Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the study was to characterize in vivo an immunodepressive murine retroviral 'model' for the possible testing of drugs against HIV infection. Urethane leukaemia virus (ULV) injected into adult BALB/c mice (10(5) focus-forming units/mouse) caused a small, significant splenomegaly from 2 to at least 9 weeks after virus inoculation. Virus was also present in up to 60% nucleated splenocytes (XC 'infectious centre assay'). Effects on splenomegaly and virus in splenocytes were assayed following various regimens of zidovudine given as 0.5 mg/ml or 0.25 mg/ml in drinking water. Regimens included continuous treatment both before and after ULV, only before, and only after ULV inoculation. Zidovudine was also given for a limited period immediately after virus, or initiated after virus infection was established. Zidovudine given continuously at and following ULV infection completely prevented splenomegaly and virus expression in splenocytes. No other regimen was as effective; however, limited zidovudine treatment immediately after virus inoculation greatly reduced the effects of virus, while the same dose initiated after virus infection was established had only a small ameliorating effect. We conclude that ULV may prove to be a useful addition to other available murine systems, and this is discussed.
Int J STD AIDS 1990 Sep
PMID:Inhibition of urethane leukaemia virus, a murine retrovirus, in mice by zidovudine. 196 87

Three nucleoside analogues, zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC), are approved for use in the treatment of patients with HIV infection. This retrospective study compares the 3 drugs and examines the overall utility of antiretroviral therapy by way of comparisons to a no treatment (No Rx) group in patients with advanced HIV disease. Patients with advanced HIV disease were enrolled in didanosine (August 1989-December 1990) or zalcitabine (October 1990-February 1992) expanded access programmes; continued on zidovudine treatment despite fulfilling criteria for zidovudine failure or intolerance; or maintained on no antiretroviral treatment. Statistical analysis revealed that patients on nucleoside analogue therapy had fewer opportunistic infections (P = 0.001) than those who received no antiretroviral treatment. The Kaplan-Meier 12-month estimate of survival was significantly longer among patients who switched from zidovudine to zalcitabine but not among patients who switched to didanosine, when compared to the other 2 groups (P = 0.05).
Int J STD AIDS
PMID:A comparison of zidovudine, didanosine, zalcitabine and no antiretroviral therapy in patients with advanced HIV disease. 772 78

To analyse the appearance of AZT-resistant HIV in HIV carriers after AZT treatment and compare the mutations responsible for resistance employing cloned HIV DNA derived from provirus and free virions in plasma, serial blood specimens were taken before and after AZT treatment. RNA in virions in plasma, proviral DNA and RNA from virus isolates by coculture of PBMCs of HIV carriers and healthy blood donors were cloned and sequenced. DNA clones were compared for their nucleotide sequences responsible for AZT resistance. AZT resistance was acquired as early as 2 months after the start of the treatment and follow-up study was performed for 16 months of the treatment. Population of DNA clones was different according to the origin of the DNA or RNA, which indicated that the provirus population in PBMC was different from that in virions in plasma. These data demonstrated the possibility of selective activation of provirus or activation of provirus in organs other than peripheral blood, although the number of cases was small.
Int J STD AIDS 1997 Jun
PMID:Difference of virus populations in HIV carriers in relation to AZT treatment. 917 48

An asymptomatic HIV-positive patient with Philadelphia chromosome positive chronic myelogenous leukemia (CML) was treated by interferon-a (IFN-a) for four years. A sustained hematological response and major cytogenetic response were achieved. However, a complete cytogenetic remission (100% Ph-negative cells) was observed when zidovudine (AZT) was introduced as treatment for HIV-related immunodepression. Moreover, this complete cytogenetic remission was confirmed by quantitative PCR showing decreased BCR-ABL rearrangement at very low level. As, there are some in vitro reports demonstrating a synergistic antiproliferative effect of IFN-a and zidovudine, we discuss the possibility of synergistic effects between AZT and IFNa in the treatment of CML.
 ...
PMID:Improving the cytogenetic response to interferon alpha by zidovudine (AZT) in an HIV-positive chronic myelogenous leukemia patient. 925 Aug 8

