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)

Over the past two decades, the recognition of viral enzymes and proteins that can serve as molecular targets of drugs has revolutionized the treatment of viral infections. Beginning with acyclovir, a number of systemically administered agents which are both relatively safe and effective for the treatment of herpetic infections and human immunodeficiency virus (HIV) infections have become widely available. Because of increased numbers of herpes virus infections, as well as the rising epidemic of HIV infections, the ophthalmologist is, more likely than ever before to be involved in the treatment of severe and frequent ocular infections caused by herpes viruses. In addition, the acute retinal necrosis (ARN) syndrome has been demonstrated to be caused by herpes viruses and a once rare retinal infection caused by cytomegalovirus is common in patients with the acquired immunodeficiency syndrome (AIDS). In this article, four systemic antiviral drugs (Vidarabine, Acyclovir, Ganciclovir, and Foscarnet) that have demonstrated usefulness in the treatment of ophthalmic disease are reviewed in detail with regard to their mechanisms, applications, effectiveness, and side effects.
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PMID:Systemic antiviral drugs used in ophthalmology. 132 32

The bisheteroarylpiperazines (BHAPs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and specifically block HIV-1 replication (Romero, D. L., Busso, M., Tan, C.-K., Reusser, F., Palmer, J. R., Poppe, S. M., Aristoff, P. A., Downey, K. M., So, A. G., Resnick, L., and Tarpley, W. G. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 8806-8810). Here we show that the radiolabeled BHAP [3H]U-88204 binds specifically to HIV-1 RT with high affinity (KD of 50 nM) and a stoichiometry of 1 mol of U-88204 per 1 mol of p66/p51 RT heterodimer. Binding of [3H]U-88204 to RT is unaffected by the presence of saturating poly(rC).oligo (dG)12-18 template-primer. Direct measurement of competition between [3H]U-88204 and other RT inhibitors for binding to RT reveals mutually exclusive competition between [3H]U-88204 and the non-nucleoside RT inhibitor BI-RG-587 (Kopp, E. B., Miglietta, J. J., Shrutkowski, A. G., Shih, C.-K., Grob, P. M. and Skoog, M.T. (1991) Nucleic Acids Res. 19, 3035-3039), indicating that both share the same binding site. Phosphonoformate in concentrations up to 50 microM shows no competition with [3H]U-88204 for binding to RT either alone or in the presence of template-primer. Dideoxynucleotide RT inhibitors affect the binding of [3H]U-88204 to RT when complementary template-primer is present. [3H]U-88204 and the dideoxynucleotide ddGTP can bind RT simultaneously, but the presence of one ligand decreases the affinity of RT for the second. Inasmuch as ddGTP approximates the nucleotide substrate of RT, the direct demonstration of an RT-dideoxynucleotide-[3H]U-88204 complex validates the use of indirect kinetic methods to assess the strength of BHAP interaction with RT and suggests that RT inhibition by U-88204 is achieved via effects on nucleotide substrate binding.
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PMID:The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase. 137 Apr 45

Foscarnet is a pyrophosphate analogue with activity against herpesviruses, human immunodeficiency virus (HIV), and other RNA and DNA viruses. Foscarnet and its analogues achieve their antiviral effects via inhibition of viral polymerases, with such inhibition not being dependent on activation or phosphorylation of the compounds by viral or cellular proteins. Current evidence indicates that foscarnet interferes with exchange of pyrophosphate from deoxynucleoside triphosphate during viral replication by binding to a site on the herpesvirus DNA polymerase or HIV reverse transcriptase. Reviewed herein are basic findings regarding the mechanism of action and antiviral activity of foscarnet and the related compound phosphonoacetic acid (PAA), as well as findings regarding potential mechanisms of viral resistance and interactions with other antiviral agents.
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PMID:Mechanism of action of foscarnet against viral polymerases. 137 Oct 38

Foscarnet exerts its antiviral effects via reversible inhibition of viral polymerases. Pharmacodynamic data indicate that herpesvirus and human immunodeficiency virus replication is inhibited by therapeutically achievable concentrations of foscarnet; however, the concentrations of foscarnet required for such inhibition have been found to vary widely. Pharmacokinetic data indicate that foscarnet is eliminated via the renal route, undergoes negligible metabolism, and appears to be distributed widely from the circulation. However, the available data indicate that the pharmacokinetics of the drug varies among patients and within the individual patient, particularly with regard to plasma drug levels; furthermore, such factors as the intracellular kinetics of the drug have yet to be well characterized. It is thus difficult to formulate optimal dosing regimens on the basis of what is known of foscarnet pharmacodynamics and pharmacokinetics. Nevertheless, dosages that produce clear-cut therapeutic benefits without unacceptable toxicity have been identified in clinical trials of foscarnet in acquired immunodeficiency syndrome (AIDS) patients with cytomegalovirus (CMV) retinitis.
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PMID:Clinical pharmacology: foscarnet. 137 Oct 39

