Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) as a prophylactic chemotherapeutic agent for the treatment of lentivirus infections, three groups of specific pathogen free cats were treated with 0, 3, or 6 mg kg-1 twice daily doses of PMEA beginning 24 h prior to virus challenge with feline immunodeficiency virus Petaluma strain. Treatment was continued for 7 weeks post challenge. During this time cats were monitored for drug toxicity, virus specific antibody response, circulating viral antigen and infectious recoverable virus. To determine the long-term influence of PMEA therapy the cats were monitored for 1 year following the cessation of treatment. The low levels of infectious virus present in blood prompted the development of quantitative polymerase chain reaction assay to enumerate viral DNA burdens in the peripheral blood mononuclear cells of the infected cats and thereby assess drug efficacy. The results indicate that, although prophylactic PMEA did not prevent infection, it did substantially limit feline immunodeficiency virus replication. Furthermore, viral DNA levels remained low in the cats receiving drug a full year (the duration of the study) after cessation of treatment.
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PMID:Evaluation of 9-(2-phosphonylmethoxyethyl) adenine therapy for feline immunodeficiency virus using a quantitative polymerase chain reaction. 133 95

The pharmacokinetics of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of retrovirus (i.e. human immunodeficiency virus) replication was determined in mice. Upon iv bolus administration of PMEA at 25, 100, or 500 mg/kg, PMEA was rapidly cleared from the plasma in a monoexponential and dose-independent manner (half-life, 7-12.5 min; distribution volume, 0.30-0.36 liter/kg; total body clearance, 1.21-2.41 liters/hr/kg). Irrespective of the initial PMEA dose, 67% of unchanged PMEA was recovered from the urine of mice within 24 hr after administration of PMEA. [3H]PMEA, administered as an iv bolus injection, mainly accumulated in the kidney, liver, and lungs. Significant amounts of monophosphorylated PMEA were detected in kidney and liver, but not other tissues, at 10, 30, and 60 min after iv administration of PMEA. Low but significant levels of PMEA were attained in the brain.
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PMID:Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxyethyl)adenine. 135 82

In the present study the therapeutic efficacy and the side effects of two antiretroviral compounds used in human acquired immunodeficiency syndrome (AIDS) research, 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine, Retrovir) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), were investigated in the treatment of cats naturally infected with feline immunodeficiency virus (FIV) and cats naturally infected with feline leukemia virus (FeLV). AZT was administered subcutaneously at a dose of 5 mg kg-1 body weight every 12 h and PMEA was administered subcutaneously at a dose of 2.5 mg kg-1 body weight every 12 h during a 3 week hospitalization. The therapeutic efficacy of both compounds was investigated. There was a stronger potency of PMEA than of AZT on the regression of stomatitis in FIV and in FeLV infected cats. In addition, in FIV infection PMEA had a stronger effect on the improvement of the general clinical status. Both antiretroviral compounds were potent agents to improve the immunologic status of FIV infected cats by raising the CD4/CD8 ratio. In FeLV infection PMEA and AZT appeared to reduce antigenemia. The hematological side effects caused by PMEA were severe and stronger than those of AZT. Therefore the advantage of PMEA in clinical and immunologic improvement was diminished by the hematologic disorders, which do not allow long term treatment with this drug in the dose used.
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PMID:Use of two virustatica (AZT, PMEA) in the treatment of FIV and of FeLV seropositive cats with clinical symptoms. 136 8

