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)

Primarily resulting as a spin-off of the search for effective anti-HSV or anti-HIV agents, several compounds have been identified as effective and promising candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA. They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well below the cytotoxicity threshold. All these nucleoside analogues require three phosphorylation steps to be active, in their triphosphate form, as inhibitors of the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to interact as chain terminators with the HBV DNA polymerase reaction. Several of these compounds (for example, famciclovir, lamivudine and adefovir) have proven to be efficacious in the duck and/or woodchuck hepatitis models, and, accordingly, famciclovir, lamivudine and adefovir have also proven to be effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV infection. Yet, famciclovir and lamivudine may lead to the emergence of resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long-term treatment. These penciclovir- and lamivudine-resistant HBV mutants still retain susceptibility to adefovir, which, in turn, has so far not been found to engender resistance mutations in HBV. As has become obvious from the experience with the treatment of HIV infections, future HBV chemotherapy may reside in combination drug therapy so as to achieve the highest possible virus reduction, thereby minimizing the likelihood of drug resistance development.
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PMID:Perspectives for the treatment of hepatitis B virus infections. 1041 52

Dideoxynucleosides, which are potent inhibitors of HIV reverse transcriptase and other viral DNA polymerases, are a common component of highly active anti-retroviral therapy (HAART) (ref. 1). Six reverse transcriptase inhibitors have been approved for human use: azidothymidine; 2'3'-dideoxycytidine; 2'3'-dideoxyinosine; 2', 3'-didehydro-3'deoxythymidine; 2',3'-dideoxy-3'-thiacytidine; and 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-++ +metha nol. Although drug-resistant HIV strains resulting from genetic mutation have emerged in patients treated with HAART (ref. 1), some patients show signs of drug resistance in the absence of drug-resistant viruses. In our study of alternative or additional mechanisms of resistance operating during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxyethyl)adenine) and azidothymidine monophosphate from cells and, thus, with resistance to these drugs. Overexpression of MRP4 mRNA and MRP4 protein severely impaired the antiviral efficacy of PMEA, azidothymidine and other nucleoside analogs. Increased resistance to PMEA and amplification of the MRP4 gene correlated with enhanced drug efflux; transfer of chromosome 13 containing the amplified MRP4 gene conferred resistance to PMEA. MRP4 is the first transporter, to our knowledge, directly linked to the efflux of nucleoside monophosphate analogs from mammalian cells.
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PMID:MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. 1047 83

Human herpesvirus virus type 7 (HHV-7) is a T-lymphotropic herpesvirus which uses the CD4 receptor as main receptor to infect its target cells. Measuring the decrease of CD4 expression during HHV-7 infection is a convenient and accurate method to monitor the efficacy of antiviral agents against HHV-7 infection. Different classes of compounds, such as heparin, pentosan polysulfate (PS), dextran sulfate (DS), aurintricarboxylic acid (ATA), phosphonoformic acid (PFA), 9-(2-phosphonylmethoxyethyl)adenine (PMEA), 2-amino-7-[(1,3-dihydroxy-2-propoxy) methyl] purine (S2242), polyvinylalcohol sulfate (PVAS) and the co-polymer of vinylalcohol sulfate with acrylic acid (PAVAS), acyclovir (ACV), ganciclovir (GCV), penciclovir (PCV), brivudin (BVDU), cidofovir (HPMPC), lobucavir, (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine] (H2G), (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and sorivudine (BVaraU), were evaluated for their anti-HHV-7 activity in the SupT1 T cell line and in purified CD4+ T lymphocytes. Antiviral activity was monitored by inhibition of: (i) CD4 expression down-regulation; (ii) giant cell formation and (iii) apoptosis induction. In general, PS, DS, PVAS, PAVAS, ATA, PFA, PMEA, S2242, lobucavir and HPMPC had comparable anti-HHV-7 activity in the two cell lines, irrespective of the parameters followed to monitor antiviral activity. One of the exceptions was heparin which had an IC50 of 9.6 microg/ml in SupT1 cells and >250 microg/ml in CD4+ T lymphocytes. The compounds PCV, GCV, H2G and PMPA showed some activity in CD4+ T lymphocytes, but not in SupT1 cells. ACV, BVDU and BVaraU did not show activity in either cell system. None of the chemokines tested, such as platelet factor-4 (PF-4), eotaxin, stromal cell-derived factor 1alpha(SDF-1alpha) and RANTES, had detectable activity against HHV-7. In contrast, the HIV-1 envelope glycoprotein, gp120, and the two anti-CD4 mAbs, 13B8-2 and OKT4, were clearly active against HHV-7 infection.
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PMID:Selective activity of various antiviral compounds against HHV-7 infection. 1048 Feb 61