Cytomegalovirus (CMV), a major opportunistic viral pathogen frequently causing disease in immunocompromised patients such as organ transplant recipients and people with AIDS, may present as pneumonitis, gastrointestinal disease, or encephalitis. Its most common manifestation in patients with AIDS is retinitis which, if left untreated, invariably progresses to extensive retinal necrosis and ultimately to blindness. Ganciclovir sodium, currently the only licensed antiviral agent for the treatment of CMV retinitis, effectively controls this infection in a majority of AIDS patients, but significant granulocytopenia or thrombocytopenia related to ganciclovir therapy often limit its clinical application. Myelosuppression may be further exacerbated in AIDS patients by such other agents as zidovudine or trimethoprim/sulfamethoxazole, often necessitating dosage reductions or discontinuation of these agents in patients receiving ganciclovir. Foscarnet sodium, a pyrophosphate analog active against both cytomegalovirus and the human immunodeficiency virus type 1 (HIV), may be an effective alternative to ganciclovir in the management of CMV retinitis. Trials with intravenous foscarnet in CMV retinitis have reported favorable results using initial daily doses of 180-230 mg/kg/d given as intermittent infusions every eight hours, followed by maintenance regimens of 60-90 mg/kg/d given as single daily one- or two-hour infusions. Foscarnet therapy may result in renal impairment, and indefinite intravenous maintenance therapy may be required to prevent recurrence of CMV infection. Despite these drawbacks, foscarnet's lack of major myelosuppressive toxicity, and its activity in suppressing HIV replication, make this a potentially safe and effective alternative agent for the management of CMV infection, especially in AIDS patients.
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PMID:Foscarnet sodium. 184 59

The clinical manifestations of cytomegalovirus (CMV) infection in persons with AIDS are described, and recent advances in the management of these syndromes with antiviral agents are reviewed. CMV infection is the most common serious opportunistic viral infection in AIDS patients. Clinical manifestations include chorioretinitis, gastroenteritis, hepatitis, pneumonia, CNS infection, adrenalitis, and a wasting syndrome. The diagnosis of CMV infection requires laboratory demonstration of a serologic response to the virus, detection of viral components or products, or isolation of the virus. Ganciclovir is an acyclic nucleoside analogue marketed for the treatment of CMV-related retinitis in immunocompromised hosts. After i.v. ganciclovir induction therapy, more than 80% of patients show improvement or stabilization of retinitis. Relapse is common in AIDS patients, however, and low-dose i.v. maintenance therapy is recommended. The most serious dose-limiting effect is neutropenia. Intravitreal injection of ganciclovir has been well tolerated and efficacious. Ganciclovir has shown some efficacy in the treatment of other life-threatening CMV infections, especially gastroenteritis, but data are limited. Ganciclovir-resistant strains have been reported. Foscarnet, a pyrophosphate analogue with activity against both human CMV and human immunodeficiency virus, is undergoing clinical trials. Foscarnet has shown promise in the therapy of CMV-related retinitis, but results for other CMV infections are disappointing. Nephrotoxicity is the major dose-limiting effect. AIDS patients with sight-threatening and rapidly progressive CMV-related retinitis should be treated with ganciclovir. Foscarnet may offer an alternative when it becomes available. More must be learned about the efficacy of these drugs in the treatment of CMV infection in patients with AIDS.
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PMID:Management of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. 216 89

Multiple drug effect analyses with mismatched double-stranded RNA (mismatched dsRNA or Ampligen) as a core drug were performed to identify other agents and mechanisms through which mismatched dsRNA may potentiate effective therapeutic intervention in human immunodeficiency virus (HIV) infection. Antiviral activities were defined by a microtiter infection assay utilizing MT-2 cells as targets and HTLV-III-B produced in H9 cells as a virus source. The scope of agents tested included rIFN-alpha A, rIFN-beta Ser 17, and rIFN-gamma as cytokines; azidothymidine and phosphonoformate (Foscarnet) as inhibitors of reverse transcription; ribavirin as a putative inhibitor of proper HIV mRNA capping; amphotericin B as a lipophile; and castanospermine as a glycoprotein processing (glucosidase I) inhibitor. Separately, each drug demonstrated dose-dependent anti-HIV activity and, when used in combination with mismatched dsRNA, demonstrated synergism. Although mismatched dsRNA was synergistic with all three IFNs for anti-HIV activity in microtiter infection assays, it did not potentiate the transient inhibition of virus production observed for IFN in cultures of H9/HTLV-III-B cells. The results of these studies suggest that the pleiotropic activities of dsRNAs differ from those of IFN and may provide synergism in combination therapy with a wide range of antiviral drugs for the treatment of the acquired immunodeficiency syndrome (AIDS).
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PMID:In vitro evaluation of mismatched double-stranded RNA (ampligen) for combination therapy in the treatment of acquired immunodeficiency syndrome. 246 50

