Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · Sep 2012
Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats.
Lipocalins tailored with high affinity for prescribed ligands, so-called anticalins, constitute promising candidates as antidotes. Here, we present an animal study to investigate both pharmacokinetic and clinical effects of an anticalin specific for the digitalis compound digoxin. Intravenous digoxin (2.5-50 μg/kg/min) was administered to rats until first changes in the ECG occurred (dose finding study) or a priori for 30 min (kinetic study). ⋯ Infusion of a lower digoxin dose (2.5 μg/kg/min) resulted in a more sustained reduction of free digoxin in plasma after DigiCal administration compared to a higher digoxin dose (25 μg/kg/min), whereas ECG and hemodynamic parameters did not markedly differ, reflecting the known relative insensitivity of rats towards digoxin toxicity. Notably, we observed a re-increase of free digoxin in plasma some time after bolus administration of DigiCal, which was presumably due to toxin redistribution from tissue in combination with the relatively fast renal clearance of the rather small protein antidote. We conclude that anticalins with appropriately engineered drug-binding activities and, possibly, prolonged plasma half-life offer prospects for next-generation antidotal therapy.
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Toxicol. Appl. Pharmacol. · Jun 2012
Differential regulation of collagen secretion by kinin receptors in cardiac fibroblast and myofibroblast.
Kinins mediate their cellular effects through B1 (B1R) and B2 (B2R) receptors, and the activation of B2R reduces collagen synthesis in cardiac fibroblasts (CF). However, the question of whether B1R and/or B2R have a role in cardiac myofibroblasts remains unanswered. ⋯ B1R, B2R, iNOS and COX-1 were expressed differently between CF and CMF, and collagen secretion was regulated differentially by kinin receptor agonists in cultured CF and CMF.
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Toxicol. Appl. Pharmacol. · Mar 2012
Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice.
Epileptic seizures and status epilepticus (SE) induced by the poisoning with organophosphorus nerve agents (OP), like soman, are accompanied by neuroinflammation whose role in seizure-related brain damage (SRBD) is not clear. Antagonists of the NMDA glutamate ionotropic receptors are currently among the few compounds able to arrest seizures and provide neuroprotection even during refractory status epilepticus (RSE). Racemic ketamine (KET), in combination with atropine sulfate (AS), was previously shown to counteract seizures and SRBD in soman-poisoned guinea-pigs. ⋯ KET/AS could also reduce the increase in mRNA and related pro-inflammatory proteins provoked by the poisoning. In conclusion, the present study confirms that KET/AS treatment has a strong potential for SE/RSE management following OP poisoning. The mechanisms involved in the reduction of central neuroinflammation remain to be studied.
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Toxicol. Appl. Pharmacol. · Jan 2012
Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon.
Oxons are the bioactivated metabolites of organophosphorus insecticides formed via cytochrome P450 monooxygenase-catalyzed desulfuration of the parent compound. Oxons react covalently with the active site serine residue of serine hydrolases, thereby inactivating the enzyme. A number of serine hydrolases other than acetylcholinesterase, the canonical target of oxons, have been reported to react with and be inhibited by oxons. ⋯ Consistent with the results for the IC(50) values, the order of reactivity for each of the three oxons with CES1 and CES2 was chlorpyrifos oxon>paraoxon>methyl paraoxon. The bimolecular rate constant for the reaction of chlorpyrifos oxon with MGL was also determined and was less than the values determined for chlorpyrifos oxon with CES1 and CES2 respectively. Together, the results define the kinetics of inhibition of three important hydrolytic enzymes by activated metabolites of widely used agrochemicals.
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Toxicol. Appl. Pharmacol. · Dec 2011
Comparative StudyDifferential state-dependent modification of rat Na(v)1.6 sodium channels expressed in human embryonic kidney (HEK293) cells by the pyrethroid insecticides tefluthrin and deltamethrin.
We expressed rat Na(v)1.6 sodium channels in combination with the rat β1 and β2 auxiliary subunits in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on expressed sodium currents using the whole-cell patch clamp technique. Both pyrethroids produced concentration-dependent, resting modification of Na(v)1.6 channels, prolonging the kinetics of channel inactivation and deactivation to produce persistent "late" currents during depolarization and tail currents following repolarization. Both pyrethroids also produced concentration dependent hyperpolarizing shifts in the voltage dependence of channel activation and steady-state inactivation. ⋯ Repetitive depolarization at either frequency increased modification by deltamethrin by ~2.3-fold but had no effect on modification by tefluthrin. Tefluthrin and deltamethrin were equally potent as modifiers of Na(v)1.6 channels in HEK293 cells using the conditions producing maximal modification as the basis for comparison. These findings show that the actions of tefluthrin and deltamethrin of Na(v)1.6 channels in HEK293 cells differ from the effects of these compounds on Na(v)1.6 channels in Xenopus oocytes and more closely reflect the actions of pyrethroids on channels in their native neuronal environment.