Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.
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PMID:Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. 170 82

Combinations of 3'-azido-3'-deoxythymidine and phosphonoformate produced a moderate synergistic inhibitory effect against human immunodeficiency virus type 1 in vitro at concentrations that are easily achieved in humans. The synergistic effect was more pronounced with increasing concentrations and was not secondary to toxic effects of the drugs. 3'-Azido-3'-deoxythymidine neither inhibited the replication of human cytomegalovirus in human embryonic lung fibroblasts nor interfered with the anticytomegalovirus effect of phosphonoformate. By using partially purified reverse transcriptase of human immunodeficiency virus type 1 and human cytomegalovirus DNA polymerase, various combinations of 3'-azido-3'-deoxythymidine-5'-triphosphate and phosphonoformate produced strong indications of additive interactions. The synergistic interactions in infected cells and the additive effects observed at the reverse transcriptase level indicate that mechanisms other than the reverse transcriptase may be of importance for the inhibition of human immunodeficiency virus replication by these two compounds. A concomitant treatment of cytomegalovirus infections, such as cytomegalovirus retinitis, with phosphonoformate in patients with acquired immunodeficiency syndrome receiving 3'-azido-3'-deoxythymidine may be appropriate, and this combination may also be useful in controlling human immunodeficiency virus infection.
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PMID:Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro. 254 87

The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells. Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir. Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet. Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.
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PMID:Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. 752 25

Up to now cytomegalovirus retinitis (CMVR) recurrence in AIDS patients was considered to be very high, even on maintenance therapy. Protease inhibitors (PI) are antiretroviral molecules which, with more efficacity than reverse transcriptase inhibitors, decrease viral charge and increase CD4's count aswell as survival. We analysed the impact of PI on CMVR evolution in a retrospective review of 18 patients with CMVR on maintenance therapy and PI treatment. In a first group, 13 patients started PI some time after CMVR diagnosis (median CD4 = 9/mm3). A second group of 5 patients developed CMVR (median CD4 = 63/mm3) after initiation of PI. In the first group, incidence of CMVR recurrences/1000 patients days was 6,45 (2323 patients days of follow-up (PDFU) before starting PI and 3,44 (4066 PDFU) after starting PI. In this group, during the follow-up's period of CD4's count inferior to 75/mm3, incidence of CMVR is 6,84/1000 patients days and becomes 0,86/1000 patients days during the follow-up's period of CD4's count superior to 75/mm3. In the second group, incidence of CMVR was 0/1000 patients days (1972 PDFU). In summary, incidence of CMVR decreases with PI's treatment. Interruption of CMVR maintenance therapy could be considered in patients with CD4's count higher than 75/mm3.
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PMID:[Impact of anti-retroviral treatment with protease inhibitors on the evolution of cytomegalovirus retinitis in the patient carrying acquired immunodeficiency syndrome]. 974 24

Ocular complication of AIDS are seen in about 75% of patients. Viral infections are predominant and can involve either external segment in the eye (Herpes type 8 in Kaposi sarcoma, molluscum contagiosum, Herpes simplex and zoster), or the posterior segment of the eye (CMV retinitis). The introduction of a Highly Active Antiretroviral Therapy (HAART) which associates two reverse transcriptase inhibitors and one antiprotease has changed the evolution of AIDS. The decrease of onset of CMV retinitis in AIDS patient is one of the best exemple. For the first time it was possible to stop the maintenance therapy against CMV retinitis in patients that have a sufficient increase in CD4+ cells and they did not present any relapse of CMV retinitis. But an increase of ocular inflammation can be observed with the onset of HAART such as uveitis or cystoid macular edema.
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PMID:[Diagnosis and treatment of ocular viral infections in AIDS patients]. 986 23

Since 1996, major advances in the treatment of AIDS have markedly changed the incidence and the prognosis of CMV retinitis. Highly active antiretroviral therapy (HAART) is a combination of nucleoside reverse transcriptase inhibitors and protease inhibitors. This new therapeutic strategy is highly efficient in reducing the HIV viral load and increasing CD(4)+ T-lymphocyte count. These biological effects are associated with an improvement of immune functions. Clinically, the completely quiescent CMV retinitis and the unusual prolonged relapse-free interval suggest a certain restoration of immune functions, making possible the discontinuation of maintenance therapy. For most authors, the decision to stop anti-CMV maintenance therapy is based on a CD4+ cell count >100 cells/microl with a low HIV viral load for at least four months. The improvement of CMV retinitis on HAART may also be associated with an intraocular inflammation called immune recovery vitritis. For some patients, this vitritis may be associated cystoid macular edema and an epiretinal membrane responsible for visual loss.
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PMID:CMV retinitis in the era of HAART. 1061 32

