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PubMed1991

Effects of NMDA and calcium channel antagonists on regional cerebral blood flow.

N-Methyl-D-aspartate (NMDA) antagonists and voltage-dependent calcium channel antagonists were tested to determine potential effects on regional cerebral blood flow in the normal rabbit brain. Ketamine had no effects on cortical or hippocampal blood flow, but was found to significantly decrease blood flow in the inferior colliculus. MK-801 decreased blood flow in almost all regions of the brain tested. On the other hand, nimodipine significantly increased flow in the cortex, hippocampus, and tegmentum. Dextromethorphan and dextrorphan, which have been shown to act at the NMDA receptor as well as the dihydropyridine calcium channel, decreased blood flow in the inferior colliculus, but showed no effects in the cortex or hippocampus. These results suggest that the neuroprotective NMDA antagonists do not increase blood flow primarily in the normal brain.

Animals↗
PubMed1991

Diversified electrophysiological properties of morphinan drugs in rats.

1. In in vivo and in vitro studies in rats, the effects of dextromethorphan (DM), dextrorphan (DX), and levorphanol (LV) were compared with those induced by kappa and sigma opiate agonists. 2. In rat hippocampal slices all the morphinans were able to pertubate the CAI hippocampal synaptic transmission, while only DX and LV affected the N-methyl-D-aspartate excitability through a possible interaction at sigma opiate receptors. 3. On the other hand EEG studies show that only DX appears to act as a full agonist at sigma opiate receptors. 4. Present data demonstrate diversified electrophysiological properties of morphinans both in in vitro and in vivo studies.

Animals↗
PubMed1991

Effects of taurine and ketamine on bovine retinal membrane lipid peroxidation.

Lipid peroxidation disrupts membrane integrity and causes structural and functional alterations in ischemic tissues. Taurine and ketamine are putative ischemic protectants that affect Ca2+ influx. Here we report the influence of these compounds on lipid peroxidation in subcellular fractions, isolated cells and intact tissue from bovine retinas. P2 membrane fractions and isolated cells were exposed to the lipid peroxidation inducers cadmium chloride (200 microM) or L-ascorbic acid (1 mM) in the presence of 0-50 mM taurine, 0-10 mM ketamine, 1 mM kynurenic acid or 1 mM dextromethorphan. The latter compounds are N-methyl-D-aspartate receptor antagonists. Lipid peroxidation in isolated eyes reperfused after 1 h of ischemia either with or without protectants was determined by thiobarbituric acid assay. Glutathione was measured in isolated retinas subjected in vitro to simulated ischemia (no glucose or oxygenation) for 60 min either alone or in the presence of taurine or ketamine. Ketamine inhibited chemical- or ischemia-induced lipid peroxidation as well as ischemic glutathione depletion. Under the same conditions, taurine failed to affect lipid peroxidation or glutathione. The data show a direct effect of ketamine on lipid peroxidation and point to separate mechanisms of action for ketamine and taurine.

Animals↗
PubMed1994

The effect of experimental ischaemia and excitatory amino acid agonists on the GABA and serotonin immunoreactivities in the rabbit retina.

The aim of the described experiments was to use immunohistochemistry to visualize the release of GABA from specific retinal amacrine cells following ischaemia and to establish the involvement of defined glutamatergic receptors. In initial experiments, rabbit retinas were exposed in vitro to excitatory amino acid agonists alone or in combination with a putative antagonist, or in physiological solution lacking oxygen and glucose, or in solution containing potassium cyanide for 45 min at 37 degrees C. The nature of the GABA immunoreactivity was then examined by immunohistochemistry. In other in vitro experiments, retinas were first allowed to accumulate exogenous serotonin before exposing the tissues to the combinations as described. These tissues were then processed immunohistochemically for the localization of serotonin. In yet other experiments, the intraocular pressure of a rabbit's eye was raised to about 110 mmHg for 60 min and a reperfusion time of 45 min allowed before dissecting the retina and processing for the localization of GABA immunoreactivity. The other eye served as a control. Of the excitatory amino acid agonists tested, only N-methyl-D-aspartate, kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid caused a change in the GABA immunoreactivity. The N-methyl-D-aspartate effect was specifically antagonized by dizocilpine maleate, dextromethorphan and memantine, and was characterized by a reduction in the number of GABA-immunoreactive perikarya. The GABA "staining" in the inner plexiform layer also appeared as four clear bands. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and kainate-induced effects were both antagonized by 6-cyano-2,3-dihydroxy-7-nitroquinoxaline-2,3-dione and partially by kynurenic acid at the concentrations used. Here, the amount of GABA-positive perikarya was greatly reduced and three immunoreactive bands appeared in the inner plexiform layer. However, for low concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid four GABA-immunoreactive bands could be identified in the inner plexiform layer. The normal GABA immunoreactivity of the inner plexiform layer also appeared to be in defined bands in retinas which received an ischaemic insult either by reducing the availability of glucose and oxygen, exposing the tissue to potassium cyanide or raising the intraocular pressure of an eye. In these cases the number of GABA-positive perikarya was also reduced. Only alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate of the excitatory amino acid agonists tested caused a release of serotonin and this process was antagonized by 6-cyano-2,3-dihydroxy-7-nitroquinoxaline-2,3-dione and partially by kynurenic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Sodium dodecyl sulfate solution is an effective between-run rinse for capillary electrophoresis of samples in biological matrices.

