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PubMed2000

Heroin modulates the expression of inducible nitric oxide synthase.

The use of heroin (diacetylmorphine) is associated with a high incidence of infectious disease, and the immunologic alterations responsible for heroin-induced changes in resistance to infection have not been well characterized. The present study tests the hypothesis that expression of inducible nitric oxide synthase (iNOS) is modulated by the administration of heroin. The initial study using rats showed that heroin administration (0, 0.01, 0.1, or 1.0 mg/kg s.c.) results in a pronounced reduction in lipopolysaccharide (LPS)-induced expression of iNOS mRNA in spleen, lung, and liver tissue as measured by RT-PCR. Heroin also produced a reduction in the level of plasma nitrite/nitrate, the more stable end-product of nitric oxide degradation. In a subsequent study, administration of the opioid receptor antagonist, naltrexone (0.1 mg/kg) prior to the injection of heroin (1.0 mg/kg) blocked the heroin-induced reduction of iNOS expression and plasma nitrite/nitrate levels indicating that the effect is mediated via the opioid-receptor. This study provides the first evidence that heroin induces an alteration of iNOS expression, and suggests that a reduction in nitric oxide production may be involved in the increased incidence of infectious diseases amongst heroin users.

Animals↗
PubMed2003

Narcotic drugs change the expression of cytochrome P450 2E1 and 2C6 and other activities of carcinogen-metabolizing enzymes in the liver of male mice.

Drug-metabolizing enzymes play a great role in the bioactivation and also detoxification of zenobiotics and carcinogens such as N-nitrosamines and polycyclic aromatic hydrocarbons (PAHs). Therefore, the present study was undertaken to investigate the effect of narcotic drugs such as cannabis (hashish) and diacetylmorphine (heroin) on the activity of N-nitrosodimethylamine N-demethylase I [NDMA-dI], arylhydrocarbon [benzo(a)pyerne] hydroxylase [AHH], cytochrome P450 (CYP), cytochrome b(5), NADPH-cytochrome c reductase, glutathione-S-transferase, and levels of glutathione and thiobarbituric acid-reactive substances (TBARS). In addition, the present study showed the influence of hashish and heroin after single (24 h) and repeated-dose treatments (4 consecutive days) on the expression of cytochrome P450 2E1 (CYP 2E1) and cytochrome P450 2C6 (CYP 2C6). The expression of CYP 2E1 was slightly induced after single-dose and markedly induced after repeated dose-treatments of mice with hashish (10 mg kg(-1) body weight). Contrarily, heroin markedly induced the expression of CYP 2C6 after single-dose and potentially reduced this expression after repeated-dose treatments. It is believed that N-nitrosamines are activated principally by CYP 2E1 and in support of this, the activity of NDMA-dI was found to be increased after single- and repeated-dose treatments of mice with hashish by 23 and 41%, respectively. In addition, single- and repeated-dose treatments of mice with hashish increased: (1) the total hepatic content of CYP by 112 and 206%, respectively; (2) AHH activity by 110 and 165%, respectively; (3) NADPH-cytochrome c reductase activity by 21 and 98%, respectively; (4) and glutathione level by 81 and 173%, respectively. Also, single-dose treatments of mice with heroin increased the total hepatic content of CYP, AHH, NADPH-cytochrome c reductase, and glutathione level by 126, 72, 39, 205%, respectively. However, repeated dose-treatments of mice with heroin did not change such activities except cytochrome c reductase activity increased by 20%. Interestingly, the level of free radicals, TBARS, was potentially decreased after single or repeated-dose treatments with either hashish or heroin. It is clear from this study that the effects of hashish are different from those of heroin on the above mentioned enzymes particularly after repeated dose treatments. It is concluded that hashish induced the expression of CYP 2E1 and other carcinogen-metabolizing enzymes activities, and this induction could potentiate the deleterious effects of N-nitrosamines and aromatic hydrocarbons, e.g. benzo(a)pyrene, upon the liver and probably other organs. Such alterations may also change the therapeutic actions of other drugs, which are primarily metabolized by the P450 system, when administered to peoples using hashish or heroin.

Animals↗
PubMed1997

Functional magnetic resonance imaging of the acute effect of intravenous heroin administration on visual activation in long-term heroin addicts: results from a feasibility study.

This preliminary report is the first demonstration of the acute effects of diacetylmorphine (heroin) administration on functional activation in the human brain using functional magnetic resonance imaging (fMRI). Four opiate addicts who received regular prescriptions for heroin, underwent fMRI using a visual activation paradigm before and after a dose of 30 mg heroin. All four showed a decrease after the heroin dose in the extent of significant activation. This method shows promise for sequential scanning to determine brain activity in response to different drugs and routes of drug administration.

Acute Disease↗
PubMed1983

Applications of rapid-scanning multichannel detectors in chromatography. Plenary lecture.

A review of progress in the field of multichannel detection in column and thin-layer chromatography is presented, together with some novel applications of a computer-based, linear photodiode array UV--visible spectrophotometer for detection in high-performance liquid chromatography (HPLC). Computer-aided methods for simultaneous monitoring of the elution profile at three wavelengths with automatic peak detection and capture of UV spectra are described. The continuous calculation of absorbance ratios during elution is discussed as an index of peak homogeneity. A novel technique for the enhancement of qualitative identification in HPLC, based on transformation of captured spectra to the second derivative or to the decadic logarithm, is proposed. These developments are exemplified by a model system of diacetylmorphine and its principal metabolites and degradation products, morphine and 6-acetylmorphine. The potential utility of three-dimensional projections of (A, lambda, t) data is discussed in the context of pharmaceutical, bioanalytical and forensic applications.

