Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats.
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Imipramine and clomipramine were administered to rats by the oral and intramuscular routes as single and multiple doses. The concentrations of both drugs and their active demethylated metabolites desipramine and desmethylclomipramine were measured in blood plasma, blood cells and brain. The concentrations of the metabolites were higher and the concentrations of the parent substances lower after oral than after parenteral administration, both in blood and in brain. In brain imipramine, despiramine and clomipramine during continuous treatment exceeded their plasma concentrations by six to ten times. The corresponding figure for desmethylclomipramine was 1-7. The extent of accumulation of the investigated substances in the brain was independent of the route of administration. (+info)
Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.
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We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine. (+info)
Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.
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It is anticipated that gamma-secretase inhibitors (gamma-Sec-I) that modulate Notch processing will alter differentiation in tissues whose architecture is governed by Notch signaling. To explore this hypothesis, Han Wistar rats were dosed for up to 5 days with 10-100 micromol/kg b.i.d. gamma-Sec-I from three chemical series that inhibit Notch processing in vitro at various potencies (Notch IC(50)). These included an arylsulfonamide (AS) (142 nM), a dibenzazepine (DBZ) (1.7 nM), and a benzodiazepine (BZ) (2.2 nM). The DBZ and BZ caused dose-dependent intestinal goblet cell metaplasia. In contrast, the AS produced no detectable in vivo toxicity, despite higher exposure to free drug. In a time course using BZ, small intestinal crypt cell and large intestinal glandular cell epithelial apoptosis was observed on days 1-5, followed by goblet cell metaplasia on days 2-5 and crypt epithelial and glandular epithelial regenerative hyperplasia on days 4-5. Gene expression profiling of duodenal samples from BZ-dosed animals revealed significant time-dependent deregulation of mRNAs for various panendocrine, hormonal, and transcription factor genes. Somatostatin, secretin, mucin, CCK, and gastrin mRNAs were elevated twofold or more by day 2, and a number of candidate "early-predictive" genes were altered on days 1-2, remaining changed for 4-5 days; these included Delta1, NeuroD, Hes1-regulated adipsin, and the Hes-regulated transcriptional activator of gut secretory lineage differentiation, the rat homolog of Drosophila atonal, Rath1. Western blotting of fecal protein from BZ-and DBZ-dosed animals exhibited increased levels of both anti-Rath1 reactive protein and anti-adipsin reactive proteins, confirming their potential value as noninvasive biomarkers of intestinal goblet metaplasia. (+info)
Population pharmacokinetics of epinastine, a histamine H1 receptor antagonist, in adults and children.
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AIMS: Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H(1) receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children. METHODS: A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling. RESULTS: The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V(1)/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V(1)/F, volume of distribution of the peripheral compartment (V(2)/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V(2)/F and Ka; body weight on V(2)/F) were not statistically significant. No effect of age on CL/F, V(1)/F or V(2)/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90-117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from 14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the C(max) and AUC (25.6 +/- 6.9 ng ml(-1) and 246.8 +/- 68.2 ng h ml(-1)) were almost same levels with those of adults after administration of 20 mg (26.9 +/- 9.1 ng ml(-1) and 281.6 +/- 90.5 ng h ml(-1)). CONCLUSIONS: A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults. (+info)
Octopamine and experience-dependent modulation of aggression in crickets.
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Intraspecific aggression is influenced in numerous animal groups by the previous behavioral experiences of the competitors. The underlying mechanisms are, however, mostly obscure. We present evidence that a form of experience-dependent plasticity of aggression in crickets is mediated by octopamine, the invertebrate counterpart of noradrenaline. In a forced-fight paradigm, the experience of flying maximized the aggressiveness of crickets at their first encounter and accelerated the subsequent recovery of aggressiveness of the normally submissive losers, without enhancing general excitability as evaluated from the animals' startle responses to wind stimulation. This effect is transitory and concurrent with the activation of the octopaminergic system that accompanies flight. Hemocoel injections of the octopamine agonist chlordimeform (CDM) had similar effects on aggression but also enhanced startle responses. Serotonin depletion, achieved using alpha-methyl-tryptophan, enhanced startle responses without influencing aggression, indicating that the effect of CDM on aggression is not attributable to increased general excitation. Contrasting this, aggressiveness was depressed, and the effect of flying was essentially abolished, in crickets depleted of octopamine and dopamine using alpha-methyl-p-tyrosine (AMT). CDM restored aggressiveness in AMT-treated crickets, indicating that their depressed aggressiveness is attributable to octopamine depletion rather than to dopamine depletion or nonspecific defects. Finally, the flight effect was blocked in crickets treated with the octopamine receptor antagonist epinastine, or with the alpha-adrenoceptor and octopamine receptor antagonist phentolamine, but not with the beta-adrenoceptor antagonist propranolol. The idea that activity-specific induction of the octopaminergic system underlies other forms of experience-dependent plasticity of aggressive motivation in insects is discussed. (+info)
Pathways of carbamazepine bioactivation in vitro: II. The role of human cytochrome P450 enzymes in the formation of 2-hydroxyiminostilbene.
