ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:Dideoxyinosine (DDI) has been recently approved for the treatment of AIDS. In anticipation of its use in HIV-infected women during pregnancy, the transfer and metabolism of DDI by the perfused human placenta have been investigated. Transfer characteristics are those of simple diffusion: clearance is the same as that for L-glucose (transfer index of 0.98 ± 0.09), it is equivalent in both directions across the placenta, and the transfer rate is proportional to the transplacental gradient over a very broad range (1 to 500μM). Because of extensive placental metabolism, only about one-half of the cleared DDI (51 ± 21%) is transferred intact to the fetal circulation. No dideoxyadenine triphos-phate, the antiviral product of DDI, could be detected in the placenta following perfusion. Comparison of the pharmacological information on DDI and zidovudine (ZDV) indicates that treatment of HIV-infected women during pregnancy with DDI will expose the fetus to much less drug than if ZDV were used. DDI may therefore be less effective than ZDV in the treatment of the infected fetus. However, the uninfected fetus of an HIV-infected woman will gain by reduced exposure to a drug that is known to be toxic.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:The functional ability of the human monoclonal antibody (HMab) F105 to neutralize commonly available laboratory strains and a selection of primary isolates of human immunodeficiency virus (HIV)-I was studied. F105 is representative of a class of human antibodies that react with conformational epitopes within the discontinuous CD4 binding site on HIV-1 envelope glycoprotein gp120. F105 binds with relatively similar affinities to native antigen expressed on the surfaces of cells infected with each of five laboratory isolates tested (IIIB, SF2, MN, RF, and CC) and neutralizes SF2, IIIB, and MN with concentrations of antibody ranging from 140 ng to 10 μg/ml. Nonetheless, neutralization by F105 alone of RF and CC is poor at modest antibody concentrations despite high affinity binding to surface gp120 on infected cells. Neutralization of HIV-1 strains by F105 is unaffected by normal sera and cooperativity is observed with serum samples from HIV-1 infected patients. Of significance, neutralization of RF and MN by F105 is enhanced by some HIV-seropositive sera at low concentrations. F105 also neutralized 30% of HIV-1 primary isolates in lymphocyte cultures. Although it is unclear how relevant in vitro studies will be to in vivo events, these data allow comparison of F105 with other HMabs to the CD4 binding site and V3 loop and provide an in vitro reference for in vivo activity. These studies demonstrate that antibody interactions among different classes of antibodies may be important in in vivo neutralization of HIV-1.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:We have previously demonstrated that in vitro production of inter-feron-α (IFN-α) in response to herpes simplex virus (HSV) by peripheral blood mononuclear cells PBMCs from patients infected with the human immunodeficiency virus (HIV-1) decreases dramatically with disease progression, with extremely low levels of IFN-α preceding and predictive of opportunistic infections. Natural killer (NK) lysis, however, was found to decay later in disease and often was within normal limits even when IFN-α production was severely compromised. The NK lysis of HSV-infected fibroblasts (HSV-FS) is dependent on an HLA-DR+accessory cell (AC) population that shares the phenotype of the predominant IFN-α-producing cell (IPC) population. To determine whether there is a correlation between AC activity and IFN-α production in these patients, we tested the ability of PBMCs from AIDS patients to provide AC help to NK cells from heterologous donors. While NK cells were highly sensitive to gamma irradiation, AC activity was relatively radioresistant. Therefore, NK cells from healthy donors were depleted of HLA-DR+ACs and added to irradiated PBMCs from either healthy or AIDS donors to test for the function of ACs in the irradiated populations. Irradiated cells from AIDS patients were found to provide normal AC activity despite decreased IFN-α production in the majority of the patients. We failed to observe NK augmenting activity in supernatants of irradiated PBMCs from IFN-deficient patients that had been stimulated with HSV-FS. We conclude that IFN-α production and AC function are either mediated by different populations of cells or represent independently regulated functions of the same cells and that IFN-α production can be compromised in patients whose AC function is intact.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:The protease of the human immunodeficiency virus type 1 (HIV-1) is essential for the processing of GAG and POL polyproteins and maturation of the virus particles. Using recombinant protease and a truncated GAG poly-protein as substrate, we developed a Western blot assay for the evaluation of inhibitors of the enzyme. Two statine-based inhibitors of the enzyme, KH161 and KH164, were effective in blocking the replication of HIV-1 in acutely infected human T4 lymphoid cells, with potency approaching that of zidovudine (ZDV) when tested in parallel. In chronically infected cells, the production of infectious virus was inhibited by KH161 and KH164, while ZDV was ineffective. Both KH161 and KH164 were also active as antivirals against the replication of murine leukemia virus (MLV) in cultured mouse cells. In an animal model of a murine retroviral disease, KH164 was shown to inhibit in a dose-dependent manner the progression of the disease induced by Friend virus complex (a mixture of Friend MLV and spleen focus-forming virus). The results suggest that the progression of the acquired immune deficiency syndrome (AIDS) may be impeded by inhibitors of HIV-1 protease.