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PubMed1975

A new method for evaluating antitussives in cats using an electrode-cannula.

An emplaced laryngo-tracheal electrode-cannula was employed to induce and to measure cough in cats anesthetized with either sodium pentobarbital or Dial--urethane. Carbetapentane citrate, codeine sulfate and dextromethorphan hydrobromide were tested for antitussive action by this method. Relative antitussive potency obtained in order of decreasing effectiveness was dextromethorphan hydrobromide, codeine sulfate and carbetapentane citrate.

Animals↗
PubMed1989

Reinforcing effects of the enkephalin analogs, EK-209 and EK-399, in rats.

The reinforcing effects of two enkephalin analogs, Tyr-D-Ala-Gly-MePhe-NHNHCOCH2CH3.AcOH (EK-209) and Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), were assessed by means of a self-administration technique with rats. The animals were trained to self-administer an intravenous dose of morphine by a lever-press response. A test drug was substituted for morphine after the rats had initiated and maintained its self-administration. When codeine, fentanyl, pentazocine or EK-209 was available, most of the rats increased the number of self-administrations as the unit dose of these drugs was decreased. When levallorphan or EK-399 was available, most of the rats did not increase responding; only one of 4 rats slightly increased the number of self-administrations as the unit dose of EK-399 was decreased. These results indicate that EK-209, like codeine, fentanyl, and pentazocine, possesses a reinforcing effect, whereas EK-399, like levallorphan, has a very weak effect, suggesting that the latter compound possesses low abuse liability.

Animals↗
PubMed1993

Non-opioid antitussives and methadone differentially influence hippocampal long-term potentiation in freely moving rats.

Long-term potentiation (LTP) of monosynaptically evoked field potentials (MEFP) in the dentate gyrus of freely moving rats following tetanization of the perforant pathway was investigated after peripheral application of substances which have been shown to influence NMDA receptor-mediated effects (dextromethorphan, methadone) as well as structurally related substances with similar antitussive effects (codeine, normethadone). The noncompetitive NMDA receptor antagonist MK 801 was also tested for comparison. Whereas under control conditions the field e.p.s.p. (excitatory postsynaptic potential) and the population spike of the MEFP were largely uninfluenced by these substances, different effects were seen after the induction of LTP. MK 801 (0.2 mg/kg i.p.) suppressed the induction of LTP of both the field e.p.s.p. and the population spike. Dextromethorphan (40 mg/kg i.p.) also prevented the potentiation of the field e.p.s.p. and the population spike, thus resembling MK 801 in its effect. Codeine (20 mg/kg i.p.), the levorotatory structural analogue of dextromethorphan had no effect. Methadone and normethadone did not influence the potentiation of the field e.p.s.p. or interfere with the induction of potentiation of the population spike but depressed its maintenance. The results obtained with MK 801 confirm those reported by others. Comparison of the effects of dextromethorphan with those of MK 801, suggests that there is a direct interaction with the NMDA receptor-ionophore complex. The effects of methadone and normethadone appear not to be linked to an interaction with opioid receptors, since naloxone did not influence the suppression of LTP caused by methadone. The possibility of interference with the NMDA receptor-ionophore complex is discussed.

Animals↗
PubMed1985

Changes in responsiveness to mu and kappa opiates following a series of convulsions.

After a series of seven electroconvulsive shocks, mice (C57BL/6J) showed a marked change in their response to opiates. Although very large doses of mu agonists induce convulsions in normal control mice, our evidence indicated that this was accomplished through nonopiate mechanisms: they could not be blocked by naltrexone and the pattern of drug potencies (codeine greater than morphine greater than levorphanol) was not consistent with an opiate response. In contrast, after electroconvulsive shock small doses of mu agonists induced convulsions that could be blocked by naltrexone and the pattern of drug potency (levorphanol greater than morphine greater than codeine) was consistent with an opiate mechanism. Kappa drugs, on the other hand, produced convulsions in both control and ECS animals, although there was an enhanced responsiveness in the latter. Furthermore, the convulsions produced by kappa drugs were blocked by naltrexone and showed stereoselectivity in both control and ECS animals. The changes in responsiveness to mu and kappa opiates cannot be explained on the basis of a general increase in seizure susceptibility, as sensitivity to the nonopiate convulsant, strychnine, was not enhanced after electroconvulsive shock. The results point to a qualitative change in response to mu agonists after electroconvulsive shock, but only a change in sensitivity to kappa agonists.

