morphinans and dimemorfan

Investigate the pharmacokinetic properties of the antitussive dimemorfan phosphate tablets in healthy male and female Chinese volunteers after single and multiple-dose administration; and to evaluate the food-effect on pharmacokinetics of dimemorfan.. 12 subjects received a single dose of 10 mg and 40 mg dimemorfan phosphate tablets, respectively in study stage 1. Another 12 subjects received a single dose of 20 mg dimemorfan phosphate tablets under fed conditions, a single dose of 20 mg dimemorfan phosphate tablets under fasting conditions and multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day, respectively in study stage 2. The washout between each treatment was 1 week. Plasma dimemorfan was quantified by a high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.. After single-dosing of 10 mg, 20 mg and 40 mg dimemorfan phosphate tablets, C. Single-dosing of dimemorfan phosphate tablets exhibited linear kinetic characteristics. Multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day caused obvious accumulation. No food effect or sex effect on the pharmacokinetics of dimemorfan phosphate tablets was observed. Chictr.org identifier: ChiCTR-ONC-14004851.

Topics: Antitussive Agents; Area Under Curve; Asian People; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Food-Drug Interactions; Humans; Male; Morphinans; Tablets; Tandem Mass Spectrometry; Young Adult

This study aimed to investigate the effects of cytochrome P450 2D6*10 (100C > T, rs1065852) genotype on the pharmacokinetics of dimemorfan in healthy Chinese subjects. Data were evaluated from 24 subjects in two pharmacokinetic studies who received an oral dose of 40 mg of dimemorfan syrup (n = 12) or dimemorfan tablet (n = 12) after providing written informed consent and being divided into three groups: subjects with CYP2D6*10 CC (n = 5), CYP2D6*10 CT (n = 11) and CYP2D6*10 TT (n = 8). CC homozygotes and CT heterozygotes were defined to be C allele carriers. The CYP2D6*10 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Dimemorfan was measured by LC-MS/MS. There was significant difference in C max, AUC0-t , AUC0-inf, V z , and CL values of dimemorfan observed among the three CYP2D6*10 genotype groups (GLM, (a) P < 0.05, co-dominant model). CYP2D6*10 under the recessive model (CC + TC vs TT) was significantly associated with pharmacokinetics of dimemorfan ((c) P < 0.05). The C max values were significantly higher in subjects with CYP2D6*10 TT (8.06 ± 4.43 ng/mL) than CYP2D6*10 CC (3.41 ± 2.79 ng/mL), CYP2D6*10 CT (3.11 ± 2.47 ng/mL), so was AUC0-inf. V z /F and CL/F of subjects with CYP2D6*10 TT homozygotes were the lowest. We demonstrated that cytochrome P450 2D6*10 (100C > T, rs1065852) polymorphism can affect the pharmacokinetics of dimemorfan in humans, not dosage forms.

Topics: Administration, Oral; Asian People; Cytochrome P-450 CYP2D6; Female; Genotype; Healthy Volunteers; Humans; Male; Morphinans; Pharmaceutical Solutions; Young Adult

Dimemorfan phosphate has been widely used for 40 years throughout the world for the treatment of coughs. This is the first report on the use of an LC-MS/MS-based assay for the determination of dimemorfan in human plasma using estazolam as an internal standard after one-step protein precipitation with acetonitrile. Chromatographic separation was achieved on a Phenomenex Luna C18 column (3 µm, 50 × 2.0 mm) using a fast gradient method, which involves water and methanol as the mobile phase (both containing 0.1% formic acid). Dimemorfan and estazolam were detected with proton adducts at m/z values of 255.8 → 155.1 and 295.0 → 267.0, respectively, in the selected reaction monitoring positive mode. The linear dynamic range of the assay was 0.04-5.00 ng/mL. The chromatographic run time for each plasma sample was <5 min. The method was proven to be accurate, precise, and repeatable. Finally, the developed method was successfully applied for the determination of dimemorfan in a pharmacokinetic study using healthy Chinese subjects.

