Effects of azaperone on cardiovascular and respiratory functions in the horse.
(17/98)
1 The butyrophenone tranquilizer, azaperone, was administered intramuscularly, at dose levels of 0.4 and 0.8 mg/kg, to ponies and its effects on cardiovascular and respiratory functions assessed. 2 Arterial blood pH, CO2 tension (PaCO2) and O2 tension (PaO2) remained relatively constant throughout the course of action of azaperone. 3 Azaperone did not modify plasma protein concentration but venous blood packed cell volume and haemoglobin concentration were reduced by 5 to 10% for at least 4 hours. These changes were probably caused by uptake of erythrocytes into the splenic reservoir. 4 Small increases in heart rate occurred for up to 60 min after administration of the drug, and this was followed by a slight bradycardia in some ponies. 5 Azaperone reduced mean arterial blood pressure (MAP) for at least 4 h, by which time its ataractic action was generally no longer apparent. The hypotension was caused, during the early phase of action at least, by a reduction in peripheral resistance, since cardiac output was increased slightly 20 min after its administration. Possible mechanisms underlying the cardiovascular changes are discussed. 6 In spite of reductions in arterial blood O2 content and MAP produced by azaperone, it is likely that tissue oxygenation was adequate, since arterial blood lactate concentrations were not increased. (+info)
Antioxidant activity of two phloroglucinol derivatives from Dryopteris crassirhizoma.
(18/98)
The rhizome of Dryopteris crassirhizoma NAKAI exhibited significant antioxidant activity, as assessed by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity in vitro. Two phloroglucinol derivatives, flavaspidic acids PB (1) and AB (2), were isolated from the rhizome of D. crassirhizoma by a bioassay-guided fractionation. 1H-, 13C-NMR, and UV analysis were used to determine the structures. Furthermore, the two compounds were tested for their antioxidant activities, such as their DPPH radical scavenging, superoxide radical scavenging, and lipid peroxidation (LPO) inhibitory activities. Compounds 1 and 2 exhibited potent antioxidant activity against the LPO inhibitory test with IC(50) values of 12.9 and 13.1 microM, respectively, compared with alpha-tocopherol (IC(50); 15.6 microM) and butylated hydroxy anisole (BHA, IC(50); 10.8 microM), while the two compounds had a moderated effect on the DPPH radical scavenging activity (IC(50); 71.7, 76.3 microM) as well as superoxide radical scavenging activity (IC(50); 58.6, 64.4 microM). The potent activity of the flavaspidic acids (1, 2) on inhibiting LPO might be due to possible stabilization as a result of chelating with iron. (+info)
Improvement of ocular blood flow with dopamine antagonists on ocular-hypertensive rabbit eyes.
(19/98)
The eyedrops of the ocular-hypotensive dopamine antagonists, trifluperidol, moperone, lenperone, and spiperone, were instilled into an ocular-hypertensive rabbit eye. The blood flows in the choroid, retina, iris root-ciliary body, and iris were measured with colored microspheres at various time periods. It was found that all these dopamine antagonists, at a concentration of 0.5%, increased the blood flow in all eye tissues. Dopamine, at a concentration of 3%, produced a biphasic action by decreasing the blood flow initially at 30 min, then increasing it at 120 min and thereafter. But 1.5% dopamine produced a monophasic action which increased the blood flow after 180 min. Since dopamine antagonists are not cholinergics or adrenolytics, they are not supposed to produce the side effects induced by pilocarpine or timolol. It is hoped that they can become satisfactory drugs for glaucoma and ocular hypertension. (+info)
Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects.
(20/98)
AIMS: Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. METHODS: In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline. RESULTS: No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. CONCLUSIONS: Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization. (+info)
The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study.
(21/98)
AIMS: To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H(1) antihistamine ebastine in healthy subjects. METHODS: Eighty-nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)(C3435T)) was assessed by means of PCR-restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice. RESULTS: Women excreted statistically greater amounts of desalkylebastine in urine (mean +/- SD (95% confidence intervals, 95% CI), 23.0 +/- 19.5 (18.1, 27.9) micromol) than men (12.4 +/- 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1(C3435T) polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 +/- 18.3 (23.1, 41.4), 22.8 +/- 14.7 (18.6, 27.0) and 21.5 +/- 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice-induced inhibition of its transport/formation (mean fold-decrease +/- SD (95% CI), 1.5 +/- 0.8 (1.0, 2.0), 1.1 +/- 0.9 (0.7, 1.4) and 0.9 +/- 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01). CONCLUSIONS: Gender and the presence of the MDR1(C3435T) polymorphism both influence the excretion of ebastine metabolites in urine. (+info)
Characterization of ebastine, hydroxyebastine, and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes: major roles for CYP2J2 and CYP3A.