The replication of feline immunodeficiency virus (FIV) in cultured cells was inhibited by 2',3'-dideoxyadenosine (ddA) and by 9-(2-phosphonylmethoxyethyl)adenine (PMEA) with IC50 values of 0.98 and 0.95 microM, respectively. The effects of the presumed active forms of these inhibitors, ddATP and PMEA-diphosphate (PMEApp), upon the FIV reverse transcriptase (RT) were examined with two different template-primer systems. Both of these compounds were potent inhibitors of the FIV RT in reactions with primed phi X-174 DNA, yielding Ki values of 8.8 nM for ddATP and 5.0 nM for PMEApp. However, they were both poor inhibitors of the reaction with poly(rU)-oligo(dA); concentrations of ddATP or PMEApp greater than 10 microM were required to inhibit this reaction by 50%. Further analysis of the reaction with poly(rU)-oligo(dA) revealed that even in the absence of inhibitors the primers were extended by less than 20 nucleotides. In contrast, high molecular weight products were obtained in reactions with phi X-174 DNA. These results suggest that the reaction of FIV RT with poly(rU)-oligo(dA) is not highly processive. The high degree of termination encountered during this reaction with poly(rU)-oligo(dA) may be responsible for the low inhibitory potential of ddATP and PMEApp.
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PMID:Inhibition of reverse transcriptase from feline immunodeficiency virus by analogs of 2'-deoxyadenosine-5'-triphosphate. 138 1

The acyclic nucleoside phosphonate analogue PMEA [9-(2-phosphonylmethoxyethyl)adenine] is a broad spectrum antiviral agent effective against DNA viruses and retroviruses. It is particularly active against the human immunodeficiency virus and, like other phosphonylmethoxyalkyl derivatives, it also inhibits HSV-1, TK- HSV-1 and HSV-2. We have evaluated the therapeutic efficacy of PMEA in the HSV-1 and TK- HSV-1 experimental keratitis models using BVDU (bromovinyldeoxyuridine) as the reference compound. As compared to placebo eyedrops, PMEA 0.2% and BVDU 0.2% eyedrops induced a rapid and significant healing (P less than 0.005) of keratitis caused by TK+ HSV-1. Treatment with PMEA 0.2% eyedrops also reduced the severity of keratitis caused by the TK- HSV-1 (P less than 0.05), whereas BVDU 0.2% eyedrops did not affect the course of TK- HSV-1 keratitis.
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PMID:Efficacy of 9-(2-phosphonylmethoxyethyl)adenine in the therapy of TK+ and TK- herpes simplex virus experimental keratitis. 165 Jun 60

Cats infected with molecularly cloned FeLV-FAIDS develop an immunodeficiency syndrome characterized by persistent antigenemia, decline in circulating CD4+ T lymphocytes, and impaired T-cell-dependent immune responses and opportunistic infection. We evaluated the capacity of PMEA to inhibit the replication of FeLV-FAIDS in vitro and to inhibit the progression of FeLV-FAIDS infection in vivo. We found that PMEA inhibited replication of FeLV-FAIDS by greater than or equal to 50% at concentrations of greater than or equal to 0.5 microgram/ml (1.63 microM) in feline fibroblasts and prevented T lymphocyte killing at concentrations of 3 micrograms/ml. PMEA administered to cats at dosages of greater than or equal to 6.25 mg/kg/day from 0 to 49 days after FeLV-FAIDS infection prevented the development of persistent antigenemia and the induction of immunodeficiency disease. In contrast to placebo treated controls, cats successfully treated with PMEA contained viral infection, developed neutralizing antibody, and resisted a second virulent virus challenge without further therapy. Manifestations of PMEA toxicity produced by higher dosages (25 or 12.5 mg/kg/day) were anemia, leukopenia, and diarrhea. These results indicate PMEA to be a potent antiretroviral agent effective in aborting fatal progression of FeLV-FAIDS infection when therapy is initiated at the time of virus exposure.
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PMID:Early therapy of feline leukemia virus infection (FeLV-FAIDS) with 9-(2-phosphonylmethoxyethyl)adenine (PMEA). 166 30

