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PubMed1992

Cytochrome P450-dependent metabolism of dextromethorphan: fetal and adult studies.

Dextromethorphan undergoes O-demethylation to dextrorphan and N-demethylation to 3-methoxymorphinan. 3-Hydroxymorphinan, a didemethylated compound, is secondarily formed. The O-demethylation pathway to dextrorphan is polymorphic and under CYP2D6 genetic control. Adult and fetal studies were performed to characterize the cytochrome P450 families involved in dextromethorphan metabolism and their ontogeny. In adult volunteers in vivo and in vitro studies demonstrate that the O-demethylation pathway to dextrorphan is dependent on CYP2D6 and is predominant in extensive metabolizers and defective in poor metabolizers of the drug. The N-demethylation pathway to 3-methoxymorphinan is accessory and is dependent on the CYP3A subfamily. In human fetal microsomes, CYP2D6 protein and activity are not detectable until birth, while CYP2D6 RNA is present in significant amounts before birth. CYP3A activity is detectable in large amounts as early as the 17th week of gestation. Fetal and adult members of the CYP3A subfamily have close, although different, properties, as demonstrated by immunoinhibition studies.

Adult↗
PubMed1990

Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet.

We compared in this double-blind crossover study the bioavailability of dextromethorphan from a dextromethorphan-salbutamol combination tablet (Redol comp) and from a plain dextromethorphan tablet (Extuson) by determining dextrorphan concentrations after single-dose oral administration in 10 healthy volunteers. The absorption of salbutamol from the combined preparation was also determined. The absorption of dextromethorphan was slightly faster from the plain dextromethorphan preparation. The peak concentration of dextrorphan was achieved at 1.5 h after Extuson and at 2 h after Redol comp (1,053.0 +/- 366.5 ng/ml and 901.5 +/- 210.9 ng/ml, NS). AUC0-12 values of dextrorphan were 4,315.6 +/- 295.0 (ng/ml)h after Extuson and 3,983.8 +/- 205.6 (ng/ml)h after Redol comp (p less than 0.05). Salbutamol was well absorbed from the combined preparation and the peak concentration was achieved at 3 h (6.57 +/- 2.95 ng/ml). Four subjects reported side-effects typical for salbutamol after the combination tablet. No side-effects were reported after the plain dextromethorphan tablet. On the basis of the present study, we conclude that the absorption of dextromethorphan from the preparations tested is almost equal and the dextromethorphan-salbutamol combination can be administered in tablet form for the treatment of cough.

Adult↗
PubMed1984

Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects.

Plasma kinetics of dextromethorphan (as dextrorphan ) and codeine were investigated after acute oral doses in 8 patients with pathological cough; after which the patients participated in an acute dose-response study of the antitussive effects of each drug administered as syrups. Maximum plasma codeine concentrations averaged 384 ng.ml-1 (s.d. +/- 78.3) occurring between 0.75 and 2h after ingestion of 60 mg codeine phosphate; in comparison mean peak plasma dextrorphan levels were 386 ng.ml-1 (s.d. +/- 107.2) and 388 ng.ml-1 (s.d. +/- 101.3) respectively, after administration of 60 mg dextromethorphan syrup and tablet formulations. Bioavailability of dextromethorphan tablets was comparable to syrup. No correlation emerged between instantaneous plasma concentrations of either dextrorphan or codeine and antitussive responses; however, peak antitussive effect was significantly related to log dose with both drugs. Antitussive effects of 30 mg codeine phosphate and 60 mg dextromethorphan hydrobromide did not differ significantly; both were superior to 30 mg dextromethorphan hydrobromide and placebo.

Administration, Oral↗
PubMed1997

Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat.

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.

Amphetamine↗
PubMed1996

Pharmacokinetics and polymorphic oxidation of dextromethorphan in a Japanese population.

