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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Tobramycin Disposition in the Lung Following Airway Administration

Li, Min 09 December 2013 (has links)
Tobramycin disposition following airway administration was evaluated by meta-analysis of human data in the literature and, experimentally, using a realistic ex vivo model, the isolated perfused rat lung preparation (IPRL). Pulmonary bioavailability of inhaled tobramycin in published studies was re-evaluated separately for CF and healthy adults, with the drug’s intrinsic pharmacokinetic (PK) parameters obtained from intravenous (IV) studies in the literature. While large variations in tobramycin’s clearance precluded accurate assessment of its bioavailability, the results were indicative of substantial pulmonary absorption, in spite of its hydrophilic and poly cationic properties. To explore its disposition kinetics and mechanisms following airway administration, tobramycin absorption was investigated as a function of dose in the IPRL. The cumulative fraction of the administered tobramycin dose reaching the perfusate versus time, was bi-exponential and dose-dependent, unlike that of the marker solutes fluorescein and mannitol, both of which showed first-order and dose-independent kinetics. A kinetic model that incorporated lung tissue binding (or sequestration) alongside passive absorption was employed successfully to describe the aminoglycoside’s disposition in the IPRL following airway administration. Tobramycin’s absorption was fast with the first-order absorption rate constants (0.065-0.070 min-1) close to those seen with fluorescein (0.076 min-1), but a dose-, and concentration-dependent slow onset tissue binding prolonged its presence in the rat lung. Binding was confirmed by independent dynamic dialysis experiments using sliced lung prepared from the intact IPRL, immediately following airway administration using an identical technique as that used in tobramycin absorption studies. Dosing solution osmolality and pH had negligible effects on the drug’s disposition in the IPRL, when these were investigated over experimental ranges that could be used clinically. While tobramycin itself was found to accelerate mannitol’s absorption, and thus affect airway epithelial integrity when administered at high doses, the effect was undetectable at a dose level in rat lungs that was believed to produce airway concentrations corresponding to those in human patients using TOBI®. These findings may partly explain the apparent success of inhaled tobramycin therapy in the treatment of pulmonary infections.
2

Toxicological and Biochemical Investigations of Alpha-Chaconine in Potato (Solanum Tuberosum L. ) Tubers: Physiologic Disposition and Tissue Binding, and Inhibition of Tissue Cholinesterases and Isoenzymes