Foscarnet has been shown to be active in vitro against the human immunodeficiency virus and all human herpesviruses including cytomegalovirus (CMV). A pharmacokinetic study was carried out as part of a clinical trial designed to evaluate the safety and efficacy of intermittently administered intravenous foscarnet for the treatment of CMV retinitis. Eight patients with acquired immunodeficiency syndrome and serious CMV retinitis received 2-h intravenous infusions of foscarnet at a dosage of 60 mg/kg of body weight every 8 h for 14 days. Serial plasma samples were collected on days 3 and 14 of therapy, and foscarnet concentrations were determined by high-pressure liquid chromatography. On day 3 of therapy, the mean (+/- standard deviation) peak and trough levels in plasma were 509 (200) and 98 (29) microM, respectively, while on day 14 levels were 495 (149) and 126 (59) microM. The mean clearance in plasma on days 3 and 14 were 1.9 (0.6) and 1.7 (0.9) ml/min per kg, respectively. On day 14, the mean half-life was 4.5 (1.2) h and the volume of distribution was 0.74 (0.60) liter/kg. As the half-life and the clearance of foscarnet in plasma correlated with changes in renal function, dosage adjustments must be made for patients with decreased renal function.
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PMID:Pharmacokinetics of intermittently administered intravenous foscarnet in the treatment of acquired immunodeficiency syndrome patients with serious cytomegalovirus retinitis. 254 91

Foscarnet was administered by continuous intravenous infusion in 15 patients with the acquired immunodeficiency syndrome (AIDS) in an open, uncontrolled study. Mean steady state serum concentrations of foscarnet was 261 mumol/l. Treatment was given for 6-21 days, median 14 days, being interrupted prematurely due to renal function impairment in seven patients, and due to other reasons in three patients. Foscarnet therapy was accompanied by improvement of some, probably cytomegalovirus (CMV) related, symptoms but did not otherwise affect the clinical condition of the patients. The occurrence of positive CMV cultures decreased significantly during therapy. Human immunodeficiency virus (HIV) detection by culture was positive in 70-80% of cultures and was unaffected by foscarnet treatment. Eight patients had detectable, free HIV antigen in serum before therapy, and in five of these HIV antigen disappeared during therapy, but reappeared 4-23 weeks after therapy. No patient lost HIV antigen, except during foscarnet therapy. No patient became HIV antigen positive during foscarnet therapy. Immunological parameters did not change during or after foscarnet therapy. Renal function impairment was seen in 9 patients (95% confidence limits, 32-84%), apparently due to reversible tubular damage. At follow-up, serum creatine was normal in all surviving patients. Concomitant medication may have contributed to the renal side-effects. Severe renal function impairment, i.e. serum creatinine above 0.25 mumol/l, was only seen in patients who at the start of foscarnet therapy were chronically affected by their disease. Thus, foscarnet reduces HIV antigen production in AIDS patients. Renal function impairment limits foscarnet use in AIDS patients, but in individuals with less severe manifestations of HIV infection, this side effect may be less frequent.
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PMID:The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lymphocyte function in AIDS patients. 296 90

Although effective therapies are available for many of the infections and tumors that occur in patients with the acquired immunodeficiency syndrome (AIDS), no therapy exists for the underlying immunodeficiency. Three approaches used to treat this immunodeficiency have included wholescale immune replacement through lymphocyte transfers, bone marrow transplantation, and thymic implantation; immunologic enhancement with biologic-response modifiers, such as gamma interferon, interleukin-2, and some drugs; and antiretroviral therapy. Because of the persistence of the etiologic virus, both immune replacement and enhancement will probably be ineffective unless effective strategies are developed against the virus. Agents that have shown antiviral activity in vitro which are currently in clinical trials include suramin, heteropolyanion-23 (HPA-23), ribavirin, and alpha interferon. Foscarnet and monoclonal antibodies have yet to enter clinical trials in the United States. It is still too early to tell if any of the antiviral agents will prove of value in the management of patients with AIDS.
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PMID:Immunologic reconstitution in the acquired immunodeficiency syndrome. 299 5


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