Cationic liposomes/DNA complexes are widely used vectors for delivering genes in clinical and experimental trials. Relatively low transfer efficiencies in vivo compared with viral gene transfer may be improved using local application. In addition, markedly increased transfer efficiency may be achieved in vitro and in vivo via optimization of known variables influencing liposomal transfection. Lipofection under different conditions was performed in various cell lines and primary porcine smooth muscle cells. Optimized conditions found in vitro were verified in vivo using a porcine restenosis model. Toxicity was monitored analyzing cell metabolism. Transfer efficiency and safety were determined using morphometry, histology, galactosidase assays, PCR, and RT-PCR. The most important variables enabling maximum transfer efficiency were firstly the appropriate selection of cationic lipids for the cell type to be transfected, secondly the DNA/liposome ratio chosen, which depended on the cell type and cationic lipids used, and thirdly the state of proliferation of the targeted cells. Transfection in vivo demonstrated two- to fivefold higher transfer efficiencies when transfer conditions were extrapolated from optimization experiments in stationary cells compared with the use of conditions established in proliferating cells. Application of the therapeutic gene for cecropin using optimized transfer conditions resulted in a significantly reduced neointima formation compared with the transfection using a control gene for ss-galactosidase. Thus, in this vascular model, initial optimization of lipofection in stationary cells in culture followed by local delivery in vivo and with selection of a suitable therapeutic gene led to markedly improved transfer efficiencies, gene expression, and biological effect. Stationary cell cultures simulate more realistically the in vivo situation and may therefore represent a better model for future in vivo experiments. In addition, the advantages of liposomes are easy handling, low toxicity, and the lack of carcinogenicity or immunogenic reactions.
The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 ,ug/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after (3-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9,-8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18 Nakamura, Chem. Abstr. 107:236733v, 1987) and ciprofloxacin (4) were synthesized in our laboratory as reported previously. Doses and concentrations of the drugs are expressed in terms of the free bases.Animals. The animals used were male Std-ddY mice weighing 22 to 38 g, male Wistar rats weighing 190 to 270 g, male beagle dogs weighing 11 to 13 kg, and male cynomolgus monkeys weighing 3.7 to 5.4 kg.Drug administration. For oral administration, AT-4140 was suspended in 0.2% carboxymethylcellulose sodium solution (for mice and rats) or 0.5% gum tragacanth solution (for monkeys) and ciprofloxacin was dissolved in deionized water to avoid its aggregation in 0.2% carboxymethylcellulose sodium solution (for mice). Both the drugs were packed in gelatin capsules for oral administration to dogs. For intravenous administration, the drugs were dissolved in physiological saline with an appropriate amount of NaOH if necessary. The drugs were administered once at a dose of 5 mg/kg to animals that had fasted overnight, unless otherwise specified.Preparation of assay samples. Blood was withdrawn by cardiac puncture from mice and rats under ether anesthesia at 0.25, 0.5, 1, 2, 4, 6, and 8 h postadministration and by * Corresponding author.venipuncture from dogs and monkeys at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous administration. Blood samples were centrifuged to separate the plasma. Organs and tissues were harvested from exsanguinated mice 0.5, 1, 2, 4, 6, and 8 h postadministration and from exsanguinated rats 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postadministration. Spinal fluid was taken from the same rats by puncturing the atlanto-occipital membrane by the method of Yaksh and Rudy (17) before exsanguination. Tissue extracts were prepared as described previously (9). Bile was collected from rats through a polyethylene catheter introduced into the common bile duct by surgery and pooled for 0 to 3, 3 to 6, and 6 to 24...
Pipemidic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido [2,3- d ]pyrimidine-6-carboxylic acid, is a new derivative of piromidic acid. It is active against gram-negative bacteria including Pseudomonas aeruginosa as well as some gram-positive bacteria. Its potency is generally greater than that of piromidic acid and nalidixic acid. Cross-resistance is not observed between pipemidic acid and various antibiotics, and most of bacteria resistant to piromidic acid and nalidixic acid are moderately susceptible to pipemidic acid. The activity of pipemidic acid is scarcely affected by the addition of serum, sodium cholate, or change of medium pH, but is subject to the influence of inoculum size. Its action is bactericidal above minimal inhibitory concentrations.
Interleukin-1 alpha can accelerate the recovery of platelets after high-dose carboplatin therapy and may be clinically useful in preventing or treating thrombocytopenia induced by chemotherapy.
The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.