Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deamination of an anti-HIV carbocyclic adenine nucleoside, 9-[c-4,t-5-bis(hydroxymethyl)cyclopent-2-en-r-1-yl]-9H-adenine [(+/-)-BCA] and (+/-)-diamino-carbovir by adenosine deaminase under high-pressure (4 kbar) was carried out. Deamination of the former gave the corresponding (-)-hypoxanthine derivative whereas that of the latter produced (-)-carbovir having anti-HIV activity. The enantiomeric excess (e.e.) of both products was nearly 100%.
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PMID:Remarkable acceleration for the deamination of carbocyclic purine nucleosides by adenosine deaminase under high-pressure. 824 11

Twenty-one 6-alkoxypurine 2',3'-dideoxynucleosides were enzymatically synthesized with nucleoside phosphorylases purified from E. coli. Eighteen analogs exhibited anti-HIV-1 activity in MT4 cells. Two analogs, 6-(hexyloxy)-(17) and 6-(heptyloxy)-(18) purine 2',3'-dideoxynucleoside, were as potent as 2',3'-dideoxyinosine (ddI, didanosine, Videx). Although the antiviral activities of 17 and 18 were equivalent, 18 was more cytotoxic. Analogs containing less than four carbons in the 6-alkoxypurine substituent exhibited weak anti-HIV-1 activity. Analogs containing more than seven carbons in the 6-alkoxypurine substituent were too cytotoxic to be effectively evaluated for antiviral activity. Several 6-alkoxypurine 2',3'-dideoxynucleosides were evaluated for substrate activity with calf intestinal adenosine deaminase (ADA). Increasing the carbon chain length of the 6-alkoxypurine substituent decreased the rate of dealkoxylation. The best substrate in this series was 6-methoxypurine 2',3'-dideoxynucleaside (1); however, the rate of dealkoxylation of 100 microM 1 was 0.17% of the rate of deamination of 100 microM 2',3'-dideoxyadenosine. Compound 17, the most potent anti-HIV-1 analog, was not a substrate for ADA. EHNA (erthro-9-(2-hydroxy-3-nonyl)adenine), a potent inhibitor of ADA, had little effect on the antiviral activities of 17 and ddI. In contrast, coformycin, a potent inhibitor of both ADA and AMP deaminase, dramatically decreased the antiviral activity of 17, but not the antiviral activity of ddI. Thus, AMP deaminase appeared to be involved in the anabolism of 17. The pharmacokinetic profile of 17, the most promising analog in this series, was determined in the rat. At least seventeen metabolites of 17, including ddI, were detected in plasma samples. This analog also had poor oral bioavailability.
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PMID:Novel 6-alkoxypurine 2',3'-dideoxynucleosides as inhibitors of the cytopathic effect of the human immunodeficiency virus. 842 65

We investigated serum levels of adenosine deaminase 2 (ADA2) and neopterin (NP) in hemophiliacs with or without infection with human immunodeficiency virus type 1 (HIV-1). The mean (+/- SD) serum ADA2 level in hemophiliacs positive for HIV-1 (45.2 +/- 17.6 U/L) and negative for HIV-1 (34.9 +/- 15.8 U/L) was significantly higher than that in healthy controls (12.0 +/- 7.0 U/L) (P < .01). The mean serum NP level was also higher in HIV-1-positive hemophiliacs (10.2 +/- 6.1 nmol/L) and HIV-1-negative hemophiliacs (7.0 +/- 2.9 nmol/L) than in the healthy controls (4.3 +/- 1.3 nmol/L). Although the HIV-1-positive hemophiliacs had higher mean ADA2 and NP levels than did hemophiliacs in the HIV-1-negative group (P < .01), the levels of most of the patients in both groups were similar. ADA2 and NP levels in serial samples from asymptomatic carriers and patients with stable AIDS showed no marked changes over a period of up to 6 years. These findings indicate that ADA2 and NP are not specific markers of HIV-1 infection in hemophiliacs. Nonspecific immunologic activation due to the repeated infusion of antihemophilic factor concentrate could be one cause for the increased serum levels of ADA2 and NP in hemophiliacs.
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PMID:Serum adenosine deaminase 2 and neopterin levels are increased in a majority of hemophiliacs irrespective of infection with human immunodeficiency virus type 1. 801 44

