monensin and tiamulin

Tiamulin, a diterpene antibiotic, is used for treatment of pulmonary and gastrointestinal infections in swine and poultry. Combined administration of tiamulin and ionophores (e.g. monensin) to farm animals may lead to intoxication manifested in severe clinical symptoms. Tiamulin metabolite complex with cytochrome P450 has been suggested to be the basis of drug-interactions. However, the formation of metabolic intermediate complex is questionable. The effect of tiamulin-treatment on cytochrome P450 activities was investigated in rats. Ethylmorphine and aminopyrine N-demethylation activities as well as monensin metabolism (O-demethylation) increased in liver microsomes of tiamulin-treated (200 mg/kg) animals. CYP3A1 induction caused by tiamulin was confirmed by the results of Western blot analysis. To test metabolic intermediate complex formation as a result of tiamulin treatment, cytochrome P450 activities were also determined in the presence of potassium ferricyanide. The findings together with those of in vitro complex formation suggested that formation of metabolic intermediate complexes of tiamulin with cytochrome P450 could be excluded. On the other hand, the results of inhibition studies showed significant decrease of ethylmorphine or aminopyrine as well as monensin demethylation in the presence of tiamulin. Our results proved that tiamulin has dual effect on cytochromes P450. It is able to induce and directly inhibit CYP3A enzymes, which are predominantly responsible for monensin O-demethylation. The direct effect of tiamulin as an inhibitor might play a more important role in toxicity than its putative effect as a chemical inducer of CYP3A enzymes.

Topics: Administration, Oral; Aminopyrine; Animals; Anti-Bacterial Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Dexamethasone; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Induction; Ethylmorphine; Female; Ionophores; Male; Microsomes, Liver; Monensin; Oxidoreductases, N-Demethylating; Phenobarbital; Rats; Troleandomycin

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart; Liver; Male; Monensin; Muscle, Skeletal; Rats

The characteristics of the toxic interaction between monensin and tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin and tiamulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg and tiamulin 40 mg/kg b.w., respectively). Monensin proved to be toxic to rats at doses of 30 and 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined administration, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect and vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous administration of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium and vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the administration of 50 mg/kg monensin alone.

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Female; Liver; Male; Monensin; Muscle, Skeletal; Rats

Studies were carried out to investigate the effects of monensin and tiamulin, and the simultaneous administration of both compounds on microsomal enzymes in rats. In Phase I of the experiments the effects of monensin and tiamulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively), while in Phase II the two compounds were administered simultaneously (monesin 10 mg/kg and tiamulin 40 mg/kg b.w., respectively). When monensin was administered by itself, it exerted no significant effect on microsomal liver enzymes. In a few cases, slight inhibition of certain enzyme activities was seen. Tiamulin provoked a dose-dependent hepatic enzyme induction. The combined administration of monensin and tiamulin at low doses (10 and 40 mg/kg, respectively) resulted in marked elevation of P450-related enzyme activities. The enzyme induction was more pronounced in females than in males. The results suggest that the simultaneous administration of tiamulin may influence the biotransformation of monensin, possibly increasing the amount of reactive metabolite(s) of the ionophore antibiotic.

Topics: Animals; Anti-Bacterial Agents; Body Weight; Cytochrome P-450 Enzyme System; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Induction; Female; Ionophores; Male; Microsomes, Liver; Monensin; Organ Size; Rats

