左旋和右旋吡喹酮在人和大鼠肝微粒体内的代谢

左旋吡喹酮[(-)PQT]在人和大鼠肝微粒体中人谢生成产物[M];在[M]色谱峰处,右旋吡喹酮[(+)PQT]无明显代谢物生成.人肝微粒体代谢(?)-PQT生成MI的K_m和V_(max)分别为58±s13μmol·L~1和1.3±s 0.6 nmol·mg~1·min~1·RF.在人肝微粒体中,(?)与(+)PQT原药消除的K_m和V_(max)比值分别为0.86±s 0.28和1.5±s 0.5;(-)-和(+)PQT人肝内在清除率分别为1.3±s 0.5和0.7±s0.3 ml·h~1·mg~1,(-)-/(+)PQT的比值平均为1.8±s 0.5(-)与(-)-PQT在大鼠肝微粒体中消除速率的比值为1.83±s 0.27,结果说明PQT对映异构体在人和大鼠肝微粒体内代谢表现较严格的立体选择性     

Antinociceptive effects of (+/-)-, (+)- and (-)-nefopam in mice

The antinociceptive activity of (+/-)-, (+)- and (-)-nefopam in mice has been examined using the hot-plate, formalin and tail-flick tests. Nefopam was administered by the intraperitoneal, intracerebroventricular (i.c.v.) and intrathecal (i.th.) routes. Intraperitoneal injection of (+/-)-nefopam (10-20 mg kg-1) had powerful analgesic effects in the hot-plate and formalin tests. In the tail-flick test it produced a weak, but significant elevation of the response latencies. In spinalized animals, however, the effect was abolished, indicating that nefopam prolonged the tail-flick latencies by activation of descending pain-modulating pathways. (+/-)-Nefopam (5-20 micrograms) elicited analgesia in the hot-plate test after i.c.v. or i.th. injection. These findings suggest that nefopam has both a spinal and a supraspinal site of action. (+)-Nefopam was significantly more potent than (-)-nefopam after both systemic and central administration.     

Effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the rat left atria and portal vein.

1. The effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the beta 1-adrenoceptor mediated responses of the rat left atria and the beta 2-adrenoceptor mediated responses of the rat portal vein to isoprenaline have been determined. 2. Racemic and (-)-metoprolol were selective beta 1-adrenoceptor antagonists. (+)-Metoprolol was devoid of beta-adrenoceptor antagonistic activity. 3. Racemic and (-)-pindolol were potent and (+)-pindolol was a modest beta-adrenoceptor antagonist. 4. (+/-)-Mepindolol and (+/-)-bopindolol were apparently competitive antagonists of the isoprenaline beta 1-adrenoceptor mediated responses of the rat left atria but non-competitive antagonists of the isoprenaline beta 2-adrenoceptor mediated responses of the rat portal vein. 5. It is suggested that (+/-)-mepindolol and (+/-)-bopindolol are slowly dissociating beta-adrenoceptor antagonists and the non-competitive antagonism can only be detected on tissues with modest receptor reserves for maximum responses to isoprenaline.     

The effects of (+/-)-methylenedioxymethamphetamine and (+/-)-methylenedioxyamphetamine in monkeys trained to discriminate (+)-amphetamine from saline

Recently, attention has been focused on (+/-)-methylenedioxymethamphetamine (MDMA), a psychotomimetic agent chemically closely related to the psychomotor stimulant methamphetamine, and also to the hallucinogen mescaline. In the present experiment, the effects of MDMA and (+/-)-3,4-methylenedioxyamphetamine (MDA) were determined in rhesus monkeys that were trained to discriminate intravenously administered (+)-amphetamine (AMPH) from saline in a two-lever, food-maintained paradigm or to discriminate intragastrically administered AMPH from saline in a signalled electric shock avoidance paradigm. MDMA produced 100% drug-appropriate responding in all six monkeys, regardless of the procedure and route of administration while MDA substituted completely for AMPH in only two of three monkeys in each paradigm. The results suggest that MDMA has subjective effects that are similar to those of AMPH while MDA is somewhat less like AMPH.     