The purpose of this review is to give an update of the recent progress in research on erythropoietin (Epo), the hormone that regulates red blood cell production. Epo is a glycoprotein with a molecular mass of approx 30 kDa, which circulates in plasma of the human with 165 amino acids with three N-linked and one O-linked acidic oligosaccharide side chains in the molecule. Both the alpha (39% CHO) and beta (24% CHO) forms are available for clinical use, and there does not appear to be any difference in the pharmacokinetics of these two forms of Epo. Radioimmunoassays and enzyme-linked immunoabsorbant (ELISA) assays are available in a kit form. Serum levels of Epo in normal human subjects range between 1 and 27 mmu/ml or approx 5 pmol/l. It seems clear that the cells in the adult mammalian kidney which produce Epo are the interstitial cells in the peritubular capillary bed and the perivenous hepatocytes in the liver. Expression of the human Epo gene sequences that direct expression in the kidney are located 6-14 kilobases 5' to the gene; whereas the sequences that control hepatocyte-specific expression are located within 0.7 KS to the 3'-flanking region and 0.5 KS to the 5'-flanking region. The signal transduction pathways postulated to be involved in the expression of Epo are: kinases A, G and C; both a constitutive factor and a second hypoxia-inducible factor-1 (HIF-1) located in the 5' end of an hypoxia inducible enhancer region of the Epo gene; and reactive oxygen species. The primary target cell in the bone marrow acted on by Epo is the colony-forming unit erythroid (CFU-E) which has the highest number of Epo receptors. It has been postulated that Epo decreases the rate which Epo-dependent progenitor cells undergo programed cell death (apoptosis). There are two major signal transduction pathways activated by the Epo receptor: the JAK2-STAT5 pathway and the ras pathway. Both pathways involve tyrosine phosphorylation. The approved clinical uses of Epo are the anemias associated with end-stage renal disease, cancer chemotherapeutic agents, and patients with HIV infection receiving AZT. Other anemias reported to respond to Epo therapy are anemia of prematurity, rheumatoid arthritis, and myelodysplasia. Other uses of Epo under investigation are in perioperative surgery and preoperative autologous blood donation.
 ...
PMID:Erythropoietin: physiologic and pharmacologic aspects. 940 40

The objective of this study was to provide population-based estimates on the cost of HIV service provision in England and the use of dual or triple antiretroviral combination therapy. Contemporary cost estimates of treating HIV-infected individuals by clinical stage of HIV infection (indexed to 1995/96 prices) were linked to the number of diagnosed HIV-infected individuals using statutory medical services in England during 1996. Two cost measures were used: the first one was based on average hospital prices derived from a number of English HIV units. These results were compared with those estimated using standard unit costs obtained through specific costing studies performed at a national HIV referral centre. Overall annual expenditure on HIV service provision was estimated for different treatment scenarios as was expenditure by clinical stage of HIV infection. Using hospital prices, in 1996 the total annual cost estimate for HIV service provision amounted to pound sterling 131 m (range pound sterling 83 m to pound sterling 233 m), or pound sterling 150 m (95% CI pound sterling 126 m to pound sterling 173 m) using standard costs, if all patients with HIV disease were treated with AZT monotherapy. For all eligible patients to be treated with dual therapy, cost estimates amounted to pound sterling 161 m (range pound sterling 126 m to pound sterling 173 m) per year using hospital prices or pound sterling 180 m (95% CI pound sterling 156 m to pound sterling 203 m) when using standard cost estimates, while for triple therapy annual estimated expenditure amounted to pound sterling 204 m per year (range pound sterling 157 m to pound sterling 306 m) when using hospital prices or pound sterling 223 m (95% CI pound sterling 199 m to pound sterling 246 m) using standard costs. Increasingly costs will be more evenly distributed across the 3 stages of HIV infection, with a greater proportion of costs generated by HIV-infected individuals before the onset of AIDS. Using non-standardized hospital prices may systematically underestimate the real cost of service provision. Monitoring prospectively the use, cost and outcome of HIV service provision in a standardized format will provide information on the actual cost impact over the next 2-3 years of combination therapy compared with the scenario-based estimates produced in this paper.
Int J STD AIDS 1998 Sep
PMID:Financing HIV service provision in England: estimated impact of the cost of antiretroviral combination therapy. 976 34

The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were pound sterling 4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to pound sterling 128 million (95% CI pound sterling 109m to pound sterling 147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling 161m (95% CI pound sterling 141m to pound sterling 181m), while for triple therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2-3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decreased by 8-9%.
Int J STD AIDS 1999 Jun
PMID:Changing cost of English HIV service provision 1996-1997. NPMS Steering Group. National Prospective Monitoring System. 1041 77

