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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our studies have shown that the acyclic nucleotide analogues PMEA and HPMPC are able to penetrate into cells and are then activated to mono- and diphosphate derivatives. The latter correspond to triphosphate analogues and presumably serve an important role in the biological activity exerted by these antiviral agents. In support of this idea, the inhibitory effect of PMEApp on HIV reverse transcriptase has been demonstrated with both RNA and DNA template-primer systems. Further studies will be undertaken to determine the effect of HPMPCpp on viral DNA polymerases. Whereas the metabolism of PMEA in CEM cells gives rise to only PMEAp and PMEApp, additional metabolites were obtained in MRC-5 cells; the identity of these metabolites remains to be determined. In the case of HPMPC, a third metabolite was obtained in addition to HPMPCp and HPMPCpp, which has been tentatively assigned as a phosphate-choline adduct by analogy with activation of cytosine-based nucleoside derivatives. The metabolism of HPMPC was unchanged between uninfected and infected cells, indicating that viral enzymes are not necessary for the activation of HPMPC. The long intracellular half-lives of the HPMPC metabolites may have implications for the antiviral efficacy of this compound. The persistence of activated metabolites suggests that infrequent dosing may be possible due to a prolonged antiviral effect. Our results on the effectiveness of infrequent dosing schedules with HPMPC in the treatment of HSV 2 infections in mice support this hypothesis. It is also possible that HPMPCp-choline may serve as a reservoir for HPMPC and therefore for the presumed active metabolite HPMPCpp.
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PMID:Biochemical pharmacology of acyclic nucleotide analogues. 207 30

Different treatment schedules have been investigated when evaluating the inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 3'-azido-2',3'-dideoxythymidine (AZT) on the replication of human immunodeficiency virus type I (HIV-I) in MT-4 cells, transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV), and MSV-induced tumor formation in newborn NMRI mice. Shortening the exposure time of HIV-I-infected MT-4 cells to PMEA or AZT led to an increase in the selectivity index of both compounds. PMEA proved markedly more efficient in suppressing MSV-induced tumor formation in mice when administered as a single dose on the day of infection than when these doses were spread over 2, 4 or 7 administrations within 1 week after the virus infection. This was not observed when the total dose of AZT was fractionated. While the infrequent dosage regimen increased the anti-retrovirus activity of PMEA, it did not increase its toxicity for the host. This unique property makes PMEA an attractive candidate for the treatment of retrovirus infections, including AIDS.
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PMID:Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. 238 80

The author gives a survey of groups of substances which have a marked and selective effect on HI thus serving as potential chemotherapeutical means against AIDS. They can be divided into three groups: 1. anionic substances, 2. 2, 3-dideoxynucleoside analogues and 3. sulphate polysaccharides. The mechanism of the effect of the substances of the 2nd group probably inhibits reverse HIV transcriptase. The substances of the 3rd group are to prevent adsorption of virus particles by the cells. The substances of the 1st group inhibit HIV transcriptase but also interfere with the adsorption process of the virus particles, or with other stages and phases of the HIV replication cycle. The crystallized substances of these groups should be further studied as potential therapeutic agents for the treatment of AIDS and other retrovirus infections (PMEA, D4T, dextran-sulphate, pentosan, polysulphate and others). The survey also includes information on the so-called anti-sense RNA.
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PMID:[Perspectives in AIDS chemotherapy]. 257 16

Long-tailed macaques chronically infected with simian immunodeficiency virus (SIV) were treated for 4 or 8 weeks with daily subcutaneous doses of the antiretroviral compound 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The efficacy of PMEA was evaluated by monitoring cell-free virus in plasma, virus titer and viral DNA in peripheral blood mononuclear cells, and absolute numbers of lymphocyte subsets. In mock-treated control macaques, virus titers changed minimally. However, in treated macaques, PMEA exhibited impressive effects, leading to the disappearance of virus in the blood within the first week of treatment and lasting through the fourth week of treatment. The results indicate that PMEA can effectively reduce SIV in chronically infected macaques and offer an optimistic perspective for therapeutic intervention against human immunodeficiency virus infection.
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PMID:Efficacy of 9-(2-phosphonylmethoxyethyl)adenine treatment against chronic simian immunodeficiency virus infection in macaques. 753 51

The acyclic purine nucleoside phosphonates, a newly described class of broad-spectrum antiviral agents, effectively inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro and in animal AIDS models. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is currently being evaluated in clinical trials in patients with AIDS. In this study, we investigated the efficacy of PMEA and a related analog, 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP), against HIV-1 isolates exhibiting various degrees of resistance to zidovudine (azidothymidine [AZT]). HIV isolates highly (approximately 50 to 200-fold) resistant to AZT were found to be about two- to eightfold less susceptible to PMEA. A comparable degree of cross-resistance to PMPDAP, a structurally related analog of PMEA, was also observed. However, the 50% effective dose values of PMEA or PMPDAP against a panel of HIV isolates showing intermediate levels (approximately 8 to 25-fold) of AZT resistance was indistinguishable from the 50% effective dose values of PMEA (0.7 to 1.7 versus 2 microM) or PMPDAP (0.4 to 1.4 versus 0.8 to 1 microM) against HIV isolates from patients who had not previously used AZT. In addition, we were unable to generate PMEA- (or PMPDAP)-resistant HIV-1 variants by > 30 serial passages of the virus in the presence of increasing concentrations of PMEA. Careful analysis of HIV-1 isolates from patients previously treated with AZT for cross-resistance to PMEA are needed to evaluate the significance of these observations.
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PMID:Susceptibilities of zidovudine-resistant variants of human immunodeficiency virus type 1 to inhibition by acyclic nucleoside phosphonates. 797 11

