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PubMed2005

Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence.

BACKGROUND: The clinical implementation and evaluation of heroin substitution programmes have been confounded by the lack of objective and validated biomarkers for illicit heroin use in patients prescribed pharmaceutical heroin. This study examined the capacity to detect illicit heroin use by gas chromatography-mass spectrometry (GC-MS) analysis of urine samples for the presence of opium impurities common to illicit, but not pharmaceutical heroin. AIMS: To characterize the diagnostic properties of the metabolites of noscapine and papaverine in comparison to morphine as a gold-standard marker of illicit heroin use; and to examine the relationships between the self-reported time since most recent heroin use and the detection of these opioids in urine. DESIGN: A cross-sectional study of 52 opioid-dependent patients in treatment (not prescribed heroin), who self-reported illicit heroin use within the preceding 2 weeks. Self-report data regarding recent drug use and a urine sample were collected. GC-MS analyses of urines were conducted and reported by laboratory staff blinded to self-report data. FINDINGS: The metabolites of papaverine (hydroxypapaverine and dihydroxypapeverine) were found to have high sensitivity, specificity and negative predictive values as markers for illicit heroin use compared to the 'gold-standard' morphine. Other opioids, including 6-mono-acetylmorphine (6-MAM), codeine and noscapine metabolites (e.g. meconine) were less adequate in detecting heroin use. CONCLUSIONS: GC-MS detection of papaverine metabolites in urine appears to be suitable method of identifying illicit heroin use for clinical and research purposes.

Adult↗
PubMed1989

Antitussive agents as N-methylaspartate antagonists: further studies.

The relative potencies of ketamine and the morphinan derivatives dextrorphan, dextromethorphan, and levorphanol as antagonists of the excitatory actions of N-methylaspartate on rat spinal neurones in vivo were examined, both following their microelectrophoretic administration and, with the exception of levorphanol, after intravenous injection. Applied microelectrophoretically, dextrorphan was a more potent N-methylaspartate antagonist than ketamine, levorphanol, or dextromethorphan. After systemic administration, however, dextrorphan was rather less potent than ketamine in this respect, whereas dextromethorphan remained less potent than either ketamine or dextrorphan. Noscapine, an antitussive that lacks anticonvulsant activity, failed to reduce selectively responses to N-methylaspartate as did papaverine, an isoquinoline structurally related to noscapine, and triprolidine, an antihistamine commonly found in proprietary cough medicines. The results are discussed with particular reference to the potential of the compounds tested as anticonvulsant and neuroprotective agents in vivo.

Animals↗
PubMed1983

High-affinity dextromethorphan binding sites in guinea pig brain. II. Competition experiments.

Binding of dextromethorphan (DM) to guinea pig brain is stereoselective, since levomethorphan is 20 times weaker than DM in competing for DM sites. In general, opiate agonists and antagonists as well as their corresponding dextrorotatory isomers are weak competitors for tritiated dextromethorphan ([3H]DM) binding sites and display IC50 values in the micromolar range. In contrast, several non-narcotic, centrally acting antitussives are inhibitory in the nanomolar range (IC50 values for caramiphen, carbetapentane, dimethoxanate, and pipazethate are 25 nM, 9 nM, 41 nM, and 190 nM, respectively). Other antitussives, such as levopropoxyphene, chlophedianol, and fominoben, have poor affinity for DM sites whereas the antitussive noscapine enhances DM binding by increasing the affinity of DM for its central binding sites. Additional competition studies indicate that there is no correlation of DM binding with any of the known or putative neurotransmitters in the central nervous system. DM binding is also not related to tricyclic antidepressant binding sites or biogenic amine uptake sites. However, certain phenothiazine neuroleptics and typical and atypical antidepressants inhibit binding with IC50 values in the nanomolar range. Moreover, the anticonvulsant drug diphenylhydantoin enhances DM binding in a manner similar to that of noscapine. Preliminary experiments utilizing acid extracts of brain have not demonstrated the presence of an endogenous ligand for DM sites. The binding characteristics of DM sites studied in rat and mouse brain indicate that the relative potencies of several antitussives to inhibit specific DM binding vary according to species. High-affinity, saturable, and stereoselective [3H]DM binding sites are present in liver homogenates, but several differences have been found for these peripheral binding sites and those described for brain. Although the nature of central DM binding sites is not known, the potent interaction of several classes of centrally acting antitussives with DM sites suggests that they may be related to the mechanism of action of this drug.