Information about protease inhibitors and other antiretroviral drugs used to treat AIDS-related opportunistic infections is provided. Specific drugs addressed include ritonavir, a protease inhibitor that received the fastest approval in history, for HIV infection; Vitrasert, an intraocular form of ganciclovir, for treating CMV retinitis; 3TC, an antiviral agent for treating HIV infection; a combination of saquinavir and ritonavir for treating HIV infection; nevirapine, a reverse transcriptase inhibitor for HIV infection; nitazoxanide, available through an FDA-approved expanded access program, for cryptosporidiosis; indinavir, an HIV protease inhibitor used for HIV infection; and a combination of ddC and AZT for HIV infection.
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PMID:[New treatments for HIV]. 1136 30

At the 36th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), updates on research on non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and newer treatments were presented. Among the research topics reviewed are results from the CAESAR study, guidelines for use of antiretrovirals, and the efficacy of new antiretroviral combinations. Also included are data tables showing the impact of viral load and CD4 count on risk of progression among 2,008 persons in trials of delavirdine; the detection of HIV RNA after 40 to 52 weeks in a trial of nevirapine/ZDV/ddI; viral load and CD4 changes in a phase I/II study of 141W94; viral load changes, principal side effects, and dropouts in a trial of ritonavir plus saquinavir; clinical endpoint results of the CAESAR trial; viral load and CD4 changes after 50 weeks of IL-2 plus indinavir; comparison of regimens for treating CMV retinitis; prevalence of Kaposi's sarcoma-associated herpesvirus antigen in HIV-positive and -negative groups; and rates of MAC bacteremia in ACTG 196/CPCRA 009, a trial comparing clarithromycin, rifabutin, and the combination for prophylaxis.
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PMID:Piloting the meanders of AIDS research. 1136 56

We report the case of a 54-year-old HIV-seropositive man who was referred to us with unilateral uveitis. The patient had been taking triple antiretroviral therapy (three reverse transcriptase inhibitors) for one week when he presented with blurring of vision in the left eye. Two weeks later, active cytomegalovirus retinitis was suspected after fundus examination and ganciclovir was immediately administered. Even if the CD4 cell count was normal (423/microliter), the diagnosis was confirmed by the presence of CMV in the anterior chamber. This case shows that an elevated CD4 count is not incompatible with CMV retinitis, especially at the beginning of the antiretroviral therapy.
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PMID:[Cytomegalovirus retinitis despite normal CD4 levels in an HIV patient. Report of a case]. 1191 43

The current armamentarium for the chemotherapy of viral infections consists of 37 licensed antiviral drugs. For the treatment of human immunodeficiency virus (HIV) infections, 19 compounds have been formally approved: (i) the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; (ii) the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate; (iii) the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz; (iv) the protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir (combined with ritonavir at a 4/1 ratio) and atazanavir; and the viral entry inhibitor enfuvirtide. For the treatment of chronic hepatitis B virus (HBV) infections, lamivudine as well as adefovir dipivoxil have been approved. Among the anti-herpesvirus agents, acyclovir, valaciclovir, penciclovir (when applied topically), famciclovir, idoxuridine and trifluridine (both applied topically) as well as brivudin are used in the treatment of herpes simplex virus (HSV) and/or varicella-zoster virus (VZV) infections; and ganciclovir, valganciclovir, foscarnet, cidofovir and fomivirsen (the latter upon intravitreal injection) have proven useful in the treatment of cytomegalovirus (CMV) infections in immunosuppressed patients (i.e. AIDS patients with CMV retinitis). Following amantadine and rimantadine, the neuraminidase inhibitors zanamivir and oseltamivir have recently become available for the therapy (and prophylaxis) of influenza virus infections. Ribavirin has been used (topically, as aerosol) in the treatment of respiratory syncytial virus (RSV) infections, and the combination of ribavirin with (pegylated) interferon-alpha has received increased acceptance for the treatment of hepatitis C virus (HCV) infections.
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PMID:Antiviral drugs in current clinical use. 1512 67


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