| 2006 | Profiling the hepatic effects of flutamide in rats: a microarray comparison with classical aryl hydrocarbon receptor ligands and atypical CYP1A inducers. | Drug Metab Dispos | The antiandrogen flutamide (FLU) is used primarily for prostate cancer and is an idiosyncratic hepatotoxicant that sometimes causes severe liver problems. To investigate FLU's overt hepatic effects, especially on inducible drug clearance-related gene networks, FLU's hepatic gene expression profile was examined in female Sprague-Dawley rats using approximately 22,500 oligonucleotide microarrays. Rats were dosed daily for 3 days with FLU at 500, 250, 62.5, 31.3, and 15.6 mg/kg/day, and hepatic RNA was isolated. FLU resulted in the dose-dependent regulation of approximately 350 genes. Employing a gene-response compendium, FLU was compared with three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene, benzo[a]pyrene, and beta-naphthoflavone, and four atypical CYP1A inducers, indole-3-carbinol (I3C), omeprazole (OME), chlorpromazine (CPZ), and clotrimazole (CLO). The FLU gene response was comparable with classical AhR ligands across a signature AhR ligand gene set that included CYP1A1 and other members of the AhR gene battery. Dose-related responses of CYP1 genes established a maximum response ceiling and discerned potency differences in atypical inducers. FLU had a sharp down-regulation of c-fos that was comparable with all the compounds except CPZ and CLO. FLU absorption, distribution, metabolism, and excretion (ADME) gene expression analysis revealed that FLU, as well as I3C and OME, induced CYP2B and CYP3A, distinguishing them from the classical AhR ligands. By using a compendium of gene expression profiles, FLU was shown to signal in rats similar to an AhR activator with additional CYP2B and CYP3A effects that most resembled the ADME gene expression pattern of the atypical CYP1A inducers I3C and OME. |
| 2003 | A comparative study of the anticholinesterase activity of several antipsychotic agents. | Pharmacol Biochem Behav | Drug-induced inhibition of plasma and tissue cholinesterase activity was evaluated in rats. The dopamine receptor antagonists haloperidol (HALO), chlorpromazine (CPZ), thioridazine (THIO), fluphenazine (FLU), clozapine (CLO) and sulpiride (SULP), used as neuroleptics, were tested. Two biochemical parameters were measured in vitro: the minimal effective concentration (MEC) for cholinesterase inhibition and the 50% inhibitory concentration (IC50). In addition, animals were tested for rotational activity after a unilateral intrastriatal injection of the drugs. The doses used for each drug were previously determined IC50s. After unilateral striatal drug injection, rats were challenged with intraperitoneal amphetamine injection in order to stimulate rotation. All drugs tested induced decreases in cholinesterase activity. Plasma MEC for THIO, FLU, HALO and CPZ were significantly lower than for CLO and SULP. In striatum, the MEC for TIO, CPZ and FLU was significantly lower than for HAL. According to plasma IC50, THIO, CPZ and CLO are potent cholinesterase inhibitors. CLO showed the lowest potency of cholinesterase inhibition in the striatum and THIO showed the highest potency in plasma and striatum. In conclusion, anticholinesterase activity is not related to D(2) receptor blockade or antipsychotic potency; and therefore the antipsychotic effects are not related to an increase in acetylcholine. All drugs induced similar contralateral rotation, except for CLO that was different from SULP and was not different from its control. Since equivalent cholinesterase inhibitory concentrations were used for all drugs and no differences in nigrostriatal behavioral effects were observed, these data suggest the participation of an important cholinergic component in this behavior. Therapeutically, the stronger the cholinesterase inhibition is, the more potent the cholinergic effects are and, consequently, the induction of extrapyramidal symptoms becomes more feasible. |
| Effects of neuroleptics on blood glucose, free fatty acids and liver glycogen levels in the rat. | Pol J Pharmacol Pharm | In fed rats the mechanisms of the action of spiroperidol (SPI), chlorpromazine (CPZ), fluphenazine (FLU) and thioridazine (TRZ) blood glucose, liver glycogen, serum free fatty acids (FFA) and K ion levels were investigated. Phenothiazines induced significant hyperglycemic responses with concomitant increase in liver glycogen, elevation of serum FFA and hypokalemia. CPZ and FLU were the most potent and TRZ was least potent in inducing above mentioned metabolic responses, which were most pronounced in 4--6 hr. SPI produced significant hyperglycemia for sorter period of time with a subsequent decrease of liver glycogen. An alpha-adrenergic antagonist, phentolamine prevented neuroleptic-induced hyperglycemia, impaired the increase of liver glycogen, partially diminished hyperlipemia and did not substantially change hypokalema occuring following neuroleptics. Antagonist of beta-adrenergic receptor, propranolol did not practically influence metabolic responses to neuroleptics. Adrenalectomy impaired substantially but did not abolish neuroleptic-induced hyperglycemia, indicating that also extraadrenal mechanisma, conceivable impairing glucose utilization and metabolism, are responsible for hyperglycemia induced by neuroleptics. This experiments suggest that phenothiazines may induce hyperglycemic response by activation of alpha-adrenergic receptors by contrast to alpha-adrenertic blocking action of these drugs in the central nervous system. |
| The effect of neuroleptics on the development of gastric ulcers in rats exposed to restraint-cold stress. | Pol J Pharmacol Pharm | Gastric ulcer development and changes in the contents of glucose, free fatty acids (FFA), and K and Ca ions in the blood were studied in rats subjected to a graded stress of immobilisation and cold. During stress the volume of secretion and the output of HCl, decreased although the concentration rose slightly. Chlorpromazine (CPZ), thioridazine (TRZ), spiroperidol (SPI), and fluphenazine (FLU) inhibited to various degrees ulcer formation during stress. SPI reduced stress-induced mucosal damages in 94%, but FLU even in doses 100 times smaller than those of the other drugs counteracted ulcer formation. CPZ, TRZ and SPI in preventive doses increased proportionally the blood glucose level both in control rats and in those subject to stress. FLU in effective doses produced no hyperglycemia either in control rats or in those exposed to stress. We conclude that the prevention of gastric ulcer development by neuroleptics may be the result of their antisecretory action and counteracting of breakdown of sympathetic activity during severe stress. |