ABSTRACT
Cellular and intestinal absorption of naked oligonucleotides (ONs) is limited and still remains a developmental challenge. A previous report in the literature suggests that ON absorption occurs via a paracellular mechanism. The aim of this study was to test this hypothesis using rat and human intestine in a Ussing chamber and in Caco-2 cells. Transport of a (35)S-labelled mixed backbone ON (MBO) across human or rat intestinal tissue or across Caco-2 cells was measured after a 2-h incubation in the presence or absence of increasing MBO concentrations or with uptake inhibitors and enhancers. MBO intestinal absorption was compared with an internal standard, mannitol. (35)S-MBO demonstrated very little absorption (<1%) across rat and human intestinal tissues. Transport appeared to be unsaturable up to 500 microM, and relatively insensitive to compounds that opened tight junctions or inhibited P-glycoprotein. However, preliminary studies with Caco-2 cells suggest a possible saturable mechanism at higher ON concentrations. Confocal fluorescence microscopy studies show that fluorescein isothiocyanate (FITC)-MBO was internalized into intestinal cells. Although some differences in ON transport were observed as a function of the transport model, MBO transport was mostly consistent with a transcellular, rather than a paracellular, absorption mechanism.
Subject(s)
Intestinal Mucosa/metabolism , Oligonucleotides/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Algorithms , Animals , Biological Transport, Active , Colon/metabolism , Humans , Ileum/metabolism , In Vitro Techniques , Intestinal Absorption , Jejunum/metabolism , Male , Mannitol/pharmacokinetics , Microscopy, Confocal , Permeability , Rats , Rats, WistarABSTRACT
A controlled trial of BCG vaccination was conducted in 1950 in Muscogee County, Ga., and Russell County, Ala. The study population consisted of 64,136 volunteers over the age of 5 years who had satisfactory skin tests with 5 tuberculin units of purified protein derivative and whose chest photofluorograms were considered by two readers to show no significant pulmonary abnormalities. Approximately half of the nonreactors to tuberculin were vaccinated with the Tice strain of BCG by a multiple-puncture method. During a 20-year period of follow-up, 207 cases of tuberculosis were identified among the persons who had been tuberculin reactors in 1950, 36 cases were identified among the controls, and 32 cases were identified among the vaccinees. The average annual case rates per 100,000 were 47.0 for reactors, 13.4 for controls, and 12.6 for vaccinees.
Subject(s)
BCG Vaccine , Tuberculosis/prevention & control , Alabama , Evaluation Studies as Topic , Follow-Up Studies , Georgia , Humans , Radiography , Tuberculin Test , Tuberculosis/diagnostic imaging , Tuberculosis/epidemiology , Tuberculosis, Pulmonary/epidemiologyABSTRACT
From 1949 to 1951, a total of 191,827 children in Puerto Rico were enrolled in a controlled trial of BCG vaccination. Of these children, 1 through 18 years of age, 82,269 were classified as reactors to tuberculin and 109,558 as nonreactors. Of the nonreactors, 31,856 refused vaccination, 27,338 were left unvaccinated as controls, and 50,674 were vaccinated with BCG. By the end of June 1969, a total of 37 cases of cancer had been diagnosed among the controls and 98 among the "vaccinees," yielding average annual rates of 7.2 and 10.3 cases per 100,000 population, respectively. The vaccinated group had a slight deficiency of leukemia cases and an excess of lymphosarcoma and Hodgkin's disease. The excess risk of cancer was concentrated among children age 10 through 18 on entry into the trial.
