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PubMed2003

Determination of heroin metabolites in human urine using capillary zone electrophoresis with beta-cyclodextrin and UV detection.

A method has been developed for the detection of a mixture of morphine, codeine, 6-acetyl morphine (6-AM) and normorphine using capillary zone electrophoresis (CZE). The method utilized urinary 6-AM as a diagnostic indicator of heroin abuse because it is not a product of either morphine or codeine metabolism. The electrophoretic separation was achieved using an uncoated (50 microm I.D.) fused-silica capillary, 77 cm long, containing the detector window 10.0 cm from the outlet end. The running buffer (pH 6.0) contained 50 mM sodium phosphate and 0.015 M beta-cyclodextrins (beta-CD). The samples were first extracted using a mixed-mode solid-phase extraction procedure and then analyzed by CZE. The UV absorbance detection was monitored at 214 nm. It has been found that beta-CDs can improve separation efficiency due to their hydrophobic cavity. The effect of the concentration of beta-CD and pH was also evaluated. The application of electrokinetic injection with field amplified sample stacking results in low detection limits (40 ng/ml for each analyte) and the method has good reproducibility, precision, accuracy, and high recovery.

Cyclodextrins↗
PubMed2001

Engineering novel biocatalytic routes for production of semisynthetic opiate drugs.

The morphine alkaloids and their semisynthetic derivatives provide a diverse range of important pharmaceutical drugs. Current production of semisynthetic opiate drugs is by chemical means from naturally occurring morphine, codeine and thebaine. Although various microbial transformations of morphine alkaloids have been identified since the 1960s, more recently there has been considerable effort devoted to engineering biocatalytic routes for producing these important compounds. Such biocatalytic routes are attractive, as they would provide an alternative to the chemical production processes which suffer from limited supply of precursors, often low yields and toxic wastes. The biotransformation of morphine and codeine to the potent analgesic hydromorphone and the mild analgesic/antitussive hydrocodone, respectively, by recombinant Escherichia coli has been demonstrated and the problems encountered when engineering such a system will be discussed.

17-Hydroxysteroid Dehydrogenases↗
PubMed2003

Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric analysis of opiates and metabolites in rat urine after inhalation of opium.

To examine the urinary excretion of opiates and their metabolites following inhalation exposure of rats to opium, analytical procedures for the simultaneous determination of the compounds in opium, the vapor derived by the volatilization of opium and the urine of rats exposed to the opium vapor were developed using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS). Seven compounds were determined in the opium, namely morphine, codeine, thebaine, noscapine, papaverine, meconic acid and meconin. All seven were extracted with 2.5% acetic acid solution and subjected to LC-APCI-MS analysis. The separation was performed on an ODS column in acetonitrile-50 mM ammonium formate buffer (pH 3.0) using a linear gradient program and quantitative analysis was carried out in the selected ion monitoring mode ([M+H](+)). For the analysis of the volatilization of opium, the opium (1 g) was added to a glass pipe, which was then heated at 300 degrees C for 20 min. Negative pressure (air flow-rate; 300 ml/min) was used to draw the vapor through a series of glass wool and methanol traps. The total amount of each compound in the vapor was estimated by measurement of the compounds trapped in the glass wool and methanol. Wister rats (n=3) were exposed to the vapor derived from the volatilization system and the urinary amounts (0-72 h) of the six opiates and metabolites including morphine-3-grucronide (M3G) and morphine-6-grucronide (M6G) were measured after solid-phase extraction. The calibration curves for those compounds in the rat urine were linear over the concentration range 10-500 ng/ml. The recoveries for each analyte from the rat urine sample spiked with standard solution were generally greater than 80%, and the relative standard deviation for the analytical procedure was less than 8% with the exception of meconin. After inhalation exposure of rats to opium, M3G (5.45-14.38 micro g), morphine (2.27-4.65 micro g), meconin (0.54-1.85 micro g), codeine (0.54-1.85 micro g), noscapine (0.34-0.40 micro g) and papaverine (0.01-0.04 micro g) were detected in the urine over 72 h. However, only trace levels of thebaine were observed despite it being one of the major alkaloids found in the opium. On the other hand, a relatively large amount of meconin was detected in the vapor and the urine as compared with the opium. It is suggested that the presence of meconin in biological fluids could be indicative of opium ingestion by inhalation.

Administration, Inhalation↗
PubMed2003

Hair analysis for opiates: evaluation of washing and incubation procedures.