The plasma concentration and cumulative urinary excretion over 34 h of dextromethorphan, free and conjugated dextrorphan, and 3-hydroxymorphinan were determined in seven healthy Japanese subjects after oral administration of 30 mg dextromethorphan hydrobromide. Conjugated metabolites were extensively present, whereas no detectable dextromethorphan or free metabolites were observed in the plasma of any subject. On average, 72% of the dose was excreted in urine within 34 h. This was detected mainly as conjugated metabolites with only slight traces of dextromethorphan and free metabolites. From the time-courses of the metabolic ratio (the ratio of urinary output of dextromethorphan to dextrorphan), the metabolic ratios seemed to become constant 7.5 h after oral administration. Phenotyping was performed using metabolic ratios in 75 unrelated healthy Japanese subjects (43 males and 32 females). The logarithmic metabolic ratio was bimodally distributed and one subject (1.3%) was identified as a poor metabolizer.

Administration, Oral↗
PubMed1996

Characterization of [3H]MK-801 binding to N-methyl-D-aspartate receptors in cultured rat cerebellar granule neurons and involvement in glutamate-mediated toxicity.

The conditions required for growth and survival of cerebellar granule neurons in vitro are known to alter the developmental regulation of NMDA receptor subunit mRNA. In the present report, we have examined the functional and pharmacological characteristics of NMDA receptors on cerebellar granule neurons at 12 days in culture (12 DIC). Under open-channel conditions in extensively washed membranes, [3H]MK-801 labeled a uniform population of sites (Kd = 3.2 +/- 0.3 nM) in a saturable manner (Bmax = 416 +/- 18 fmol/mg); however, biexponential association and dissociation kinetics indicated the possible existence of at least two NMDA receptor populations that differ in pharmacological properties. The kinetically derived equilibrium dissociation constants for the high- and low-affinity binding components were 0.56 and 771 nM, respectively. The equilibrium competition analysis of MK-801 and other channel-blocking compounds as displacers of [3H]MK-801 revealed the presence of high- and low-affinity binding sites with relative apportionments of 70% and 30%, respectively. The rank-order potency profile of competitor binding at the high-affinity site was (+)-MK-801 > TCP > dextrorphan > dextromethorphan > (+)-ketamine. When tested for the ability to protect 12 DIC cerebellar granule neurons from acute glutamate-induced toxicity, the neuroprotective rank-order potency of these compounds was MK-801 > TCP > dextrorphan > (+)-ketamine > dextromethorphan, which correlated significantly with the high-affinity competition binding profile and thus established the role of NMDA receptors in glutamate toxicity. The findings of these experiments indicate that NMDA receptors on 12 DIC cerebellar granule neurons are a heterogenous population that functionally mediate glutamate-induced neurotoxicity. The heterogenous [3H]MK-801 binding sites may represent NMDA receptor channels composed of different subunits.

Animals↗
PubMed1979

Drugs that antagonize limb flick behavior induced by D-lysergic acid diethylamide (LSD) in cats.

In cats observed in their home cages limb flicks (LF) are a sensitive measure of the behavioral effects of LSD. LF induced by LSD (50 microgram/kg) were blocked by dextrorphan (0.6 mg/kg), dextromethorphan (0.6 mg/kg), and imipramine (5 mg/kg) at doses that did not produce ataxia or sleep. Levorphanol (0.6 mg/kg), a narcotic that is a congener of dextrorphan, did not block LF induced by LSD possibly because it produced an excitatory effect when given alone. Pentobarbital at low doses (2 and 4 mg/kg) increased the number of LF induced by LSD but at a high dose (8 mg/kg) decreased LF induced by LSD either by producing ataxia, so the cats tended to remain immobile, or by producing sleep. Chlorpromazine (CPZ) at three doses (2, 4, and 8 mg/kg) attenuated the effects of LSD on LF, but did not block LF as completely as the above three blocking drugs, and produced ataxia and sleep.

Animals↗
PubMed1975

The stimulus properties of morphine and ethanol.

The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1-3 mg/kg) and dextrorphan (3-100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.

Animals↗
PubMedDate not supplied

Adjunctive brainstem behaviors in the rat.