A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or bis(amides) provided the corresponding monoesters or monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug. The oral bioavailability of PMEA employing this method was determined to be 7.8%. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.
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PMID:Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). 802 25

On the basis of three different models (namely: ddU, AZT and PMEA), mononucleotide phosphotriester derivatives were designed to be able to liberate the corresponding monophosphate (or phosphonate) inside the cell through a reductase-mediated activation process. It was demonstrated that the use of bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters of ddUMP (11), AZTMP (12) and PMEA (17) resulted in intracellular delivery of the parent monophosphate (or phosphonate). This point was corroborated by observation of an anti-HIV effect of, 11 in various cell lines, for 12 in CEM TK- cells and by the enhanced activity observed for 17. Furthermore, the reported decomposition data in cell extracts fully confirm the validity of this approach and show unambiguously the potential for intracellular reductase-mediated activation of the starting drug.
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PMID:Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process. 827 10

The target protein (enzyme) with which antiviral agents interact determines their antiviral activity spectrum. Based on their activity spectrum, antiviral compounds could be divided into the following classes: (1) sulfated polysaccharides (i.e., dextran sulfate), which interact with the viral envelope glycoproteins and are inhibitory to a broad variety of enveloped viruses (i.e., retro-, herpes-, rhabdo-, and arenaviruses): (2) SAH hydrolase inhibitors (i.e., neplanocin A derivatives), which are particularly effective against poxvirus, (-)RNA viruses (paramyxovirus, rhabdovirus), and (+/-)RNA virus (reovirus); (3) OMP decarboxylase inhibitors (i.e., pyrazofurin) and CTP synthetase inhibitors (i.e., cyclopentenylcytosine), which are active against a broad range of DNA, (+)RNA, (-)RNA, and (+/-)RNA viruses; (4) IMP dehydrogenase inhibitors (i.e., ribavirin), which are also active against various (+)RNA and (-)RNA viruses and, in particular, ortho- and paramyxoviruses; (5) acyclic guanosine analogs (i.e., ganciclovir) and carbocyclic guanosine analogs (i.e., cyclobut-G), which are particularly active against herpesviruses (i.e., HSV-1, HSV-2, VZV, CMV); (6) thymidine analogs (i.e., BVDU, BVaraU), which are specifically active against HSV-1 and VZV because of their preferential phosphorylation by the virus-encoded thymidine kinase; (7) acyclic nucleoside phosphonates (i.e., HPMPA, HPMPC, PMEA, FPMPA), which, depending on the structure of the acyclic side chain, span an activity spectrum from DNA viruses (papova-, adeno-, herpes-, hepadna-, and poxvirus) to retroviruses (HIV); (8) dideoxynucleoside analogs (i.e., AZT, DDC), which act as chain terminators in the reverse transcriptase reaction and thus block the replication of retroviruses as well as hepadnaviruses; and (9) the TIBO, HEPT, and other TIBO-like compounds, which interact specifically with the reverse transcriptase of HIV-1 and thus block the replication of HIV-1, but not of HIV-2 or any other retrovirus.
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PMID:Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. 843 May 18

We determined the anti-human immunodeficiency virus type 1 (anti-HIV-1) activities of various dideoxy-nucleoside analogs by using phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBMs) and resting PBMs (R-PBMs) as target cells. The comparative order of anti-HIV-1 activity in PHA-PBMs was azidothymidine (AZT) > dideoxycytidine (ddC) > dideoxythymidinene (d4T) > dideoxyinosine (ddI) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) > 2'-beta-fluoro-dideoxyadenosine (F-ara-ddA), while that in R-PBMs was ddC > ddI, PMEA, and F-ara-ddA, >> AZT and d4T. A pronucleotide, bis-(S-acetylthioethanol)phosphotriester-ddAMP, which bypasses the anabolic monophosphorylation step for the intracellular delivery of ddAMP, was highly active both in PHA-PBMs and R-PBMs. These data may have basic and clinical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy with dideoxynucleosides, and in the development of active pronucleotides.
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PMID:Comparative analysis of anti-human immunodeficiency virus type 1 activities of dideoxynucleoside analogs in resting and activated peripheral blood mononuclear cells. 858 44

Various compounds could be considered to be vaginal microbicides, preventing heterosexual transmission of HIV (i.e. virucidal agents such as nonoxynol 9 and chlorhexidine) and antiviral agents interfering with either virus adsorption/fusion [polyanionic substances such as polysulfates (i.e. PVAS, PAVAS), polysulfonates, polycarboxylates, polyoxometalates and negatively charged albumins], or fusion/uncoating (bicyclams), or reverse transcription [dideoxynucleoside analogues, acyclic nucleoside phosphonates such as PMEA and PMPA, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT, and alpha-APA derivatives]. In particular, combination of two or more of these compounds seems to be an attractive approach to interrupt transmission of HIV at different stages of the infectious process.
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PMID:Development of vaginal microbicides for the prevention of heterosexual transmission of HIV. 860 57


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