The effects of (+/-)-, (+)- and (-)-celiprolol and bromoacetylalprenololmentane at the beta-adrenoceptors of rat isolated cardiovascular preparations

The effects of (+/-)-, (+)- and (-)-celiprolol and of bromoacetylalprenololmentane (BAAM, an irreversible beta-adrenoceptor antagonist) on the contractile responses of the electrically driven rat right ventricle strip to isoprenaline and on the relaxant responses of the rat aorta to procaterol, have been studied. Racemic and (-)-celiprolol or BAAM treatment of the ventricle produced non-parallel rightward shifts of the isoprenaline response curves with a reduction in the maximal response. Sotalol produced parallel rightward displacements of the procaterol response curves of the aorta with no effect on the maximal relaxations. Racemic and (+)- and (-)-celiprolol or BAAM treatment of the aorta produced non-parallel rightwards shifts of the procaterol relaxant curves with a reduction in the maximal relaxation. The BAAM data was used to demonstrate that the KA (dissociation constant) for isoprenaline at beta 1-adrenoceptors was 1.46 x 10(-7) M and for procaterol at beta 2-adrenoceptors was 2.34 x 10(-5) M. Calculation of receptor occupancy demonstrated that to produce a maximal response of the rat right ventricle, had to occupy 87% of the beta 1-adrenoceptors. Likewise, for a maximal response of the rat aorta, procaterol had to occupy 81% of the beta 2-adrenoceptors. It is suggested that the use of tissues with small beta-adrenoceptor reserves has shown that (+/-)- and (-)-celiprolol are slowly dissociating, rather than readily reversible, beta-adrenoceptor antagonists.     

Pharmacokinetics of (+)-, (-)- and (+/-)-verapamil after intravenous administration

The pharmacokinetics of (+)-, (-)-, and (+/-)-verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (-)- and (+)-isomers. The values for CL, V, Vz, and Vss of the (-)-isomer were substantially higher as compared to the (+)-isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (-)- and 5, 25 and 50 mg of (+)-verapamil. Protein binding for the two isomers was also different. The fu of (-)- (0.11) was almost twice as much as that of (+)-verapamil (0.064). Pharmacokinetic parameters of (+/-)-verapamil, which was administered to three subjects who had received (+)- and (-)-verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (-)-verapamil the extraction ratio of the (-)-isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (-)-verapamil will be substantially less. Since the (-)-isomer is more potent than the (+)-isomer, the present findings could explain the reported differences in the concentration-effect relationship after i.v. and oral administration of racemic verapamil.     

Systemic hemodynamic effects of dopamine, (+/-)-dobutamine and the (+)-and (-)-enantiomers of dobutamine in anesthetized normotensive rats

The hemodynamic effects of dopamine, (+/-)-dobutamine (racemic mixture) and the (+)- and (-)-enantiomers of dobutamine were evaluated in anesthetized normotensive rats. Dopamine and (+/-)-dobutamine produced hemodynamic effects in anesthetized rat that were qualitatively similar to those reported for these compounds in man. The increase in cardiac output produced by dopamine and (+/-)-dobutamine was due mainly to an increase in stroke volume, with heart rate being only minimally affected. Dopamine produced a large increase in mean arterial pressure and slightly increased total peripheral vascular resistance, whereas (+/-)-dobutamine only modestly increased blood pressure and significantly reduced total peripheral resistance. The (-)-enantiomer of dobutamine, which possesses mainly alpha 1-adrenoceptor agonist activity, produced marked increases in cardiac output, stroke volume, total peripheral resistance and mean arterial pressure, but did not significantly increase heart rate. In contrast, (+)-dobutamine, which possesses predominantly beta 1-and beta 2-adrenoceptor agonist activity, elicited only a modest increase in cardiac output which was due entirely to increased heart rate since stroke volume was not increased. Total peripheral vascular resistance and mean arterial blood pressure were both reduced by (+)-dobutamine, characteristic of a beta-adrenoceptor agonist. The increase in cardiac output and blood pressure produced by (+/-)-dobutamine, but not the positive chronotropic effect, were significantly inhibited by alpha 1-adrenoceptor blockade with prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenergic receptor subtype activation by (+)-, (-)- and (+/-)-norephedrine in the pithed rat

