Effect of vitamin E and vitamin C combination on experimental influenza virus infection.

Successful antioxidant treatment of the so-called "free radical diseases" has been reported in the literature. In this study we examined the preventive effect of vitamin E and vitamin C, alone and in combination, on the damage caused by influenza virus infection (IVI). Male mice (ICR), infected with influenza virus A/2/68/(H3N2) (1.5 of LD(50)), were administered single once-daily doses of vitamin E (60 mg/kg b.w.) and vitamin C (80 mg/kg b.w.) intraperitoneally (3 days before virus inoculation). On the 5th and 7th day, respectively, after virus inoculation, animals were decapitated. Monooxygenase enzyme activity (ethylmorphine N-demethylase, amidopyrin N-demethylase, analgin N-demethylase, aniline hydroxylase, cytochrome P-450 content and NADPH-cytochrome C reductase [CCR]) was determined in liver 9000 x g supernatant. Primary and secondary products of lipid peroxidation (LPO; conjugated dienes [CD] and TBA-reactive substances) were measured in blood plasma, lung and liver 9000 x g supernatant. Vitamin E effectively restored LPO-levels increased by IVI. The effect of vitamin C was similar, but slighter. The combination (vitamin E + C) had greater effect on LPO levels than their separate administration. P-450-dependent monooxygenase activity was significantly restored and more pronounced cytochrome P-450 content and NADPH-CCR activity was noted. The preventive effect of vitamin E was stronger than the effect of vitamin C, but the combination (vitamin E + C) had the strongest effect. The superior protective effect of the combination is probably due to vitamin C's repairing effect on vitamin E's tocopheroxyl radical.

Antioxidant properties of rimantadine in influenza virus infected mice and in some model systems.

Influenza virus infection is associated with development of oxidative stress in lung and blood plasma, viz. increase of primary and secondary lipid peroxidation products. It was established that rimantadine treatment led to a decrease of the products of lipid peroxidation in tissues of mice experimentally infected with influenza virus A/Aichi/2/68 (H3N2). The effect is strongest in blood plasma (a decrease of about 50%) and weaker in the lung (about 20%). To elucidate the mechanism of this action of rimantadine, experiments were carried out with some model systems. The capability of rimantadine to scavenge superoxide radicals (scavenging properties) was studied in a system of xanthine-xanthine oxidase to generate superoxide. The amount of superoxide was measured spectrophotometrically by the NBT-test and chemiluminesce. Rimantadine does not show scavenging properties and its antioxidant effect observed in vivo, is not a result of its direct action on the processes of lipid peroxidation and/or interaction with antioxidant enzymes. The antioxidant properties of rimantadine were investigated by measurement of induced lipid peroxidation in a Fe2+ and (Fe2+ - EDTA) system with an egg liposomal suspension. Our findings with model systems do not prove an antioxidant or prooxidant effect of the drug on the processes of lipid peroxidation. Apparently, the observed antioxidant effect of rimantadine in vivo is not connected directly with free radical processes in the organism.

Interaction of dexamethasone with acetylsalicylic acid in mice.

The effect of acetylsalicylic acid (ASA, 160 mg/kg b.wt.) and dexamethasone (DEX, 15 mg/kg b.wt.) on ASA antinociception and toxicity when administered orally alone or in combination for 4 consecutive days was studied in male albino mice. ASA antinociception decreased after repeated ASA administration. Bleeding time was prolonged and the intestinal ASA esterase activity was increased, which was probably related to the increased ASA general toxicity in ASA-treated animals. There were no changes in the blood alkaline content, in the ulcerogenic or hepatotoxic effect of ASA, nor in the hepatic monooxygenase activity (ethylmorphine N-demethylase and aniline hydroxylase and the cytochrome P450 and b-5 content). DEX administered alone exerted a significant antinociceptive effect, increased both acute ASA toxicity and aniline hydroxylase activity and decreased body growth. However, DEX did not change the bleeding time, the alkaline blood content nor the intestinal esterase activity. The combination of ASA and DEX did not increase the ASA antinociceptive effect nor the general and specific toxicity of ASA. DEX in combination even abolished the effect of ASA on intestinal ASA esterase and on bleeding time. DEX also increased the hepatic cytochrome P450 content and did not change the ulcerogenic effect of ASA nor the alkaline blood content.

Influence of hydrocortisone on the analgesic effect, toxicity and metabolism of aspirin in mice.

1. Hydrocortisone (HC; 80 mg/kg body weight, intraperitoneally for 4 days), both alone and in combination with acetylsalicylic acid (ASA; 160 mg/kg body weight, orally, for 4 days), decreased ASA general and specific toxicity via metabolic modulation of drug-metabolizing enzyme systems (intestinal ASA-esterase and hepatic UDP-glucuronyltransferase) and did not change the ASA analgesic effect. 2. ASA alone, given 4 for days, did not change the specific ASA toxicity, but increased its general acute toxicity, which was probably due to alterations in some intestinal and hepatic metabolizing enzyme systems.

