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Free radicals, hydroxyperoxides and H 2 O 2 are all known to damage cell components. This study was designed to compare the concentrations of hydroxyperoxide and free radical scavengers in the cardiac muscles of old rats in the hyper-or hypothyroid condition, to determine whether rates of peroxidation would differ with age, thyroid status, or both.Rats were rendered hyper-or hypothyroid by administration of -thyroxine or methimazole for 4 weeks. Among the old rats, the lipid peroxide (LPO) concentrations, measured as thiobarbituric acid (TBA) reactants, were significantly greater in the hyperthyroid than in the euthyroid state and the LPO concentrations measured as TBA+Fe 3+ reactants, which may be precursors of LPO, were significantly greater in the hyperthyroid state, whereas in young rats, the LPO concentrations measured by TBA or TBA+Fe 3+ methods did not differ significantly in the hyperthyroid state. In the euthyroid state, the concentration of LPO measured as TBA+Fe 3+ reactants was significantly reduced with age. Xanthine oxidase (XOD) activity also was markedly increased with age, being more pronounced in the hyperthyroid than in the euthyroid state. The Mn and Cu/Zn superoxide dismutase activities were greater in the hyperthyroid than in the euthyroid state. Glutathione peroxidase activity decreased with age in the euthyroid and, particularly, in the hyperthyroid state. Catalase activity was not affected in the old rats. Concentrations of -tocopherol in the old rats were high in the hyperthyroid state and low in the hypothyroid state, whereas the levels of -and -tocopherols in these rats were unchanged in both conditions as compared with the euthyroid state findings.Data suggest that the site of free radical generation differs in older rats, with additional shifts in the location of intracellular lipid peroxidation being noted during hyperthyroidism. Thus, as rats age, the reduction of the free radical scavenger system and the increase in LPO and XOD activities might induce myocardial dysfunction.

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The therapeutic effect of cefozopran (SCE-2787), a new semisynthetic parenteral cephalosporin, against experimental infections in mice was examined. Cefozopran was more effective than cefpiramide and was as effective as ceftazidime and cefpirome against acute respiratory tract infections caused by Kiebsiella pneumoniae DT-S. In the model of chronic respiratory tract infection caused by K. pneumoniae 27, cefozopran was as effective as ceftazidime. The therapeutic effect of cefozopran against urinary tract infections caused by Pseudomonas aeruginosa P9 was superior to that of cefpirome and was equal to those of ceftazidime and cefclidin. In addition, cefozopran was more effective than ceftazidime and was as effective as flomoxef in a thigh muscle infection caused by methicillin-sensitive Staphylococcus aureus 308A-1. Against thigh muscle infections caused by methicillin-resistant S. aureus N133, cefozopran was the most effective agent. The potent therapeutic effect of cefozopran in those experimental infections in mice suggests that it would be effective against respiratory tract, urinary tract, and soft tissue infections caused by a variety of gram-positive and gram-negative bacteria in humans.The search for new drugs effective as antibacterial agents requires the thorough evaluation of drugs not only in vitro but also in vivo (i.e., in the control and management of experimental infections). Systemic infections induced by an intraperitoneal injection of a bacterial suspension have been commonly used for the evaluation of new antibiotics. Such infections, however, are not always representative of infectious diseases in humans. It is therefore important to evaluate antibiotics by using animal models of infection which more closely mimic the actual situation in humans.This paper deals with the in vivo evaluation of cefozo- (Fig. 1), cefpirome, and cefclidin were prepared in the Research and Develop-* Corresponding author. ment Division of Takeda Chemical Industries, Ltd. Ceftazidime (Nippon Glaxo Co., Ltd., Tokyo, Japan), cefpiramide (Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan), and flomoxef (Shionogi & Co., Ltd., Osaka, Japan) were obtained commercially. MICs of each antibiotic were determined by an agar dilution method using an inoculum of ca.104 CFU and are shown in each table.Experimental infections and antibiotic treatment. (i) Respiratory tract infection. Acute respiratory tract infection caused by K pneumoniae DT-S was induced as described previously (19). Briefly, K pneumoniae DT-S was grown overnight at 37°C in brain heart infusion broth (Difco Laboratories, Detroit, Mich.), and cells were collected by centrifugation, washed with phosphate-buffered saline (Dulbecco formula [modified] without magnesium and calcium; Flow Laboratories, Inc., McLean, Va.), and suspended in the same buffered saline to give a suspension of ca. 109 CFU/ml. The bacterial suspension was placed in a nebulizer (Vaponefrin pocket nebulizer; USV Pharmaceutical Co., Tuckahoe, N.Y.) and aerosolized at a pressure of 1.2 kg/cm2 for ...

Clinical and experimental data suggest that thyroid hormone affects the actions of catecholamine (CA). However, the serum or tissue levels of CA during thyroid disorders have not been well defined. Accordingly, we investigated the levels of CA and their metabolites in the cardiac muscle, the cerebral cortex, and the plasma of rats with hyperthyroidism and hypothyroidism versus euthyroid animals. The Neurochem analyzer system (ESA, Inc., Bedford, MA) was used in such determinations. The cardiac muscles of hyperthyroid rats exhibited a 16% decrease in the levels of 1-dopa, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) as compared with those in euthyroid rats. The levels of norepinephrine (NE) in cardiac muscle of these rats increased significantly (5.2-fold) relative to the levels in euthyroid rats. NE was undetectable in the cardiac muscles of the hypothyroid rats. Epinephrine (E) and dopamine (DA) were not detected in the cardiac muscles of the rats with either thyroid disorder. Levels of E and 3,4-dihydroxymandelic acid (DOPEG) were detected only in the cerebral cortex of hyperthyroid rats. The cerebral cortex levels of 3-methyoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), metanephrine (MN), and homovanillic acid (HVA) were all significantly increased in the hyperthyroid versus the euthyroid rats. The cerebral cortex levels of DA, NE, normetanephrine (NMN), and VMA in the hyperthyroid rats all showed a significant decrease. Levels of NE, NMN, and DOPAC in the cerebral cortex increased significantly in the hypothyroid rats. The level of VMA was undetectable in cerebral cortex of such animals. Data from studies on cardiac muscle and cerebral cortex indicate that the changes in CA and CA metabolites are responsible in part for the cardiovascular and the central nervous system symptoms observed in hyperthyroidism and hypothyroidism.