Hair analysis of drugs of abuse has been a subject of interest from a clinical, social and forensic perspective for years because of the broad time detection window after intake in comparison to urine or blood. However, the correct and reliable interpretation of opiates findings in an authentic hair sample requires optimalisation and standardisation of decontamination and incubation procedures. Comparing various published methods, we have found some variability in them and no unequivocal recommended procedure for starting with a method directly. Therefore, various combinations of solvents, of various polarity, as washing solvents were tested for removing opiates from the external surface of real hair samples. The yields of opiates from these washings were compared with the yields from the interior of the hair matrix after digestion with various procedures. The opiates after digestion were cleaned up from resulting solution on extraction columns with mixed solid-phase and analysed by GC-MS in standard EI mode after silylation. The efficiencies of neutral (Söerensen buffer, pH 7.4), acid (0.1 M HCl) and basic (1 M NaOH) digestion of the hair matrix were evaluated and the relative recoveries for morphine, codeine, dihydrocodeine and hydrocodone were compared. As it is very problematic to imitate the reference hair sample with a specific amount of analytes incorporated inside, which can be used for calibration to get a close estimate of the quantities of analytes inside the solid authentic sample, the total digestion of a hair sample in basic medium was considered to be a very important reference basis for quantitative determinations. The ratios of hydrolysis of labile 6-acetylmorphine or acetylcodeine were tested and evaluated in practical routine conditions of acid or neutral digestion of hair. Comparing the three methods of incubation of authentic hair samples, the methods using 1 M NaOH or 0.1 M HCl yielded higher recoveries of total equivalents of morphine or codeine, whereas the incubation in Söerensen buffer allowed the reflection of real ratios of labile metabolites and/or parent compounds in an original sample. This method has been shown to be capable of detecting hydrocodone in hair with other opiates concomitantly and to indicate the drug abuse pattern of a person at various time intervals in the past.

Gas Chromatography-Mass Spectrometry↗
PubMed2005

Post-craniotomy analgesia: current practices in British neurosurgical centres--a survey of post-craniotomy analgesic practices.

BACKGROUND AND OBJECTIVE: An evaluation of post-craniotomy analgesia within the University Hospital of Wales Neurosurgical Unit, Cardiff, found that many patients were experiencing moderate to severe pain post-craniotomy. It was therefore decided to undertake a nationwide survey of analgesic practices in order to establish best practice guidelines and benchmark with other units. METHOD: A postal questionnaire was sent to the senior nurse of every Neurosurgical Directorate within the UK inquiring about the current, standard analgesic practices for post-craniotomy patients in their unit. RESULTS: Completed replies were received from 23 of the 33 centres (70%). Intramuscular (i.m.) codeine phosphate was found to be the principal first-line analgesic used post-craniotomy. Only three centres used morphine as the first-line analgesic and only one centre used patient controlled analgesia routinely. The majority of centres (82%) used balanced analgesia. Pain assessments were only carried out in 57% of centres and no centre used a validated pain assessment tool specifically for dysphasic patients. CONCLUSIONS: Codeine phosphate continues to be the mainstay of post-craniotomy analgesia, however, it is proposed that patient controlled analgesia with morphine is an efficacious and safe alternative.

Analgesia↗
PubMed1980

Synthesis and analgesic activity of some 14 beta-substituted analogues of morphine.

Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 beta-mercaptocodeine with lithium aluminum hydride. 14 beta-Bromo- and 14 beta-chlorocodeinone were prepared by the reaction of thebaine with N-bromosuccinimide and N-chlorosuccinimide, respectively. These 14 beta-substituted codeine and codeinones were O-demethylated to the corresponding morphine analogues with boron tribromide. With the exception of 14 beta-nitromorphinone, which was weak in activity, all the other 14 beta-substituted morphine derivatives were approximately equal in potency to normorphine in the guinea pig ileum preparation.

Analgesics↗
PubMed1977

Synthesis and antitussive activity of aminotetra- (and -hexa-) hydrodibenzofurans.

The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with that of codeine, was found in the 4alpha-amino series. The 4-methylpiperazin-1-ylpropionamide (28) was found to be the most active of the compounds synthesized and was equipment with codeine. The effects of structural modification upon antitussive activity were investigated in numerous analogues but no enhancement of activity was achieved over that of 28.

Animals↗
PubMed1989

Transdermal delivery of narcotic analgesics: comparative permeabilities of narcotic analgesics through human cadaver skin.

Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 x 10(-3), 5.6 x 10(-3), and 1.2 x 10(-2) cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 x 10(-6), 4.9 x 10(-5), and 1.4 x 10(-5) cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have Koctanol/water values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.

Administration, Cutaneous↗
PubMed2002

Prick tests to aeroallergens: is it possible simply to wipe the device between tests?

BACKGROUND: Improperly performed skin prick tests (SPT) can lead to wrong allergy diagnosis and incorrect treatment. To overcome false-positive results it is recommended to change the puncture device between each test, although very few studies have examined the real drawbacks (false-positives) and advantages (time and cost savings) of using only one device. METHODS: Two groups of 20 patients with rhinitis or asthma, sensitized to either house-dust mites or grass pollens, had successive serial SPT to 9% codeine phosphate and the relevant allergen using the same needle or lancet, wiped between each test. RESULTS: With both the needle and the lancet, there were 12.5-67.5% false-positive results using the house-dust mite or grass pollen allergen extracts, respectively. There were no false-positive results with the 9% codeine phosphate. CONCLUSIONS: Our study shows that this technique is not reliable as it provoked an unacceptable number of false-positive results.

Adolescent↗
PubMedDate not supplied

Synthesis of the skeleton of the morphine molecule by mammalian liver.

The possibility that morphine could be synthesized in animals has long been considered and a pathway in mammalian brain analogous to that in the opium poppy has been proposed. Substances have been detected in mammalian brain that are recognized by antisera raised against morphine. Recently we reported the presence of three such immunoreactive substances in bovine hypothalamus and adrenal, and in rat brain, and the definitive identification of two of them by gas chromatography-mass spectrometry as morphine and codeine. Incorporation of a labelled precursor has demonstrated the biosynthesis of morphine in the opium poppy from tyrosine-derived units (see Fig. 1). Intramolecular coupling of reticuline to form salutaridine is the critical step that generates the morphine skeleton (morphinan) and the stereochemistry of the morphinan series. We now report the conversion in vivo and in vitro of reticuline to salutaridine by rat liver, but this conversion is not detectable in rat brain and bovine adrenal. This is the first direct demonstration of the synthesis of a morphinan in an animal tissue and also supports the hypothesis that morphine and codeine in brain and adrenal are of endogenous origin.

Adrenal Glands↗
PubMed2005

Synthesis and binding studies of 2-arylapomorphines.

From codeine, four different 2-aryl substituted apomorphines were synthesised in 6 steps each. Oxidation of codeine with IBX followed by acid catalysed rearrangement gave morphothebaine, which was selectively triflylated at the 2-position and subsequently O-acetylated at the 11-position. The resulting triflate was coupled in a Suzuki-Miyaura type reaction with a series of 4-substituted arylboronic esters which, after deprotection, gave the desired 2-aryl apomorphines. The analogues were tested for affinity towards a range of dopaminergic, serotonergic and adrenergic receptors. 2-(4-Hydroxyphenyl)-apomorphine exhibited high affinity for the dopamine D2 receptor. A putative ligand-receptor interaction was put forward.

Animals↗
PubMed2003

Usefulness of specific immunotherapy in patients with severe perennial allergic rhinitis induced by house dust mite: a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: To evaluate the effectiveness of specific immunotherapy (SIT) in patients with severe house dust mite (HDM)-induced perennial allergic rhinitis using diary cards and objective endpoints. PATIENTS AND METHODS: Thirty-six adult patients were selected with moderate to severe allergic rhinitis due to HDM allergy uncontrolled by regular anti-allergic drugs. Twenty-eight patients completed the study, 22 of these patients also had mild asthma. Subjects were stratified for HDM sensitivity on the basis of their 4-week diary card score and the size of their immediate and late-phase skin reaction to HDM. The groups were well matched for all relevant parameters. Patients were randomized to receive active preparation (Alutard(R)-SQ, ALK, Dermatophagoides pteronyssinus extract) or an identical placebo preparation. Increasing doses were administered until the maintenance dose was reached. This dose was then given once a month for 12 months. RESULTS: Clinical efficacy was evaluated by symptom medication diary cards recorded for 4 weeks after 12 months of continuous treatment and compared with pre-treatment scores. Skin test reactivity was re-measured after 12 months of treatment to HDM, cat dander and codeine phosphate. After 1 year of treatment, the actively treated group showed a 58% reduction in diary card symptom scores (P<0.002) and a 20% reduction in the use of rescue medication. The placebo group had a 32% reduction in symptom scores (P=NS), but no reduction in rescue medication requirements. The active group showed 36% reduction in skin prick test sensitivity to D. pteronyssinus (P=0.006), while the placebo group values were unchanged. Skin reactivity to codeine was unchanged in both groups. No significant adverse reactions to SIT were encountered. CONCLUSIONS: One year of SIT for D. pteronyssinus in patients with poorly controlled rhinitis (+/-mild asthma) produced clinically useful improvement as shown by symptom-medication diary cards and reductions in immediate skin reactions compared with placebo treatment.