UNLABELLED: Adjunctive behaviors refers to behaviors that are "out of context" and/or excessive in amount. The terminology was first used for unexplained behaviors associated with food pellet ratio contingencies in food deprived rats (Falk, 1971). Clinically, unrelated and complex excessive behaviors were also noted with brainstem and diencephalic discharges (Andy, 1986, 1989 and 1995; Andy and Jurko, 1986). The objective of this study was to develop a model of brainstem generated adjunctive behaviors in the rat. METHOD: Sixty-one adult rats were used. Kindling was induced by mechanical and DC electrical perturbations in the midbrain. Nine different treatment groups were established in which lesions and drugs were used separately and in different combinations. Cocaine was used to accentuate, and dextrorphan to attenuate the kindling process. Behaviors were visually analyzed and recorded by video camera; they were not quantified. DC stimulation and EEGs were doen with Grass instruments. Recording and stimulation sights were verified histologically. RESULTS: A total of 45 different behaviors were elicited. DC stimulation kindled subjects had significantly more behaviors than did electrode insertion alone and cocaine alone. However, cocaine combined with DC stimulation increased the number and intensity of the kindled behaviors. Dextrorphan tended to facilitate catatonic and sleep states. Behaviors occurred randomly and were unrelated, even when they occurred in clusters. The behaviors were associated with four abnormal EEG discharge patterns. CONCLUSION: We speculate that brainstem behaviors are innate adjunctive drives that are generated in the brainstem reticular formation. They are monitored by the cortex and partially modified by environmental and cortical inputs.

Animals↗
PubMed1992

Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone.

The opioid antagonist, naltrexone, was used to identify some of the receptor mechanisms responsible for the discriminative stimulus effects of cyclorphan in the pigeon. Subjects were trained to discriminate 10 mg/kg IM injections of either morphine or dextrorphan from saline injections in a two key drug discrimination procedure in which responding was maintained by food presentation. The dextrorphan-trained birds generalized to l-cyclorphan at 10 mg/kg; naltrexone did not alter the l-cyclorphan dose-response curve for this effect. In the morphine-trained group, l-cyclorphan produced only partial generalization, and naltrexone greatly increased the dose of l-cyclorphan necessary to produce this effect. These results are consistent with the conclusion that in morphine-trained pigeons the partial generalization to l-cyclorphan is mediated by opioid receptors. Moreover, limited intrinsic efficacy at mu opioid receptors may be the characteristic of l-cyclorphan that prevents full generalization in morphine-trained pigeons. d-Cyclorphan produced partial generalization in both groups, but the involvement of opioid receptor mechanisms could not be confirmed, as 1 mg/kg naltrexone did not antagonize d-cyclorphan in either group.

Animals↗
PubMed2006

Effects of N-methyl-D-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias.

RATIONALE: Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma. OBJECTIVE: The objective of the present study was to elucidate the role of N-methyl-D-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats. METHODS: Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit. RESULTS: All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05). CONCLUSIONS: These results suggest that NMDA receptors may play a significant role in the pathophysiology of tardive dyskinesia. Furthermore, antagonists showing selectivity for NMDA receptors containing the NR2B subunit may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further testing.

Allosteric Regulation↗
PubMed2005

Dextromethorphan metabolic phenotyping in an Iranian population.

OBJECTIVE: CYP2D6 polymorphism of drug metabolism represents an important source of interindividual and interethnic variation in drug response. Since this polymorphism has not been studied in an Iranian population, the present study was undertaken. METHODS: Two hundred healthy unrelated Iranian subjects participated in this study. Phenotyping was based on high-performance liquid chromatography determination of the dextromethorphan/total dextrorphan molar ratios as metabolic ratios (MRs) in plasma samples collected at 3 h after oral administration of 30 mg dextromethorphan hydrobromide. Since the dextromethorphan detection limit of 5 ng/ml achieved in the simultaneous assay for dextromethorphan and its metabolites was not adequate to identify intermediate metabolizers (IMs), 80 of 200 samples selected randomly were also assayed using a modified, more sensitive procedure with a dextromethorphan detection limit of 1 ng/ml. RESULTS: Poor and extensive metabolizers (EMs) could be identified distinctly. A 520-fold interindividual variation in dextromethorphan MRs was observed in this study. In contrast to undetectable dextrorphan and hydroxymorphinan concentrations, clearly determinable dextromethorphan concentrations higher than 10 ng/ml were observed in plasma samples of poor metabolizers (PMs). Considering the antimode of 0.3, five (2.5%, 95% confidence interval of 0.34-4.66) volunteers were identified as PMs. Using the more sensitive method, dextromethorphan was quantified in 4 (one PM) of 80 samples. Excluding the PM, a Shapiro-Wilk test indicated a non-normal distribution of MRs (P < 0.01) in the latter population. CONCLUSIONS: From this study it can be concluded that the frequency of PMs in an Iranian population is 2.5% (95% confidence interval of 0.34-4.66). IMs could be identified using dextromethorphan plasma assays with detection limits of at least 1 ng/ml. However, the phenotype-genotype relationships in this respect remain to be established.