In serum, the enzyme adenosine deaminase (ADA) is known to be divided into two isoenzymes, ADA1 and ADA2, which have different molecular weights and kinetic properties. The present study investigated ADA isoenzyme levels in the sera of patients infected with retroviruses associated with adult T-cell leukemia (ATL), human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), and AIDS, ADA isoenzyme activities were found to be significantly (P < 0.001) higher in the sera of patients with ATL, HAM, and AIDS than in the sera of healthy controls. In the case of the ADA subtypes in the sera of patients with ATL, ADA1 activity was significantly (P < 0.001) elevated in patients with the acute and lymphoma types of ATL compared with that in patients with the chronic and smoldering types of ATL. ADA2 activity was significantly elevated in the sera of patients with the acute, lymphoma, and chronic types of ATL (P < 0.001) compared with that in patients with smoldering ATL and HTLV-1 carriers. In the case of patients with human immunodeficiency virus type 1 (HIV-1) infection, ADA1 and ADA2 activities in the sera of patients with AIDS and HIV-1 antibody-positive individuals were significantly (P < 0.001) higher than those in the sera of HIV-1 antibody-negative individuals. A significant elevation in ADA2 activity was also seen in the sera of AIDS patients (P < 0.01) compared with that in the sera of HIV-1 antibody-positive individuals. These results suggest that the magnitude of elevation of ADA isoenzyme levels in serum correlates well with the clinical conditions of the patients with these diseases. Measurement of the activities of ADA isoenzymes may therefore provide an additional parameter for distinguishing the subtypes of ATL and may prove to be useful as prognostic and therapeutic monitors in diseases associated with HTLV-1 and HIV-1 infections.
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PMID:Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections. 854 45

2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are potent and selective inhibitors of the replication of the human immunodeficiency virus type 1 (HIV1) in several cell culture systems. Equipotent in terms of antiviral activity, both compounds selectively inhibit the reverse transcription of HIV-1 by virtue of their conversion into ddATP. In human lymphoid cells ddAdo is converted to the active metabolite, ddATP, but it also undergoes rapid deamination, via adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and ddATP), as well as to IMP and to adenylate ribonucleotides. With the main object of blocking the deamination of ddAdo, we studied its anti-HIV-1 activity in the presence of different adenosine deaminase inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl) adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase inhibitors tested by us showed a significant increase in the antiviral activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA and CF concentrations up to 250 and > 12,500 times lower than their respective maximum non toxic doses. In combination with EHNA or CF, ddAdo could be used at concentrations up to ten times lower than those required to obtain the same degree of inhibition when ddAdo (or ddIno) was used alone. The use of EHNA or CF in combination with ddAdo at concentrations that inhibit the multiplication of HIV-1, allowed uninfected cells to maintain their normal multiplication rates. In fact, in combination experiments, cytotoxic effects were evident only with doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those required to inhibit HIV-1 significantly. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
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PMID:Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives. 859 Mar 88

A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds are intended to be more lipophilic than the currently approved anti-HIV drugs for better blood-brain barrier penetration. Subsequent adenosine deaminase (ADA)-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI). The new compounds, synthesized from the corresponding 6-chloro analog, include F-ddN which contain methylamino, ethylamino, dimethylamino, hydroxylamino, methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in the 6-position. The 6-nitro analog was isolated as an unexpected product during the preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity, the ethylamino and dimethylamino compounds are ca. 100 times more lipophilic than ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results in hydrolysis of the group in the 6-position rather than glycosylic bond cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rates which vary from slightly slower (NO2, 1.7x) to much slower (NHEt, 5000x) than F-ddA. The 6-dimethylamino analog is the only compound which possesses anti-HIV activity (ED50 18 microM) without ADA hydrolysis. With the exception of the two inactive alkoxyamino compounds, the other prodrugs exhibited cellular protection in the HIV-1/PHA-PBM system with IC50 potencies of 7-40 microM.
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PMID:Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-Amino prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine. 864 1