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Conversion of the carbamazepine metabolite, 2-hydroxycarbamazepine, to the potentially reactive species, carbamazepine iminoquinone (CBZ-IQ), has been proposed as a possible bioactivation pathway in the pathogenesis of carbamazepine-induced hypersensitivity. Generation of CBZ-IQ has been proposed to proceed through the intermediate, 2-hydroxyiminostilbene (2-OHIS); however, data suggested that 2-hydroxycarbamazepine is oxidized by cytochromes P450 (P450s) directly to CBZ-IQ, followed by NADPH-mediated reduction to 2-OHIS. In vitro studies were conducted to identify the P450s responsible for converting 2-hydroxycarbamazepine to 2-OHIS and to determine functional consequences of this bioactivation pathway. Formation of 2-OHIS in human liver microsomes (HLMs) was consistent with monophasic, Michaelis-Menten kinetics. The sample-to-sample variation in the rate of 2-OHIS formation correlated significantly (r2 > or = 0.706) with CYP3A4/5 and CYP2B6 activities in a panel of HLMs (n = 10). Studies with a panel of cDNA-expressed enzymes revealed that CYP3A4 preferentially catalyzed 2-OHIS formation; CYP3A4 formed 2-OHIS at a rate >10 times that of other enzymes capable of forming 2-OHIS (CYP1A1, CYP2C19, and CYP3A7). Inhibitors of CYP3A enzymes markedly impaired 2-OHIS formation in HLMs, whereas inhibitors of other P450s resulted in < or = 20% inhibition. Although CYP3A4 was primarily responsible for converting 2-hydroxycarbamazepine to 2-OHIS, neither 2-hydroxycarbamazepine, 2-OHIS, nor CBZ-IQ caused time-dependent inactivation of CYP3A activity. No thiol adducts were formed directly from 2-hydroxycarbamazepine. However, glutathione- and N-acetylcysteine-conjugates were formed with 2-OHIS or CBZ-IQ as substrates. Thus, CYP3A4-dependent secondary oxidation of 2-hydroxycarbamazepine represents a potential carbamazepine bioactivation pathway leading to the formation of thiol-reactive metabolites, intermediates that may play a role in the etiology of idiosyncratic toxicity attributed to carbamazepine. (+info)
Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration.
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BACKGROUND AND PURPOSE: In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. EXPERIMENTAL APPROACH: The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. KEY RESULTS: The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. CONCLUSIONS AND IMPLICATIONS: In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord. (+info)
Optimization of the SPME parameters and its online coupling with HPLC for the analysis of tricyclic antidepressants in plasma samples.
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Solid-phase microextraction (SPME)-liquid chromatography (LC) is used to analyze tricyclic antidepressant drugs desipramine, imipramine, nortriptyline, amitriptyline, and clomipramine (internal standard) in plasma samples. Extraction conditions are optimized using a 2(3) factorial design plus a central point to evaluate the influence of the time, temperature, and matrix pH. A Polydimethylsiloxane-divinylbenzene (60-mum film thickness) fiber is selected after the assessment of different types of coating. The chromatographic separation is realized using a C(18) column (150 x 4.6 mm, 5-microm particles), ammonium acetate buffer (0.05 mol/L, pH 5.50)-acetonitrile (55:45 v/v) with 0.1% of triethylamine as mobile phase and UV-vis detection at 214 nm. Among the factorial design conditions evaluated, the best results are obtained at a pH 11.0, temperature of 30 degrees C, and extraction time of 45 min. The proposed method, using a lab-made SPME-LC interface, allowed the determination of tricyclic antidepressants in in plasma at therapeutic concentration levels. (+info)