Animals↗
PubMed1989

Subsensitivity to the cough-depressant effects of opioid and nonopioid antitussives in morphine-dependent rats: relationship to central serotonin function.

The present study was designed to determine whether morphine-dependent rats have a decreased sensitivity to the cough-depressant effects of both opioid and nonopioid antitussives. Morphine dependence was induced by treatment with morphine-admixed food (0.5 mg/g of food) for 7 days. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The cough-depressant effect was evaluated as the antitussive ED50 calculated by the method of Litchfield and Wilcoxon. The effects of both opioid (morphine and dihydrocodeine) and nonopioid (dextromethorphan and noscapine) antitussive drugs were diminished in morphine-dependent rats. The values of ED50 of these antitussive drugs in morphine-dependent rats were about 3-fold higher than those in control rats. A significantly lower number of serotonin receptors was found in the brainstem of morphine-dependent rats (Bmax: 2.88 +/- 0.32 pmoles/mg protein) than in controls (Bmax: 4.93 +/- 0.50 pmoles/mg protein). It is possible that the decreased sensitivity to both opioid and nonopioid antitussive drugs, in terms of the depression of the cough reflex, in morphine-dependent rats may be due to changes in the number of serotonin receptors.

Animals↗
PubMed1994

Impurities, adulterants and diluents of illicit heroin. Changes during a 12-year period.

Changes in the content of impurities, adulterants and diluents are described for 383 samples of illicit heroin seized in the western part of Denmark during the 12-year period 1981 through 1992. A wide range in purity was found within each year, whereas the average purity did not vary much from one year to another. The average purity of wholesale samples (45%) was only slightly higher than the purity of retail samples (36%). The SW Asian type of heroin, containing high concentrations of noscapine, predominated from the mid-eighties. Heroin base and heroin hydrochloride each accounted for approximately half of the samples during the eighties. However, in recent years the base form has become predominant. During the early eighties caffeine and procaine were the most frequent additives next to sugars. During the middle and late eighties an increasing number of heroin samples were cut with phenobarbital and methaqualone. During the early nineties the occurrence of phenobarbital and methaqualone has decreased, whereas paracetamol in combination with caffeine has become predominant. Re-analyses of samples which had been kept in storage for several years showed that most samples had not changed after being stored in the dark for a couple of years at room temperature. However, storage for more than 5 years often resulted in decomposition, particularly in samples consisting of the SW Asian type of heroin.

Acetaminophen↗
PubMed1999

Development of a predictive model for batch membership of street samples of heroin.

Street samples (n = 31) of heroin were analysed by gas chromatography with flame ionisation detection to determine opiate, noscapine and papaverine content. Using this data, the chromatograms obtained could be resolved into eight groups by visual examination of the data. The concentrations of opiates were significantly correlated (P < 0.05) with the exception of the pairs 6-O-monoacetylmorphine/noscapine and morphine/6-O-monoacetylmorphine. This precludes the use of simple cluster analysis for determining and predicting the relationship of different street samples. Application of Fisher's linear discriminant analysis to the data set indicated that 91.9% of the samples could be discriminated including pairs which could not be discriminated by eye. A blind trial (n = 2) resulted in the correct assignment to street sample. Application of such methods may provide, in the future, a powerful tool for the prediction of batch membership of drugs at the street level.

Chromatography, Gas↗
PubMed1996

Gas chromatographic/mass spectrometric detection of narcotine, papaverine, and thebaine in seeds of Papaver somniferum.

In addition to codeine and morphine, three more compounds: narcotine (noscapine), papaverine, and thebaine were found in Indian and Netherlands poppy seeds (Papaver somniferum L). The compounds were detected by a GC/MS technique and the identities were confirmed by comparing retention times and ion ratios with the known references. The concentrations of codeine, morphine, thebaine, papaverine, and narcotine were 44, 167, 41, 67, and 230 micrograms/g in Indian poppy seeds, and were 1.8, 39, 1.0, 0.17, 0.84 micrograms/g in Netherlands poppy seeds, respectively. Because these compounds may be urinary products after poppy seed consumption, the lowest detectable concentrations of codeine, morphine, thebaine, papaverine, and narcotine in urine are of interest and were found to be 4, 4, 5, 0.4, and 4 ng/ml, respectively. The detection of urinary narcotine, papaverine, or thebaine may be utilized to differentiate poppy seed consumption from illicit codeine, morphine, or heroin use.

