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At least 19 recordsLinked to original sources

PubMed1995

Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group.

BACKGROUND AND PURPOSE: Dextrorphan hydrochloride is a noncompetitive N-methyl-D-aspartate antagonist that is neuroprotective in experimental models of focal brain ischemia. The purpose of this study was to determine the maximum loading dose and maintenance infusion of dextrorphan hydrochloride that are well tolerated in patients with an acute stroke. METHODS: An intravenous infusion of dextrorphan or placebo was begun within 48 hours of onset of a mild-to-moderate hemispheric stroke. Initially, patients were treated with either placebo (n = 15) or dextrorphan (n = 22) using a 1-hour loading dose (60 to 150 mg) followed by a 23-hour ascending-dose maintenance infusion (maximum total dose, 3310 mg). Subsequently, 29 patients were treated with dextrorphan in an open trial using a 1-hour loading dose (145 to 260 mg) followed by an 11-hour constant rate (30 to 70 mg/h) infusion. RESULTS: Transient and reversible adverse effects, including nystagmus, nausea, vomiting, somnolence, hallucinations, and agitation, commonly occurred in dextrorphan-treated patients. Loading-dose escalation was stopped because of rapid-onset, reversible, symptomatic hypotension in 7 of 21 patients treated with doses of 200 to 260 mg/h. At the highest rates of maintenance infusion (> 90 mg/h), 3 patients developed deep stupor or apnea. The maximum tolerated loading dose was 180 mg/h, and the maximum tolerated maintenance infusion was 70 mg/h. Maximum plasma levels of 750 to 1000 ng/mL were obtained in 9 patients. There was no difference in neurological outcome at 48 hours between the dextrorphan-treated and placebo-treated patients. CONCLUSIONS: The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of dextrorphan. These doses were associated with well-defined pharmacological effects compatible with N-methyl-D-aspartate receptor antagonism.

Acute Disease↗

PubMed1992

High affinity [3H]dextrorphan binding in rat brain is localized to a noncompetitive antagonist site of the activated N-methyl-D-aspartate receptor-cation channel.

[3H]Dextrorphan recognition sites were characterized in rat brain membranes. The pharmacological profile and regional distribution of [3H]dextrorphan binding sites appear to distinguish these sites from those labeled either by [3H]dextromethorphan or by putative sigma receptor radioligands. Data from thoroughly washed forebrain membranes suggest that [3H]dextrorphan predominantly labels a high affinity site defined by the activated state of the N-methyl-D-aspartate (NMDA) receptor-channel complex. Regulation of [3H]dextrorphan binding by specific modulators of NMDA receptor function suggests that [3H]dextrorphan binding is predominantly localized to a domain of the receptor-channel complex also recognized by the prototypical noncompetitive antagonist radioligands (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) and [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The critical relationship between [3H]dextrorphan binding and activation of the NMDA receptor-complex is suggested by the profound dependence of [3H]dextrorphan binding on glutamate in well washed membranes. Basal specific [3H]dextrorphan binding is nearly totally suppressed by the specific competitive NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5), in a glutamate- but not glycine-surmountable manner. Glutamate and glycine each stimulate [3H]dextrorphan binding in a concentration-dependent manner, effecting maximal increases from control of up to 30- and 14-fold, respectively. The NMDA receptor specificity of the modulation of [3H]dextrorphan binding by glutamate and glycine is indicated by the sensitivity of their effects to competitive antagonism by D-AP5 and 3-amino-1-hydroxy-2-pyrrolidone (HA-966), respectively, and by the accordant rank orders of potency of glycine analogs as modulators of [3H]dextrorphan binding and as ligands at the strychnine-insensitive glycine site. The divalent cations Mg2+ and Zn2+ and the polyamines spermine and spermidine regulate [3H]dextrorphan binding in a manner consistent with radioligand interaction at the noncompetitive NMDA antagonist domain. Mg2+ and spermidine regulate [3H]dextrorphan binding biphasically in well washed forebrain membranes, whereas Zn2+ monotonically inhibits [3H]dextrorphan binding. Mg2+ and spermidine regulate [3H]dextrorphan binding with qualitative similarity and in a contrasting fashion to their regulation of [3H]MK-801 and [3H]TCP binding. First, spermidine and Mg2+ are significantly more potent modulators of [3H]dextrorphan binding than of [3H]MK-801 and [3H]TCP binding in well washed membranes; second, whereas the potencies of spermidine and Mg2+ as modulators of [3H]MK-801 and [3H]TCP binding are significantly increased by glutamate and glycine in well washed membranes, their potencies as regulators of [3H]dextrorphan binding appear to be unaffected by glutamate and glycine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