Monensin (MON) is an ionophore antibiotic widely used in veterinary practice as a coccidiostatic or a growth promoter. The aims of this study were to characterize the P-450 isoenzyme(s) involved in the biotransformation of the ionophore and to investigate how this process may be affected by tiamulin and other chemotherapeutic agents known to produce toxic interactions with MON when administered concurrently in vivo. In liver microsomes from untreated rats (UT) or from rats pretreated, respectively, with ethanol (ETOH), beta-naphthoflavone (betaNAF), phenobarbital (PB), pregnenolone 16alpha-carbonitrile (PCN), or dexamethasone (DEX), the rate of MON O-demethylation was the following: DEX > PCN > PB >> UT = ETOH > betaNAF; similar results were obtained by measuring total MON metabolism. In addition, the extent of triacetyloleandomycin-mediated P-450 complexes was greatly reduced by the prior addition of 100 microM MON. In DEX-treated microsomes, MON O-demethylation was found to fit monophasic Michaelis-Menten kinetics (K(M) = 67.6 +/- 0.01 microM; V(max) = 4.75 +/- 0.76 nmol/min/mg protein). Tiamulin markedly inhibited this activity in an apparent competitive manner, with a calculated K(i) (Dixon plot) of 8.2 microM and an IC(50) of about 25 microM. At the latter concentration, only ketoconazole or metyrapone, which can bind P-450 3A, inhibited MON O-demethylase to a greater extent than tiamulin, whereas alpha-naphthoflavone, chloramphenicol, or sulphametasine was less effective. These results suggest that P-450 3A plays an important role in the oxidative metabolism of MON and that compounds capable of binding or inhibiting this isoenzyme could be expected to give rise to toxic interactions with the ionophore.

Topics: Animals; Antifungal Agents; Antineoplastic Agents; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dealkylation; Diterpenes; Drug Interactions; Enzyme Induction; In Vitro Techniques; Kinetics; Male; Microsomes, Liver; Monensin; Oxidation-Reduction; Oxidoreductases, N-Demethylating; Rats; Rats, Wistar

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Chickens; Coccidiostats; Cytochrome P-450 Enzyme System; Diterpenes; Drug Combinations; Enzyme Induction; Female; Liver; Male; Microsomes, Liver; Monensin; Species Specificity; Turkeys

The sensitivity of 332 strains of Serpulina hyodysenteriae isolated in Hungary between 1978 and 1992 was tested against seven chemotherapeutic drugs frequently used for the treatment of swine dysentery, and the changes in the patterns of resistance were also monitored. All the strains remained sensitive to carbadox, with minimum inhibitory concentrations (MIC) of only 0.05 to 0.40 microgram/ml at present. The susceptibility of the strains to dimetridazole has gradually decreased, but about half of the strains are still sensitive, with large numbers of "moderately sensitive' strains; the MIC values varied within wide limits (0.1 to 50 micrograms/ml). Most of the strains were resistant to tylosin, with MIC values from 0.1 to 100 micrograms/ml. The number of strains resistant to lincomycin has gradually increased, but about half of the strains remain sensitive; the MIC values ranged from 0.2 to 100 micrograms/ml. Recently, tiamulin has proved the most effective antibiotic, but some resistant strains have already emerged (MIC values 0.05 to 50 micrograms/ml). Monensin was good for the prevention of swine dysentery, but resistance may evolve quickly; the MIC values ranged from 0.4 to 25 micrograms/ml. For sedecamycin, the MIC values (6.25 to 100 micrograms/ml) were much higher than expected.

Topics: Animals; Anti-Bacterial Agents; Brachyspira hyodysenteriae; Carbadox; Dimetridazole; Diterpenes; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Dysentery; Hungary; Lincomycin; Macrolides; Microbial Sensitivity Tests; Monensin; Spirochaetales Infections; Swine; Swine Diseases; Tylosin

The effect exerted by the simultaneous administration of tiamulin (40 mg/kg body mass) and a lowered dose (12 mg/kg of feed) of monensin combined with the antioxidant duokvin on the conductivity of peripheral nerve and the electrophysiological function of the heart was studied in two trials comprising 3 x 6 broiler chickens. For the study of peripheral nerve function, chickens were anaesthetized with pentobarbital sodium, the sciatic nerve (n. ischiadicus) was exposed in the sciatic arc, and bipolar stimulating and efferent electrodes were inserted directly beside the nerve, at an average distance of 20 mm from each other. For the recordings, the nerve was stimulated with 16 supramaximal impulses of 0.02 ms duration, applied at 15-s intervals. The responses given to the stimulus were recorded with the help of a polygraph and evaluated with a computer in online mode. For the study of cardiac function, the chickens were anaesthetized with methomidate. The electrocardiograms were taken in Einthoven's lead II with the help of needle electrodes, and then evaluated with computer in online mode. In control chickens, maximum conduction velocity was 30.70 +/- 0.52 m/s on the average. That value did not change after a single treatment with monensin-duokvin + tiamulin, while it underwent a slight but statistically significant decrease after two treatments. Studies on the electrical function of the heart revealed no signs of dysfunction in either of the treated groups as compared to the control.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Chickens; Coccidiostats; Diterpenes; Drug Combinations; Drug Synergism; Heart; Ionophores; Monensin; Peripheral Nervous System; Quinolines