It is common practice in capillary electrophoresis to perform some sort of capillary washing step(s) between separations. In many analyses little consideration is given to optimization of the wash, and typically a rather standard washing procedure is used involving a few minutes wash with 0.1 M NaOH followed by a few minutes reconditioning with the run buffer. As an alternative to this procedure, we have investigated the use of wash solutions containing sodium dodecyl sulfate (SDS). This type of wash has been used in the analyses of both small molecules and proteins, with encouraging results. After the SDS wash, the electroosmotic flow has been shown to be restored to values close to normal in a capillary which had previously been coated with plasma proteins. Separation efficiency for a test compound (dextromethorphan) is improved if an SDS rather than a HCl-NaOH wash is used after injection of plasma. In a direct-injection analysis of plasma proteins using a pH 10 borate buffer, an SDS-based washing procedure (total time, 1 min) gave better migration-time reproducibility than an NaOH-based wash, which took 5 min in total.

Blood Proteins↗
PubMed1994

Increased trimipramine plasma levels during fluvoxamine comedication.

A depressive patient, a non-responder to trimipramine (TRI), was comedicated first with citalopram (CIT) and then with fluvoxamine (FLUV). Both the TRI-CIT and TRI-FLUV combination treatments led to a worsening of the depressive state and to the appearance of panic attacks. The addition of FLUV to TRI resulted in a twofold increase of the plasma levels of TRI and to a slight increase of its N-demethylated and 2-hydroxylated metabolites. These results suggest that the interaction between FLUV and TRI occurred at the level of cytochrome P-450IID6 and cytochrome P-450meph in this patient, phenotyped as an extensive metabolizer of both dextromethorphan and mephenytoin. The adverse effects were possibly due to (a) a pharmacokinetic interaction between CIT and FLUV with TRI and/or (b) alterations in serotonergic and/or dopaminergic neurotransmission.

Aged↗
PubMed2005

Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy.

OBJECTIVE: The purpose of this study was to determine whether drug metabolism (CYP1A2, CYP2D6 and CYP3A) activity varies in the pregnant state compared with the nonpregnant state. STUDY DESIGN: Subjects were studied at 14 to18 weeks of gestation, 24 to 28 weeks of gestation, and 36 to 40 weeks of gestation and again at 6 to 8 weeks after the delivery. Twenty-five subjects completed all 4 study periods and had evaluable data. Salivary caffeine clearance was used as a measure of CYP1A2 activity; dextromethorphan O- and N-demethylation were used to assess CYP2D6 and CYP3A activity, respectively. RESULTS: CYP1A2 activity was significantly reduced at all periods of the pregnancy as compared with the postpartum period during the first (-32.8% +/- 22.8%), second (-48.1% +/- 27%), and third periods (-65.2% +/- 15.3%), respectively. In contrast, CYP2D6 activity was increased significantly throughout the pregnancy (25.6% +/- 58.3% at 14-18 weeks of gestation, 34.8% +/- 41.4% at 24-28 weeks of gestation, and 47.8% +/- 24.7% at 36-40 weeks of gestation) as compared with the postpartum period. CYP3A activity was consistently, significantly increased (35%-38%) during all stages of the pregnancy. CONCLUSION: Opposing changes in drug metabolism occur during pregnancy, with CYP1A2 activity decreased and CYP2D6 and CYP3A activities increased. The direction of dosing adjustments during pregnancy will depend on the drug and the enzyme that is responsible for its metabolism.