In the past year, a number of human gene therapy trials involving the adoptive transfer of genetically modified T lymphocytes have been reported. These include trials of adenosine deaminase gene transfer in children with severe combined immunodeficiency syndrome, a gene-marking study of Epstein-Barr virus-specific cytotoxic T cells, and trials of gene-modified T cells expressing suicide or viral resistance genes in patients infected with HIV. Additional strategies for T-cell gene therapy currently being pursued in the clinic involve the engineering of novel T-cell receptors that impart antigen specificity for virally infected or malignant cells.
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PMID:T-cell gene therapy. 893 44

CD26, known to be the adenosine deaminase (ADA)-binding protein, has been implicated in HIV infection. Several studies have revealed a correlation between depletion of CD4+/CD26+ T lymphocytes, increased serum levels of ADA, and the evolution of AIDS in infected individuals. We show that in human B and T cell lines, irrespective of CD4 expression, 125I-labeled ADA binding to CD26 is inhibited by recombinant soluble HIV-1 envelope glycoprotein gp120 and by HIV-1 infectious particles. Accordingly, an anti-CD4 mAb, which inhibits the binding of gp120 to CD4 and blocks viral infection, did not affect inhibition of 125I-labeled ADA binding to CD26 by HIV particles. On the other hand, mAbs directed against the V3 loop and the C-terminal region of gp120 abolished completely the inhibitory effect. Overlapping synthetic peptides covering the entire gp120 sequence were tested to map the region in gp120 responsible for ADA binding inhibition. Only peptides in the C3 region significantly inhibited the binding of ADA to CD26. These results provide indirect evidence for the interaction of gp120 with CD26 and indicate that a specific function of gp120 is the inhibition of ADA binding to CD26 in both CD4+ and CD4- cells. Because ADA deficiency leads to severe combined immunodefiency syndrome, it remains possible that HIV particle-mediated blockade of ADA-CD26 interaction may have significant consequences in the pathogenesis of AIDS.
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PMID:Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles. 910 36

Cryptococcosis is the commonest fungal infection of the CNS and it is an important cause of morbidity and mortality in immunodeficient patients [1]. It has been occasionally described in immunocompetent patients [2]. We report a patient with no predisposing factors who was treated with flucytosine and amphotericin B for cryptococcal meningitis. Following treatment, she developed a reversible acute cerebellar syndrome that was probably secondary to the administration of flucytosine, an adverse effect that has not previously been described [3, 4]. An 87-year old women with no relevant personal or family history was admitted to the hospital for headache, fever, and confusion over the past week. The vital signs, general and neurological examination were normal. In laboratory tests, the urine, urea nitrogen, glucose, bilirubin, electrolytes, aspartate aminotransferase, creatine kinase, alkaline phosphatase, haematocrit, white-cell count, and platelet were also normal. A lumbar puncture was performed which showed: 60 typical lymphocytes per ml, adenosine deaminase (ADA) activity 6 U.l-1 (normal under 4 U.l-1), proteins 75.7 mg.dl-1, and glucose 13 mg.dl-1 with a glycaemia of 120 mg.dl-1. The microbiology study showed staining and a positive culture for Cryptococcus neoformans, and an antigen titre of 1/2080. The serology for HIV infection was negative, and other predisposing factors for this fungal infection, such as immunological defects, a lymphoreticular malignancy and sarcoidosis were excluded. A CT scan of the cranial-thoracic-abdominal regions was normal and tumour markers were absent.
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PMID:Acute cerebellopathy as a probable toxic effect of flucytosine. 911 68

From 1994 to 1995, 80 cases which belonged to 78 patients were diagnosed. The rate was 56.6 cases/100,000 inhabitants/year in 1994 and 51.2 in 1995. The ratio male/female was 2:1 for the two years. Diagnose in hospital was 73% and in health centre 27%. Acid-fast stain and/or positive culture of M. Tuberculosis (MT) and another mycobacteria were obtained in 82.5% cases. The MT resistances were about 3.6. It was usually placed in lungs in 69.2%. The 5.1% patients were positive for HIV. Only one patient died (1.8%) who suffered from a miliary form. The favorite administered treatment (78.2%) was six months with three drugs. The adenosine deaminase (ADA) was discriminate for 80% of pleuritis. The average stay was 17.6 days. Important differences in each town councils rates.
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PMID:[Tuberculosis epidemiology in the Cervo (Lugo) health area]. 918 11


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