Topics: Adolescent; Adult; Antitussive Agents; Chromatography, High Pressure Liquid; Cough; Female; Humans; Male; Morphinans; Sensitivity and Specificity; Tandem Mass Spectrometry; Young Adult

To develop a sensitive and reproducible HPLC-MS/MS method for analyzing dimemorfan in human plasma and urine.. Dimemorfan was extracted from plasma and urine by redistilled ether, with lidocaine serving as the internal standard (IS). The analysis was performed on a column of ultimate C18 (50 mm x 4.6 mm, 5 microm) with the mobile phase consisting of methyl alcohol-water-formic acid = 75:25 : 0.05 at a flow rate of 0. 2 mL/min. Dimemorfan was detected by API 3000 mass spectrometer, with multiple reaction monitoring after protonated with ESI in positive electron ionization mode. The ion pairs being detected were (m/z) 256.4-->155. 3 (dimemorfan) and 235.4-->86.1 (lidocaine), respectively.. The regression equation for dimemorfan showed excellent linearity (r = 0.995 7) from 0. 025 to 5.0 ng/mL of plasma with detecting limitation of 0.025 ng/mL and perfect linearity (r = 0.9983) from 0.1 to 20.0 ng/mL of urine with detecting limitation of 0.1 ng/mL. The method recoveries of dimemorfan in plasma and urine were ranging from 103.38% to 106.88% and 90.05% to 101.40%, respectively. The maximum intra-day and inter-day relative standard deviations (RSD) of concentration of dimemorfan were 5.92% and 5. 70% (for plasma), 10.35% and 8.80% (for urine), respectively.. This new method was validated to be accurate and sensitive to determinate the concentration of dimemorfan in plasma and urine samples, and can be applied for pharmacokinetic studies of dimemorfan.

Topics: Chromatography, High Pressure Liquid; Humans; Morphinans; Tandem Mass Spectrometry

Dimemorfan was extracted from human plasma samples (100 μL) using MonoTip C(18) tips, which were packed with a C(18)-bonded monolithic silica gel attached to the inside of the tip. The samples, which contained dimemorfan and trimeprazine as an internal standard (IS), were mixed with 300 μL of distilled water and 50 μL of 1M glycine-sodium hydroxide buffer (pH 10). The mixture was extracted onto the C(18) phase of the tip by 20 sequential aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C(18) phase were then eluted with methanol by five sequential aspirating/dispensing cycles. The eluate was injected directly into a gas chromatograph and detected by a mass spectrometer with selected ion monitoring in positive electron ionization mode. An Equity-5 fused silica capillary column (30 m × 0.32 mm i.d., film thickness 0.25 μm) gave adequate separation of the dimemorfan, IS, and impurities. The recoveries of dimemorfan and the IS spiked into plasma were ≥83%. The regression equation for dimemorfan showed excellent linearity from 0.25 to 32.0 ng/100 μL of plasma, and the limit of detection was 0.125 ng/100 μL of plasma. The maximum intra-day and inter-day relative standard deviations were 13%, while accuracy ranged from 88% to 105%. Dimemorfan was stable for at least 12 h at 4°C, 4 weeks at -80°C, and three freeze-thaw cycles in plasma. This new method is expected to have application as a pretreatment for the rapid, simple, and quantitative determination of dimemorfan in plasma samples.

Topics: Antipruritics; Antitussive Agents; Humans; Morphinans; Plasma; Solid Phase Extraction; Trimeprazine