Adefovir dipivoxil is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir (PMEA), the prototype compound of the acyclic nucleoside phosphonates. It has better oral bioavailability than the parent compound. Adefovir dipivoxil 120mg once daily significantly reduced viral load compared with placebo when added to standard antiretroviral therapy in a 6-month, double-blind study in patients with HIV infection. Viral suppression was maintained during an additional 6-month nonblind extension phase. The drug was most effective in patients with baseline isolates containing the M184V lamivudine resistance mutation according to data from a virological substudy of a large placebo-controlled trial. Adefovir dipivoxil 60mg was as effective as 120mg (both once daily) after 20 weeks' treatment in a randomised double-blind study in antiretroviral-experienced (protease inhibitor-naive) patients. Viral suppression was generally maintained in patients who developed new reverse transcriptase mutations during adefovir dipivoxil monotherapy or combination therapy for up to 12 months. No clear pattern of particular clinical resistance mutations has emerged. GI disturbances, hepatic effects and delayed renal abnormalities are the principal adverse events seen with adefovir dipivoxil. Reductions in serum free carnitine levels may occur and coadministration of L-carnitine is recommended.
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PMID:Adefovir dipivoxil. 1049 75

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.
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PMID:A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection. 1060 55

Two prominent members of the ATP-binding cassette superfamily of transmembrane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug resistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotics and (anticancer) drugs from normal and tumor cells. The MRP subfamily consists of at least six members, and here we report the functional characterization of human MRP5. We found resistance against the thiopurine anticancer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in MRP5-transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the cells that overproduce MRP5. In polarized Madin-Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is routed to the basolateral membrane and these cells transport S-(2,4-dinitrophenyl)glutathione and glutathione preferentially toward the basal compartment. Inhibitors of organic anion transport inhibit transport mediated by MRP5. We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.
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PMID:Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. 1084 50

The heterosubstituted nucleoside analogue dOTC [( )-2'-deoxy-3'-oxa-4'-thiocytidine, BCH-10652] is a racemic compound structurally related to 3TC (lamivudine), but has the oxygen and sulphur in the furanosyl ring transposed. Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM). Investigation of the activity of dOTC and its enantiomers against laboratory strains of HIV-1 with defined resistance to 3TC, AZT (zidovudine), ddl (didanosine), PMEA (adefovir), nevirapine and saquinavir indicated that sensitivity was maintained (<3-fold change in EC50) in all cases, with the exception of HIV-1RF 3TC-resistant viruses. The degree of resistance recorded for dOTC (four- to sevenfold), (-)dOTC (five- to eightfold) and (+)dOTC (five- to >18-fold) against these M1841 or M184V mutants, was significantly less than that recorded for 3TC (>100-fold). In addition, the inhibitory effect of the compounds against clinical isolates of HIV-1 recovered from patients with suspected resistance to 3TC and AZT was investigated. Clinical isolates were genotyped using the Murex Line Probe Assay (LiPA) and subgrouped into wild-type, 3TC-resistant and dual 3TC/AZT-resistant, as well as undefined or mixed genotype populations. Compared with the mean EC50 values obtained with genotypically and phenotypically wild-type clinical isolates, the mean EC50 values calculated for isolates phenotypically resistant to 3TC or 3TC and AZT were only 2.6-, 1.6- and 8.2-fold higher for dOTC, (-)dOTC and (+)dOTC, respectively. When the rate of emergence of virus resistant to dOTC and its enantiomers in vitro was investigated, virus resistant to (+)dOTC was readily selected for (<10 passages), and a methionine (ATG) to isoleucine (ATA) amino acid change at codon 184 was identified. In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases. In addition, virus passaged 20 times in the presence of dOTC also had a partial lysine (AAA) to arginine (AGA) exchange at position 65. These viruses showed only low-level resistance to dOTC and its enantiomers, but were highly resistant to 3TC. The antiviral effects of dOTC in combination with the nucleoside RT inhibitors AZT, 3TC, d4T (stavudine) and ddl, the non-nucleoside RT inhibitor nevirapine and the protease inhibitors saquinavir, ritonavir and indinavir was investigated. Two-way drug combination assays were carried out in peripheral blood mononuclear cell (PBMC) cultures by measuring the reduction in p24 viral antigen levels, and data was analysed using the MacSynergy II program. dOTC in combination with 3TC or d4T showed a moderate synergistic effect while all other combinations had an additive interaction.
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PMID:Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC]. 1095 Mar 91