Protection after transient focal cerebral ischemia by the N-methyl-D-aspartate antagonist dextrorphan is dependent upon plasma and brain levels.

Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = -0.50, p less than 0.02 for ischemic neuronal damage; r = -0.66, p less than 0.001 for ischemic MRI high signal). All the rabbits with plasma levels greater than 2,000 ng/ml had less than 12% cortical ischemic neuronal damage and less than 34% MRI high signal. All rabbits with plasma levels greater than 3,000 ng/ml showed less than 7% ischemic neuronal damage and less than 11% MRI high signal. Plasma levels of approximately 2,500 ng/ml correlated with brain dextrorphan levels of approximately 6,000 ng/g. Unanesthetized rabbits with plasma levels of approximately 2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent glutamate or NMDA-induced injury in neuronal culture.

Animals↗

PubMed1993

Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine.

To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Dose-dependent and time-dependent pharmacokinetics in the dog after intravenous administration of dextrorphan.

The disposition of dextrorphan after single ascending iv doses and multiple iv dosing regimens was studied in Marshall beagle dogs. A dose-dependent decrease in plasma clearance was observed after the administration of single iv doses of 0.88 mg/kg, 2.64 mg/kg, and 8.8 mg/kg of dextrorphan (i.e. mean plasma clearance values +/- SD were 100 +/- 25 vs. 68 +/- 28 vs. 48 +/- 20 ml/min.kg, respectively; p less than 0.001). Upon multiple dosing, the plasma clearance of dextrorphan increased in a time-dependent fashion for the two highest doses, approaching values observed for the 0.88 mg/kg/day iv dosing regimen. Female dogs exhibited a greater increase in plasma clearance with time. For all dogs, however, dextrorphan plasma clearance approached or exceeded hepatic plasma flow rate, suggesting the possibility of extrahepatic metabolism or elimination. Modest dose- and time-dependent changes in the steady-state volume of distribution of dextrorphan also were observed. The AUC of the conjugated metabolites of dextrorphan decreased in a time-dependent manner for the 8.8 mg/kg/day dosing regimen. The nonlinear kinetics of dextrorphan after iv administration appeared to occur only after potentially toxic dosing regimens of dextrorphan hydrochloride. We postulate mechanisms to explain the dose- and time-dependent kinetics of dextrorphan observed in the beagle dog.

Animals↗

PubMed1988

Anticonvulsant effects of dextrorphan in rats: possible involvement in dextromethorphan-induced seizure protection.

The major metabolite of the non-opioid anticonvulsant/antitussive dextromethorphan is dextrorphan. In the present study, the effects of dextrorphan were determined in an experimental model of seizure activity (maximal electroshock convulsions) (MES). Subcutaneous administration of dextrorphan produced dose-related blockade of tonic hindlimb extension (THE) and a decrease in the duration of tonic forelimb extension (TFE). The anticonvulsant effect of dextrorphan was linear and maximally efficacious. Compared to the prototypical anticonvulsant drug diphenylhydantoin, dextrorphan was 2.5 times more potent (ED50's = 30 mumol/kg and 12 mumol/kg, respectively). Pretreatment with naloxone failed to antagonize dextrorphan-induced blockade of THE. Moreover, pretreatment with dextrophan failed to significantly enhance the anticonvulsant potency of diphenylhydantoin. It is likely that the anticonvulsant effects of dextrorphan are related to its actions at the phencyclidine/N-methyl-D-aspartate receptor complex, whereas the anticonvulsant effects of dextromethorphan have been attributed to binding to a specific dextromethorphan site in the brain. Therefore, we suggest that while metabolism to dextrorphan could possibly contribute to the anticonvulsant effects of dextromethorphan, it is probably through an unrelated receptor mechanism.