The influence of the simultaneous administration of monensin and tiamulin on the motor nerve conduction velocity and the refractory periods of the N. ischiadicus was studied on 4-week old cockerels. The combined administration of the two substances resulted in significant decrease of the conduction velocities of the peripheral nerve, while the relative and absolute refractory periods were seen to increase significantly as a result of the medications. The observed alteration of the peripheral nerve function in the early phase can already attribute to the development of the serious clinical signs of the toxic interaction. The simultaneous application of monensin and tiamulin caused also changes in the electrocardiogram which was expressed in a prolongation of the RS interval and the ST segment. At the same time the heart rate was reduced.

Topics: Animals; Anti-Bacterial Agents; Chickens; Diterpenes; Drug Interactions; Electrocardiography; Male; Monensin; Peripheral Nerves

The influence of Monensin, Tiamulin and the simultaneous administration of the two substances on the microsomal, mixed function oxidases was studied on cockerels. Monensin was seen to cause a slight depression in the amount of cytochrome P-450 and cytochrome b5 as well as in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and p-nitroanisole-O-demethylase. Tiamulin induced a moderate increase in the amount of cytochrome P-450 and in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and aminopyrine-N-demethylase. The combined administration of monensin and tiamulin resulted in marked induction of the microsomal enzymes; the amount of cytochrome P-450 reduced by metyrapone or carbon monoxide increased 2.5 or 2-times, respectively, and the activities of the tested microsomal hydroxylases and demethylases showed also an expressed increase. At the same time the formation of lipid peroxides also markedly increased and the GSH concentration was reduced. In conclusion, the results of the investigations indicate that the simultaneous application of monensin and tiamulin cause a marked induction of the drug-metabolizing microsomal enzymes and a significant increase in the lipid peroxide formation.

Topics: Animals; Anti-Bacterial Agents; Chickens; Diterpenes; Drug Interactions; Lipid Peroxides; Male; Microsomes; Mixed Function Oxygenases; Monensin

The anti-mycoplasma effects of the ionophores (lasalocid sodium, monensin and nigericin) were compared with that of tylosin tartrate and tiamulin in vitro. Forty-four strains representing 14 avian and 10 mammalian Mycoplasma species and serotypes and 5 Acholeplasma species were tested. The ionophores showed average minimal inhibitory concentration (MIC) values between 3.65 and 4.93 micrograms ml-1 for all strains, the MIC values for glucose-fermenting strains were between 2.26 and 3.75 micrograms ml-1, significantly lower than for arginine-hydrolysing strains (9.27-13.12 micrograms ml-1). These values were significantly higher than those obtained with tylosin tartrate (0.45 micrograms ml-1) or tiamulin (0.13 micrograms ml-1). The ionophores were more efficacious against acholeplasmas (0.06-0.25 micrograms ml-1) than against mycoplasmas.

Topics: Acholeplasma; Animals; Anti-Bacterial Agents; Coccidiostats; Diterpenes; Ionophores; Lasalocid; Leucomycins; Microbial Sensitivity Tests; Monensin; Mycoplasma; Nigericin; Tylosin

