Tacrine, the first approved drug against Alzheimer's disease (AD), was withdrawn from clinical use due to serious adverse effects. The main concern was the human hepatotoxicity, stemming probably from the liver biotransformation and clinically manifested as hepatocellular necrosis, and lobular hepatitis. Concerning the biotransformation, 7-OH-tacrine metabolite is generally suspected of being a precursor of toxic quinone methide, which binds to intracellular -SH proteins and/or depletes intracellular glutathione, and by that probably causes the hepatotoxicity. However, to study these toxic effects, proper animal model is needed to monitor the interspecies differences of metabolism. To fully describe in vivo ADMET parameters of tacrine, five experimental pigs (Sus scrofa f. domestica), as the most physiologically human-like in vivo model showing similar tacrine biotransformation, were used. We studied tacrine and its metabolites ADMET characteristics after both acute i.g. single dose and chronic 42 days p.o daily dose administration of 200 mg of tacrine. Tacrine and its two major metabolites show Tmax in plasma of 360 min, so the absorption is much slower than in human (Tmax = 120 min) and are primarily distributed to the gastro-intestinal tract and CNS. Furthermore, due to the lower activity of CYP1A2 in pigs, tacrine is biotransformed much less efficiently than in humans. This study showed that tacrine accumulates only in adipose tissue, and organ histology and plasma biochemistry assessment revealed no signs of hepatotoxicity even after chronic tacrine administration. Pigs are therefore an unsuitable human-like animal model for evaluating tacrine toxicity.
- MeSH
- biotransformace MeSH
- cholinesterasové inhibitory toxicita farmakokinetika MeSH
- játra * účinky léků metabolismus patologie MeSH
- lékové postižení jater * metabolismus patologie MeSH
- lidé MeSH
- prasata MeSH
- Sus scrofa MeSH
- takrin * farmakokinetika toxicita metabolismus analogy a deriváty MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Susceptibility in vitro and trends in resistance to antimicrobials were determined by a dilution micromethod in a group of Actinobacillus pleuropneumoniae, Pasteurella multocida, Mannheimia haemolytica and Escherichia coli isolates from clinical cases of cattle and swine diseases in the Czech Republic from 2007 to 2011. A high susceptibility of pig and cattle respiratory pathogens to antimicrobials was found, with the exception of the moderate prevalence of M. haemolytica resistance to ampicillin. In contrast to respiratory pathogens, low susceptibility of E. coli of pig and cattle isolates to ampicillin and amoxicillin/clavulanic acid was noted. Regarding resistance trends, an increase in levels of resistance among E. coli isolates to ampicillin and amoxicillin/clavulanic acid was identified, but the resistance of respiratory isolates was low, with the exception of M. haemolytica. For the period of 2007-2011, there was a significant and almost continuous increase in sales (compared with population correction unit) of ceftiofur, cefquinome and other beta lactams for pigs. Consumption peaked in 2010. In the case of amoxicillin in combination with clavulanic acid, data showed a significant decrease in sales from 2007 to 2008, followed by a period of fluctuation. In cattle, within the groups of 3rd and 4th generation cephalosporins and for the whole group of other betalactams for the period of 2007-2011, there was a significant and almost continuous increase in sales (compared with population correction unit). Consumption peaked in 2010. In the case of ceftiofur, there was a huge increase noted from 2010. In the case of amoxicillin in combination with betalactamase inhibitor (clavulanic acid) data shows a significant decrease from 2007 to 2008, followed by a period of fluctuation in sales.
- MeSH
- Actinobacillus pleuropneumoniae účinky léků MeSH
- bakteriální léková rezistence genetika MeSH
- beta-laktamy metabolismus MeSH
- Escherichia coli účinky léků MeSH
- infekce bakteriemi čeledi Pasteurellaceae epidemiologie veterinární MeSH
- infekce vyvolané Escherichia coli epidemiologie veterinární MeSH
- inhibitory beta-laktamasy farmakologie MeSH
- Mannheimia haemolytica účinky léků MeSH
- mikrobiální testy citlivosti veterinární MeSH
- nemoci prasat epidemiologie mikrobiologie MeSH
- nemoci skotu epidemiologie mikrobiologie MeSH
- Pasteurella multocida účinky léků MeSH
- prasata MeSH
- prevalence MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- angiolipom komplikace chirurgie MeSH
- duodenoskopie MeSH
- gastrointestinální krvácení etiologie MeSH
- lidé MeSH
- nádory duodena komplikace chirurgie MeSH
- polypy střeva komplikace chirurgie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
