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 development of reduced susceptibility to zidovudine (AZT) has been documented in isolates of human immunodeficiency virus (HIV) from patients receiving prolonged therapy with the drug. Resistance emerges more quickly and to a higher degree in patients in later stages of disease. Progressive stepwise reductions in susceptibility occur with sequential isolates in conjunction with the cumulative acquisition of mutations in the gene for reverse transcriptase. Cross resistance to other compounds has been observed to date only with nucleosides possessing a 3'-azido moiety. The clinical significance of reduced drug susceptibility and strategies to deal with this issue are under investigation.
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PMID:AZT resistance in isolates of HIV. 205 36

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.
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PMID:Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. 207 27

1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (2'-N3ddThd) was synthesized from 1-(5-O-trityl-2,3-anhydro-beta-D-lyxofuranosyl)thymine by two different procedures. Method A prepared the title compound by opening of the oxirane ring with LiEt3BH followed by mesylation of the 2'-hydroxyl function, introduction of the 2'-azido substituent and deblocking of the 5'-function. In method B nucleophilic opening of 3'-deoxy-5'-O-(tert-butyldimethylsilyl)-5-methyl-2,2'-anhydrouridine+ ++ was carried out with sodium azide in hexamethylphosphoramide in the presence of benzoic acid. Single X-ray crystallographic studies indicated a solid state conformation (3T2), which was opposite to that of the A form of AZT (2T3) but closely resembled that of 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine (2'-FddThd) (3T2) and of 3'-azido-2',3'-dideoxy-2,6-diaminopurine riboside (3'-N3ddDAP) (3T2). Whereas the latter displayed significant inhibitory activity against human immunodeficiency virus (HIV) replication, 2'-FddThd and 2'-N3ddThd were essentially inactive.
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PMID:2'-Azido-2',3'-dideoxythymidine: synthesis and crystal structure of a 2'-substituted dideoxynucleoside. 208 11

In 4 years (1984-1987), 183 bone marrow examinations were performed on 155 human immunodeficiency virus (HIV) antibody positive patients. One hundred and fifty three had category IV AIDS. One-third of the marrows yielded specific information. This included opportunistic infection, in particular Mycobacterium Avium Intracellulare Complex (MAI) (24%), malignancy (4%), consistent with ITP (9%) and iron deficiency (1%). In the remaining two thirds of the bone marrows the most frequent non-specific abnormalities were dyserythropoiesis, erythroid hypoplasia, reticuloendothelial iron block, granulomas, lymphoid aggregates, plasmacytosis and histiocytosis. Common peripheral blood findings were anemia, lymphopenia, anisocytosis, rouleaux and atypical lymphocytes. Peripheral blood and bone marrow examinations on 16 patients on AZT are included. These patients have more pronounced blood and bone marrow abnormalities. The causes of these abnormalities are multifactorial and include low T4 levels, severe viral and other infections and therapy with marrow toxic drugs.
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PMID:Peripheral blood and bone marrow findings in patients with acquired immune deficiency syndrome. 209 Oct 4

The mode of transmission of AIDS is via sexual intercourse, injection of drugs, and from infected mother to child. Incubation time averages 11 years according to the latest studies. Survival after the development of the disease amounts to 14.4 months in the U.S., only 11% live longer than 3 years. Treatment with AZT can prolong survival by months. An effective drug or a vaccine is not in sight, and the reliability of the human immunodeficiency virus (HIV) antibody test has been questioned. There were 4544 AIDS cases reported to the German AIDS registry as of February 28, 1990; and there were 4653 cases as of March 31, 1990. The risk groups are homosexuals (70%), iv drug abusers, and heterosexual partners of infected persons. In the last 6 months there were 3,341 new cases of infection reported, and assuming that only 50% are tested, there are approximately 14,000 new infections per year. Among blood donors there were 2 cases/100,000 in 1987, but high risk individuals have been excluded from giving blood. In the US there were about 1 million infected people; there were 121,645 cases reported at the end of February, 1990. It is estimated that there will be 52,000-57,000 new cases in 1990, and 61,000-89,000 cases in 1993. The Centers for Disease Control conducts several hundred studies in risk areas; there were 6.4% positive tests from 2.5 million tests taken at 5013 counselling and test centers. In some part of New York and Miami over 3% of neonates are infected. In Kampala, Uganda, up to 10% of pregnant women were infected in 1985 and up to 24% in 1987. At the end of February 1990 there were 222,740 AIDS cases reported: 121,645 in the US, 9555 in Brazil, and 8883 in France. In the early 1980's there were about 100,000 infected worldwide, and today they are more than 6 million. It is estimated that at the end of 1989 there were 100,000-150,000 HIV infected in Germany.
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PMID:[Dimensions of the challenge introduced by HIV and AIDS]. 209 75