Modulation of acute monensin toxicosis in swine was evaluated in 2 studies. In study 1, 56 weanling male pigs were allotted to 14 groups of 4 each. Pigs in 7 groups were given tiamulin in the drinking water (to supply 7.7 mg/kg of body weight/day) for 3 days before and for 2 days after monensin administration. Monensin was given as a single oral dose (at 0, 7.5, 15, 25, 50, 75, or 100 mg/kg) to pigs in groups with or without tiamulin exposure. Prominent acute clinical signs of monensin toxicosis (hypermetria, hind limb ataxia, paresis, knuckling of hind limbs, and recumbency) developed by 2 to 6 hours after dosing in pigs given 15 or 25 mg of monensin/kg with tiamulin exposure, but not in pigs given the 15 or 25 mg of monensin/kg without tiamulin exposure. Also, the extent of monensin-induced skeletal muscle damage at 4 days after monensin dosing was enhanced in pigs given 7.5, 15, or 25 mg of monensin/kg and exposed to tiamulin. In study 2, 48 weanling male pigs were allotted to 8 groups of 6 each. Four groups of pigs were given 20 mg of monensin/kg orally, and 4 groups were given 100 mg of monensin/kg orally. For each monensin dose, a group was treated 24 hours before monensin administration with (i) selenium (Se)-vitamin E preparation, 0.25 mg of Se and 68 IU of d-alpha-tocopheryl acetate (vitamin E)/kg, IM; (ii) vitamin E only, 68 IU of d-alpha-tocopheryl acetate/kg; (iii) Se only, 0.25 mg of Se/kg; or (iv) vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Synergism; Male; Monensin; Selenium; Swine; Swine Diseases; Vitamin E

Simultaneous administration of monensin and tiamulin to pigs resulted in enhanced myotoxicity. Skeletal muscles of tongue, diaphragm and legs were preferentially affected, whereas the masseter, longissimus thoracis and cardiac muscles, including the left auricle, were spared. Histochemical examination revealed an involvement of both type I and II fibers of skeletal muscles.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Synergism; Food Additives; Furans; Histocytochemistry; Male; Monensin; Muscles; Muscular Diseases; Swine; Swine Diseases; Weaning

Healthy turkeys receiving 80 ppm monensin in their feed were injected at 26, 40 and 61 days of age with tiamulin at dosages of 12.5 and 25 mg/kg body weight. The aim of the study was to develop a regime for medicating with tiamulin turkeys receiving monensin in their feed, and which would circumvent the known toxicity created by the simultaneous administration of the two drugs. One injection of 12.5 mg/kg tiamulin up to the age of 61 days or 2 injections of 12.5 mg/kg tiamulin up to 40 days of age caused no mortality or adverse reaction.

Topics: Age Factors; Animal Feed; Animals; Anti-Bacterial Agents; Diterpenes; Drug Synergism; Furans; Growth Disorders; Injections, Intramuscular; Male; Monensin; Mycoplasma Infections; Poultry Diseases; Turkeys; Water

Topics: Animals; Anti-Bacterial Agents; Body Weight; Chickens; Diterpenes; Drug Interactions; Drug Tolerance; Electrolytes; Feeding Behavior; Furans; Monensin

Topics: Animal Feed; Animals; Diterpenes; Drug Interactions; Furans; Monensin; Swine; Swine Diseases

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Interactions; Female; Furans; Male; Monensin; Muscular Diseases; Swine; Swine Diseases

Topics: Animals; Chickens; Diterpenes; Drug Interactions; Furans; Monensin; Poultry Diseases

The anticoccidial activities of monensin and lasalocid have been studied separately and in combination with tiamulin, a new pleuromutilin derivative. Combinations of constant tiamulin concentration (.0125%) in drinking water with various levels of polyether anticoccidials (6.3 to 125 ppm) in feed and conversely of constant levels of anticoccidials with various concentrations of tiamulin were used. The prophylactic efficacy of these combined treatments in battery raised broiler chickens infected with Eimeria tenella was evaluated. Assessment of the parameters mortality, weight gain, dropping scores, lesion scores, and oocyst output showed that simultaneous application of tiamulin significantly improved the anticoccidial activity of the polyethers. As tiamulin alone is without anticoccidial activity, this phenomenon was considered to result from an interaction between tiamulin and the polyethers leading to a slower metabolic degradation of the latter. Thus tissue levels adequate for maximum anticoccidial activity would be attained with lower polyether dose levels. Experiments using isolated perfused rat liver showed that elimination of monensin was reduced by 60% in the presence of tiamulin.

Topics: Animals; Anti-Bacterial Agents; Chickens; Coccidiosis; Coccidiostats; Diterpenes; Drug Synergism; Drug Therapy, Combination; Female; In Vitro Techniques; Lasalocid; Liver; Monensin; Poultry Diseases; Rats