Animals↗

PubMed1983

Discriminative stimulus effects of dextrorphan in pigeons.

Pigeons were trained to discriminate between dextrorphan (10 mg/kg) and saline in a task in which 20 consecutive key pecks on either the left or right key, depending on whether dextrorphan or saline had been administered, produced food. During sessions in which stimulus generalization to other drugs was evaluated, 20 consecutive responses on either the dextrorphan- or saline-appropriate key produced food. Dextromethorphan and dexoxadrol produced dose-related stimulus control of behavior similar to that produced by dextrorphan. In contrast, the l-isomers of these compounds, levomethorphan, levoxadrol and levorphanol, at doses up to and including those that markedly decreased the rate of responding, produced responding primarily on the saline-appropriate key. In addition, both the d- and l-isomers of methadone, codeine, morphine, butorphanol and profadol resulted in predominantly saline-appropriate responding. l-Cyclorphan, dl-, l- and d-SKF-10,047 and l- and d-cyclazocine produced dose-related dextrorphan-appropriate responding, whereas, l-oxilorphan (the 14-hydroxymorphinan analog of cyclorphan), dl-, l- and d-pentazocine, l- and d-ethylketazocine and l-naltrexone resulted in either responding exclusively on the saline-appropriate key or responding that was intermediate between that appropriate for saline and dextrorphan. Although levorphanol alone produce little or no dextrorphan-appropriate responding, the coadministration of naltrexone (1.0 mg/kg) and high doses of levorphanol, but not levoxadrol, resulted in responding similar to that produced by dextrorphan.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Biphasic action of dextrorphan on penicillin induced bursting in rat hippocampal slice.

Effects of dextrorphan (DX), a metabolite of the over-the-counter antitussive, dextromethorphan, were investigated in rat hippocampal slices exposed to the epileptogenic agent penicillin. At 50 microM and 100 microM concentrations dextrorphan suppressed late components of the epileptiform CA1 field potential elicited by afferent electrical stimulation, and partially suppressed the intracellularly recorded paroxysmal depolarization shift. These effects were not due to non-specific changes in cell excitability, since resting cell membrane potential, input resistance, and the ability of cells to fire action potentials in response to direct depolarizing current were unaffected. The depressant effect of 100 microM dextrorphan was probably due to actions at the NMDA receptor, since pretreatment with the competitive NMDA antagonist D-APV prevented any further depressant effects of dextrorphan in this model. In contrast, at a 10 microM concentration DX enhanced the amplitude of evoked epileptiform field potentials and intracellularly recorded EPSPs. These findings support a role for dextrorphan and similar agents as anticonvulsants at high concentrations, but raise a caution regarding possible excitatory actions of dextrorphan at low concentrations.

2-Amino-5-phosphonovalerate↗

PubMed1993

High-performance liquid chromatography determination of dextromethorphan and dextrorphan for oxidation phenotyping by fluorescence and ultraviolet detection.

