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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As human immunodeficiency virus type 1 (HIV-1) has become better understood, numerous drugs have been developed that act at virus-specific sites. These are challenging our ability to evaluate them thoroughly and rapidly. Zidovudine (AZT) remains the mainstay of anti-HIV-1 drugs. Recent controlled trials indicate it should be used early in infection (in those with CD4 cell counts less than 500/mm3) and in lower doses (500-600 mg/day). Prolonged AZT treatment in patients with AIDS, however, is often associated with viral resistance. Newer reverse transcriptase-inhibiting nucleoside derivatives are currently in phase II-III clinical trials. Other HIV-1 replicative sites under attack in clinical studies include binding and entry of virus, envelope protein glycosylation, and viral assembly and release. Agents that target HIV-1 proteinase, integrase, ribonuclease H, and products of regulatory genes such as tat are under development. Combination therapies that target different viral replicative sites likely will allow use of individual agents below their toxic concentrations and help prevent drug resistance. Innovative programs for expanded access to experimental drugs are needed that will permit expeditious clinical trials, optimize the gathering of useful information, and permit the widest access to promising treatments.
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PMID:Chemotherapy of human immunodeficiency virus infections: current practice and future prospects. 169 Dec 43

Multinucleated giant cell (syncytium) formation induced by the interaction between the gp120 glycoprotein expressed on the surface of cells infected with human immunodeficiency virus type (HIV-1) and the CD4 receptor of uninfected CD4-positive (CD4+) cells may play an important role in the depletion of T4 lymphocytes in acquired immune deficiency syndrome (AIDS) patients. Using a double fluorescence cell-staining technique and analysis of the cells by the fluorescence-activated cell sorter (FACS), we have demonstrated that giant cell formation between persistently HIV-1-infected HUT-78 cells and uninfected MOLT-4 cells results in a selective destruction of the uninfected CD4+ MOLT-4 cells. Apparently, bystander CD4+ cells may serve as targets for the killing effect of the HIV-1-infected cells, and this killing effect is preceded by fusion between the target (uninfected) and aggressor (infected) cells. Pentosan polysulfate, dextran sulfate, and various other sulfated polysaccharides, but not heparin, have proved to inhibit this cell fusion process and hence protect the target CD4+ cells against destruction by the killer HIV-1-infected cells. Azidothymidine does not interfere with this process. Assuming that fusion between HIV-infected and uninfected CD4+ cells is a crucial event in the pathogenesis of AIDs, any compounds that specifically interfere with this process may be therapeutically advantageous in the treatment of this disease.
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PMID:Sulfated polysaccharides as potent inhibitors of HIV-induced syncytium formation: a new strategy towards AIDS chemotherapy. 169 Dec 88

Zidovudine is now used extensively in an effort to control infection with the human immunodeficiency virus (HIV). The drug is associated with major hematologic toxicity, especially anemia and granulocytopenia. Conservative management of hematologic toxicity includes dosage reduction or cessation of therapy, diagnosis and treatment of chronic debilitating diseases, and supportive care, such as blood transfusions. New investigational agents, including hematopoietic growth factors, are being studied to combat the toxicities associated with zidovudine. The efficacy of these agents has yet to be established. Recent advances in drug efficacy at reduced dosage and in combination therapy promise to permit use of zidovudine with markedly reduced toxicity.
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PMID:Hematologic toxicity of zidovudine in HIV-infected patients. 169 80

The incidence of acquired immunodeficiency syndrome and the number of people infected with the human immunodeficiency virus (HIV) is likely to increase into the 1990s and perhaps beyond. Zidovudine, a 2',3'-dideoxynucleoside approved for the treatment of acquired immunodeficiency syndrome, provides immunologic, virologic, and survival benefits. However, because its hematologic toxicity can be dose-limiting, investigations are ongoing with other 2',3'-dideoxynucleosides. After zidovudine, the first of these agents to be tested was 2',3'-dideoxycytidine (ddC), the most potent inhibitor of HIV reverse transcriptase among the dideoxynucleosides tested thus far. Concentrations of ddC as low as 0.5 microM provide protection against HIV in cultured T cells (and monocytes), even at high multiplicities of infection. Like the other dideoxynucleosides, activation of ddC is dependent on intracellular phosphorylation to its 5'-triphosphate form. Efforts are under way to alter enzymatically the intracellular ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate, its endogenous counterpart. ddC has relatively straightforward pharmacokinetics; it has a plasma half-life of about 1.2 hours and an oral bioavailability of about 87 percent. Approximately 75 percent of the drug is excreted unchanged in the urine. Patients treated with ddC have experienced both immunologic and virologic benefit, although long-term high doses are limited by the development of painful peripheral neuropathy. Significant hematologic toxicity is not evident in most patients; low-dose regimens of ddC alone, as well as alternating or in combination with zidovudine, are being tested in an effort to retain antiviral activity while minimizing treatment toxicities.
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PMID:Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus. 169 46