Ninety-seven isolates of human immunodeficiency virus (HIV) from 73 individuals were assayed for susceptibility to zidovudine (AZT). All isolates from 41 individuals with no known therapy with zidovudine were uniformly susceptible to the drug in vitro. In contrast to isolates from subjects with AIDS or AIDS-related complex, isolates from subjects with fewer signs and symptoms or high CD4 lymphocyte counts developed reduced susceptibility at slower rates and lower levels of resistance. Patients receiving lower doses of zidovudine at both early and late stages of disease did not develop resistance more readily than patients receiving higher doses of drug.
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PMID:Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. 211 76

A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (beta-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddI) induced cell filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at less than 100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 micrograms/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT greater than ddA greater than or equal to ddI greater than or equal to ddG greater than ddT = D4T greater than ddC. ddA and ddI had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit Bacillus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.
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PMID:Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides. 211 27

Detailed knowledge of the structure of the human immunodeficiency virus (HIV) triggered a rapid development of methods for diagnosing the infection. The enzyme-linked immunoadsorbent assay (ELISA) determining the presence of antibodies to the protein components of the virus in toto is highly sensitive and provides thus the basic screening approach. It is however somewhat less specific and therefore all positive results are verified by the Western blot method which detects individual HIV proteins and possesses a 99.9% specificity. In sporadic cases the latent period between HIV infection and the possibility to establish antibody response may extend to six months and even longer. The polymerase chain reaction (PCR) revealing the presence of DNA HIV in infected cells is suitable for detecting these seronegative patients. It is also the method of choice in diagnosing HIV infection in children of infected mothers since HIV antibodies are in newborns mostly of maternal origin. HIV antibodies, particularly the antigen p 24, can be quantified in serum by using ELISA. As their amounts correlate with the severity of the disease determination of antigen p 24 concentration is an indicator of the therapeutic efficacy of preparations such as AZT. The recently developed quantitative PCR is a further potentially valuable method for assessing the therapeutic effect since treatment should reduce the amount of cellular HIV DNA. With the exception of testing the sensitivity of HIV strains to antiretrovirus preparations, HIV cultures are rarely set up since they are technically demanding and involve a considerable risk.
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PMID:Laboratory tests used in diagnosis and treatment of AIDS. 212 31

Infection of macaque monkeys with simian immunodeficiency virus (SIV) has been established as an excellent animal model system for studying the pathogenesis of an HIV-like virus and for evaluating newly developed antiretroviral drugs and vaccines. Based on their genetic, antigenic, and biologic properties, the simian immunodeficiency viruses are the closest known relatives of the human AIDS viruses, and experimental infection of macaque monkeys results in a disease that is remarkably similar to human AIDS. Infected macaques show diarrhea, weight loss, hematologic abnormalities including lymphopenia and thrombocytopenia, lymphadenopathy/lymphoid hyperplasia that progresses to lymphoid depletion, immunosuppression with marked reduction in CD4+ cells and in the CD4+/CD8+ cell ratio, and opportunistic infections. A majority of such macaques die from an AIDS-like disease within one to three years of infection. An acutely lethal variant of SIV has been identified that results in death in susceptible macaques within 7-12 days of infection. Preliminary prophylactic treatment trials with AZT in macaque monkeys exposed to the acutely lethal SIV variant indicate that some protection is provided when AZT treatment is initiated within 24 hours of virus exposure. Other studies with the more chronic SIV infection model, however, failed to show any prophylactic efficacy of CS-87, AZT, D4T, or FDT.
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PMID:Nonhuman primate models for evaluation of AIDS therapy. 212 64

Using the murine LP-BM5 retrovirus-induced immunodeficiency model, the therapeutic value of zidovudine (AZT) was analyzed. Continuous low dose (60 mg/kg per day) oral AZT administration for 6 weeks increased survival time by 5-6 weeks. Decreasing the duration of therapy to 3 weeks decreased the mean survival time. Extending the therapy from 6 to 14 weeks increased the median survival time (8 weeks). This dose was nontoxic and reduced virus titers, splenomegaly, and lymphadenopathy. AZT also retarded the immune dysfunction syndrome characteristic of this model. Hypergammaglobulinemia was reduced by AZT and was also a marker for disease progression. AZT reduced hyperproliferation of large blast cells and delayed the loss of splenic B cells.
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PMID:Zidovudine (AZT) reduces virus titer, retards immune dysfunction, and prolongs survival in the LP-BM5 murine induced immunodeficiency model. 215 68


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