Comparative study on the metabolism of the ergot alkaloids ergocristine, ergocryptine, ergotamine, and ergovaline in equine and human S9 fractions and equine liver preparations.

1. Ergopeptine alkaloids like ergovaline and ergotamine are suspected to be associated with fescue toxicosis and ergotism in horses. Information on the metabolism of ergot alkaloids is scarce, especially in horses, but needed for toxicological analysis of these drugs in urine/feces of affected horses. The aim of this study was to investigate the metabolism of ergovaline, ergotamine, ergocristine, and ergocryptine in horses and comparison to humans. 2. Supernatants of alkaloid incubations with equine and human liver S9 fractions were analyzed by reversed-phase liquid-chromatography coupled to high-resolution tandem mass spectrometry with full scan and MS2 acquisition. Metabolite structures were postulated based on their MS2 spectra in comparison to those of the parent alkaloids. All compounds were extensively metabolized yielding nor-, N-oxide, hydroxy and dihydro-diole metabolites with largely overlapping patterns in equine and human liver S9 fractions. However, some metabolic steps e.g. the formation of 8'-hydroxy metabolites were unique for human metabolism, while formation of the 13/14-hydroxy and 13,14-dihydro-diol metabolites were unique for equine metabolism. Incubations with equine whole liver preparations yielded less metabolites than the S9 fractions. 3. The acquired data can be used to develop metabolite-based screenings for these alkaloids, which will likely extend their detection windows in urine/feces from affected horses.

Toxicokinetics of ergovaline in the horse after an intravenous administration.

The toxicokinetics of ergovaline (an ergopeptine mycotoxin present in some grasses infected with endophytic fungus of the genus Neotyphodium) were studied after intravenous administration of a single dose of 15 microg/kg bwt in four gelding horses. Plasma ergovaline concentrations were measured by high performance liquid chromatography, and the kinetic data were described by a three-compartment model. The elimination half-life and the total clearance of ergovaline were found to be 56.83 +/- 13.48 min and 0.020 +/- 0.004 L/min x kg, respectively. According to the toxicological data previously reported in the horse, and in spite of the very low dose administered, clinical signs were observed, including excessive coolness of the ears and the nose, excessive sweating and prostration.

Rapid analysis of ergovaline in ovine plasma using high-performance liquid chromatography with fluorimetric detection.

A rapid high-performance liquid chromatographic method for the determination of the mycotoxin ergovaline in ovine plasma is described here. Ergotamine was used as an internal standard. A simple extraction procedure with diethyloxide was carried out, before chromatography on a C8 column, with the excitation and emission wavelengths fixed at 250 and 420 nm respectively, on a fluorimetric detector. The method, which was found to be linear between 3.5 and 15 ng/ml, had good specificity, precision and accuracy. The limit of quantification and the limit of detection were 3.5 and 1.2 ng/ml, respectively. A preliminary application of the described assay to a plasma kinetic study, after intravenous administration of a single dose of ergovaline (17 micrograms/kg body mass) to four sheep, showed a very rapid decrease of the plasma ergovaline levels. The terminal half-life and the total clearance of the mycotoxin were found to be 23.6 min and 0.020 l/min kg-1 body mass, respectively.

[Drug treatment of migraine attacks. Pharmacological considerations]. / Medikamentell behandling av migreneanfall. Farmakologiske betraktninger.

In the 1990s, the Decade of the Brain, significant progress has been made in our understanding of the pathophysiological events that take place during a migraine attack. Simultaneously, a big step forward has been made as regards drug therapy. The development of the 5-Hydroxy Tryptamine ID (5HT1D)-agonist sumatriptan has changed the lives of many migraine sufferers. This review describes attack management with analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergotamines and sumatriptan. Adverse events associated with ergotamines and use of sumatriptan are focused upon, with special attention to the pharmacokinetic and pharmacodynamic aspects of both these drugs. Sumatriptan has both vascular and neurogenic effects, both of which may be necessary for a good clinical outcome.