Adult↗
PubMed1984

Disruption of ongoing maternal responsiveness in rats by central administration of morphine sulfate.

The ability of central morphine administration to disrupt established maternal responsiveness in rats was examined. Studies focused on the direct administration of morphine sulfate (M) to the preoptic area (POA), a region known to be involved in the expression of maternal behavior in this species. In the first experiment, crystalline M was administered via bilateral 28 g cannulae to the POA or ventromedial hypothalamus (VMH) of 31 ovariectomized, estrogen-primed, nulliparous, pup-induced, maternal females. All subjects were tested twice for maternal responsiveness; once after M-filled cannulae and once after blank inserts were lowered into place. Behavioral tests lasted for 1 h after foster young were introduced into the test cage, and retrieval, grouping and crouching responses were recorded. Thirteen of 14 females with cannulae placements in the POA showed disruption of maternal responsiveness following morphine treatment. In contrast, only 4 of 17 females with VMH implants showed some deficit in maternal behavior following opiate administration. Results of a second experiment established that M-filled implants placed in the POA of lactating females were capable of disrupting the responsiveness of nursing females toward their own young. Finally, the specificity of morphine's central effects were examined in a third experiment in which lactating females received bilateral POA infusions of morphine (0.5 microgram, n = 7), dextrorphan (an inactive stereoisomer of an active opioid compound; 1.0 microgram, n = 7) or saline alone (n = 6). Whereas maternal behavior was disrupted in all morphine-treated subjects, infusions of dextrorphan or saline had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Stereospecificity of an opiate action on the excitable membrane of frog skeletal muscle fibres.

Intracellular microelectrode studies were conducted to examine the actions of the optical isomers levorphanol and dextrorphan on the isolated frog sartorius muscle preparation. Both isomers, in bath concentrations which had minimal effect on action potential amplitude and gNa (3 X 10(-5) M), caused a large depression of gK. High bath concentrations (3 X 10(-4) M) of both drugs caused an initial depression of sodium and potassium conductance processes, gNa and gK, respectively, however only levorphanol, but not dextrorphan, could produce a specific, late-occurring depression of gNa that could be blocked by the opiate antagonists, nalorphine or naloxone. These findings indicate that the late-occurring depressant effect on gNa is stereospecific and reinforce previous findings which demonstrated that opiate drugs interact with opiate receptors associated with the sodium channels of the frog muscle fibre membranes.

Action Potentials↗
PubMed1984

Depression by morphine and levorphanol of activity in sympathetic nerve fibres in anaesthetized rats.

In urethane-anesthetized rats, the effects of intravenous injections of morphine, levorphanol, dextrorphan, pentazocine and naloxone were studied studied on the activity in nerve fibres of the cervical sympathetic trunk, and on mean arterial blood pressure and heart rate. Impulse frequency in sympathetic nerve fibres was recorded with tungsten microelectrodes and proved to be more sensitive to drug action than blood pressure or heart rate. Morphine 1 and 2 mg/kg dose dependently reduced sympathetic impulse frequency, blood pressure and heart rate; morphine 0.5 mg/kg was ineffective. Levorphanol 1 and 2 mg/kg dose dependently reduced sympathetic impulse frequency and blood pressure but did not affect heart rate. Dextrorphan (the dextro-isomer of levorphanol) 2 and 4 mg/kg had no effect on the parameters tested. Pentazocine 3 and 6 mg/kg did not cause a consistent change in sympathetic impulse frequency, blood pressure and heart rate. Naloxone 0.2 mg/kg abolished the depressant effects of morphine and levorphanol and, when given alone, increased sympathetic impulse frequency. Naloxone 1 mg/kg increased blood pressure but did not affect heart rate. It is concluded that morphine can reduce blood pressure and heart rate by causing opiate-specific central sympathetic depression.

