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)

In studies examining potential interactions between ganciclovir (GCV) and either zidovudine (AZT) or didanosine (DDI) in H9 cells, GCV was found to consistently reduce the anti-human immunodeficiency virus type 1 potency of both AZT and DDI. In the presence of GCV, the 50% effective doses of AZT and DDI were increased three- to sixfold, depending on the molar ratio of drugs and the measure of human immunodeficiency virus type 1 replication (p24 antigen, reverse transcriptase activity, or infectious virus yield). Multiple dose-effect analysis revealed strong antagonism between GCV and either AZT or DDI (combination indices, 2.2 to 6.7). This antagonistic effect occurred at drug concentrations that were well below the cytotoxic range. At higher drug concentrations, the combination of GCV and AZT was synergistically cytotoxic (combination indices, less than 1.0), whereas GCV and DDI were only additively cytotoxic (combination indices, ca. 1.0). Thus, the combination of GCV with AZT or DDI may result in antiviral antagonism and either synergistic (AZT-GCV) or additive (DDI-GCV) cytotoxicity.
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PMID:Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. 151 Apr 5

Reports of in vitro resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine (AZT) have raised concerns about the development of resistance to other dideoxynucleosides in clinical use. To address this, we have developed a screening assay which supports the growth of clinical isolates and have applied this to a series of paired isolates from patients entered into a phase I trial of didanosine (DDI). Thirteen patients (10 with AIDS, 3 with AIDS-related complex) who had been exposed to AZT for a mean of 6.5 months (range, 1 to 13 months) were treated with DDI at 750 mg/day. Paired isolates were obtained pretherapy and after a mean of 58 weeks (range, 21 to 90) of DDI therapy by coculture of peripheral blood mononuclear leukocytes (PBLs) with phytohemagglutinin-stimulated donor PBLs. Isolates were passaged only one additional time in PBLs and then tested in parallel in a microtiter assay with phytohemagglutinin-stimulated donor PBLs as targets. PBLs were infected with 10(5) 50% tissue culture infectious doses per 10(7) cells and exposed to DDI (1 to 50 microM) or AZT (0.01 to 100 microM), and supernatants were assayed for the HIV p24 antigen at 7 days postinfection. Control AZT-susceptible and resistant isolates were included. The median pre- and posttherapy DDI susceptibilities of the 13 pairs of isolates were 10.0 microM (range, 1 to 25 microM) and 17.5 microM (range, 2.5 to 50 microM), respectively (P = 0.036; Wilcoxon signed-rank test). These studies thus indicated that (i) the susceptibility to DDI tends to mildly decrease with drug exposure; (ii) the susceptibility to AZT improves with time off AZT; (iii) baseline susceptibilities to DDI have a wide range, and the CD4 response may correlate with the initial susceptibility; and (iv) a PBL-based microtiter assay is useful for screening clinical isolated for dideoxynucleoside susceptibility profiles.
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PMID:Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. 151 Apr 14

A comparison of the activity against human immunodeficiency virus 1 of zidovudine (AZT) and poly I poly C double-stranded RNA both alone and in combination in MT4 cells and primary monocyte/macrophage (M/M) cultures was made. The inhibition of the HIV-induced cytopathic effect or reverse transcriptase production by AZT in MT4 cells was not modified by the combination of the two agents. In contrast, AZT inhibition of reverse transcriptase production in the supernatant of M/M cultures was enhanced by the addition of poly I poly C. The inhibitory effect of the drug combination was more marked in M/M than in MT4 cells, indicating that the evaluation of compounds involving the induction of an antiviral state should be tested not only CD4+ T cells but also in monocyte-macrophages.
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PMID:Anti-human immunodeficiency virus effects of zidovudine in combination with double-stranded RNA poly I poly C in T cells and monocytes-macrophages. 152 May 35