Animals↗
PubMed1975

Simultaneous detection of a wide variety of commonly abused drugs in a urine screening program using thin-layer identification techniques.

A single-step extraction method and thin-layer identification techniques capable of testing a wide variety of drugs of abuse are presented. These techniques are well suited for large and/or small drug programs involved in urine testing because they provide substantial economic benefits and improve clinical functioning. The drugs are absorbed on a 6 X 6 cm piece of paper loaded with cation-exchange resin and then eluted from the paper at pH 10.1 using ammonium chloride-ammonia buffer. The simultaneous thin-layer detection of sedatives, hypnotics, narcotic analgesics, central nervous system stimulants and miscellaneous drugs is accomplished by spotting the solution of extracted residue on a 20 X 20 cm Gelman pre-coated silica gel glass microfiber sheet (ITLC Type SA). A two-stage solvent system is used in order to obtain a chromatogram with optimum separation of a wide range of drugs. This system can separate methadone and/or cocaine from propoxyphene, methaqualone, methylphenidate, pentazocine, pipradrol, Doxepin, chlorpromazine, phenazocine, naloxone, naltrexone, imipramine and trimeprazine; amphetamine from phenylpropanolamine and dimethyltryptamine; codeine from dextromethorphan; methamphetamine from dimethyltryptamine, etc. Different detection reagents are then applied in succession to different marked areas of the developed chromatogram. This elegant method of extraction and spraying has enabled us to detect morphine base at a sensitivity level of 0.15 mug/ml, amphetamine sulfate at 1.0 mug/ml, methamphetamine hydrochloride at 0.5 mug/ml, phenmetrazine hydrochloride at 0.5 mug/ml, codeine phosphate at 0.5 mug/ml, methadone hydrochloride at 1.0 mug/ml, secobarbital at 0.36 mug/ml and phenobarbital at 0.5 mug/ml in urine. The minimum volume of urine needed to achieve these sensitivities is 20 ml. The cost of analysis per urine specimen using these techniques for concomitant screening of these drugs is less than US$ 1.

1-Propanol↗
PubMed1996

Determination of morphine analogues, caffeine and amphetamine in biological fluids by capillary electrophoresis with the marker technique.

A reliable method was sought for the fast screening and simultaneous determination of amphetamine, morphine, heroin (acetomorphine), codeine (methylmorphine) and caffeine in biological fluids and drug seizures. Capillary zone electrophoresis (CZE) and micellar electrokinetic capillary chromatography (MEKC), with detection at 200 and 220 nm, were investigated for analytes in human serum and urine. When adequate separation was not achieved in preliminary studies with CZE, further development was focused on the MEKC method. Glycine buffer containing sodium lauryl sulfate (pH 10.5) was used for the MEKC separations. The analytes and carboxylic acids used as marker compounds could be screened by a short-capillary method in less than 2 min. In the simultaneous determination of the drugs in urine and serum a longer separation of 18 min was preferred so that all the compounds, the markers and the endogenous compounds absorbing at the detection wavelength could be adequately separated in a single run. The migration times of the compounds increased in the order caffeine, morphine, heroin, codeine and amphetamine. The repeatability of the separation was tested by using two carboxylic acids as marker compounds in the determination of the migration indices of the analytes. The relative standard deviations for the migration indices were less than 1%, which is accurate enough for the determination of the drugs in biological fluids.

Amphetamine↗
PubMed1977

Reinforcing properties of intravenous procaine in rhesus monkeys.