Gas Chromatography-Mass Spectrometry↗
PubMed2006

The significance of putative urinary markers of illicit heroin use after consumption of poppy seed products.

After consumption of poppy seeds various substances were detected in urine or blood samples using an immunoassay and a sophisticated liquid chromatographic-tandem mass spectrometric procedure. These compounds are widely considered to be putative markers of heroin (HER) abuse whereas acetylcodeine was regarded as a marker for illicit preparations ("street HER"). Besides positive urinary opiate immunoassay results during a 48 hours monitoring period, peak concentrations of morphine (MOR), codeine and their glucuronides appeared 4 to 8 hours after ingestion of poppy seeds, and concentrations of total MOR higher than 10 microg/mL were observed. Also, in serum samples taken up to 6 hours after consumption, MOR glucuronides were found. Free MOR was only detected in traces (1 to 3 ng/mL) within 2 hours of consumption. In addition, 3 of 6 onsite opiate sweat tests revealed positive results 6.5 hours after ingestion. Furthermore, it was demonstrated that neither noscapine (NOS) nor papaverine (PAP) was detectable in urine or blood samples after the consumption of poppy seeds containing up to 94 microg NOS and up to 3.3 mug PAP. NOS and PAP were rapidly metabolized, whereas desmethylpapaverine and, especially, its glucuronide were found in urine samples of poppy seed consumers even 48 hours after consumption. According to these results PAP metabolites should not be regarded as markers of illicit HER abuse. In conclusion, only acetylcodeine can be regarded as a specific marker but has the problem of a short half-life. Therefore, we suggest that NOS and PAP, but not their metabolites, might be used cautiously as additional markers of illicit HER abuse as they have not been detected after oral intake of poppy seeds in normal doses. But it must be kept in mind that in some cases poppy seeds with an unusually high content of these alkaloids could be available, and that these substances are also agents in some pharmaceuticals.

Biomarkers↗
PubMed1999

[Pierre-Jean Robiquet].

Famous french pharmacist, born in Rennes, professor at the Paris Ecole de pharmacie and fellow of the Academie royale des sciences, Pierre-Jean Robiquet discovered many natural products, among them two alkaloids narcotine (noscapine) and codeine.

Alkaloids↗
PubMed2003

[Influence of fertilizers on yield and yield components of opium from Papaver somniferum Linn].

The effect of fertilizer on the yield and yield components of opium from Papaver somniferum L.cv.Ikkanshu were investigated from 1993 to 1995. The weight of opium per one capsule was tendency to increase in the order of peat moss > pulverized charcoal > compound fertilizer, but the differences among the results were not significant. Furthermore, no difference in the capsule weight per 100 m2 and the yields of opium and alkaloids per 100 m2 were detected. The significant difference was only observed when the data were compared among the weights and yields of different years. The difference among the yield of opium was mainly due to the weight of opium per one capsule. The weight of opium per one capsule showed a high correlation with capsule husk weight. The alkaloids contents in opium obtained with a different fertilizer application showed no difference. Morphine content at the first lancing was about 11%, and the value decreased with the order of lancing. On the contrary, the codeine and the thebaine content did not change during lancing and the value were 6-7% and 3%, respectively. The papaverine and the noscapine content decreased in the order of lancing.

Codeine↗
PubMed2005

[Analysis of two year heroin seizures in the Liege area].

The results of heroin analysis from seizures in the Liege area during the last two years are presented in this article. Between January 2003 and January 2005, 50 samples were analysed in the Laboratory of Clinical Toxicology and Forensic Toxicology of the University of Liege. Mean heroin concentration was 14,7%. Noscapine and papaverine, other opium alcaloïds, were simultaneously present with heroin. As diluents, we only identified caffein and acetaminophen.

Acetaminophen↗
PubMedDate not supplied

[Comparative gas chromatographic studies of heroin samples. Results of a pilot project in West Germany in 1982].