Our recent efforts have been directed at the development of selective inhibitors of different classes of viruses, including adeno, pox, and herpesviruses [herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)], (+/-)RNA viruses (reo- and rotavirus), (-)RNA viruses (influenza, parainfluenza, measles, respiratory syncytial, vesicular stomatitis and rabies virus) and retroviruses [i.e. human immunodeficiency virus (HIV), the causative agent of AIDS]. In this search, the following molecular targets were envisaged: for DNA viruses in general, the viral DNA polymerase; for herpes simplex virus and varicella-zoster virus, the viral DNA polymerase via a specific phosphorylation by the viral 2'-deoxythymidine (dThd) kinase; for (+/-)RNA and (-)RNA viruses, S-adenosylhomocysteine (SAH) hydrolase, a key enzyme in transmethylation reactions required for the maturation of viral mRNA; for retroviruses, reverse transcriptase as initiator of virus replication and/or cell transformation; and for several enveloped viruses (i.e. retro-, herpes- and rhabdoviruses), virus adsorption to the outer cell membrane. Several new compounds have been developed that appear to act at these targets: i.e. (E)-5-(2-bromovinyl)-2'-deoxyuridine [bromovinyldeoxyuridine (BVDU)] and derivatives thereof [i.e. carbocyclic BVDU (C-BVDU)] as well as derivatives of acyclovir (i.e. 8-substituted acyclovir derivatives) as inhibitors of herpesviruses; (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other phosphonylmethoxyalkylpurines and -pyrimidines as inhibitors of DNA viruses and retroviruses; acyclic and carbocyclic analogues of adenosine [such as (S)-9-(2,3-dihydroxypropyl)adenine [S)-DHPA), carbocyclic 3-deazaadenosine (C-c3Ado), (RS)-3-adenin-9-yl-2-hydroxypropanoic acid (AHPA) alkyl esters, neplanocin A, 3-deazaneplanocin A and the 5'-nor derivatives of neplanocin A and 3-deazaneplanocin A] as inhibitors of (+/-)RNA and (-)RNA viruses; 2',3'-dideoxynucleoside analogues as inhibitors of retroviruses; and sulfated polysaccharides (i.e. heparin, dextran sulfate, pentosan polysulfate, mannan sulfate), sulfated polyvinylalcohol and co-polymers of sulfated polyvinylalcohol with acrylic acid as inhibitors of retro-, herpes- and rhabdoviruses.
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PMID:Selective virus inhibitors. 169 49

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of retrovirus (i.e., human immunodeficiency virus) replication in vitro and in vivo. Uptake of PMEA by human MT-4 cells and subsequent conversion to the mono- and diphosphorylated metabolites (PMEAp and PMEApp) are dose-dependent and occur proportionally with the initial extracellular PMEA concentrations. Adenylate kinase is unable to phosphorylate PMEA. However, 5-phosphoribosyl-1-pyrophosphate synthetase directly converts PMEA to PMEApp with a Km of 1.47 mM and a Vmax that is 150-fold lower than the Vmax for AMP. ATPase, 5'-phosphodiesterase, and nucleoside diphosphate kinase are able to dephosphorylate PMEApp to PMEAp, albeit to a much lower extent than the dephosphorylation of ATP. PMEApp has a relatively long intracellular half-life (16-18 hr) and has a much higher affinity for the human immunodeficiency virus-specified reverse transcriptase than for the cellular DNA polymerase alpha (Ki/Km: 0.01 and 0.60, respectively). PMEApp is at least as potent an inhibitor of human immunodeficiency virus reverse transcriptase as 2',3'-dideoxyadenosine 5'-triphosphate. Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity.
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PMID:Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. 170 39

A new class of compounds, 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines, is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds, 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines, which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2,6-diaminopurine, termed (RS)-FPMPA and (RS)-FPMPDAP, respectively, are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts, PMEA and PMEDAP. Also, (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp, akin to PMEA diphosphate (PMEApp), acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity.
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PMID:9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. 171 Dec 14

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) are selectively inhibitory to human immunodeficiency virus and other retroviruses. We have now investigated the effects of different PMEA and PMEDAP treatment schedules in newborn mice infected with Moloney murine sarcoma virus (MSV). Administration of a single dose of PMEA or PMEDAP on the day of MSV inoculation conferred a greater protective effect against MSV-induced tumor formation than when this dose was divided over two, four or seven injections per week. Also, the therapeutic index of PMEA and PMEDAP was increased if administered as a single dose. Furthermore, PMEA and PMEDAP afforded a marked antiviral protection if administered within one day before MSV infection. Thus, single doses of PMEA or PMEDAP, when administered shortly before or after MSV infection, appear to be effective in preventing the manifestations of the retroviral disease.
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PMID:Single-dose administration of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) in the prophylaxis of retrovirus infection in vivo. 177 76


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