Our objective was to characterize the effect of zidovudine therapy on AIDS dementia complex (dementia) free survival among HIV-infected men and women in a population-based cohort with free access to antiretroviral therapy in the province of British Columbia. Time to diagnosis of dementia among individuals was examined on the basis of zidovudine duration, CD4+ cell count at first treatment, gender, and transmission group [men having sex with men (MSM), intravenous drug users (IDU), heterosexuals]. We restricted the analysis to subjects with CD4+ cells counts within 12 months prior to treatment start date. Among 641 participants eligible for analysis, median duration of follow-up was 3.6 years, under which 86 (9.3%) events of dementia occurred. Participants were less likely to develop dementia with: increased zidovudine exposure (OR=0.26, 95% CI: 0.14-0.49), at least 260 CD4+ cells/mm3 (median) (OR=0.52, 95% CI: 0.34-0.78), and MSM risk group (OR=0.57, 95% CI: 0.35-0.94). Those infected through heterosexual contact had an increased risk (RR=2.04, 95% CI: 1.02-4.07). Using Cox's proportional hazards model, controlling for CD4+ cell count at treatment start date, independent predictors of dementia-free survival were: duration of zidovudine (OR=0.28, 95% CI: 0.15-0.52) and MSM transmission group (OR=0.61, 95% CI: 0.37-1.00). In this observational treatment cohort, factors associated with dementia-free survival include duration of zidovudine (AZT) therapy and MSM transmission group. It is not clear from these data whether the AZT protective effect is exclusive to this agent or whether other therapies might offer a similar protective effect.
Int J STD AIDS 2000 Jan
PMID:The impact of zidovudine on dementia-free survival in a population of HIV-positive men and women on antiretroviral therapy. 1066 2

The purpose of this report was to present findings from a pilot study conducted to explore the associations between sociodemographic, drug use, and health belief factors and perceived compliance with zidovudine (AZT) among African-American drug users. Data were collected in Washington, DC, USA from individuals who were African-American; were recent or current drug injectors or crack smokers; were HIV-seropositive, and were receiving treatment for HIV infection. Participants were recruited through local organizations that provide services to HIV-infected persons. Participants were interviewed using a questionnaire that solicited sociodemographic, lifetime and current drug use, current sexual behaviours, health status, HIV and drug treatment history, and health belief data. Analyses were limited to individuals currently using an illicit substance and who had received AZT during their medical treatment. Parametric (Pearson's r) and nonparametric (Spearman's rho) statistics were used to assess correlations between perceived compliance with AZT dosing and independent variables. As the study was intended to be both descriptive and exploratory, the level of statistical significance was set at 0.10, rather than the customary 0.05. Antiretroviral medications recognized and recalled by participants are presented. The most commonly recalled medication was AZT. Slightly less than one-third of participants reported being completely compliant with an AZT regimen. Perceived compliance was found to be negatively associated with 5 variables: age, homelessness, number of injections in the previous 30 days, trading sex for drugs, and the perception that AIDS is no longer a serious disease since the development of new antiretroviral medications. Intensity of feelings of joy, fear, and the belief that taking more anti-HIV medications would result in better health were found to be positively correlated. Bivariate associations between perceived compliance and sociodemographic, drug use, sexual behaviour, and health belief variables suggest further avenues of study and potential points for intervention to increase compliance with antiretroviral medications among racial/ethnic minority drug users receiving treatment for HIV infection.
Int J STD AIDS 2000 Jan
PMID:Perceived compliance with AZT dosing among a sample of African-American drug users. 1066 3

Intermittent administration of recombinant interleukin-2 (rIL-2) to individuals infected with human immunodeficiency virus (HIV) has been shown to raise and maintain the absolute number of circulating CD4(+) T cells to normal or near normal levels. One of the signaling pathways triggered by IL-2 is the Janus kinase-signal transducer and activator of transcription (JAK-STAT). In particular, IL-2 activates the tyrosine kinases JAK1 and JAK3 and the transcription factors STAT3 and STAT5. We have previously observed that most HIV(+) individuals, unlike healthy seronegative controls, show a constitutive activation of STAT1 and a C-terminal truncated isoform of STAT5 (STAT5 Delta). In the present study, we have analyzed the protein level and activation state of STAT5 isoforms expressed in peripheral blood mononuclear cells of two HIV-infected individuals who showed a good or a poor response to intermittent IL-2 administration, respectively, and of a single individual before and after initiation of Zidovudine monotherapy. We provide evidence that both therapeutic interventions enhanced the expression and activation of the C-terminal truncated isoform of STAT5 (STAT5 Delta) in vivo.
 ...
PMID:Expression and activation of a C-terminal truncated isoform of STAT5 (STAT5 Delta) following interleukin 2 administration or AZT monotherapy in HIV-infected individuals. 1128 43


1 2 Next >>