To characterize the human cytochrome P450 (P450) forms involved in dimemorfan oxidation (DFO), human liver microsomes, and recombinant P450s were investigated. Liquid chromatography-mass spectral analysis suggested that metabolite (M)1 ([M + H](+) m/z at 272.200) and M2 ([M + H](+) m/z at 242.190) were d-3-hydroxymethyl-N-methylmorphinan and d-3-methylmorphinan, respectively. Kinetic analyses of microsomal DFO showed that the substrate concentration showing a half-maximal velocity (S(50)) of M1 formation was less than that of M2. Microsomal M1 and M2 formation activities correlated significantly with the CYP2D6 marker, dextromethorphan O-demethylation activity. The M2 formation activity was also correlated with the CYP3A4 marker, nifedipine oxidation activity. Microsomal M1 and M2 formation was most sensitive to the inhibition by a CYP2D6 inhibitor, paroxetine and a CYP3A4 inhibitor, ketoconazole, respectively. The immunoinhibition-defined P450 contributions indicated the participation of CYP2C9, CYP2C19, and CYP2D6 in the M1 formation and CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in the M2 formation. Among recombinant P450s, CYP2D6 had the highest intrinsic clearance with a K(m) value of 0.02 mM in forming M1. CYP2B6, CYP2C9, and CYP2C19 had the K(m) or S(50) values smaller than those (1 mM) of CYP2D6 and CYP3A4 in forming M2. These results indicated the participation of multiple P450 forms in DFO.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antitussive Agents; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Female; Humans; Isoenzymes; Kinetics; Male; Mass Spectrometry; Microsomes, Liver; Middle Aged; Morphinans; Oxidation-Reduction; Plasmids; Recombinant Proteins

Dimemorfan (DF) has been known to possess neuroprotective properties. While this promising compound deserves further biological evaluation, synthetic methods have not improved since Murakami group unveiled the synthetic efforts in 1972. Herein a succinct synthesis toward DF from commercially available 3-hydroxymorphinan (3-HM) is disclosed. Other morphinan analogs have been effectively prepared by adopting the similar methodology.

Topics: Dextromethorphan; Morphinans; Neuroprotective Agents

Dimemorfan, an antitussive and a sigma-1 (sigma(1)) receptor agonist, has been reported to display neuroprotective properties. We set up an animal model of ischemic stroke injury by inducing cerebral ischemia (for 1 h) followed by reperfusion (for 24 h) (CI/R) in rats to examine the protective effects and action mechanisms of dimemorfan against stroke-induced damage. Treatment with dimemorfan (1.0 microg/kg and 10 microg/kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative sigma(1) receptor agonist, PRE084 (10 microg/kg, i.v.), ameliorated the size of the infarct zone by 67-72% or 51-52%, respectively, which was reversed by pre-treatment with the selective sigma(1) receptor antagonist, BD1047 (20 microg/kg, i.v.). Major pathological mechanisms leading to CI/R injury including excitotoxicity, oxidative/nitrosative stress, inflammation, and apoptosis are all downstream events initiated by excessive accumulation of extracellular glutamate. Dimemorfan treatment (10 microg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1beta, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammation-related signals (p38 mitogen-activated protein kinase, nuclear factor-kappaB, and signal transducer and activator of transcription-1), expression of neuronal and inducible nitric oxide synthase, oxidative/nitrosative tissue damage (lipid peroxidation, protein nitrosylation, and 8-hydroxy-guanine formation), and apoptosis in the ipsilateral cortex after CI/R injury. Dimemorfan treatment at the time of reperfusion, although did not prevent an early rise of glutamate level, significantly prevented subsequent glutamate accumulation after reperfusion. This inhibitory effect was lasted for more than 4 h and was reversed by pre-treatment with BD1047. These results suggest that dimemorfan activates the sigma(1) receptor to reduce glutamate accumulation and then suppresses initiation of inflammation-related events and signals as well as induction of oxidative and nitrosative stresses, leading to reductions in tissue damage and cell death. In conclusion, our results demonstrate for the first time that dimemorfan exhibits protective effects against ischemic stroke in CI/R rats probably through modulation of sigma(1) receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events.

