ABSTRACT
Tumor necrosis factor-alpha (TNF alpha), a potential regulator of HIV-1 replication, is involved in the progression of AIDS and associated disorders such as muscle wasting, fever and gastrointestinal problems. HIV-seropositive patients were assigned to receive zidovudine (ZDV; 100 mg 4-5 times/d) alone (n = 14), pentoxifylline (PTX; 400 mg every 8 h), a drug known to block TNF alpha release (n = 7), or PTX and ZDV (n = 11) for 12 weeks in a prospective, open-label study. Weekly compliance checks and biweekly blood and 24-h urine samples were obtained for immunological assessments. Baseline TNF alpha levels were elevated in all study patients, independent of disease stage. There were no appreciable differences in immunologic variables (CD4 counts, total and unbound p24 antigen, TNF alpha, beta 2-microglobulin, and urinary neopterin levels) between groups. The mean HIV-1 viral load, as measured by a quantitative polymerase chain reaction technique, was 1.9-fold above baseline values after 12 weeks of ZDV and PTX compared with 8- to 9-fold greater levels in patients given either agent alone (p < 0.05). TNF alpha levels correlated with viral load (r = 0.67; p < 0.0001) in patients given the combined drug regimen. Virological evidence of lack of progression in AIDS patients suggests the beneficial use of ZDV and PTX in delaying progressive HIV-1 disease compared with each drug alone.
Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , HIV-1/drug effects , Pentoxifylline/pharmacology , Zidovudine/pharmacology , Acquired Immunodeficiency Syndrome/microbiology , Adult , CD4-CD8 Ratio , DNA, Viral , Drug Therapy, Combination , Female , HIV-1/isolation & purification , Humans , Leukocyte Count , Male , Middle Aged , Pentoxifylline/administration & dosage , Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Zidovudine/administration & dosageABSTRACT
The ratio of metabolite to parent dapsone concentrations at 3 hours after dosing has been used as a marker of acetylator phenotypes. The absorption of dapsone is somewhat erratic with peak concentrations often found after the 3-hour determination. The present study done in 30 healthy, male volunteers compared ratios of metabolite to parent dapsone concentrations 3 hours after dosing with AUC values calculated during a 24-hour period as well as extrapolated to infinity. A single oral dose of 100 mg of dapsone was given to fasting subjects and serial blood samples were obtained over a 24-hour period and assayed by high-performance liquid chromatography for parent and acetylated metabolite. Dapsone pharmacokinetic parameters of AUC (23.4 +/- 8.6 micrograms.h/ml), half-life (24.8 +/- 11.5 hours) and apparent clearance values (81 +/- 30 ml/min) were consistent with those reported previously. Using established criteria for acetylation phenotyping, 20 percent of the subjects (6 of 30) demonstrated rapid acetylation. Bimodality in the ratios, independent of the experimental indices used to differentiate genetic metabolism, was not readily apparent. The data suggest that large variability in the pharmacokinetics of dapsone may sufficiently obscure the evidence of polymorphic metabolism. The use of dapsone as a marker of acetylator phenotyping should be limited to patient populations.
Subject(s)
Dapsone/pharmacokinetics , Acetylation , Adult , Biomarkers , Dapsone/analogs & derivatives , Humans , Male , PhenotypeABSTRACT
Rats exercise trained by swimming one hour daily five days per week for three months developed cardiac hypertrophy. The NE concentration (0.469 mug/g) and total NE content (0.741/mug) of the hypertrophied hearts were not significantly different from levels in hearts of unexercised control rats.