Three analogs of thymidine, D4T [2',3'-didehydro-2',3'-dideoxythymidine; 1-(2,3-dideoxy-beta-D-glyceropent-2-enofuranosyl)thymine], FddT (3'-fluoro-3'-deoxythymidine), and AZT (3'-azido-3'-deoxythymidine), were compared in biological tests designed to assess their potential utility as anti-human immunodeficiency virus (HIV) agents. The in vitro potencies of these compounds against HIV infection in CEM cells were measured, with FddT and AZT being more potent than D4T. The cytotoxicities of D4T, FddT, and AZT for CEM cells were comparable. The triphosphates of these three derivatives inhibited purified HIV reverse transcriptase, and their affinities for this polymerase were found to be 1 or 2 orders of magnitude greater than that for the normal substrate, dTTP. D4T was less toxic than FddT or AZT for cultured human and mouse bone marrow cells (granulocyte-macrophage CFU). The three compounds had similar toxicities for human progenitor erythrocyte burst-forming units. In a 30-day mouse toxicity study, AZT and FddT produced a similar spectrum of hematopoietic toxicities. These toxic effects occurred at much lower doses of FddT than of AZT. At the higher doses of FddT, a significant incidence of lethality occurred. By contrast, D4T was considerably less toxic than both AZT and FddT in this study. The dose-limiting toxicity of D4T in mice was hepatotoxicity. The very different phosphorylation patterns of D4T, its lower toxicity, and its comparable potency relative to FddT and AZT suggest that the potential of D4T as an anti-HIV agent should be further explored.
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PMID:Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. 169 57

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.
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PMID:Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC). 169 83

On July 27, 1989, the International Conference on Molecular Aspects of Immune Response and Infectious Diseases devoted a symposium to the subject of the use of intravenous gamma globulin (IVIG) in acquired immunodeficiency syndrome (AIDS). The information presented confirmed that IVIG benefits human immunodeficiency virus (HIV)-infected children with recurrent infections and that much remains to be learned about the influence of IVIG in adult AIDS. The symposium participants recognized the urgent need to develop randomized clinical trials using a control group to assess the efficacy of a treatment with IVIG in PGL (persistent generalized lymphadenopathy), ARC (AIDS-related complex), and AIDS. To prepare this report, a committee was established, including individuals with expertise in immunology, immunopharmacology, microbiology, virology, infectious diseases, general medicine, and pediatrics and representing research experience in academia and hospitals. After an introduction to the report with a summary of immunotherapeutic agents under evaluation to treat HIV infection, section 1 lays out the present understanding of the disease pathogenesis. Section 2 then outlines the treatment of HIV-seropositive individuals, discussing the uncertainties that any treatment entails. Section 3 discusses the rationale for treating HIV-infected individuals with IVIG, and Section 4 examines the major differences between IVIG and hyperimmunoglobulins for the treatment of HIV infection. Section 5 looks at IVIG as a mean to delay the emergence of opportunistic infections and restore immunocompetence in AIDS and related illnesses, and Sections 6 and 7 suggest a pilot protocol on the use of IVIG in association with low-dose or standard-dose zidovudine (AZT).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Report of the symposium on the use of intravenous gammaglobulin in adults infected with the human immunodeficiency virus. 169 38