Adolescent↗
PubMed2006

Heterotropic and homotropic cooperativity by a drug-metabolising mutant of cytochrome P450 BM3.

Recently, we described a triple mutant of the bacterial cytochrome P450 BM3 as the first mutant with affinity for drug-like compounds. In this paper, we show that this mutant, but not wild-type BM3, is able to metabolise testosterone and several drug-like molecules such as amodiaquine, dextromethorphan, acetaminophen, and 3,4-methylenedioxymethylamphetamine that are known substrates of human P450s. Interestingly, the metabolism of 3,4-methylenedioxymethylamphetamine and acetaminophen could be stimulated up to 70-fold by the addition of caffeine, a known activator of rat P450 3A2. With testosterone metabolism, homotropic cooperativity was observed. This shows that heterotropic and homotropic cooperativity, known to occur in the P450 3A family, can also take place in BM3. BM3 therefore can be used as a model system to study atypical kinetics in mammalian P450s. Second, this study shows that BM3 can be engineered to a drug-metabolising enzyme, making it a promising candidate to use as biocatalyst in drug discovery and synthesis.

Acetaminophen↗
PubMed2006

Effects of dextrorotatory morphinans on alpha3beta4 nicotinic acetylcholine receptors expressed in Xenopus oocytes.

We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects, and a recent report showed that DM reduces the adverse effects of morphine and blocks alpha3beta4 nicotinic acetylcholine receptors, a major target of anti-addictive agents. Here, we investigated the effects of DM, three of its analogs (DF, 3-methyl-17-methylmorphinan; AM, 3-allyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on neuronal alpha3beta4 nicotinic acetylcholine receptor channel activity expressed in Xenopus laevis oocytes, using the two-microelectrode voltage clamp technique. We found that intraoocyte injection of neuronal alpha3 and beta4 nicotinic acetylcholine receptor subunit cRNAs elicited an inward current (IACh) in the presence of acetylcholine. Co-treatment with DM, DF, AM, CM or HM inhibited IACh in a dose-dependent, voltage-independent and reversible manner. The IC50 values for DM, DF, AM, CM and HM were 19.5+/-5.2, 15.8+/-4.5, 16.3+/-1.7, 10.1+/-2.8, and 13.5+/-4.0 microM, respectively. The order of potency for the inhibition of IACh was CM>HM>DF=AM>DM in oocytes expressing alpha3beta4 nicotinic acetylcholine receptors. The inhibitions of (IACh) by DM, DF and HM, AM and CM were non-competitive. These results indicate that AM, CM and HM could be novel non-competitive agents regulating alpha3beta4 nicotinic acetylcholine receptor channel activity.

Animals↗
PubMed2006

Modeling film-coat non-uniformity in polymer coated pellets: a stochastic approach.

The objective of the present study is to include coating thickness non-uniformity in the development of a drug release model using coated ion-exchange pellets through the use of stochastic approaches. Drug release from ion-exchange resins was described using a Nernst-Plank model. Complexes of a model drug (dextromethorphan) and Dowex 50WX4-200 were prepared using a modified batch method and coated with Kollicoat SR 30D polymer. The deterministic model, validated using experimental drug release profiles for different coating thicknesses at 0%, 10%, 15%, 20% (w/w), was in agreement with the experimental data with a maximum root mean square error (RMSE) of 2.4%. An arbitrary Lagrangian-Eulerian approach was pursued to develop models of spherical pellets with non-uniform coating thicknesses. The Monte Carlo method was used to simulate the effect of the level of coating deformity on the cumulative drug release profile. Considering the co-existence of equal percentages of deformed and undeformed pellets in a batch, the cumulative release profile can vary by approximately +/-6% as a result of coating non-uniformity. The release profile obtained for a model of an arbitrary pellet with an actual non-uniform coating profile was in good agreement with the average release profile for the models of the theoretical randomly deformed pellets. The developed mathematical model is a useful tool to evaluate and predict release profiles of polymer coated ion-exchange resin complexes.

Algorithms↗
PubMed2004

A simplified analytical method for a phenotyping cocktail of major CYP450 biotransformation routes.