The lever pressing behavior of rhesus monkeys was maintained by a fixed ratio 10 schedule of intravenous cocaine (3 monkeys) or codeine (2 monkeys) injections during 2 hour sessions. Saline or various doses of procaine hydrochloride were substituted for the baseline reinforcer for 6 consecutive sessions. Each substitution was separated by 3 or more days of cocaine or codeine reinforced responding. At one or more doses, procaine substitution resulted in response rates higher than saline control in all 5 animals. High response rates (greater than 30 injections per session) were obtained in 4 of the 5 monkeys. In addition, procaine self-administration was studied in two naive monkeys given 23 hour per day access to procaine following an initial 10 days of saline contingent operant level responding. At a dose of 0.3 mg/kg/injection, both animals initiated responding for procaine reinforcement. Drug intake varied widely from day to day, however each animal took over 1200 injections per day (over 360 mg/kg) at least once during the 30 days of access. With the exception of decreased food intake, there was little evidence for behavioral toxicity from these doses. Following a second 10 days of saline self-administration, both animals were given access to 3.0 mg/kg/injection procaine. A substantially greater intake of procaine was observed which was associated with marked toxicity.

Animals↗
PubMed1985

Skin test reactivity in infancy.

Skin tests represent a major tool in the diagnosis of reaginic allergy; however, their interpretation does not appear to be without difficulty in children under the age of 3 yr. Seventy-eight infants from birth to 24 mo were prick tested and compared with 30 nonallergic adult subjects. Skin tests were performed without bleeding by use of two strengths of histamine hydrochloride (1 and 10 mg/ml), a mast cell degranulating agent (codeine phosphate, 50 mg/ml), and allergenic extracts. Negative control solution elicited a small wheal (less than 1.5 mm) in two infants who were excluded from further results. A clear and significant (p less than 0.001) hyporeactivity to both histamine and codeine phosphate was observed in infancy, especially before the age of 6 mo. Six infants were allergic and presented positive prick tests to either food or inhalant allergens. These tests were confirmed by serum specific IgE and a suggestive clinical history. The size of the allergen-induced prick test wheal ranged from 2 to 5 mm in diameter, suggesting that prick test wheals may be smaller in infants. This study confirms that prick tests can be performed and interpreted without difficulty in infants, keeping in mind the small wheal size induced by both positive control solutions and allergen-induced prick tests.

Allergens↗
PubMed1986

Efficacy of doxepin in the treatment of chronic idiopathic urticaria.

Doxepin hydrochloride, a tricyclic antidepressant, was evaluated in a double-blind, placebo-controlled crossover trial for the treatment of chronic idiopathic urticaria in 16 adults. Efficacy was evaluated by symptom scores, concomitant antihistamine use, and suppression of histamine- and codeine-induced wheal response. Doxepin-treated subjects experienced fewer lesions (p less than 0.001), less waking hours with lesions (p less than 0.01), lesser degree of itch and/or discomfort (p less than 0.001), and less swelling or angioedema (p less than 0.001) as compared to placebo-treated subjects. Doxepin-treated subjects required less daily concomitant antihistamine use (mean 0.13 tablets versus 1.48 tablets, p less than 0.05). Doxepin also significantly suppressed histamine- and codeine-induced cutaneous wheal response as compared to placebo. Lethargy was commonly observed but diminished with continued use. Dry mouth and constipation were also commonly observed. We conclude that doxepin is an effective agent for the treatment of chronic idiopathic urticaria.

Chlorpheniramine↗
PubMed1991

Skin test reactivity in patients suffering from lung and breast cancer.

Mast cells and histamine-mediated reactions may be altered in patients with cancer. In an attempt to characterize the possible skin defects in patients with cancer, we tested 22 patients suffering from lung cancers, 30 from breast cancers, and 30 age-matched normal individuals, using several compounds, in investigating the pathophysiology of the skin response. Histamine hydrochloride (10 and 100 mg/ml) and codeine phosphate (9%) were tested by prick test. Substance P (50 and 500 ng per injection site), phentolamine (20 micrograms per injection site), and carbachol (1 microgram per injection site) were tested by intradermal skin tests. Skin mast cells were also microscopically examined in 10 patients with lung cancer, five with breast cancer, and 10 normal subjects. The mean wheal sizes induced by all the tested substances were similar in patients with cancer and chronic bronchitis and in normal individuals. The flare to histamine, codeine phosphate, and substance P was completely abolished in 7/22 patients with lung cancer, but the lack of flare was not related to the age of the patients, nor to the staging of cancer, nor to metastasis. The mean numbers of alcian blue-stained or toluidine blue-stained positive mast cells were similar in normal subjects and in subjects with cancer. This study does not confirm the skin hyporeactivity of patients with cancer.