From 1.4. -30.10.1982 all heroin samples weighing more than 5 g seized in the States of Baden-Württemberg, Hesse and by the Bundeskriminalamt were analyzed by capillary gas chromatography during a pilot project. For comparison of samples ratios of concentrations of heroin (including its decomposition products 0(6)-acetylmorphine and morphine) and its natural by-products of synthesis acetylcodeine, papaverine, and narcotine (noscapine) were determined. The application of these parameters and further qualitative and quantitative criteria for heroin comparison for investigative and legal purposes are discussed.

Chromatography↗
PubMedDate not supplied

Role of opioidergic and serotonergic mechanisms in cough and antitussives.

This paper provides an overview of our current understanding of the serotonergic and opioidergic mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, ip, markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effects of 8-OH-DPAT, dihydrocodeine and dextromethorphan were significantly reduced by pretreatment with methysergide, but not with ketanserin. Therefore it is possible to speculate that 5-HT1 receptors, in particular the 5-HT1A receptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective mu-opioid receptor agonist, and U-50,488H, a highly selective kappa-opioid receptor agonist, have potent antitussive effects when administered either icv or ip. However, we did not observe a cough-depressant effect of DPDPE, a selective delta-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by mu- and kappa-opioid receptors. On the other hand, naloxonazine, a selective mu 1-opioid receptor antagonist, had no effect on the antitussive effects associated with icv DAMGO. These results indicate that mu 2- rather than mu 1-opioid receptors are involved in mu-opioid receptor-induced antitussive affects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sigma sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sigma sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

[Analysis of regional trends in narcotic studies between 1980 and 1986].

During the period of survey, the number of narcotic drug seizures by the law, especially cannabis resin, has increased considerably. The details on this development are presented. The following main analytical results were obtained: the median concentration of THC in cannabis resin has increased up to 8.6%, in cannabis plants the THC content has fluctuated between 1% and 3%. In the heroin samples since 1982, diamorphin has predominated in the base form; the diamorphin content had dropped to 32%, which is connected with a rise simultaneous in the concentration of noscapine (up to 9%). The concentration of cocaine hydrochloride had diminished at the end of the period to 62%; on the other hand, the amphetamine sulfate content increased to 69%. LSD trips used from 10 to 120 micrograms per trip. Methadone occurred mostly in the form of tablets containing 5 mg methadone hydrochloride.

Amphetamine↗
PubMed1995

Determination of opium alkaloids in crude opium using non-aqueous capillary electrophoresis.

A method for the quantitative determination of the opium alkaloids morphine, codeine, thebaine, noscapine and papaverine in crude opium and in drug preparations based on non-aqueous capillary electrophoresis has been developed. The non-aqueous mode provides high separation selectivity and new possibilities for regulating the selectivity in capillary electrophoresis. The nature of the organic solvent, the acidity of the electrolytes as well as the temperature surrounding the capillary exhibit a major influence on the separation selectivity.

Dimethyl Sulfoxide↗
PubMed2004

Validated assay for the determination of markers of illicit heroin in urine samples for the control of patients in a heroin prescription program.

A fully validated procedure for the simultaneous determination of morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), 6-acetylmorphine (6AM), codeine (COD), codeine-6-glucuronide (C6G), acetylcodeine (AC), noscapine (NOS) and papaverine (PAP) based on liquid chromatography followed by electrospray mass spectrometry applying multiple reaction monitoring (LC-ESI-MS/MS) in urine samples is described. The extraction was carried out on a Zymark Rapid Trace Workstation using C18 solid-phase extraction cartridges. The separation was performed in 19 min on an Agilent 1100 HPLC system, using a Phenomenex C18 AQUA column (4 microm, 150 mm x 2 mm), which is coupled with an Applied Biosystems API 2000 mass spectrometer. Deuterated analogues were used as internal standards. The limits of detection were in the range of 0.1 ng/ml (PAP) to 7.4 ng/ml (M6G), the coefficients of correlation were higher than 0.996, the precisions ranged from 3% to 12% and the absolute recoveries were between 45% (M3G) and 98% (MOR). Analyses of samples from patients of a heroin prescription program demonstrated the usefulness of the procedure for the analytical differentiation between prescribed synthetic heroin (diamorphine) use and non-prescription heroin abuse on the basis of urine analysis. After the ingestion of pharmaceutical heroin only general markers for heroin use were detected, which are MOR, M3G, M6G and 6AM, respectively. When illicit heroin was abused, additionally to further general markers (COD, C6G) specific markers for non-prescription heroin abuse (AC, NOS, PAP) were found. However, it must be kept in mind that only AC may be regarded as absolute specific marker of non-prescription heroin, because all other compounds may appear in urine after ingestion of opiate alkaloids containing medicines or foods (e.g. poppy seeds). Therefore, patients of a heroin prescription program should be advised not to ingest such products.