The incidence of cytomegalovirus (CMV) retinitis in AIDS has declined significantly due to the use of highly active antiretroviral therapy (HAART). However, patients with HIV, especially those failing HAART, may still suffer with CMV retinitis, which can lead to significant loss of vision and blindness. Ganciclovir has traditionally been considered the recommended treatment for CMV retinitis; however, due to side effects and the possibility of developing viral resistance, other agents may be preferred in certain situations. Foscarnet, which has similar efficacy to ganciclovir but a different side effect profile, is more difficult to administer and is less well-tolerated. Intravenous cidofovir, which may be more effective than either iv. ganciclovir or foscarnet, can also be used as a first line agent; however, it is associated with toxicity (renal and ocular) and thus needs careful use. Local therapy for CMV retinitis has been a significant advance. The intraocular ganciclovir implant has the highest efficacy of the approved agents and is well-tolerated. Fomivirsen, an oligonucleotide injected intravitreally, is a newly approved agent which offers alternative treatment. Intravitreal ganciclovir or foscarnet, although not approved, have been used successfully in some patients especially those with recurrent or refractory disease. The development of new anti-CMV agents has been stalled by the decreased incidence of the disease. Valganciclovir, a prodrug of ganciclovir, offers excellent oral bioavailability and is the closest to approval of all the new anti-CMV drugs. High ganciclovir blood levels are achieved without the complications associated with the requirement for long-term iv. access. The monoclonal antibody (mAb) MSL-109, did not offer a significant advantage when added to traditional anti-CMV therapy. Development plans of other agents such as cyclic HPMPC and lobucavir have been put on hold by their respective manufacturers. Adefovir is a nucleotide analogue that possesses anti-CMV activity, but is currently only being pursued for the treatment of hepatitis B virus. Other compounds possessing significant anti-CMV activity, including BAY 38-4766 and GW1263W94 are still in the early stages of development.
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PMID:Therapeutic developments in cytomegalovirus retinitis. 1106 Jun 72

Recent use of zidovudine (ZDV) to reduce vertical transmission of HIV disease in newborns has demonstrated varied, but in some studies, dramatic results, with reports of reduction from approximately 8% to 25%. With this potential of efficacy in saving lives, knowledge of access to prenatal care for HIV-infected pregnant women is urgent. The current study used face-to-face and phone survey methods and employed a 77-item questionnaire to assess barriers to prenatal care in two groups of HIV-positive and HIV-negative women (n = 106). All participants had a child(ren) under 4 years of age and were currently enrolled in a primary care or family HIV clinic. Results showed that HIV-positive women had specific concerns regarding access of perinatal care that included disclosure and fear of anger from health care providers. Barriers such as transportation, insurance and child care, among others, were not predictive of the level of prenatal care received, but results may be biased by the small number of women who had not received adequate care and the general selection process from women who were currently attending clinics. A high level of prenatal care was recorded across both cohorts. Misconceptions about vertical transmission and ZDV efficacy were demonstrated, including that more than 80% of all participants stated there was a greater than 50% chance of a pregnant untreated HIV-positive woman transmitting the virus; the documented transmission rate for untreated birth mothers is 20% to 25%. In addition, HIV-negative women showed little knowledge about vertical transmission and the use of ZDV, putting this group at risk in the future. Better educational methods to more women about perinatal HIV transmission and ADV could be imperative in significantly improving reduction of vertical transmission.
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PMID:Prenatal care and HIV infection. 1136 26

PMPA, an experimental anti-HIV drug, is a member of a new class of drugs called nucleotide analogs. PMPA gained attention when it was reported that it completely protected macaque monkeys from SIV (a virus closely related to HIV). No other potential treatment has been able to do this. It is difficult to tell how quickly nucleotide analogs can work because, for unknown reasons, viral loads show only modest reductions even when other information suggests that they may be working better than the viral loads imply. PMPA is undergoing standard animal toxicology tests in preparation for human trials. The first nucleotide analog likely to reach widespread human use is bis-POM PMEA, since it is already in human trials.
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PMID:PMPA in perspective. 1136 50


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