An efficient, fast and reliable analytical method was developed for the simultaneous evaluation of the activities of five major human drug metabolising cytochrome P450 (1A2, 2C9, 2C19, 2D6 and 3A4) with a cocktail approach including five probe substances, namely caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam. All substances were administered simultaneously and a single plasma sample was obtained 2h after the administration. Plasma samples were handled by liquid-liquid extraction and analysed by gradient high performance liquid chromatography (HPLC) coupled to UV and fluorescence detectors. The chromatographic separation was achieved using a Discovery semi-micro HS C18 HPLC column (5 microm particle size, 150 mm x 2.1 mm i.d.) protected by a guard column (5 microm particle size, 20 mm x 2.1 mm i.d.) The mobile phase was constituted of a methanol, acetonitrile and 20mM ammonium acetate (pH 4.5) with 0.1% triethylamine mixture and was delivered at a flow rate of 0.3 mL min(-1). All substances were separated simultaneously in a single run lasting less than 22 min. The HPLC method was formally validated and showed good performances in terms of linearity, sensitivity, precision and accuracy. Finally, the method was found suitable for the screening of these compounds in plasma samples.

Biotransformation↗
PubMed2004

Characterization of the non-competitive antagonist binding site of the NMDA receptor in dark Agouti rats.

The ability of non-competitive NMDA antagonists and other selected compounds to inhibit [3H]MK-801 binding to the NMDA receptor in brain membranes was evaluated in female, dark Agouti rats. In homologous competition binding studies the average apparent affinity (KD) of [3H]MK-801 for its binding site was 5.5 nM and the binding site density (Bmax) was 1.83 pmol/mg protein. Inhibition of [3H]MK-801 binding by non-competitive NMDA antagonists was best described with a one-site competition model and the average Hill coefficients were -1. A series of eight non-competitive NMDA antagonists inhibited [3H]MK-801 binding with the following rank order of affinity (K(i), nM): MK-801 (5.5) > dexoxadrol (21.5) > or = TCP (24.2) > phencyclidine (100.8) > (+)-SKF 10,047 (357.7) > dextrorphan (405.2) > ketamine (922.2) > dextromethorphan (2913). These inhibition binding constants determined in dark Agouti rat brain membranes were significantly correlated (P = 0.0002; r2 = 0.95) with previously reported values determined in Sprague-Dawley rats [Wong et al., 1988, J. Neurochem. 50, 274-281]. Despite significant differences in metabolic capability between these strains, the central nervous system NMDA receptor ion channel shares similar characteristics.

Animals↗
PubMed2003

Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats.

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.

Analgesics, Opioid↗
PubMed2002

Reduced (+/-)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro.

"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles (*)2, (*)10, and (*)17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (V(max)/K(m)) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (K(m)). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6(*)2, (*)17, and, particularly, (*)10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.

Alleles↗
PubMed1997

Induction of CYP2D6 in pregnancy.

Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.

Adult↗
PubMed1999

Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists.

The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450-mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2-receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.

Adult↗
PubMed2001

Uncompetitive NMDA receptor antagonists potentiate morphine antinociception recorded from the tail but not from the hind paw in rats.

We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA receptor antagonists dextromethorphan (2.5--30 mg/kg), memantine (2.5--15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25--10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.

Analgesics↗
PubMed2001

Role of the NMDA receptor subunit in the expression of the discriminative stimulus effect induced by ketamine.

Ketamine, which is a non-competitive NMDA receptor antagonist, has been used as a dissociative anesthetic agent. However, chronic use of ketamine produces psychotomimetic effects, such as nightmares, hallucination and delusion. Therefore, the present study was designed to ascertain the role of the NMDA receptor and sigma receptor in the discriminative stimulus effect induced by ketamine. Fischer 344 rats were trained to discriminate between ketamine (5 mg/kg, i.p.) and saline under a fixed-ratio 10 food-reinforced procedure. Non-competitive antagonists for both NR2A- and NR2B-containing NMDA receptors, such as phencyclidine (0.1--1 mg/kg, i.p.) and dizocilpine (3--30 microg/kg, i.p.), and the NR2A-containing NMDA receptor-preferred antagonist dextromethorphan (3--56 mg/kg, i.p.) fully substituted for the ketamine cue in a dose-dependent manner. By contrast, the NR2B-containing NMDA receptor antagonist ifenprodil (5--20 mg/kg, i.p.) exhibited no generalization. Additionally, the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonic acid ((+/-)-CPP; 0.3--5.6 mg/kg, i.p.) and a sigma receptor ligand DTG (0.3--3 mg/kg, s.c.) displayed no generalization to the ketamine cue. These results suggest that NR1/NR2A subunit containing NMDA antagonism may be critical for the production of the ketamine cue.

Animals↗