Adult↗
PubMed1999

Molecular cloning and functional expression of codeinone reductase: the penultimate enzyme in morphine biosynthesis in the opium poppy Papaver somniferum.

The narcotic analgesic morphine is the major alkaloid of the opium poppy Papaver somniferum. Its biosynthetic precursor codeine is currently the most widely used and effective antitussive agent. Along the morphine biosynthetic pathway in opium poppy, codeinone reductase catalyzes the NADPH-dependent reduction of codeinone to codeine. In this study, we have isolated and characterized four cDNAs encoding codeinone reductase isoforms and have functionally expressed them in Escherichia coli. Heterologously expressed codeinone reductase-calmodulin-binding peptide fusion protein was purified from E. coli using calmodulin affinity column chromatography in a yield of 10 mg enzyme l-1. These four isoforms demonstrated very similar physical properties and substrate specificity. As least six alleles appear to be present in the poppy genome. A comparison of the translations of the nucleotide sequences indicate that the codeinone reductase isoforms are 53% identical to 6'-deoxychalcone synthase from soybean suggesting an evolutionary although not a functional link between enzymes of phenylpropanoid and alkaloid biosynthesis. By sequence comparison, both codeinone reductase and 6'-deoxy- chalcone synthase belong to the aldo/keto reductase family, a group of structurally and functionally related NADPH-dependent oxidoreductases, and thereby possibly arise from primary metabolism.

Alcohol Oxidoreductases↗
PubMed1997

Ketoprofen and carotico-cavernous fistula.

Whilst treating a patient with traumatic direct carotico-cavernous fistula, pain relief was difficult to achieve. Adequate doses of ibuprofen and codeine were ineffective, but single doses of ketoprofen alleviated pain in a reproducible manner. Although similar in analgesic efficacy to codeine, and a potent inhibitor of cyclooxygenase like ibuprofen, ketoprofen has other actions which may account for the differential response seen. This observation may help elucidate the nature of local mediators involved in the pathogenesis of vascular headache pain.

Adult↗
PubMed1991

Genetics of Alkaloids in Papaver somniferum.

Based on numerical and graphic analyses of 6 x 6 diallele cross progenies (n (2) = 36) over two environments, dominance was found to be most prevalent (in overdominance range without being inflated by non-allelic interactions) in parents for latex yield, and morphine, codeine, thebaine, and narcotine contents. However, the additive component was also significant for the former three traits. Dominant alleles mostly with positive effects were, by and large, asymmetrically distributed in parents except for narcotine content. Heritability estimates were moderate and corresponded with low genetic advance estimates for morphine, codeine, and thebaine contents. Ample genetic diversity among parents was reflected for all traits except narcotine content. On an overall basis, heterosis breeding was suggested to be a rewarding proposition for genetic improvement of the opium poppy ( PAPAVER SOMNIFERUM L.).

Journal Article↗
PubMed2002

The African-specific CYP2D617 allele encodes an enzyme with changed substrate specificity.