The ability of (+/-)-norephedrine (phenylpropanolamine) and its component isomers, (+)-and (-)-norephedrine, to activate adrenergic receptor subtypes in the cardiovascular system of the urethane/chloralose-anaesthetized pithed rat has been investigated. At all adrenoceptor subtypes, (-)-norephedrine was the most potent agonist followed by (+/-)- then (+)-norephedrine. The greatest activity was observed at the alpha 1-receptor, with little activity observed at either beta 1 or beta 2-adrenoceptors. Reserpinization shifted the (-)-norephedrine dose-response curve slightly to the right, indicating that only a minor portion of its activity is due to the release of stored endogenous catecholamines. These results suggest that most of the cardiovascular activity of the compounds is through the direct activation of alpha 1-adrenoceptors.     

Terpenoid biotransformation in mammals IV Biotransformation of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid in rabbits

1. The metabolism of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydro-abietic acid was studied in rabbits.

2. Each of these sesquiterpenoids was converted to primary, secondary or tertiary alcohols, among which the primary alcohol was predominant.

3. A vinylic methyl group and an exomethylene group were easily hydroxylated and converted to a glycol via an epoxide in many cases.

4. Eight new metabolites were determined by chemical and spectroscopic methods.     

Terpenoid biotransformation in mammals. IV Biotransformation of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid in rabbits

The metabolism of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid was studied in rabbits. Each of these sesquiterpenoids was converted to primary, secondary or tertiary alcohols, among which the primary alcohol was predominant. A vinylic methyl group and an exomethylene group were easily hydroxylated and converted to a glycol via an epoxide in many cases. Eight new metabolites were determined by chemical and spectroscopic methods.     

Effects of (+/-)-, (+)- and (-)-celiprolol on the rat left atria and portal vein.

Differing effects of (+/-)-celiprolol at beta-adrenoceptors have been reported. The effects of (+/-)-, (+)- and (-)-celiprolol on the contractile responses of the rat left atria and portal vein have therefore been studied. (+/-)-Celiprolol did not augment the responses of the atria to electrical stimulation and is therefore not an agonist at beta 1-adrenoceptors. Prolonged treatment with (+/-)-celiprolol attenuated the contractile activity of the vein and this effect was blocked by ICI 118,551 and is therefore mediated by agonism at beta 2-adrenoceptors. The pA2 values for (+/-)-, (+)- and (-)-celiprolol at the beta 1-adrenoceptors of the atria were 8.0, 6.0 and 8.6, respectively. On the protal vein, (+/-)- and (-)-celiprolol produced non-parallel rightward shifts of log isoprenaline attenuation curves with a reduction in isoprenaline maximum responses. This effect of (+/-)-celiprolol on the vein was not due to slowly reversible antagonism, as the inhibitory effect of (+/-)-celiprolol was readily reversible.     

Optically pure (+)-nicotine from (+/-)-nicotine and biological comparisons with (-)-nicotine.

Optically pure (+)-nicotine has been obtained from (+/-)-nicotine using a combination of d-tartaric acid and di-p-toluoyl-l-tartaric acid. As the di-d-tartrate salt, (+)-nicotine is less potent than (-)-nicotine di-l-tartrate in producing lethality in mice, on blood pressure in anesthetized rats, and in the isolated guinea-pig ileum, indicating substantial stereospecificity for nicotine receptors. Potency ratios are 0.14, 0.06, and 0.019, respectively.     

Relaxant and beta 2-adrenoceptor blocking activities of (+/- )-, (+)- and (-)-pindolol on the rat isolated aorta

The KCl contracted rat aorta is relaxed by procaterol, (+/- )-, (+)- and (-)-pindolol. The relaxations to procaterol, but not to (+/- )-pindolol, were prevented by ICI 118,551 at 10(-6) M. The relaxations to (+/- )-pindolol are, therefore, not due to beta-adrenoceptor agonism. At 10(-7) M ICI 118,551, (+/- )-, (+)- and (-)-pindolol were beta 2-adrenoceptor antagonists as they inhibited the relaxant responses of the aorta to procaterol.     