Topics: Analysis of Variance; Animals; Brain Infarction; Brain Ischemia; Chemokine CCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Glutamic Acid; Lipid Peroxidation; Male; Morphinans; Morpholines; NF-kappaB-Inducing Kinase; Nitric Oxide Synthase; Peroxidase; Protein Serine-Threonine Kinases; Rats; Rats, Long-Evans; Receptors, sigma; Reperfusion Injury; Sigma-1 Receptor; Signal Transduction; STAT1 Transcription Factor

Dimemorfan (a sigma1 receptor agonist) showed neuroprotective properties in animal models of inflammation-mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear.. The effects of dimemorfan on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)- induced neutrophils and lipopolysaccharide (LPS)-activated microglial cells, as well as LPS-induced endotoxin shock in mice were elucidated.. Dimemorfan decreased PMA- and fMLP-induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of sigma1 receptors, possibly by blocking ROS production and G-protein-mediated intracellular calcium increase. Dimemorfan also inhibited LPS-induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha (TNF-alpha), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up-regulation through interfering with nuclear factor kappa-B (NF-kappaB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg(-1), i.p., at three successive times after LPS) decreased plasma TNF-alpha, and neutrophil infiltration and oxidative stress in the lung and liver.. Our results suggest that dimemorfan acts via sigma1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kappaB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro-inflammatory cytokines. These effects may contribute its anti-inflammatory action and protective effects against endotoxin shock in mice.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Calcium; Cytokines; Fluorescent Antibody Technique; Humans; I-kappa B Proteins; Inflammation; Lipopolysaccharides; Macrophage-1 Antigen; Mice; Morphinans; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Reactive Oxygen Species; Shock, Septic; Tetradecanoylphorbol Acetate; Transcription Factor RelA; Up-Regulation

Chronic cough is defined as that which is persisting at least for trhee weeks without an evident cause. It is very common on the otorhinological practice to receive patients with chronic cough in order to rule out that their chronic cough is not produced because of an alteration in the high respiratory system. We show a clinical case with chronic cough and we make reference to the physical exploration, diagnostical method, and possibilities of medical and surgical treatment.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Ulcer Agents; Antitussive Agents; Chronic Disease; Cough; Esophageal pH Monitoring; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Lansoprazole; Middle Aged; Morphinans; Radiography, Thoracic; Rhinitis, Vasomotor; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Turbinates

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.

Topics: Animals; Dextromethorphan; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Morphinans; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures

Dimemorfan (d-3-methyl-N-methylmorphinan), an analogue of dextromethorphan, is commonly used as a non-opioid antitussive. To clarify the contribution of cytochrome P450 (P450) in dimemorfan N-demethylation, effects of selective inducers and inhibitors were studied in ICR mice. Phenobarbital (PB)- and dexamethasone (Dex)-treatments caused 5-fold increases of liver microsomal dimemorfan N-demethylation activity. In untreated mouse liver microsomes, demethylation activity was strongly inhibited by a CYP3A inhibitor, ketoconazole. In PB-and Dex-treated mouse liver microsomes, ketoconazole caused strong inhibition, whereas orphenadrine caused a decrease of less than 20%. Pretreatment of control mouse liver microsomes with anti-CYP3A inhibited demethylation activity, whereas pre-treatment with anti-CYP2B had no effect. In PB-and Dex-treated mouse liver microsomes, the demethylation activity was inhibited by both anti-CYP3A and anti-CYP2B. In control mice, the intrinsic clearance of dimemorfan from N-demethylation was 5.8 microl min(-1)mg protein(-1). In PB- and Dex-treated mice, the correlation coefficient of fitting using one-enzyme and two-enzyme models were similar. The intrinsic clearances of induced mouse liver microsomes were similar. These results revealed that CYP3A played a major role in hepatic demethylation in untreated mice. Both CYP3A and CYP2B were involved in this demethylation in PB- and Dex-treated mice.

Topics: Animals; Cytochrome P-450 CYP2B1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dexamethasone; Enzyme Activation; Ketoconazole; Kinetics; Linear Models; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Morphinans; Orphenadrine; Oxidoreductases, N-Demethylating; Phenobarbital

Our previous study reported that an antitussive drug, dimemorfan, attenuates cholinergic dysfunction-induced amnesia in mice and acts like a sigma1 receptor agonist. This study further showed that dimemorfan (30 microM), like the putative sigma1 receptor agonist (+)-SKF-10047 (10 microM), significantly enhanced 25 mM KCl-evoked [3H]acetylcholine release from rat hippocampal but not striatal slices, which was antagonized by a sigma1 receptor antagonist haloperidol (0.3 microM).

