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)

The safety and activity of several antiretroviral agents are being evaluated for treatment of acquired immunodeficiency syndrome (AIDS) in infants and children. Intermittent oral and intravenous regimens and continuous intravenous infusion of the dideoxynucleoside, 3'-azido-3'-deoxythymidine (zidovudine, AZT), have been shown to be beneficial in improving neuro-developmental function and growth velocity in pediatric patients with AIDS. AZT, however, is limited by the associated development of neutropenia and anemia, which frequently necessitates transfusions. Another dideoxynucleoside, 2',3'-dideoxycytidine (ddC), also shows theoretical promise in the treatment of the pediatric AIDS population. This agent is not associated with the hematologic toxicity induced by AZT but does produce a painful sensory peripheral neuropathy. Sequential therapy with AZT and ddC may limit the toxic effects associated with the use of these drugs individually. Dideoxyinosine and soluble recombinant CD4 are two newer antiretroviral agents that are under investigation for the management of AIDS in infants and children. The activity of recombinant CD4 in preventing the transplacental transmission of human immunodeficiency virus is also being evaluated.
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PMID:Treatment of human immunodeficiency virus-infected infants and young children with dideoxynucleosides. 215 4

The deoxynucleoside analogues 2',3'-dideoxy-cytidine (ddC) and 3'-azido-3'-deoxythymidine (zidovudine, AZT) are active as single agents in conferring immunologic and virologic benefits in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Both drugs, however, produce dose-limiting toxicities. AZT is associated with unacceptable levels of bone marrow suppression, and ddC can cause painful peripheral neuropathy. The different toxicity profiles of these two drugs provide the rationale for testing them in alternating dosing combinations in an attempt to retain the antiretroviral activity of each against human immunodeficiency virus, while reducing the toxicities of both. A preliminary trial showed that 200 mg AZT given orally every four hours for seven-day periods, alternating with ddC at 0.03 mg/kg body weight orally every four hours for seven-day periods is a promising treatment regimen. An expanded multicenter study is evaluating ddC at 0.01 mg/kg and 0.03 mg/kg alternating with AZT at 200 mg in weekly or monthly periods. Weekly intermittent doses of AZT at 200 mg and ddC at 0.03 mg/kg are also being tested. The rationale and methods of the trial are discussed.
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PMID:Alternating and intermittent regimens of zidovudine (3'-azido-3'-deoxythymidine) and dideoxycytidine (2',3'-dideoxycytidine) in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. 215 5

Zidovudine (AZT) prolongs life in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex but often causes dose-limiting bone marrow suppression in this population. This has prompted a search for salvage therapies for use in persons who cannot tolerate continuous AZT treatment. One approach involves alternating administration of AZT and 2',3'-dideoxycytidine. 2',3'-Dideoxycytidine is a potent inhibitor of human immunodeficiency virus in vitro and in vivo. Although it does not cause clinically significant bone marrow suppression, its usefulness at high continuous doses is limited by the occurrence of painful peripheral neuropathy. Because the toxicities of these nucleosides are non-overlapping, intermittent or alternating schedules may limit the toxicity of each agent while extending active antiretroviral therapy in these patients. In an ongoing study, patients have been randomly assigned to weekly intermittent, weekly alternating, and monthly alternating regimens of AZT and 2',3'-dideoxycytidine. The study will determine the best-tolerated regimen and provide insights into the use of toxic nucleoside analogues in persons with advanced human immunodeficiency virus disease.
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PMID:Salvage therapy for zidovudine-intolerant HIV-infected patients with alternating and intermittent regimens of zidovudine and dideoxycytidine. 215 6

The dideoxynucleosides 3'-azido-3'-deoxythymidine (zidovudine, AZT) and 2',3'-dideoxycytidine (ddC) are potent inhibitors of human immunodeficiency virus (HIV) in vitro and improve surrogate measures of HIV infection in vivo. Long-term administration of AZT has been associated with significant hematologic toxicity and has resulted in virus with reduced in vitro susceptibility. Although ddC does not have significant hematologic toxicity and has not shown cross-resistance with AZT in vitro, ddC has been associated with a severe dose-related peripheral neuropathy. Given the independent activity of each agent, their non-overlapping toxicity profiles, and the absence of cross-resistance, it was hypothesized that concurrent administration of AZT and ddC in low doses might be at least as active as either drug given individually at higher doses in the treatment of HIV infection. It was further hypothesized that combined low doses of both drugs would reduce the incidence of serious side effects and the development of resistance. A phase I/II dose-finding trial of six different regimens of combination AZT and ddC in persons with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex was initiated to test these hypotheses.
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PMID:AIDS Clinical Trials Group: phase I/II study of combination 2',3'-dideoxycytidine and zidovudine in patients with acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex. 215 7