To estimate the cumulative incidence of acquired immunodeficiency syndrome (AIDS) in thalassaemia major patients (TMP) human immunodeficiency virus (HIV-1) infected through transfusion, 79 seropositive TMP were studied. At inclusion, mean age was 12.4 +/- 6.6 years; 40 were men; 21 were splenectomized. Centers for Disease Control, 1986 (CDC) stages and prescription of zidovudine were noted at least once a year. Cumulative incidence of AIDS and standard error were calculated using non parametric life table method. Age, sex, acute infection and splenectomy associations with progression to AIDS were tested using Breslow statistic. The median follow-up period was 4 years 11 months. At the end of the study period, 43 TMP were in CDC stage II, 23 in CDC stage III and 13 in CDC stage IV, including seven AIDS cases, of whom three had died. Four subjects died of other causes. Only two patients were treated with AZT prior to the occurrence of AIDS. Rate of progression to AIDS was not associated with acute infection, splenectomy, age, or sex. A cumulative AIDS incidence rate of 1.4% (SE 1.3%) was observed at 3 years and of 9% (SE 4%) at 5 years.
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PMID:Incidence of AIDS in HIV-1 infected thalassaemia patients. European and Mediterranean W.H.O. Working Group on Haemoglobinopathies and Cooleycare. 152 Jun 8

3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog which has potent activity against the acquired immunodeficiency virus, is actively secreted by the mammalian kidney. In order to study the mechanism of renal drug transport, the effect of AZT on the organic cation and organic anion transport systems in rat renal brush border membrane vesicles was examined by using a rapid filtration assay. The following prototypic substrates were used: [3H]N1-methylnicotinamide and [3H]tetraethylammonium for organic cations and p-[3H]aminohippurate for an organic anion. AZT inhibited pH-driven [3H]N'-methylnicotinamide transport (pHi = 6.0, pH0 = 7.5), but not as effectively as mepiperphenidol (MEPI), a known organic cation transport blocker; the corresponding IC50 values for AZT and MEPI were 2500 and 25 microM, respectively. Counterflow studies, which examined the capability of the drug to cross the plasma membrane, indicated that [3H] tetraethylammonium and MEPI trans-stimulated [3H]tetraethyl-ammonium uptake, but AZT did not. To clarify further the actions of AZT on the organic cation transporter, kinetic studies were undertaken. A Hanes-Woolf transformation of the data revealed that both AZT and MEPI inhibited [3H]N'-methylnicotinamide transport in a competitive manner. The specificity of competition was studied by looking at the effect of AZT on the organic anion transporter. Probenecid, a classical inhibitor of organic anion transport, blocked p-[3H]aminohippurate transport, but AZT did not. We conclude that AZT is a weak inhibitor of the renal brush border organic cation transport system.
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PMID:Effect of 3'-azido-3'-deoxythymidine (AZT) on organic ion transport in rat renal brush border membrane vesicles. 153 Sep 72

A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37-62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model-independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half-life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3-47.8 microns and area under the curve from 0.5-26.1 mg x hour/L. These differences resulted in corresponding differences in clearance (range 66-3176 ml/min/1.73 m2) and volume of distribution (range 16-825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.
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PMID:Zidovudine pharmacokinetics in five HIV seronegative patients undergoing continuous ambulatory peritoneal dialysis. 154 40

The replication cycle of human immunodeficiency virus type 1 (HIV-1) consists of four distinct stages, each of which can be targeted for specific antiviral chemotherapy. The stages are (1) the attachment of virus to the CD4 receptor at the cell surface; (2) the uncoating of viral nucleic acid and its conversion via viral reverse transcriptase activity to DNA; (3) cellular multiplication, accompanied by the replication of integrated proviral DNA and production of viral RNA and proteins; and (4) the assembly and liberation of progeny virus from the cell and the potential reinitiation of the replication cycle in previously uninfected cells. Since each of these steps represents a potential target for anti-HIV chemotherapy, it is apparent that the rationale for the use of antiviral drugs is not dissimilar from the manner in which antineoplastic agents are targeted to specific stages in the replication cycle of tumor cells. As in the case of anticancer chemotherapy, it is hoped that combinations of drugs, which act against different steps in the viral replication cycle, might have synergistic potential. AZT or zidovudine is the most widely used drug to date to impede the replication of HIV-1; it is significant that this compound was designed initially with anticancer chemotherapy in mind. Although AZT therapy has been reasonably successful, this drug has had important toxic side effects. As in the case of many cancer chemotherapeutic agents, drug resistance to AZT is likely to be an important problem, and there have been several reports of the isolation of drug-resistant variants of HIV-1.
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PMID:Strategies in the treatment of AIDS and related diseases: the lessons of cancer chemotherapy. 155 Oct 24

