Pharmacokinetic profiles of the active metamizole metabolites in healthy horses

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among other secondary metabolites, 4-aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 9 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (Cmax), time to maximum concentration (Tmax) and AUMC0-last of MAA were statistically different between the i.v. and i.m. groups. The AUCIM/AUCIV ratio of MAA was 1.06. In contrast, AUC0-last of AA was statistically different between the groups (P < 0.05) with an AUCIM/AUCIV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug

PHARMACOKINETIC ASSESSMENT OF THE MARKER ACTIVE METABOLITES 4-METHYLAMINO-ANTIPYRIN AND 4-ACETYLAMINO-ANTIPYRINE AFTER INTRAVENOUS AND INTRAMUSCULAR INJECTION OF METAMIZOLE IN HEALTHY HORSES

Objective: Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine, and dogs. MT is rapidly hydrolyzed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared to other minor metabolites. Among the others secondary metabolites also 4-aminoantipyrine (AA) results also active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after 25 mg/kg MT by intravenous (IV) and intramuscular (IM) administrations in healthy horses. Materials & Methods: Six healthy racehorses, aged 9 to 13 years and weighing 480 to 590 kg, were randomly allocated to two equal treatment groups according to a 2x2 crossover study. Blood was collected at predetermined times within 24 h and plasma was analysed by a validated HPLC UV method. No behavioural changes or alterations in health parameters were observed in the IV or IM groups of animals during or after (up to 7 days) the drug administration. Results & Conclusion: Plasma concentrations of MAA after IV and IM administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time of that found for MAA, but in smaller amount. Maximum concentration (Cmax), time to maximum concentration (Tmax) and AUMC 0-last of MAA were statistically different between IV and IM group (P<0.01). The AUCIM/AUCIV ratio of MAA was 1.06. Differently, AUC 0-last of AA was statistically different between the groups (P<0.05) with a AUCIM/AUCIV ratio of 0.54. The present study showed that no relevant difference in the MAA plasma concentration was found after IM and IV administration of MT

Individual and combined mycotoxins deoxynivalenol, nivalenol, and fusarenon-X induced apoptosis in lymphoid tissues of mice after oral exposure

Lymphocytes are involved in the adaptive immune response and are highly sensitive to type B trichothecenes. In grains and their products, deoxynivalenol (DON)is the most widely distributed trichothecene. It usually co-occurs with other type B members, such as nivalenol (NIV)and fusarenon-X (FX), because they are all produced by the same Fusarium fungi. However, the combined effects of mycotoxins are complex and cannot be predicted based on individual toxicity. Thus, the adverse effects of combined toxins are of increasing concern. The aim of this study was to compare the toxicity to lymphoid tissues of mice of DON alone or mixed with NIV or FX. Forty, 3-week-old male ICR mice were given a single oral administration of a vehicle control, one toxin, binary, or ternary mixtures and then sacrificed at 12 h after exposure. Mice treated with FX alone showed marked nuclear condensation and fragmentation of lymphocytes in the cortical thymus and germinal center of Peyer's patches and spleen. Similarly, these animals clearly displayed TUNEL- and Caspase-3-positive cells in the regions. In contrast, minimal changes were noticed in the lymphoid tissues of mice receiving combined toxins when compared to this toxin alone. In addition, oral exposure to FX alone significantly up-regulated the relative expression of Bax, Caspase-3, Caspase-9, and Trp53. These data increase our understanding of the toxic actions of DON, NIV, and FX alone or in combination to lymphocytes and can be used to assess the possible risk associated with their co-occurrences in foodstuffs to human and animal health