To establish the usefulness of fluorescence detection to quantify urinary concentrations of dextromethorphan and dextrorphan for oxidation phenotyping, we determined the molar concentration ratio of dextromethorphan to dextrorphan in 38 subjects by UV and fluorescence detection. Dextromethorphan and dextrorphan concentrations were quantified after overnight hydrolysis of urine samples and organic solvent extraction with heptane and butanol. The compounds were separated by high-performance liquid chromatography using a phenyl column and a mobile phase consisting of acetonitrile and an aqueous mixture of 0.01 M heptane sulfonic acid and 0.01 M phosphate buffer. The eluents were detected in series by a UV detector (280 nm) and fluorescence detector (excitation 280 nm and emission 310 nm). The dextromethorphan to dextrorphan molar concentration ratio by UV and fluorescence detection was highly correlated (r = 0.997) and not statistically different (p = 0.1036). However, increased sensitivity with fluorescence detection enabled detection of lower dextromethorphan and dextrorphan concentrations when compared with UV detection. Fluorescence detection was able to detect dextromethorphan as low as 0.02 microgram/ml, which may be helpful in phenotyping individuals with extremely rapid metabolism of dextromethorphan. Fluorescence detection also produced chromatograms with significantly less interference and allows a more accurate quantitation of dextromethorphan and dextrorphan concentrations.

Chromatography, High Pressure Liquid↗

PubMed1994

Dextrorphan and dextromethorphan: comparative antitussive effects on guinea pigs.

Dextromethorphan, after administration, is rapidly and extensively transformed into dextrorphan. The aim of this study was to compare the cough-suppressing activity of 6, 12, 24, 48 mg/kg, i.p., of dextrorphan (dextro rotatory isomer of racemorphan) with that of dextromethorphan, using the model of citric acid-induced coughing in the unanaesthetized, unrestrained guinea pig. A significant dose-effect relationship of dextrorphan in reducing citric acid-induced cough was observed. This effect was comparable with that of dextromethorphan. However, at 48 mg/kg, i.p., dextromethorphan had a toxic effect while dextrorphan did not. Because dextrorphan is the major metabolite of dextromethorphan and has antitussive activity comparable to that of dextromethorphan, clinical use of dextrorphan is suggested.

Animals↗

PubMed1990

Identification and initial characterization of high-affinity [3H]dextrorphan binding sites in rat brain.

We have identified specific high-affinity [3H]dextrorphan binding sites in rat forebrain. [3H]Dextrorphan binds saturably and reversibly to an apparently homogenous class of sites characterized by a Bmax of 2.62 +/- 0.06 pmol/mg protein and KD of 60 +/- 4 nM. Glycine and glutamate independently increase [3H]dextrorphan binding in a concentration-dependent manner. The pharmacological profiles of [3H]dextrorphan binding characterized by equilibrium competition experiments together with these data suggest that [3H]dextrorphan labels a site at or near the N-methyl-D-aspartate receptor.

Animals↗

PubMed1981

Stereospecific dextrorphan tolerance in rats.

1 Levorphanol was 20 times more potent than dextrorphan in decreasing food-reinforced fixed ratio 15 responding in male Sprague Dawley rats. 2 Chronic dextrorphan (100 mg/kg, i.p.; every 8 h) resulted in the development of dextrorphan tolerance. The dextrorphan dose-effect curve was shifted to the right three fold. 3 In contrast to dextrorphan, nontolerance developed to the effects of levorphanol. 4 These data support the hypothesis that (+)-isomers of opioids produce pharmacologically distinct CNS effects.

Animals↗

PubMed1993

Comparative pharmacokinetics of oral dextromethorphan and dextrorphan in the rabbit.

The pharmacokinetics of dextromethorphan (CAS 125-71-3) and its metabolite dextrorphan (CAS 125-73-5) was compared. The drugs were administered orally at the same molar dose of 0.085 mmol/kg. Plasma levels of dextromethorphan, dextrorphan, and metabolites 3-hydroxymorphinan and 3-methoxymorphinan were determined by HPLC with fluorimetric detection. Dextromethorphan was rapidly and extensively metabolized and the plasma profiles of dextrorphan, administered directly or as metabolite of dextromethorphan, were similar. The concentrations of 3-hydroxymorphinan were higher after dextromethorphan than dextrorphan. 3-Methoxymorphinan was detectable only 60 and 120 min after dextromethorphan. This work proposes the therapeutic use of dextrorphan instead of its precursor dextromethorphan.