Adult↗
PubMed1985

Use of gut cyclic motor activity to evaluate a stimulant (narcotic) and inhibitor (anticholinergic) of gastrointestinal-tract activity in the unanesthetized dog.

The use of gut cyclic motor activity to evaluate both a stimulant and inhibitor of gastrointestinal contractile activity in the unanesthetized dog is described. In the interdigestive (fasted) state, there is a cyclic alternation of intense periods of contractions (burst) with quiescent periods (basal). Codeine phosphate, a narcotic agent, caused a dose-dependent increase in the number and duration of circular muscle contractions when administered in the basal phase. Hyoscine N-butyl-bromide, an anticholinergic drug, caused a dose-dependent reduction in both amplitude and frequency of burst-phase contractions. When a combination of codeine phosphate and hyoscine N-butylbromide was administered simultaneously in the basal or burst phase, the hyoscine N-butylbromide prevailed and had the dominant effect. This is a useful in vivo model to evaluate the effects of drugs on the gastrointestinal tract.

Animals↗
PubMed1985

Analeptic effect of opiate receptor agonists in rabbits.

Eight opiate agonists, administered by the intracerebroventricular (i.c.v.) route, were evaluated as analeptics in pentobarbital-anesthetized rabbits. Morphine, codeine, ethylketocyclazocine, N-allylnormetazocine, meperidine and methadone, but not etorphine or D-Ala2-Met-enkephalin, given i.c.v. 40 min after pentobarbital (30 mg/kg i.v.), produced significant shortening of the duration of anesthesia as determined by the loss of the righting reflex. No apparent relationship was found between this and analgesic potency, nor with the specific receptor subtypes with which these agonists are known to interact. With active compounds, such as morphine, codeine and methadone, producing narcotic sedation, it was necessary to pretreat the animals with naltrexone to unmask the analeptic effect. It is concluded that the analeptic effect produced by certain opiate drugs is not specifically related to any of the subtypes of opiate receptors thus far described.

Animals↗
PubMed1993

Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers?

It has recently been shown that O-demethylation of the opioid drug codeine to morphine depends on the sparteine/debrisoquine oxygenase (CYP2D6) which in man exhibits genetic polymorphism. Morphine may be an endogenously formed substance in mammalians. Therefore, it may be hypothesized that the final step in an endogenous synthesis of morphine from codeine also depends on CYP2D6. CYP2D6, which is present in the liver and presumably also in the brain, is not expressed in subjects who are poor metabolisers of the sparteine/debrisoquine type. We have determined sensitivity to painful stimuli in 94 extensive metabolisers and 82 poor metabolisers of sparteine in 2 phasic (pain thresholds to heat and pressure) and 1 tonic (cold pressor test) experimental pain model. Extensive and poor metabolisers did not differ significantly in the 2 phasic pain models neither with respect to pain detection nor pain tolerance thresholds. However, for the cold pressor test, peak pain ratings and area under the pain rating-time curve during 2 min were significantly higher in poor than in extensive metabolisers (P = 0.0024 and 0.044). Furthermore, a substantially higher fraction of poor metabolisers prematurely withdrew their hand from the ice water during the cold pressor test due to intolerable pain (32 vs. 18%, P = 0.0545). We conclude that poor metabolisers of sparteine may be less tolerant to tonic pain than extensive metabolisers, and we hypothesize that this may be related to an inherited defect in endogenous synthesis of morphine via CYP2D6 in the brain.

Adult↗
PubMed1991

Evidence for peripheral mechanisms mediating the antitussive actions of opioids in the guinea pig.

