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

The efficacy of pre- and postexposure treatment with the antiviral compound (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) was tested against simian immunodeficiency virus (SIV) in macaques as a model for human immunodeficiency virus (HIV). PMPA was administered subcutaneously once daily beginning either 48 hours before, 4 hours after, or 24 hours after virus inoculation. Treatment continued for 4 weeks and the virologic, immunologic, and clinical status of the macaques was monitored for up to 56 weeks. PMPA prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. These results suggest a potential role for PMPA prophylaxis against early HIV infection in cases of known exposure.
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PMID:Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. 1698 28

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

The (S)- and (R)-enantiomers of 9-(2-phosphonylmethoxypropyl) derivatives of adenine (PMPA) and 2,6-diaminopurine (PMPDAP) were evaluated for their inhibitory effect on HIV replication in several human cell systems, including natural peripheral blood lymphocytes (PBL) and freshly isolated monocyte/macrophages (M/M). The (R)-enantiomers of PMPDAP and PMPA were approximately 10-to-100-fold more effective against HIV than their (S)-enantiomeric counterparts. The antiviral efficacy of (R)-PMPA was comparable to that of the prototype acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The most potent and selective HIV inhibitor was (R)-PMPDAP. Its 50% effective concentration ranged from 0.01 microM for HIV-1/Ba-L in M/M to 1-2.8 microM for HIV-1/IIIB and HIV-1/HE in C8166, CEM, Molt/4, MT-4 and PBL cells. Both (R)-PMPA and (R)-PMPDAP were not toxic to the host cells at 300 microM.
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PMID:Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems. 860 88

This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.
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PMID:In search of a selective antiviral chemotherapy. 933 68

Adefovir (PMEA, 9-(2-phosphonomethoxyethyl)adenine), an acyclic nucleoside phosphonate analogue is active against retroviruses, hepadnaviruses and herpesviruses. Adefovir dipivoxil, an orally bioavailable prodrug of adefovir is currently in phase III clinical trials for the treatment of HIV and phase II clinical trials for the treatment of HBV infections. PMPA (9-(2-phosphonomethoxypropyl)adenine) is a related acyclic nucleoside phosphonate analogue that has demonstrated potent anti-SIV activity in rhesus macaques and recently has shown marked anti-HIV activity in a phase I clinical study. Since the standard of care for AIDS patients has become combination therapy, the effects of other antiretroviral compounds (d4T, ddC, AZT, ddI, 3TC, nelfinavir, ritonavir, indinavir, and saquinavir) on the anti-HIV activity of adefovir and PMPA were investigated in vitro. Adefovir and PMPA both demonstrated strong synergistic anti-HIV activity in combination with AZT. Adefovir demonstrated minor to moderate synergistic inhibition of HIV replication in combination with PMPA, d4T, ddC, nelfinavir, ritonavir, and saquinavir. PMPA demonstrated minor synergistic inhibition of HIV replication in combination with ddI and nelfinavir (and adefovir). All other combinations showed additive inhibition of HIV replication in vitro. Importantly, no antagonistic interactions were measured for any of the adefovir or PMPA combinations.
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PMID:Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. 944 65

Acyclic nucleotide analogues exhibit strong activity against a broad range of viruses, including HIV-1 and -2. We have investigated their effects on in vitro secretion of cytokines and production of nitric oxide (NO) by murine peritoneal macrophages, factors known to play a role in virus replication. Included in the study were the most prominent compounds of the series: 9-(2-phosphonomethoxyethyl)adenine, 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine, the (R)- and (S)-enantiomers of 9-(2-phosphonomethoxypropyl) adenine [(R)- or (S)-PMPA], (R)- and (S)-enantiomers of 9-(2-phosphonomethoxypropyl)-2,6-diaminopurine [(R)- or (S)-PMPDAP], 9-(2-phosphonomethoxyethyl)guanine (PMEG), and (S)-enantiomer of 1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine [(S)-HPMPC]. PMEG, (R)-PMPA, and (S)-PMPA greatly enhanced the secretion of both tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), (R)-PMPDAP stimulated only TNF-alpha, other test compounds were ineffective. None of them influenced the secretion of IL-2 or interferon-gamma (IFN-gamma). Both TNF-alpha and IL-10 have been found to be major factors determining enhancing effects of PMEG, (R)-PMPA, and (S)-PMPA on production of NO generated by exogenous IFN-gamma. The study points to a possible implication of immunomodulatory properties in the antiviral effects of some acyclic nucleotide analogues. In addition, our data support the view that endogenous IL-10 can stimulate certain macrophage functions.
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PMID:Immunomodulatory properties of antiviral acyclic nucleotide analogues: cytokine stimulatory and nitric oxide costimulatory effects. 963 59