3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTTP) was an efficient substrate for the human immunodeficiency virus 1 reverse transcriptase. It was incorporated into both homopolymer and defined sequence DNA-primed RNA templates and DNA-primed DNA templates. The substrate and inhibitor kinetics of both AZTTP and dTTP were dependent on the template-primer and reaction conditions used. dTMP was incorporated into poly(rA).oligo(dT) and into a defined sequence DNA-primed RNA template (when the other three 2'-deoxynucleoside 5'-triphosphates were present) as a conventional substrate, with steady-state Km values of 5-10 microM. The results suggest that the reverse transcriptase was capable of processive DNA polymerization on these DNA-primed RNA templates. In contrast, in the absence of the other three 2'-deoxynucleoside 5'-triphosphates, the time course for incorporation of dTMP into the same defined sequence DNA-primed RNA template was biphasic. A burst of product formation was observed followed by a slow steady-state rate with a Km value of 0.082 microM. AZTMP incorporation into poly(rA).oligo(dT) and into the defined sequence DNA-primed RNA template produced similar biphasic time courses and steady-state Km values. These results were consistent with rate-limiting dissociation of the polymerase.template-primer complex after "forced" termination of polymerization. AZTMP and dTMP were both incorporated into the homopolymer DNA-primed DNA template, poly(dA).oligo(dT), and a defined sequence DNA-primed DNA template as conventional substrates. Their Km values were similar (2-10 microM). The absence of biphasic time courses suggested that dissociation of the DNA-primed DNA templates from the enzyme, after forced termination, was not rate-limiting. This was consistent with a more distributive mode of DNA polymerization. With the defined sequence template-primers and poly(dA).oligo(dT), Ki values for both dTTP and AZTTP were comparable to their Km values. Thus, AZTTP appeared to be a simple competitive substrate-inhibitor with respect to dTTP. AZTTP inhibition of dTMP incorporation into poly(rA).oligo(dT) was linear competitive at low concentrations (0-100 nM) of AZTTP (Ki = 35 nM) but became hyperbolic (decreasing potency) at concentrations of AZTTP above this range. A mechanism for this nonlinear inhibition is discussed.
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PMID:Human immunodeficiency virus reverse transcriptase. Substrate and inhibitor kinetics with thymidine 5'-triphosphate and 3'-azido-3'-deoxythymidine 5'-triphosphate. 170 Jul 87

The antiviral activity against human immunodeficiency virus type 1 of the two structurally related thymidine analogs azidothymidine and fluorothymidine, both alone and in combination, was tested. Fluorothymidine was tenfold more active than azidothymidine. The selectivity indices of the two compounds were similar. The combination of azidothymidine and fluorothymidine showed clearly synergistic antiviral activity, and diminished cytotoxicity. The inhibition of reverse transcriptase from human immunodeficiency virus type 1 by the triphosphates of azidothymidine and fluorothymidine, both alone and in combination was also tested. Azidothymidine triphosphate was a fourfold stronger inhibitor than fluorothymidine triphosphate. The combination of the two showed only additive (and not synergistic) effects upon reverse transcriptase. The combination of azidothymidine and fluorothymidine showed both synergistic antiviral activity and diminished cytotoxicity, and may therefore represent a promising therapeutic strategy. The additive (and not synergistic) inhibition of reverse transcriptase by the combination of the triphosphates indicates that in cell culture additional factors other than inhibition of the reverse transcriptase by the triphosphates influence the antiviral activity of the combination. Such factors might include effects upon normal nucleoside metabolism or metabolism of the analogs. Alternatively, one of the nucleosides might have an additional mechanism of action besides inhibition of the reverse transcriptase.
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PMID:Synergistic inhibition of human immunodeficiency virus replication in vitro by combinations of 3'-azido-3'-deoxythymidine and 3'-fluoro-3'-deoxythymidine. 170 16

Carbovir (the carbocyclic analog of 2'-3'-didehydro-2',3'-dideoxyguanosine) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. Assays were developed to assess the mechanism of inhibition by the 5'-triphosphate of carbovir of HIV-1 reverse transcriptase using either RNA or DNA templates that contain all four natural nucleotides. Carbovir-TP was a potent inhibitor of HIV-1 reverse transcriptase using either template with Ki values similar to that observed by AZT-TP, ddGTP, and ddTTP. The kinetic constants for incorporation of these nucleotide analogs into DNA by HIV-1 reverse transcriptase using either template were similar to the values seen for their respective natural nucleotides. In addition, the incorporation of either carbovir-TP or AZT-TP in the presence of dGTP or dTTP, respectively, indicated that the mechanism of inhibition by these two nucleotide analogs was due to their incorporation into the DNA resulting in chain termination. Carbovir-TP was not a potent inhibitor of DNA polymerase alpha, beta, or gamma, or DNA primase. Given the potent activity of carbovir-TP against HIV-1 reverse transcriptase and its lack of activity against human DNA polymerases, we believe that further evaluation of this compound as a potential drug for the treatment of HIV-1 infection is warranted.
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PMID:Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs. 170 54


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