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acetylcholine; Animals; Antipsychotic Agents; Atropine; Carbachol; Cholinergic Agonists; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Haloperidol; Hippocampus; In Vitro Techniques; Male; Morphinans; Muscarinic Antagonists; Phenazocine; Potassium Chloride; Rats; Tritium

A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5 microg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5 mg/kg), dimemorfan (6.25 or 12.5 mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Behavior, Animal; Blotting, Northern; Blotting, Western; Calcium Channels, L-Type; Cell Count; Densitometry; Dose-Response Relationship, Drug; Drug Interactions; Electrophoretic Mobility Shift Assay; Hippocampus; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Morphinans; Motor Activity; Phencyclidine; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Reaction Time; RNA; Seizures

(1) Dimemorfan, an antitussive for more than 25 years, has previously been reported to be a relative high-affinity ligand at sigma-1 (sigma(1)) receptor with the K(i) value of 151 nM. (2) To test whether dimemorfan has anti-amnesic effects similar to a sigma(1) receptor agonist, this study examined its effects on scopolamine- and beta-amyloid peptide-(25-35)-induced amnesia in mice. (3) Dimemorfan (10-40 mg kg(-1), i.p.) administered 30 min before the training trial, immediately after the training trial, or 30 min before the retention test significantly improved scopolamine (1 mg kg(-1), i.p.)- or beta-amyloid peptide-(25-35) (3 nmol mouse(-1), i.c.v.)-induced amnesia in a step-through passive avoidance test. Dimemorfan (5-40 mg kg(-1), i.p.) pretreatment also attenuated scopolamine (8 mg kg(-1), i.p.)-induced amnesia in a water-maze test. And, these anti-amnesic effects of dimemorfan, like the putative sigma(1) receptor agonist (+)-N-allylnormetazocine ((+)-SKF-10047), were antagonized by a sigma receptor antagonist haloperidol (0.25 mg kg(-1), i.p.). (4) These results indicated that dimemorfan has anti-amnesic effects and acts like a sigma(1) receptor agonist.

Topics: Amnesia; Amyloid beta-Peptides; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphinans; Peptide Fragments; Phenazocine; Receptors, sigma; Scopolamine

Dextromethorphan ((+)-3-methoxy-N-methylmorphinan, DM) has been shown to have both anticonvulsant and neuroprotective effects. The mechanisms of these CNS effects of DM have been suggested to be associated with the low-affinity, noncompetitive, N-methyl-d-aspartate (NMDA) antagonism of DM and/or the high-affinity DM/sigma receptors. DM is largely O-demethylated into the phencyclidine (PCP)-like compound dextrorphan (DR), which may limit its therapeutic use by producing PCP-like adverse effects, such as hyperlocomotion. Dimemorfan ((+)-3-methyl-N-methylmorphinan, DF), an analog of DM, which has been safely used as an antitussive for more than 20 years, is also known not to form DR. This study therefore characterized the binding of DF to the sigma receptors and NMDA-linked PCP sites and examined the anticonvulsant as well as locomotor effects of DF in mice in comparison with those of DM and DR. We found that DF, DM, and DR were relative high-affinity ligands at sigma-1 receptors (Ki=151, 205, 144 nM, respectively) while all of them were with low affinity at sigma-2 receptors (Ki=4-11 microM). Only DR exhibited moderate affinity for PCP sites (Ki=0.9 microM), whereas DF (Ki=17 microM) and DM (Ki=7 microM) were much less active. DF, DM and DR produced prominent anticonvulsant effects in mice as measured by the supramaximal electroshock test with comparable potency (ED50 approximately 70 micromol/kg, i.p.). At the tested doses (20-260 micromol/kg, i.p.), DM and DR exhibited biphasic effects on the locomotor activity whereas DF produced a consistent dose-dependent decrease. These results revealed that, unlike DM and DR, DF did not cause a PCP-like hyperlocomotion adverse effect that is parallel with the PCP sites binding data. Furthermore, since they have equipotent anticonvulsant effects and similar binding affinities to sigma-1 receptors, the very low affinity of DF at PCP sites may suggest that acting on the PCP sites may not be the requisite for mediating the anticonvulsant activity of these DM analogs. With the history of safety and relative less adverse effects, DF appears to be worth further studying on its CNS effects other than the antitussive effect.