1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting mu-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs. 2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively. 3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were approximately 2.2 and approximately 12 micrograms/kg, respectively. 4. Aerosilized codeine (approximately 72 micrograms/kg, n = 5) significantly inhibited coughing by 62 +/- 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 +/- 6%, n = 7). 5. Inhalation of DALDA (approximately 7.2 micrograms/kg, n = 7) also significantly inhibited coughing. 6. The antitussive effect of inhaled morphine (approximately 7.2 micrograms/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally. 7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.

Administration, Inhalation↗
PubMed1993

High-performance liquid chromatographic determination of morphine and its metabolites in plasma using diode-array detection.

An isocratic high-performance liquid chromatographic method has been developed for the determination of morphine, codeine, normorphine, morphine 3-glucuronide and morphine 6-glucuronide in plasma using a diol column and diode-array detection. Samples were extracted using solid-phase extraction with recoveries in excess of 90%. The limit of determination was 1 ng/ml for morphine, codeine and morphine 3-glucuronide, and 10 ng/ml for normorphine and morphine 6-glucuronide. Inter- and intra-day precision were better than 10%.

Chromatography, High Pressure Liquid↗
PubMed1996

Characterization of the genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine and dihydromorphine by micellar electrokinetic capillary chromatography.

The genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine (DHC) and dihydromorphine (DHM) by micellar electrokinetic capillary chromatography is described. Ten healthy subjects which are known to be extensive metabolizers for debrisoquine ingested 60 mg of DHC and collected their 0-12 h urines. In these samples, about 1% of the administered DHC equivalents are shown to be excreted as DHM. Premedication of 50 mg quinidine sulfate to the same subjects is demonstrated to significantly reduce (3-4 fold) the amount of O-demethylation of DHC, a metabolic step which is thereby demonstrated to co-segregate with the hydroxylation of debrisoquine. Thus, in analogy to codeine and other substrates, extensive and poor metabolizer phenotypes for DHC can be distinguished. Using the urinary DHC/DHM metabolic ratio to characterize the extent of O-demethylation, the metabolic ratio ranges of extensive and poor metabolizers in a frequency histogram are shown to partially overlap. Thus, classification of borderline values is not unequivocal and DHC should therefore not be employed for routine pharmacogenetic screening purposes. Nevertheless, the method is valuable for metabolic research and preliminary data demonstrate that the same assay could also be used to explore the metabolism of codeine.

Codeine↗
PubMed1979

Assay of major and minor constituents of opium samples and studies of their origin.

Samples of opium from different countries as well as from various regions of India were studied for their morphine and codeine content by gas-liquid chromatography (GLC) as their silyl ethers in a single step. Non-phenolic alkaloids (thebaine, papaverine and narcotine) were extracted with dichloromethane for GLC after conversion of the meconic acid, morphine and codeine in opium into insoluble salts with lime water. The data on alkaloidal constituents have been utilised in a determination of the origin of seized opium samples in this preliminary study.

Alkaloids↗
PubMed1993

Variability of opiates concentrations in human hair according to their anatomical origin: head, axillary and pubic regions.

The concentrations of morphine and codeine were investigated in hair from the head, axillary and pubic regions obtained from 20 fatal heroin cases. Hair preparation involves decontamination procedure in dichloromethane at 37 degrees C for 15 min, solubilization in sodium hydroxide at 100 degrees C for 5 min, neutralization with hydrochloric acid and centrifugation. After extraction in chloroform/isopropanol/n-heptane (50:17:33; v/v) at pH 9.2, drugs were derivatized with BSTFA + 1% TMCS and separated on a 12-m BP-5 capillary column. Quantification was done by GC/MS using selected ion monitoring. The highest morphine concentrations were found in public hair (0.80-41.34 ng/mg), followed by hair of the head (0.62-27.10 ng/mg), and axillary hair (0.40-24.20 ng/mg). Codeine was also detected in all samples, and the codeine/morphine ratios ranged from 0.54 to 0.273. The differences observed in drug concentration in the three kinds of hair are discussed in the light of the existing literature.

Adult↗