Eleven compounds have now been licensed for the treatment of HIV (human immunodeficiency virus) infections: the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV, AZT), didanosine (DDI), zalcitabine (DDC), stavudine (D4T) and lamivudine (3TC), the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and delavirdine, and the protease inhibitors saquinavir, ritonavir, indinavir and nelfinavir. Several other compounds that interact with the reverse transcriptase or protease or other targets of the viral replication cycle are in clinical or preclinical development. High expectations are vested in the acyclic nucleoside phosphonates PMEA and PMPA (which have proved clearly efficacious against HIV infections in phase II/III and phase I/II trials, respectively) and the bicyclam derivatives, which have recently been shown to block HIV infection through interference with the viral co-receptor CXCR4 (fusin). It has become increasingly clear that only the concomitant use of several anti-HIV agents combined can completely suppress HIV replication and offer the potential for a complete cure. To this end, the different compounds should be administered from the start at sufficiently high doses, and treatment should be started as soon as possible after the infection. Under these conditions, HIV-drug resistance development could be prevented, and progression to AIDS, arrested. Whether this procedure would also be able to eradicate the virus from the organism still needs to be proven.
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PMID:New perspectives for the treatment of HIV infections. 964 21

(R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA) is an acyclic nucleoside phosphonate that has been shown to be effective in the treatment of AIDS although it has a shorter separation between the adenine and phosphorus than dideoxy-AMP and dAMP. By using pre-steady state kinetic methods, we examined the incorporation of the diphosphate of PMPA, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP), and dATP catalyzed by wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, an exonuclease-deficient T7 DNA polymerase (T7 exo-), and wild-type rat DNA polymerase beta in order to evaluate the selectivity of PMPA as an antiviral inhibitor. With a DNA/DNA or DNA/RNA 22/43-mer duplex, the diphosphate of PMPA (PMPApp) is as effective as ddATP in reactions catalyzed by HIV-1 reverse transcriptase in that both analogs have similar substrate specificity constants (kp/Kd) which are only 5-fold lower than dATP. In contrast, PMPApp is a much weaker inhibitor of the reaction catalyzed by T7 exo- (with the DNA/DNA 22/43-mer duplex) in that PMPApp has a 5 x 10(-4)-fold lower kp/Kd than ddATP and dATP. The lower kp/Kd of PMPApp is due to a 1000-2000-fold lower incorporation rate (kp) and a 35-45-fold lower binding constant (Kd). Similarly, PMPApp is 800-fold less inhibitory toward polymerase beta with the DNA/DNA 22/43-mer duplex, whereas in studies with a single nucleotide gapped DNA (22-20/43-mer) PMPApp is 13-fold less inhibitory than ddATP. Although parallel studies will need to be performed using appropriate human polymerases, these results begin to define the mechanistic basis for the reported lower toxicity of PMPA in the treatment of AIDS.
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PMID:Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine. 976 48

9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its closely related structural analogue (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) are potent inhibitors of retroviruses and hepatitis B virus. In its oral prodrug form (adefovir dipivoxil), PMEA is currently the subject of advanced phase II/III clinical trials for the treatment of HIV infections. PMEA has also been shown to be a potent differentiation-inducing agent. In the present study, PMEA was found to have a strong differentiation-inducing effect on rat choriocarcinoma (RCHO) cells, comparable to that of methotrexate, which is the drug of choice for the chemotherapy of choriocarcinoma in humans. PMEA induced differentiation of choriocarcinoma trophoblast cells in a concentration-dependent manner within the 2- to 50-microM concentration range, as ascertained by giant cell formation, alkaline phosphatase induction, progesterone secretion, and the disappearance of a cytotrophoblast-specific surface antigen. PMEA had to be exposed to the rat choriocarcinoma cell cultures for at least 2-3 days to achieve optimal growth inhibition and differentiation of the tumor cells. Unlike PMEA, (R)-9-(2-phosphonylmethoxypropyl)adenine failed to induce differentiation of proliferating cytotrophoblasts into nonproliferating, hormonally active giant cells. This points to the specificity of PMEA as an inducer of choriocarcinoma cell differentiation.
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PMID:Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl) adenine (PMEA) in the rat choriocarcinoma (RCHO) tumor cell model. 977 47

Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study disease pathogenesis and to develop intervention strategies aimed at delaying disease. In the present study, we demonstrate that very early events of infection greatly determine the ultimate disease course, as short-term antiviral drug administration during the initial viremia stage significantly delayed the onset of AIDS. Fourteen newborn macaques were inoculated orally with uncloned, highly virulent SIVmac251. The four untreated control animals showed persistently high virus levels and poor antiviral immune responses; they developed fatal immunodeficiency within 15 weeks. In contrast, SIV-infected newborn macaques which were started on 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) treatment at 5 days of age and continued for either 14 or 60 days showed reduced virus levels and enhanced antiviral immune responses. This short-term PMPA treatment did not induce detectable emergence of SIV mutants with reduced in vitro susceptibility to PMPA. Although viremia increased in most animals after PMPA treatment was withdrawn, all animals remained disease-free for at least 6 months. Our data suggest that short-term treatment with a potent antiviral drug regimen during the initial viremia will significantly prolong AIDS-free survival for HIV-infected infants and adults.
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PMID:Early short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine treatment favorably alters the subsequent disease course in simian immunodeficiency virus-infected newborn Rhesus macaques. 1007 44


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