(22/98)
Ebastine undergoes extensive metabolism to form desalkylebastine and hydroxyebastine. Hydroxyebastine is subsequently metabolized to carebastine. Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified. Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine. In HLMs, ebastine was metabolized to desalkyl-, hydroxy-, and carebastine; hydroxyebastine to desalkyl- and carebastine; and carebastine to desalkylebastine. Of the 11 cDNA-expressed P450s, CYP3A4 was the main enzyme catalyzing the N-dealkylation of ebastine, hydroxyebastine, and carebastine to desalkylebastine [intrinsic clearance (CL(int)) = 0.44, 1.05, and 0.16 microl/min/pmol P450, respectively]. Ebastine and hydroxyebastine were also dealkylated to desalkylebastine to some extent by CYP3A5. Ebastine hydroxylation to hydroxyebastine is mainly mediated by CYP2J2 (0.45 microl/min/pmol P450; 22.5- and 7.5-fold higher than that for CYP3A4 and CYP3A5, respectively), whereas CYP2J2 and CYP3A4 contributed to the formation of carebastine from hydroxyebastine. These findings were supported by chemical inhibition and kinetic analysis studies in human liver microsomes. The CL(int) of hydroxyebastine was much higher than that of ebastine and carebastine, and carebastine was metabolically more stable than ebastine and hydroxyebastine. In conclusion, our data for the first time, to our knowledge, suggest that both CYP2J2 and CYP3A play important roles in ebastine sequential metabolism: dealkylation of ebastine and its metabolites is mainly catalyzed by CYP3A4, whereas the hydroxylation reactions are preferentially catalyzed by CYP2J2. The present data will be very useful to understand the pharmacokinetics and drug interaction of ebastine in vivo. (+info)
The effect of H1 antagonists carebastine and olopatadine on histamine induced expression of CC chemokines in cultured human nasal epithelial cells.
(23/98)
BACKGROUND: CC chemokines have been shown to play an important role in inducing selective recruitment of inflammatory cells into local allergic inflammatory sites. CC chemokines are also known as histamine releasing factors. We previously showed that histamine enhances transcription of CC chemokines from nasal mucosa which leads to further induction of histamine release. This cyclic cascade may cause prolonged allergic inflammation. The aim of this study is to clarify the relationship between histamine and CC chemokine production by using human nasal epithelial cells (HNECs) and to examine the potential of H1 receptor (H1R) antagonists in new therapeutic approaches for the treatment of nasal allergy. METHODS: HNECs were isolated from the nasal turbinates of patients diagnosed with nasal allergy. HNEC monolayers were cultured for 48 hours with or without histamine (10(-3) to 10(-5) mol/L). Furthermore, an H1R antagonist, either carebastine or olopatadine, was added to the supernatant (10(-3) to 10(-7) mol/L) 30 minutes before incubation with histamine. The expression of Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) in the culture media were measured by ELISA. RESULTS: The release of RANTES and MCP-1 was significantly upregulated by histamine compared with the control group. Both carebastine and olopatadine inhibited the release of CC chemokine production to the control level in both groups. CONCLUSIONS: This study suggests that the interaction between histamine and CC chemokines may prolong allergic inflammation in human nasal mucosa. We also demonstrate the potential use of H1R antagonists in new therapeutic approaches to the treatment of nasal allergy through inhibiting this histamine-CC chemokine interaction. (+info)
Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine.
(24/98)
CYP4F enzymes, including CYP4F2 and CYP4F3B, were recently shown to be the major enzymes catalyzing the initial oxidative O-demethylation of the antiparasitic prodrug pafuramidine (DB289) by human liver microsomes. As suggested by a low oral bioavailability, DB289 could undergo first-pass biotransformation in the intestine, as well as in the liver. Using human intestinal microsomes (HIM), we characterized the enteric enzymes that catalyze the initial O-demethylation of DB289 to the intermediate metabolite, M1. M1 formation in HIM was catalyzed by cytochrome P450 (P450) enzymes, as evidenced by potent inhibition by 1-aminobenzotriazole and the requirement for NADPH. Apparent K(m) and V(max) values ranged from 0.6 to 2.4 microM and from 0.02 to 0.89 nmol/min/mg protein, respectively (n = 9). Of the P450 chemical inhibitors evaluated, ketoconazole was the most potent, inhibiting M1 formation by 66%. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, inhibited M1 formation in a concentration-dependent manner (up to 95%). Immunoinhibition with an antibody raised against CYP4F2 showed concentration-dependent inhibition of M1 formation (up to 92%), whereas antibodies against CYP3A4/5 and CYP2J2 had negligible to modest effects. M1 formation rates correlated strongly with arachidonic acid omega-hydroxylation rates (r(2) = 0.94, P < 0.0001, n = 12) in a panel of HIM that lacked detectable CYP4A11 protein expression. Quantitative Western blot analysis revealed appreciable CYP4F expression in these HIM, with a mean (range) of 7 (3-18) pmol/mg protein. We conclude that enteric CYP4F enzymes could play a role in the first-pass biotransformation of DB289 and other xenobiotics. (+info)