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Biomedical subjects

J P Sabo

Publications and source records attributed to J P Sabo.

7 recordsLinked to original sources
PubMed2000

Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection.

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts < 200 cells/mm3and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddI], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Adult↗
PubMed1999

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers.

The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean +/- S.D., Cl = 1.4 +/- 0.3 L/h) and a prolonged elimination phase (t(1/2beta) = 52.8 +/- 14.8 h; MRT = 81.4 +/- 22.4 h). Nevirapine absolute bioavailability was 93 +/- 9% and 91 +/- 8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production-line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose.

Administration, Oral↗
PubMed1994

Isotype choice for chimeric antibodies affects binding properties.

Construction of a series of chimeric antibodies (murine variable region and human constant region) derived from the murine antibody BIRR1, which recognizes intercellular adhesion molecule 1 (ICAM-1), has revealed differences in the relative binding abilities of the chimeric antibody to antigen. The chimeric antibodies show a ranking of their ability to compete with BIRR1 for antigen on the surface of cells with the order BIRR1 = cIgG1 (100%) > cIgG4 (30%) > cIgG2 (10%) as demonstrated by solid-phase competitive enzyme-linked immunosorbent assay. Papain digestion yielded Fab fragments that were purified to homogeneity. Competitive enzyme-linked immunosorbent assay showed that the chimeric and murine Fab binding constants were equivalent. A solution-phase binding assay (analyzed by size exclusion high performance liquid chromatography) between the intact mAbs and recombinant soluble ICAM-1 further established that the binding constants involving the Fab arms of the two antibodies were equivalent. In summary, the murine and chimeric anti-ICAM-1 antibodies bind cellular ICAM-1 with equivalent affinities but with differing avidities.

Animals↗
PubMed1991

BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine.

A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.

Antigens, Viral↗
PubMed1983

Effects of the Clara cell toxin, 4-ipomeanol, on pulmonary function in rats.

The naturally occurring compound, 4-ipomeanol (IPO, 1-[3-furyl]-4-hydroxy-1-pentanone), selectively damages the nonciliated epithelial (Clara) cells of the terminal bronchioles. Because information is not available concerning functional changes in IPO-treated lungs, an investigation was undertaken to evaluate the in vivo pulmonary ventilatory, mechanical, and gas exchange functions of female Long-Evans rats 24 h after treatment with a single intraperitoneal dose of 1 or 5 mg IPO/kg body wt. A preliminary toxicity study established the 24-h LD50 for intraperitoneally administered IPO at 19 +/- 3 (SD) mg/kg. Significant increases in lung fluid occurred in animals treated with 15 mg IPO/kg, and histological evidence of pulmonary edema was observed in animals treated with 10 mg IPO/kg. Treatment of rats with 5 mg IPO/kg caused a significant decrease in tidal volume and a significant increase in respiratory rate and functional residual capacity-to-total lung capacity ratio (%). In rats treated with 1 mg IPO/kg, pulmonary functions were minimally affected. The functional changes observed in IPO-treated animals can be attributed to swelling and possible dysfunction of Clara cells, with subsequent alveolar interstitial edema and stimulation of juxtapulmonary capillary receptors, or to a direct effect of the toxin on respiratory control mechanisms.

Animals↗
PubMed1981

Acute toxicity of latex microspheres.

The distribution and acute lethality of i.v. administered 3 micrometers latex spheres were determined in rats. The results extend previous studies demonstrating the similarity between dog and rat in the dynamics of microspheres in these species and the inverse relationship between sphere diameter and hemodynamic toxicity. The results suggest that 3 micrometers spheres may be safe imaging agents or drug delivery systems for spleen and liver when administered slowly. Acute hemodynamic toxicity appears to be a function of the total volume of the spheres injected.

Animals↗