Zidovudine (3'-azido-3'-deoxythymidine; AZT) inhibited replication of an immunodeficiency-inducing strain of feline leukemia virus (FeLV-FAIDS) in vitro at concentrations of 0.5-0.005 micrograms/ml. A 25-30% additional antiviral effect was achieved in vitro when AZT was combined with human recombinant alpha interferon 2a (IFN alpha). Oral administration of AZT (20 mg/kg three times daily) to cats resulted in plasma concentrations of 3 micrograms/ml at 2 h post-administration with a T1/2 of approximately 1.60 h. Administration of AZT alone or in combination with IFN alpha or interleukin-2 (IL-2) throughout a 6-week treatment period enabled cats to resist challenge with FeLV-FAIDS. In contrast, those cats treated with IFN alpha or IL-2 alone became persistently antigenemic (core protein p27) in parallel with placebo-treated controls. Antigenemia remained undetectable in AZT-treated cats throughout an 80-day period post-inoculation (38 days after treatment was withdrawn). However, latent FeLV-FAIDS in bone marrow was detectable by in vitro culture of progenitor cells in the presence of hydrocortisone. Serial analysis of circulating p27 antigen, neutralizing antibody, and quantification of latent, reactivatable virus indicated that those animals receiving AZT in combination with IFN alpha were most able to resist FeLV-FAIDS challenge. This work provides additional evidence that early presymptomatic treatment employing combination chemoimmunotherapy can be effective in medical intervention of retroviral infection.
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PMID:Zidovudine in combination with alpha interferon and interleukin-2 as prophylactic therapy for FeLV-induced immunodeficiency syndrome (FeLV-FAIDS). 216 83

Several 2'-fluoroarabino-2',3'-dideoxy- and 2'-fluoro-2',3'-unsaturated 2',3'-dideoxy pyrimidine nucleoside analogues are reported. The saturated analogues 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)thymine (2'-threo-FddT, 33), 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)uracil (2'-threo-FddU, 22) were readily prepared from the corresponding 2'-deoxy-2'-fluoroarabinosyl nucleoside analogue by radical deoxygenation of the 3'-OH. The unsaturated compounds 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2-enofuranosyl)thymine (2'-Fd4T, 40) and 1-[5-O-(mono-methoxytrityl)-2-fluoro-2,3-dideoxy-beta-D-glycero-pen t-2- enofuranosyl]uracil (39) were synthesized by an elimination reaction of the O-2,3'-anhydro-2'-fluoro-lyxo derivatives under basic conditions. The cytidine analogues 28 and 41 were prepared by amination of the corresponding uridine derivatives; compounds 28 and 41 were deprotected to give 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)cytidine (2'-threo-FddC, 29) and 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2- enofuranosyl)cytosine (2'-Fd4C, 42), respectively. All of these novel compounds were evaluated in vitro against human immunodeficiency virus (HIV) (LAV isolate). 2'-threo-FddC (29) was the most active of the newly synthesized substances against HIV with an ID50 of 0.8 microgram/mL; ddC had an ID50 of 0.007 micrograms/mL. Because of its potency in the initial tests, 29 was further evaluated in both T cells and macrophage/monocyte cell lines, with several different isolates of HIV. Although 2'-threo-FddC (29) exhibited good antiviral activity in these systems it was less active than AZT in these assays. At 1 microM the inhibition of CFU-GM by 29 was found to be 35-40%; this is slightly higher than seen with AZT.
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PMID:Synthesis and anti-HIV activity of several 2'-fluoro-containing pyrimidine nucleosides. 216 62

Dideoxynucleosides (zidovudine[AZT], dideoxycytidine[ddC], and dideoxyinosine[ddI]) are promising new agents for the management of human immunodeficiency virus type 1 (HIV-1) infections. In light of recent data demonstrating defects in the polymorphonuclear leukocyte (PMN) bactericidal activity of HIV-1-infected patients and since many chemotherapeutic agents affect PMN function, we examined their effects on the function of PMNs from both healthy and HIV-1-infected individuals in vitro. AZT (0.1 to 25 microM), ddC (0.01 to 1 microM), and ddI (0.2 to 50 microM) had no effect on viability, chemotaxis to N-fromylmethionyl leucyl phenylalanine, phagocytosis of Candida albicans or Staphylococcus aureus, or superoxide production following stimulation by N-formylmethionyl leucyl phenylalanine. Killing of C. albicans was not affected by AZT but was enhanced by 0.1 and 1 microM ddc (a 1 microM, killing was 26.0 +/- 2.02% compared with 17.0 +/- 0.73% for controls: P = 0.006) and 0.2 to 50 microM ddI (at 10 microM, killing was 25.0 +/- 0.68% compared with 17.8 +/- 0.91% for controls; P = 0.002). Killing of S. aureus was unchanged by AZT and ddC but was significantly enhanced by ddI at 0.2 to 20 microM (at 2 microM, killing was 71.2 +/- 5.57% compared with 51.4 +/- 6.29% for controls; P = 0.0045). In addition, the preexisting defective bactericidal capacity of PMNs from HIV-1-infected patients was enhanced by ddI (P less than 0.025). Potential enhancement by these dideoxynucleosides of certain PMN functions of HIV-1-infected patients deserves further study.
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PMID:Effects of antiretroviral dideoxynucleosides on polymorphonuclear leukocyte function. 217 34