Zidovudine delays the progression of disease in asymptomatic or mildly symptomatic patients infected with human immunodeficiency virus (HIV), but it can cause serious adverse reactions, a fact which makes zidovudine treatment undesirable to some patients. In this study, zidovudine was offered to HIV-infected patients with CD4 leukocyte counts between 200 and 500 cells/microL, and the acceptance or refusal of therapy was recorded over a 4-month period. Of 73 patients approached, 49 (67%) consented to the therapy (23 asymptomatic and 26 with AIDS-related complex). The high acceptance rate of zidovudine among both asymptomatic and mildly symptomatic HIV patients raises the question of finding additional financial resources and health care providers for close monitoring of side effects.
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PMID:Consent to treatment with zidovudine among HIV-infected patients. 155 Dec 13

Zidovudine is associated with hematologic toxicity and may also impair the rapidly proliferating intestinal epithelium. However, patients with human immunodeficiency virus (HIV) infection receiving zidovudine gain body weight, indicating improved absorptive function. In the present study, 33 HIV-infected patients with gastrointestinal symptoms who were undergoing duodenoscopy and who had no detectable secondary intestinal pathogens were investigated; 12 of them received zidovudine. HIV antigen p24 was detected in duodenal biopsy specimens by immunohistology in 3 of 12 patients with zidovudine treatment and in 10 of 21 patients without zidovudine treatment. Morphometry of duodenal specimens showed reduced villus surface area (P less than 0.05) without crypt hyperplasia independent of zidovudine therapy and reduced numbers of crypt mitoses in patients with mucosal HIV infection (P less than 0.001) compared with controls. In the duodenal brush border, patients with mucosal HIV infection (P = 0.006) and patients without zidovudine treatment (P = 0.009) had absent lactase/beta-glucosidase activity more frequently than controls, and all HIV-infected patients (P less than 0.025) except zidovudine recipients had decreased alkaline phosphatase activity compared with controls. These findings show a hyporegenerative atrophy of the small intestine and enterocyte dysmaturation associated with mucosal HIV infection. Improved enterocyte maturation, indicated by increased brush border enzyme activity, may contribute to the clinical benefit of HIV-infected patients from zidovudine therapy.
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PMID:Effects of zidovudine treatment on the small intestinal mucosa in patients infected with the human immunodeficiency virus. 156 58

Because the time from primary infection to symptoms in human immunodeficiency virus type 1 (HIV-1) infection is typically 8-10 years, the use of surrogate markers to monitor disease progression and therapeutic efficacy is of interest. An acid dissociation procedure that disrupts the p24 antigen-antibody complexes found in early HIV-1 infection has greatly increased the sensitivity of p24 detection assays. The utility of p24 antigen after acid treatment as a surrogate marker of disease progression and therapeutic effect in asymptomatic HIV-infected subjects receiving zidovudine (AZT) was determined. After acid treatment, the sensitivity of p24 antigen detection increased fivefold. The proportion of subjects who were antigenemic increased over the 48-week follow-up in the placebo group; approximately 50% of subjects who were p24 antigen-positive at entry and who received AZT showed clearance or a greater than 50% reduction in baseline p24 antigen levels at 16 and 32 weeks. Thus, acid treatment of plasma may allow the use of p24 antigen as a marker of disease progression and therapeutic response.
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PMID:Acid dissociation increases the sensitivity of p24 antigen detection for the evaluation of antiviral therapy and disease progression in asymptomatic human immunodeficiency virus-infected persons. 156 43


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