Toxicity and enzyme-inducing effect of the antiviral compound mopyridone in mice.

Mopyridone (CAS 82822-14-8, MP) is a new antiviral compound with low acute toxicity in mice. Phenobarbital (PB) induction did not alter MP oral acute toxicity, while methylcholanthrene (MC) and dexamethasone (DEX) induction increased it. MP (1/10 of LD50, 5 days) increased aniline hydroxylase activity (by 158%) and cytochrome P-450 content (by 43%), but has no significant effect on liver N-demethylase activity (ethylmorphine N-demethylase, amidopyrine N-demethylase and benzphetamine N-demethylase) in mouse liver 10,000 x g supernatant. The inducing effect of MP was similar to the effect of MC and differed from the effect of PB. The combination MP + PB exerted an additive inducing effect on aniline hydroxylase (by 390%) and cytochrome P-450 content (by 183%) without affecting PB induced N-demethylases. The character of the MP + PB interaction was similar to that of the MC + PB interaction and suggested different inducing mechanisms of MP and PB. The participation of some cytochrome P-450 isozymes, induced by MC and DEX, in biotransformation of MP to more toxic product(s) was suggested.

Effects of acetysal, dexamethasone and their combination on drug metabolizing enzyme systems in rat liver microsomes.

After 4 days of acetysal treatment (160 mg/kg body weight orally), the following were established: a higher acute toxicity of acetysal, an inducing effect on amidopyrin N-demethylase and analgin N-demethylase activity and increases in cytochrome P-450 and cytochrome b5 content. Aniline hydroxylase activity decreased, thiopental sleeping time was prolonged and UDP-glucuronyltransferase activity was not changed. Dexamethasone, at a dose of 5 mg/kg body weight p.o. for 4 days, did not change acetysal acute toxicity but at a dose of 100 mg/kg i.p. increased it. Thiopental sleeping time was shortened by dexamethasone (100 mg/kg i.p.) but was not changed by dexamethasone at 5 mg/kg p.o., alone or in combination. Dexamethasone at 5 mg/kg increased analgin N-demethylase and UDP-glucuronyltransferase activities, did not change cytochrome P-450 content and decreased aniline hydroxylase activity. The combination with 5 mg/kg dexamethasone increased the activity of amidopyrin N-demethylase, analgin N-demethylase and UDP-glucuronyltransferase and decreased those of amitriptyllin N-demethylase and aniline hydroxylase and cytochrome P-450 content. Ethylmorphine N-demethylase, benzphetamine N-demethylase, NADPH-cytochrome c reductase and glutathione S-transferase activities were not affected significantly by acetysal, dexamethasone or their combination. Hepatic carboxyl esterase was depressed by dexamethasone (5 mg/kg) and was increased by the combination. Lipid peroxidation was not changed by dexamethasone (5 mg/kg) but was decreased by acetysal and the combination.

Acute toxicity and effects on hepatic oxidative drug metabolism of mopyridone.

Mopyridone (CAS 82822-14-8) is a new chemotherapeutic with a strong antiviral effect (vs. influenza- and toga viruses) and certain advantages over the chemotherapeutics known so far. Toxicological studies reveal its low oral and intraperitoneal toxicity in mice and rats. The 5- and 14-day administration of mopyridone (37.5 mg/kg b.w., orally) to male rats established a growing tendency to the shortening of hexobarbital sleeping time, associated with moderate changes in the hepatic oxidase activity on the 15th day, most pronounced for amidopyrine N-demethylase (by 37%) and less for benzphetamine N-demethylase (by 17%). Aniline hydroxylase activity was slightly diminished (by 18% and 16%, resp.). No significant changes in the components of the electron-transport chain of cytochrome P-450 were established--the content of cytochrome P-450, cytochrome b-5 and cytochrome C reductase, both after 5- and 14-day mopyridone administration.

Effect of desoxycorticosterone on the activity of drug-metabolizing enzyme systems.

Single administration of desoxycorticosterone acetate (DOCA) in a dose of 50 mg/kg body mass intramuscularly in male Wistar rats revealed dose-dependent potentiation of hexobarbital sleeping time and inhibition of the activity of the oxidases with mixed functions in substrates of types I (hexobarbital, ethylmorphine) and II (aniline), although this is not accompanied by changes in the components of the electron-transport chain. It is assumed that DOCA may possibly inhibit the metabolism of the above mentioned substrates, being an alternative substrate of oxidases with mixed functions. In an acute experiment DOCA does not influence the activity of esterases (liver esterase A and intestinal esterase B), but the compound has an inhibitory effect on some synthetase reactions--cytosol glutathione-S-transferase. Repeated administration of DOCA for 3-27 days in doses of 10 and 20 mg/kg i.m. does not have an enzyme-inducing effect. There are no significant changes in the oxidases with mixed functions and in the content of cytochrome P-450. The effects of DOCA on drug metabolism after a single and after repeated application are compared with the effects of hydrocortisone.