Calibration↗
PubMed2004

Simultaneous determination of ingredients in a cold medicine by cyclodextrin-modified microemulsion electrokinetic chromatography.

Cyclodextrin-modified microemulsion electrokinetic chromatography (CD-MEEKC) was used to simultaneously determine 14 active ingredients (thiamine nitrate, anhydrous caffeine, acetaminophen, riboflavin, guaifenesin, pseudoephedrine hydrochloride, ascorbic acid, ethenzamide, DL-methylephedrine hydrochloride, dihydrocodeine phosphate, ibuprofen, noscapine, carbinoxamine maleate, and bromhexine hydrochloride) in a cold medicine. Separation of the ingredients was optimized by changing the SDS concentration and oil type and the addition of 2-propanol and cyclodextrin (CD) to the separation solution. The separation selectivity was improved dramatically by changing CD type. All of the active ingredients and formulation excipients were successfully separated with the use of a separation solution consisting of 0.81% (w/w) pentane, 6.61% (w/w) 1-butanol, 2% (w/w) 2-propanol, 4.47% (w/w) SDS, and 86.11% (w/w) 10 mM sodium tetraborate solution with 3 mM 2,6-di-O-methyl-beta-CD. The established method was then validated and demonstrated to be applicable to the determination of the active ingredients in a model cold medicine. No interference from the formulation excipients was observed. Good linearities were obtained with correlation coefficients above 0.999. Recovery and precision ranged from 99.1 to 100.7% and from 0.5 to 2.8% R.S.D., respectively. The detection limit for ingredients ranged from 0.6 to 4.2 microg ml(-1). Good agreement was obtained between the established method and the traditional HPLC method. These results suggest that CD-MEEKC can be used for the determination of multiple ingredients in cold medicine.

Chromatography, High Pressure Liquid↗
PubMed2005

Yeast DEL assay detects clastogens.

Chromosomal rearrangements, including DNA deletions are involved in carcinogenesis. The deletion (DEL) assay scoring for DNA deletions in the yeast Saccharomyces cerevisiae is able to detect a wide range of carcinogens. Among approximately 60 compounds of known carcinogenic activity, the DEL assay detected 86% correctly whereas the Ames Salmonella assay detected only 30% correctly [R.J. Brennan, R.H. Schiestl, Detecting carcinogens with the yeast DEL assay, Methods Mol. Biol. 262 (2004) 111-124]. Since the DEL assay is highly inducible by DNA double strand breaks, this study examined the utility of the DEL assay for detecting clastogens. Ten model compounds, with varied mechanisms of genotoxicity, were examined for their effect on the frequency of DNA deletions with the DEL assay. The compounds tested were: actinomycin D, camptothecin, methotrexate and 5-fluorodeoxyuridine, which are anticancer agents, noscapine and furosemide are therapeutics, acridine, methyl acrylate and resorcinol are industrial chemicals and diazinon is an insecticide. The in vitro micronucleus assay (IVMN) in CHO cells, a commonly used tool for detection of clastogens, was performed on the same compounds and the results of the two assays were compared. The results of our study show that there is 70% concordance in the presence of metabolic activation (rat liver S9) and 80% concordance in the absence of metabolic activation between the DEL assay and the standard in vitro micronucleus assay. The lack of cytotoxicity observed for four of the ten compounds examined indicates limited diffusion of lipophilic compounds across the yeast cell wall. Thus, the development of a more permeable yeast tester strain is expected to greatly improve concordance of the DEL assay with the IVMN assay. The yeast DEL assay is inexpensive, amenable to automation and requires less expertise to perform than the IVMN. Thus, it has a strong potential as a robust, fast and economical screen for detecting clastogens in vitro.

Animals↗