel series of [ddN]-[TSAO-T] heterodimers as potential bi-functional inhibitors of HIV-1 RT. Studies in the linker and ddN region. 1043 37

Phosphate and H-phosphonate derivatives of anti-HIV nucleoside analogues (AZT and d4T) were prepared as potential prodrugs of the bio-active free nucleotide and they were evaluated for their inhibitory effects on the replication of HIV-1 in several cell culture systems. One compound exhibited an important anti-HIV-1 activity and proved to be significantly more efficient than the parent nucleoside.
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PMID:Synthesis and anti-HIV activity of some novel arylphosphate and H-phosphonate derivatives of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine. 1044 31

The use of inhibitors of purine nucleoside metabolism has been advocated for the treatment of HIV-1 infection. Abacavir is the first clinically available guanosine analogue HIV-1 reverse transcriptase inhibitor, and the most potent nucleoside analogue yet developed. Mycophenolic acid (MA), a specific inhibitor of lymphocyte proliferation that is currently in use in organ transplantation, acts on inosine monophosphate dehydrogenase to block conversion of inosine monophosphate to guanosine monophosphate. We found abacavir and MA inhibited HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) and in monocyte-derived macrophages (MDMs). Inhibition was potent and synergistic to an extent not previously observed with other antiretroviral combinations. MA was effective at concentrations (0.25 microM) far below those used for immunosuppression in organ transplantation. An HIV strain encoding the M184V mutation was susceptible to the combination of MA and abacavir. However, the combination of MA and zidovudine (ZDV) or stavudine (d4T) was antagonistic. Although the translation of these observations must be carefully evaluated in clinical trials, the judicious combination of antiretrovirals and inhibitors of nucleoside metabolism may emerge as an important strategy in the treatment of HIV infection.
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PMID:Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. 1045 16

The phosphoramidate triester prodrugs of anti-human HIV 2', 3'-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5'-monophosphate (ddNMP), resulting in an improved formation of ddN 5'-triphosphate and, hence, higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of 2',3'-didehydro-2', 3'-dideoxythymidine (d4T) in both wild-type and thymidine kinase-deficient CEM cells, the concept is far less successful for the 3'-azido-2',3'-dideoxythymidine (AZT) triesters. We now investigated the metabolism of triester prodrugs of d4T and AZT using pure enzymes or different biological media. The efficiency of the first activation step, mediated by carboxylesterases, consists of the formation of the amino acyl ddNMP metabolite. The efficiency of this step was shown to be dependent on the amino acid, alkyl ester, and ddN moiety. Triesters that showed no conversion to the amino acyl ddNMP accumulated as the phenyl-containing intermediate and had poor, if any, anti-HIV activity. In contrast to the relative stability of the triesters in human serum, carboxylesterase-mediated cleavage of the prodrugs was found to be remarkably high in mouse serum. The subsequent conversion of the amino acyl ddNMP metabolite to ddNMP or ddN was highest in rat liver cytosolic enzyme preparations. Although L-alaninyl-d4TMP was efficiently converted to d4TMP, the main metabolite formed from L-alaninyl-AZTMP was the free nucleoside (AZT), thus explaining why d4T prodrugs, but not AZT prodrugs, retain anti-HIV activity in HIV-infected thymidine kinase-deficient cell cultures. The rat liver phosphoramidase responsible for the formation of ddNMP was shown to be distinct from creatine kinase, alkaline phosphatase, and phosphodiesterase.
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PMID:Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. 1049 51


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