Alozie, Sydney Obodoechina 01 May 1977 (has links)
The distribution, absorption, metabolism and tissue binding of radioactivity were studied in hamsters after oral and intraperitoneal administration of alpha-chaconine- (3H). The material was well absorbed from the gastrointestinal tract and nearly 22 percent of the label was excreted via urine and feces in 7 days. The excretion was higher in urine (21 percent) than in feces ( < 1 percent). Tissue concentrations of radioactivity peaked at 12 hours following oral administration, with the highest concentrations found in lungs, liver, spleen, skeletal muscle, kidney and pancreas, with heart and brain containing moderate amounts. Concentrations of radioactivity in tissues following intraperitoneal administration were significantly higher than those observed after oral treatment. Excretion of chloroform-soluble products in the feces was 10 times higher than that of the chloroform-insoluble metabolites after both oral and intraperitoneal administration. In the urine, the activity was predominantly in the chloroform-insoluble form and the chloroform-soluble metabolites were relatively minor in amounts (0.27, 0.85, and 2.45 percent versus 0.005, 0.14 and 0.19 percent of dose for 12, 24 and 72 hours, respectively). After 7 days, the chloroform-soluble metabolites in urine increased to 20 percent of the excreted radioactivity, while the amount of chloroform-insoluble metabolites was less than 1 percent. Subcellular distribution of the labeled compound indicated the highest concentration of radioactivity in the nuclear and microsomal fractions of brain, liver and heart tissues. A small amount of radioactivity, shown by a minor peak, was also observed in the fractions between the mitochondrial and microsomal fractions on a sucrose gradient. Binding of radioactivity was observed in brain, testes, kidney, lung, liver and heart . All of the label in the brain appeared to be in the bound form . The results indicated that alpha-chaconine is slowly absorbed from the gastrointestinal tract after oral administration, and persists in various tissues, much of it in bound (non-extractable) form (in nuclear and microsomal fractions). Excretion of alpha-chaconine- (3H) and its metabolites was investigated after oral and intraperitoneal administration in hamsters. The separation of the glycoalkaloid and its metabolites in feces and urine was accomplished by thin-layer chromatography. An increase in the concentration of excreted alpha-chaconine metabolites in feces and urine was observed. In urine over 50 percent of the eliminated radioactivity during the initial 24 hours was due to the aglycone, solanidine. The fraction of the total dose administered which was excreted represented only 27 percent (26 percent in feces and less than 1 percent in urine) during the 7 day test period. Contrary to the general belief that potato glycoalkaloid absorption is poor following oral administration, only 5 percent or less was excreted in feces during the initial 72 hours, a fact explained by the binding of radioactivity to tissues. Inhibition of acetylcholinesterases by alpha-chaconine was studied. The inhibition of purified erythrocyte acetylcholinesterase and horse serum cholinesterase by alpha-chaconine was found to be a mixed-type with kinetic constants. An inhibition constant (Ki) for both the specific and pseudocholinesterases was 8.3 x 10-6 M and 4.0 x 10-4 M, respectively. Kinetic constants obtained for both enzymes were as follows: Vmax of 7.14 x 10-5 and 3.76 x 10-4 max moles/liter/min, respectively, and Km of 6.2 x 10-5 and 1.33 x 10-4, respectively. The distribution of acetylcholinesterase among the subcellular fractions of rat brain homogenate separated by sucrose density gradient centrifugation was determined, as well as the inhibition pattern of these fractions following in vitro incubation with 0.016 M alpha-chaconine. Enzyme activity was found to be distributed equally between the mitochondrial and microsomal fractions, with the nuclear fraction having the least activity. Percentage inhibition of the various fractions obtained was: whole homogenate 43, nuclear fraction 55, mitochondria 35, and microsomes 33. Brain acetyl cholinesterase activity of animals given intraperitoneal doses (10, 30, 60 mg / Kg) of alpha-chaconine was 79, 55 and 18 percent of the control group. Acetylcholinesterase activity of heart and plasma of animals administered alpha-chaconine did not show the dose-related response observed in the brain. Inhibition of heart acetylcholinesterase was 61 percent, while plasma gave 51 percent for the rats given a dose of 10 mg/Kg and no inhibition for rats given 30 mg/ Kg. Acrylamide gel electrophoretic separation of cholinesterases in aqueous homogenates from whole brain and heart of adult male rats administered alpha-chaconine was investigated. Brain acetylcholinesterase isoenzymes were found to be inhibited by 30 and 60 mg/ Kg dosage levels of alpha-chaconine administered intraperitoneally. Electrophoretic separation of plasma from the treated animals resulted in five anodally migrating zones having properties of cholinesterases. These sites hydrolyze acetylthiocholine and alpha-naphthylacetate, and all were inhibited by alpha-chaconine except the slowest migrating band (band 5). Inhibition of isoenzyme activity of bands 1 and 2 is observed for the groups administered 10 and 30 mg/Kg alpha-chaconine with the percentage inhibition of both bands (l and 2) being 40 and 77 percent for animals given 10 mg/Kg and 100 and 75 percent for the latter group. Isoenzyme bands 3 and 4 were completely absent in the alkaloid treated animals. Inhibition of non-specific cholinesterase isoenzymes (butyrylthiocholine hydrolyzable bands) by alpha-chaconine was clearly demonstrated. In vitro inhibition of plasma, erythrocyte and brain esterase isoenzymes was estimated by incubating gels with 10-4 M alpha-chaconine after the electrophoretic separations. With this concentration of alpha-chaconine, the various isoenzymes in rat plasma, erythrocyte and brain showed some response to the inhibitory potency of alpha-chaconine. The slower-moving isoenzyme bands were inhibited to 100 percent with the different concentrations of inhibitor. The fast migrating isoenzyme bands in plasma and erythrocytes were least affected by alpha-chaconine (10-4 M), with no inhibition. Plasma protein isoenzymes from adult male rats were not affected by alphachaconine.

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