The metabolism and biosynthesis of (+/-)-o-octopamine and (+/-)-o-synephrine in the rat

The metabolism of (+/-)-o-octopamine and (+/-)-o-synephrine by rats was studied quantitatively by a gas chromatography-mass spectrometry-selected ion monitoring (g.c.-m.s.-s.i.m.) method using deuterated internal standards. When o-octopamine was injected intraperitoneally into rats four metabolites were excreted in the urine: (i) unconjugated o-hydroxymandelic acid (OHMA) (16%), (ii) unconjugated o-hydroxyphenylglycol (OHPG) (4.5%), (iii) an acid-hydrolysable conjugate of OHPG (28%) and (iv) unconjugated o-octopamine (10%). When o-synephrine benzoate was similarly administered six metabolites were excreted in urine: (i) unconjugated OHMA (13.5%), (ii) unconjugated OHPG (3.3%), (iii) an acid-hydrolysable conjugate of OHPG (15.6%), (iv) unconjugated o-synephrine (10%), (v) an acid-hydrolysable conjugate of o-synephrine (8.5%) and (vi) unconjugated o-octopamine (0.3%). Adult rats normally excreted OHMA (1.0 micrograms day-1) but OHPG, o-octopamine and o-synephrine could not be detected in urine. After the administration of a monoamine oxidase inhibitor, unconjugated o-octopamine (0.3 micrograms day-1) was excreted in urine but OHPG and o-synephrine could not be detected. o-Tyramine given to rats afforded urinary o-octopamine (75 ng day-1) and this was increased 10-fold upon co-administration of a monoamine oxidase inhibitor and o-tyramine.     

Plasma levels of (+) and (-)-propranolol and 4-hydroxypropranolol after administration of racemic (+/-)-propranolol in man.

1 We have given fifteen healthy volunteers single doses of racemic (+/-)-propranolol orally (40 mg) and intravenously (5-10 mg) to find out how large the variation was of the ratio between (-)- and (+)-propranolol plasma levels in relation to that of total levels of propranolol and 4-hydroxypropranolol. 2 Total propranolol (+/-)-levels 2 h after a 40 mg oral dose of (+/-)-propranolol varied from 21 to 580 nmol/l and those of 4-hydroxypropranolol from 0 to 33 nmol/l. Their levels did not correlate. The ratio between (-)- and (+)-propranolol levels varied from 0.99 to 2.04. The plasma half-lives of the two isomers were usually similar. 3 We conclude that in most single doses studies on relationships between plasma concentrations and effects (beta-adrenoceptor blockade) it is not necessary to quantitate (+)- and (-)-propranolol levels separately since total (+/-) plasma propranolol levels varied much more than the ratio between (-)- and (+)-propranolol.     

Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine

This study utilized drug discrimination procedures to assess the functional consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin depletion, and to determine whether concomitant injections of fluoxetine averted these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)-MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant procedure. After dose generalization tests were completed, training was suspended, and subjects were administered saline injections twice daily for four days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline, to ascertain that discriminative stimulus control was maintained in the absence of training over a two-week period. All subjects received two additional weeks of training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline (SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections, S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA generalization tests, and rose from 2.78% to 22.14% during SAL generalization tests. This disruption did not occur, however, in rats administered the combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated rats. Postmortem neurochemical assays indicated that 5-HT levels were significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL, compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5-HIAA levels were significantly lower in the prefrontal cortices of both (+/-)-MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control. These results support previous findings that fluoxetine protects against (+/-)-MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug discrimination is a sensitive assay in which to examine behavioral correlates of (+/-)-MDMA-induced serotonergic deficits, and the protection against these deficits by fluoxetine.     

The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (+/-)-indobufen

The racemic compound indobufen and its (+)- and (-)-enantiomers have been compared for their effects on blood platelet function and rat carrageenan pleurisy. The antiplatelet properties were studied in-vitro in human platelets by measuring the inhibition of platelet aggregation and generation of serum thromboxane (Tx) B2. In-vivo, the antiplatelet and anti-inflammatory properties were studied in rats by measuring the inhibition of serum TxB2, the amount of 6-keto-PGF1 alpha in pleural exudate and pleural exudate volume. In all tests the (+)-enantiomer was slightly more potent than the racemate, while the (-)-enantiomer was far less potent. In the same rats, treatment with the lowest doses of the compounds giving 90% inhibition of serum thromboxane B2 generation was associated with occasional macroscopic lesions of the gastric mucosa.