Administration, Oral↗

PubMed1987

Dextrorphan: an antagonist for phencyclidine receptors.

Radio-binding assay, bioassay and HPLC detection were used to observe the antagonistic effects of dextrorphan on PCP's actions. Dextrorphan displayed high affinity to PCP receptor in the rabbit mesenteric blood vessels. It had weak PCP-like bioactivity, but could antagonize PCP's action dose-dependently in vitro study with the rabbit ear artery preparation and shifted the dose-response curve of PCP to the right. After PCP administration, the content of norepinephrine in the vascular bath medium was increased, which was reversed by dextrorphan. Thus suggests that dextrorphan is an antagonist with very mild agonistic action for PCP receptors.

Animals↗

PubMed1989

The N-methyl-D-aspartate (NMDA) receptor antagonist, dextrorphan, prevents the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats.

Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.

3,4-Methylenedioxyamphetamine↗

PubMed1990

Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus.

Dextrorphan (+)-tartrate, purified by repeated crystallization to remove all traces of the enantiomer levorphanol, binds to mu, delta, and kappa sites on guinea-pig brain membranes with lower affinities (by a factor of 400-3200) than levorphanol. In the guinea-pig ileum myenteric plexus longitudinal muscle preparation (GPI), dextrorphan, at 100-200 microM, inhibits the electrically stimulated twitch, but this action is not blocked or reversed by naloxone; both (+)- and (-)-naloxone produce similar non-opioid twitch inhibition at comparable concentrations. At 10-20 microM, dextrorphan blocks and reverses the twitch inhibition due to mu and kappa agonists, but the blockade can be overcome only partially by increasing the agonist concentration. We conclude that dextrorphan is an opioid ligand with low affinity and with antagonist effect on opioid receptors in the GPI.

Animals↗

PubMed1977

Prenatal administration of levorphanol or dextrorphan to the rat: analgesic effect of morphine in the offspring.

We have recently demonstrated that prenatal administration of morphine to the rat results in tolerance to the analgesic effects of morphine in the offspring at 3 to 11 weeks of age. To extend these findings, levorphanol or dextrorphan was administered to female CFE rats during days 5 to 12 of gestation. Control animals were injected with 0.9% saline on the same schedule. At 5 weeks of age all offspring were tested with graded doses of morphine in the hot-plate test for analgesia. Morphine produced a dose-related increase in analgesia in all offspring, but the effect of morphine in the offspring of levorphanol-treated females was significantly reduced compared to the offspring of saline-treated females; the analgesic effect of morphine did not differ between the offspring of the dextrorphan- and saline-treated females. The analgesic effect of morphine remained reduced in 9-week old offspring of levorphanol-treated females compared to the corresponding offspring of females that had received saline. Diminished analgesic activity of morphine in the offspring of levorphanol-treated females compared to the offspring of females that had received dextrorphan or saline was still observed even when the offspring were rendered tolerant to morphine by daily drug injections over a period of 5 days. Thus, the protracted tolerance to the analgesic effects of morphine can also be produced by a morphine congener (levorphanol), but not by its analgesically inactive (+) isomer (dextrorphan).

Analgesics, Opioid↗

PubMed1986

Dextrorphan: an antagonist for phencyclidine receptor.

Radio-binding assay, bioassay and HPLC detection were used to observe the antagonistic effects of dextrorphan on PCP's actions. Dextrorphan displayed high affinity to PCP receptors and it had weak PCP-like bioactivity, but could antagonize PCP's action dose-dependently in vitro and shift the dose-response curve to the right. PCP increased the contents of norepinephrine in bath medium, which was reversed by dextrorphan. Thus, the results suggest that dextrorphan is a partial antagonist for PCP receptors.

Animals↗