OBJECTIVE: The effects of the CYP2D6*17 and *29 alleles on substrate specificity and enzyme activity were studied by correlating CYP2D6 genotype to phenotype with 4 probe drugs (codeine, debrisoquine, dextromethorphan, metoprolol) in black Tanzanians and white Swedes. METHODS: The black Tanzanian subjects represented the following 6 genotypic groups: A, (CYP2D6*1 or *2)/(*1 or *2) (n = 13); B, CYP2D6*17 /*17 (n = 5); C, CYP2D6*29 /*29 (n = 4); D, CYP2D6*1 /*17 (n = 5); E, CYP2D6*5/*17 (n = 4); and F, various genotypes (n = 4). The white subjects were from 4 groups, as follows: A, (CYP2D6*1 or *2)/(*1 or *2) (n = 7); B, (CYP2D6*1 or *2)/(*3, *4, or *5) (n = 7); C, homozygous for defect alleles (n = 7); and D, duplicated CYP2D6 gene (n = 2). RESULTS: The metabolic ratios of the 4 probe drugs correlated significantly (r (s) = 0.69-0.92; P <.001) in both populations. Tanzanian subjects homozygous for the CYP2D6*17 allele were slower metabolizers when debrisoquine or dextromethorphan was used as the probe drug than when codeine or metoprolol was used, showing a different substrate specificity of CYP2D6.17 than of CYP2D6.1 and CYP2D6.2. This was confirmed with analysis of covariance of the different metabolic ratios for a subgroup of subjects carrying only the CYP2D6*17 mutated allele (n = 9) compared with all other subjects (n = 44). The metabolic ratios of dextromethorphan and metoprolol differed significantly among Tanzanian subjects homozygous for the CYP2D6*29 allele compared with those with CYP2D6*1 or *2 alleles. CONCLUSION: We found differences in the disposition of 4 CYP2D6 probe drugs in black Tanzanians compared with Swedes. The differences were caused by the presence of CYP2D6.17 and CYP2D6.29. The results show that CYP2D6.17 exhibits altered substrate specificity compared with CYP2D6.1 and CYP2D6.2.

Adrenergic Agents↗
PubMed2005

How human neuroblastoma cells make morphine.

Recently, our laboratory demonstrated that human neuroblastoma cells (SH-SY5Y) are capable of synthesizing morphine, the major active metabolite of opium poppy. Now our experiments are further substantiated by extending the biochemical studies to the entire morphine pathway in this human cell line. L-[1,2,3-13C3]- and [ring-2',5',6'-2H3]dopa showed high isotopic enrichment and incorporation in both the isoquinoline and the benzyl moiety of the endogenous morphine. [2,2-2H2]Dopamine, however, was exclusively incorporated only into the isoquinoline moiety. Neither the trioxygenated (R,S)-[1,3-13C2]norcoclaurine, the precursor of morphine in the poppy plant, nor (R)-[1,3,4-2H3]norlaudanosoline showed incorporation into endogenous morphine. However, (S)-[1,3,4-2H3]norlaudanosoline furnished a good isotopic enrichment and the loss of a single deuterium atom at the C-9 position of the morphine molecule, indicating that the change of configuration from (S)- to (R)-reticuline occurs via the intermediacy of 1,2-dehydroreticuline. Additional feeding experiments with potential morphinan precursors demonstrated substantial incorporation of [7-2H]salutaridinol, but not 7-[7-2H]episalutaridinol, and [7-2H,N-C2H3]oripavine, and [6-2H]codeine into morphine. Human morphine biosynthesis involves at least 19 chemical steps. For the most part, it is a reflection of the biosynthesis in opium poppy; however, there is a fundamental difference in the formation of the key intermediate (S)-reticuline: it proceeds via the tetraoxygenated initial isoquinoline alkaloid (S)-norlaudanosoline, whereas the plant morphine biosynthesis proceeds via the trioxygenated (S)-norcoclaurine. Following the plant biosynthetic pathway, (S)-reticuline undergoes a change of configuration at C-1 during its transformation to salutaridinol and thebaine. From thebaine, there is a bifurcate pathway leading to morphine proceeding via codeine or oripavine, in both plants and mammals.

Alkaloids↗
PubMed1993

Opiate-like substances in an invertebrate, an opiate receptor on invertebrate and human immunocytes, and a role in immunosuppression.

The presence of morphine-like and codeine-like substances was demonstrated in the pedal ganglia, hemolymph, and mantle tissues of the mollusc Mytilus edulis. The pharmacological activities of the endogenous morphine-like material resemble those of authentic morphine. Both substances were found to counteract, in a dose-dependent manner, the stimulatory effect of tumor necrosis factor alpha or interleukin 1 alpha on human monocytes and Mytilus immunocytes, when added simultaneously to the incubation medium. The immunosuppressive effect of this opiate material expresses itself in a lowering of chemotactic activity, cellular velocity, and adherence. Codeine mimics the activity of authentic morphine, but only at much higher concentrations. Specific high-affinity receptor sites (mu 3) for morphine have been identified on human monocytes and Mytilus immunocytes. In Mytilus recovering from experimentally induced stress, the return of "altered" immunocytes to a more inactive state appears to be due to a significant rise in the content of morphine-like material in the pedal ganglia and hemolymph at this time. Thus, morphine may have a role in calming or terminating the state of immune alertness.

Animals↗