The alveolar macrophage (AM), as a representative human tissue macrophage, was used in an in vitro system to examine the anti-human immunodeficiency virus type-1 (HIV-1) activity of zidovudine (AZT) and granulocyte-macrophage colony-stimulating factor (GM-CSF). AMs were infected with the IIIB strain of HIV-1 and exposed to AZT (1 mumol/L), GM-CSF (30 U/mL), a combination of AZT (1 mumol/L)/GM-CSF (30 U/mL), or medium control. At 10 or 20 days post-infection, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear leukocytes (PBMLs) were added to the AM cultures as stimulated target cells. AZT effectively suppressed HIV replication and prevented transfer/amplification in target PBMLs as long as the drug was maintained in the medium. GM-CSF neither suppressed nor augmented HIV replication. The combination of AZT/GM-CSF was comparable with AZT alone in suppressing both the initial infection of AMs and the transfer to target PBMLs as long as the agents were maintained in the cultures. However, when the drugs were removed at the same time that PHA-stimulated PBMLs were added to the culture, the combination of AZT/GM-CSF was found to be more effective than AZT alone in preventing the transfer/amplification of HIV in the target lymphocytes. These results suggest that (1) AZT is effective in inhibiting HIV-1 infection in mononuclear phagocytes; (2) GM-CSF neither inhibits nor augments the replication of the IIIB strain of HIV in human AMs; and (3) the combination of AZT and GM-CSF may have an enhanced anti-HIV-1 activity compared with AZT alone. Clinical trials with the two agents in combination appear warranted.
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PMID:Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages. 217 2

Sixteen patients seropositive for human immunodeficiency virus (HIV) at different stages participated in an open trial using the lipid mixture AL-721. Seven patients were antigen negative and asymptomatic and the other nine antigen positive, three of whom were virtually asymptomatic. AL-721 was given per os once a day at a dose of 10 g in a fat-free breakfast for up to 16 months. The presence of HIV antigens in the serum was monitored by enzyme immunoassay (EIA) using two commercial kits. In five of the nine antigen-positive patients the concentration of HIV antigens was reduced to basal level after about 3 months of AL-721 treatment; three of these responders were asymptomatic, one had persistent generalized lymphadenopathy, and the other had Kaposi's sarcoma. In one of the antigen-positive patients who did not respond to AL-721, the addition of AZT to the treatment resulted in a marked decrease in antigen level. Another AIDS patient receiving this combination therapy from onset of the trial showed a similar decrease. The other two nonresponding patients were at a stage of full-blown AIDS. These results suggest that AL-721, an innocuous compound, may be effective in reducing the serum HIV level in patients at the preclinical stage.
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PMID:Reduction of circulating HIV antigens in seropositive patients after treatment with AL-721. 217 57

The emergence of human immunodeficiency virus resistant to 3'-azido-3'-deoxythymidine (zidovudine, AZT) in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex has been documented. Isolates from non-AZT-treated persons or those who had received AZT for less than six months showed a narrow range of susceptibility to the drug; on the other hand, isolates from those who had received AZT for six months or more consistently showed reduced susceptibility. Five highly AZT-resistant isolates were also insensitive to other compounds containing a 3'-azido group. No cross-resistance was found to other nucleoside analogues, including 2',3'-dideoxycytidine and 2',3'-dideoxyinosine. That cross-resistance occurred only in compounds containing a 3'-azido group suggests that mutations in the reverse transcriptase gene prohibit the enzyme from using nucleoside triphosphate containing a 3'-azido group. Progressive, stepwise increases in resistance have been associated with the sequential accumulation of specific amino acid changes in the reverse transcriptase gene. It is not yet known whether the resistant phenotype as determined in vitro results in clinical resistance to AZT. The gradual appearance of resistant isolates, the variable course of human immunodeficiency virus infections, and the absence of a consistent pattern of resurgent p24 antigen will make the emergence of AZT resistance difficult to correlate with clinical status or other markers. The combination of AZT with other drugs that do not share cross-resistance is a promising area for investigation to identify regimens that are more active and less likely to induce resistance.
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PMID:Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus. 218 29


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