Adrenergic Fibers↗
PubMed1992

Dextrorotatory opioids and phencyclidine exert anticonvulsant action in prepiriform cortex.

We have investigated the ability of an array of putative noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists to suppress convulsions induced by a unilateral, focal injection of (-)-bicuculline methiodide (118 pmol) into the rat prepiriform cortex. The anticonvulsant potency of these compounds, (+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) greater than dextrorphan greater than or equal to 1-(1-phenylcyclohexyl)piperidine hydrochloride (PCP) greater than dextromethorphan greater than (+)-pentazocine, upon microinjection into the prepiriform cortex, was highly correlated (r = 0.971; P less than 0.01) with their respective affinities for the [3H]dextrorphan-labelled NMDA receptors in rat forebrain membranes. These results suggest that noncompetitive antagonism of NMDA receptors underlies the anticonvulsant action of these compounds.

Animals↗
PubMed1984

Interaction of dextrorotatory opioids with phencyclidine recognition sites in rat brain membranes.

The potencies of several dextrorotatory opioids, including four pairs of enantiomers, as inhibitors of specific [3H]PCP binding to rat brain synaptic membranes has been determined. Of the compounds tested unlabeled phencyclidine (PCP) was the most potent followed by (-)-cyclazocine greater than dextrorphan greater than (+) ketamine greater than (+) cyclazocine greater than (+)- SKF10 ,047 greater than levorphanol greater than dextromethorphan greater than (-) SKF10 ,047 greater than (-)-ketamine greater than (+/-) pentazocine and greater than (+/-) ethylketocyclazocine. The opiate mu receptor ligands, morphine, naloxone and naltrexone were virtually inactive as competitors of specific [3H]PCP binding. Unlike the stereostructural requirements for opiate mu receptors where activity resides predominantly in the levorotatory enantiomers, the present results support the contention that binding to the [3H]PCP labeled recognition site may reside in either the levorotatory or the dextrorotatory enantiomer. The specific binding of [3H]PCP which was defined as total binding minus that occurring in the presence of 10 microM dextrorphan was found to be of a high affinity, saturable, reversible and sensitive to thermal degradation. These results suggest that certain dextrorotatory morphinan derivatives may prove to be useful probes in further investigations of the molecular characteristics of the [3H]PCP binding site in brain membrane preparations.

Animals↗
PubMed1989

Differentiation of phencyclidine and sigma receptor types affecting the central inspiratory termination mechanism in cat.

The effects of 1) the phencyclidine receptor ligand TCP, 2) sigma receptor ligands (+)3-PPP and DTG, and 3) N-methyl-D-aspartate receptor blockers MK-801 and dextrorphan were determined on a brainstem mechanism which controls the termination of the inspiratory phase of the breathing cycle. Inspiratory bursts were recorded from the phrenic nerve in decerebrate paralyzed cats ventilated by means of a phrenic driven servoventilator. The central mechanism which terminates inspiration was tested by withholding lung inflation, thus suppressing the contribution of the vagal feedback from the lungs to inspiratory termination. TCP increased the duration of test inspiration (tTi) by 17% at 0.03 mg/kg and by 14-fold (from 1.6 to 23 s) at 1 mg/kg. With dextrorphan, tTi was significantly increased at 3 mg/kg. In contrast, (+)3-PPP and DTG did not increase tTi at doses up to 10 mg/kg, although MK-801 (0.03 mg/kg), given after the sigma ligands, increased tTi by 59-90%. It is concluded that phencyclidine but not sigma receptor ligands block the central mechanism which terminates inspiration and that the likely site of action is the NMDA receptor complex.

Animals↗