Topics: Animals; Anticonvulsants; Antitussive Agents; Behavior, Animal; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Electroshock; Locomotion; Male; Mice; Morphinans; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Phencyclidine; Receptors, sigma; Sigma-1 Receptor

Ion-selective electrodes (ISEs) responsive to the antitussives dextromethorphan and dimemorfan were constructed by the fixation of an ion-exchanger, ammonium tetraphenylborate, on a Millipore membrane by means of a plasma-polymerization technique. The electrodes showed a Nernstian response over the range of 10(-5)-10(-2) M dextromethorphan and dimemorphan, and the working pH range was 5-7. The interference from common cations such as Na+, K+ and Ca2+ was negligible but some organic cations interfered weakly. The electrodes were applied successfully for the determination of the drugs in pharmaceutical preparations.

Topics: Dextromethorphan; Electrodes; Levorphanol; Membrane Potentials; Morphinans

Dinemorphan, an antitussive drug, is N-demethylated in vitro by mouse liver microsomes with biphasic kinetics showing two apparent Km and Vmax. Moreover, dinemorphan N-demethylation is inhibited by CO, SKF-525A, metyrapone and it is specifically catalyzed by a phenobarbital-inducible form of cytochrome P-450.

Topics: Animals; Antitussive Agents; Kinetics; Male; Methylcholanthrene; Mice; Microsomes, Liver; Morphinans; Oxidoreductases, N-Demethylating; Phenobarbital

Topics: Animals; Antineoplastic Agents; Antitussive Agents; Carcinoma, Ehrlich Tumor; Dextromethorphan; Female; Levorphanol; Lipid Metabolism; Mice; Mice, Inbred Strains; Morphinans; Neoplasms, Experimental; Sarcoma 180

Dextromethorphan, dimemorfan, dihydrocodeine and oxymethebanol, centrally acting antitussives, were examined for their effect on Ehrlich carcinoma cells and sarcoma-180 cells in vitro or in vivo. The tumor cells were suspended in Hanks balanced salt solution (pH 7.4) supplemented with 2% bovine albumin, and they were incubated with and without 1 mM drugs at 37 degrees C for 120 min. The incubation of the tumor cells with dextromethorphan or dimemorfan resulted in a decrease in the proportion of the viable cells (less than 25% after 120 min). However, no significant change was observed in the proportion of the viable tumor cells during the incubation with and without the other drugs (80-83% after 120 min). In addition, mice given the tumor cells i.p. were injected intraperitoneally with drugs (20-80 mg/kg/day) once daily for 5 successive days, and their survival time was observed. There was a slight difference in the survival time between mice treated with and without dextromethorphan or dimemorfan. However, a significant difference was found in the survival time between mice treated with and without dextromethorphan when mice given Ehrlich carcinoma cells were injected with the drug (40 mg/kg/time) twice a day for 5 days (about 18 days and 29 days). These results indicate that dextromethorphan and dimemorfan are cytotoxic to the tumor cells in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Antitussive Agents; Carcinoma, Ehrlich Tumor; Cell Survival; Cells, Cultured; Codeine; Dextromethorphan; Female; Mice; Morphinans; Sarcoma 180; Thebaine

Topics: Cesarean Section; Female; Humans; Hysterectomy; Morphinans; Pathology; Placenta Accreta; Pregnancy; Pregnancy Complications; Rupture, Spontaneous; Uterine Rupture