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin (600 mg and 800 mg) and placebo was conducted at six medical centers. Two hundred fifteen adults were enrolled over a 5-month period and randomized to receive ribavirin 800 mg daily (74 subjects), ribavirin 600 mg (71 subjects), or placebo (70 subjects). Active treatment was administered for 24 weeks followed by a 4-week wash-out period. Fifteen patients receiving placebo, 10 receiving ribavirin 600 mg, and 18 receiving ribavirin 800 mg developed AIDS during the 28-week study period. Ribavirin at daily doses of 600 mg or 800 mg for 24 weeks did not significantly affect the rate of progression to AIDS as defined by the Centers for Disease Control, in univariate analysis, Kaplan-Meier survival analysis, or Cox proportional hazards modeling. Although in the proportional hazards analysis, the dose-response regression coefficients indicated a reduction of 43% in the hazard of progression to AIDS among patients on active treatment, it was not statistically significant (p= 0.19). Furthermore, there was no evidence that ribavirin had a significant effect upon any immunologic or virologic parameter measured, including CD4 count, CD4:CD8 ratio, lymphocyte proliferative response, skin test reactivity, interferon-γ production, peripheral blood mononuclear cell culture for human immunodeficiency virus (HIV), or level of HIV p24 antigen in serum. The most prominent adverse effect of ribavirin was induction of a mild reversible hemolytic anemia (mean fall in hematocrit, 5%). No severe or unremitting drug reaction was documented.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:We evaluated the effect of zidovudine on HIV-induced lesions of the brain by comparing the neuropathological findings in 82 treated and 120 untreated patients who died from AIDS. We observed a statistically significant reduction of the number of cases with multinucleated giant cells (MGCs) in the brain and MGC-associated neuropathological damage in patients treated with zidovudine. The effects of zidovudine were time and dose related in the first 12 months of treatment, while longer periods of therapy produced no further results. The antiretroviral treatment particularly affected the frequency of diffuse demyelinating lesions of the cerebral white matter. In the patients who died with HIV-induced brain lesions but no other opportunistic brain diseases, the percentage of cases with clinical history of severe dementia was significantly lower in the group treated with zidovudine.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:This three-phase study was designed to determine if a pharmacoki-netic drug-drug interaction exists between zidovudine and oxazepam. Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. Zidovudine concentrations were determined by radioimmunoassay. Oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p= 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p= 0.25), and 1.38 h versus 1.15 h (p= 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h,p= 0.16). The mean pharmacoki-netic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively. When pharmacokinetic values for single drug and combination therapy were compared, only the oral clearance for oxazepam during concomitant therapy was found to be statistically different from single drug therapy (11.2 L/h vs. 9.8 L/h, p = 0.035). All subjects noted somnolence and fatigue during phases of oxazepam administration. In addition, 5 of 6 participants reported headaches in the combination study phase versus one of six participants with oxazepam alone (p< 0.025) and none of six for zidovudine alone (p< 0.005). Therefore, for patients receiving treatment with combination zidovudine and benzodiazepines like oxazepam and who complain of headaches, administration of the benzodiazepine should be discontinued before concluding that the headaches are due solely to zidovudine or HIV-related pathologies.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Summary:The corticotropin-adrenocortical response to cold pressor challenge was investigated in a study of human immunodeficiency virus (HIV) infection. Data obtained from 16 HIV-1-positive and 28 HIV-1-negative subjects are presented in this report. After the insertion of a venicatheter and following 30 min of rest, the subjects immersed one of their hands in an ice-water mixture for 2 min, and serial blood samples were obtained for the determination of ACTH and cortisol levels. The results show a significant blunting in the ACTH response and marginally lower levels of cortisol, over all time points, in HIV-1-positive subjects compared to that in HIV-1-negative subjects.

ISSN:0894-9255    

出版商:OVID    

年代:1993

数据来源: OVID