Chromatography, High Pressure Liquid↗
PubMed1982

Determination of heroin and its metabolites by high-performance liquid chromatography.

A method is described for the simultaneous determination of heroin (3,6-diacetylmorphine, DAM) and its two active metabolites 6-acetylmorphine and morphine in blood by high-performance liquid chromatography using a normal-phase column and a UV detector at 218 nm. The compounds are stabilized in blood by rapid freezing and recovered by a multistep liquid--liquid extraction. The mobile phase is acetonitrile--methanol (75:25, v/v) buffered to apparent pH 7 with ammonium hydroxide and acetic acid. Using l-alpha-acetylmethadol as an internal standard, UV detection and a 1-ml biofluid sample, the lower limit of sensitivity is 12.5 ng/ml. Commonly used narcotic analgesics including codeine, propoxyphene, meperidine, methadone and levorphanol do not interfere with the analysis. The method has been applied to blood samples from humans and rats. Extracts of blood from a patient who had received an intravenous dose of 14 mg of DAM contained DAM and both of its active metabolites.

Animals↗
PubMed2002

Identification of impurities and statistical classification of methamphetamine tablets (Ya-Ba) seized in Thailand.

Impurity profiles of methamphetamine tablets seized in Thailand have been investigated. The samples are extracted with small amounts of ethyl acetate under alkaline condition and the extracts are analyzed by capillary gas chromatography. Nine compounds (1,2-dimethyl-3-phenylaziridine, ephedrine, methylephedrine, N-formylmethamphetamine, N-acetylmethamphetamine, N-formylephedrine, N-acetylephedrine, N,O-diacetylephedrie, methamphetamine dimer) are identified as impurities in methamphetamine tablet. Caffeine and ethyl vanillin are also detected as diluents and/or adulterants, and acetylcodeine monoacetylmorphine and diacetylmorphine are contained in many samples. In addition, trans-3,4-dimethyl-5-phenyl-2-oxazolidone is newly found as an impurity. For characterization and comparison of methamphetamine tablet exhibits, intensely and commonly detectable nine peaks are selected as the factor for multivariate analysis. The procedures reported here permit classification of 250 analyzed exhibits into five groups and characterization of classified groups.

Central Nervous System Stimulants↗
PubMed2003

The distribution of controlled drugs on banknotes via counting machines.

Bundles of paper, similar to sterling banknotes, were counted in banks in England and Wales. Subsequent analysis showed that the counting process, both by machine and by hand, transferred nanogram amounts of cocaine to the paper. Crystalline material, similar to cocaine hydrochloride, could be observed on the surface of the paper following counting. The geographical distribution of contamination broadly followed Government statistics for cocaine usage within the UK. Diacetylmorphine, Delta(9)-tetrahydrocannabinol (THC) and 3,4-methylenedioxymethylamphetamine (MDMA) were not detected during this study.

Automation↗
PubMed1998

The detection of acetylcodeine and 6-acetylmorphine in opiate positive urines.

Acetylcodeine (AC), an impurity of illicit heroin synthesis, was investigated as a urinary biomarker for detection of illicit heroin use. One hundred criminal justice urine specimens that had been confirmed positive by GC/MS for morphine at concentrations > 5000 ng/ml were analyzed for AC, 6-acetylmorphine (6AM), codeine, norcodeine and morphine. The GC/MS analysis was performed by solid phase extraction and derivatization with propionic anhydride. Total codeine and morphine concentrations were determined by acid hydrolysis and liquid/liquid extraction. AC was detected in 37 samples at concentrations ranging from 2 to 290 ng/ml (median, 11 ng/ml). 6AM was also present in these samples at concentrations ranging from 49 to 12 600 ng/ml (median, 740 ng/ml). Of the 63 specimens negative for AC, 36 were positive for 6AM at concentrations ranging from 12 to 4600 ng/ml (median, 124 ng/ml). When detected, the AC concentrations were an average of 2.2% (0.25 to 10.2%) of the 6AM concentrations. There was a positive relationship between AC concentrations and 6AM concentrations (r = 0.878). Due to its very low concentration in urine, AC was found to be a much less reliable biomarker for illicit heroin use than 6AM in workplace or criminal justice urine screening programs. However, AC detection could play an important role in determining if addicts in heroin maintenance programs are supplementing their supervised diacetylmorphine doses with illicit heroin.

Biomarkers↗
PubMed2002

New aspects in the treatment of heroin dependence with special reference to neurobiological aspects.

The Swiss trials on medical prescription of injectable diacetylmorphine (pharmaceutical heroin) for "severe" heroin dependence provoked very controversial commentaries. Despite methodological shortcomings, the evaluation of the Swiss heroin trials yielded some interesting findings. Study participants showed substantial improvements in health and well-being and noticeable declines in illicit drug use and criminal activities. Heroin prescription may thus be helpful for some of those who continue to regularly use illicit heroin while maintained on methadone or who refuse other available treatment options. However, research-based evidence suggests that the intravenous (IV) application of heroin under medical supervision may have untoward side effects. Recent studies have shown that heroin injections produce transient, but significant decreases in systemic and cortical oxygenation most likely secondary to respiratory depression. Among others, these effects are the subject of ongoing studies.

Adult↗
PubMed2003

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation.

Opioid drugs act primarily on the opiate receptors; they also exert their effect on other innervations resulting in non-opioidergic behavioural deficits. Similarly, opioid neurobehavioural teratogenicity is attested in numerous behaviours and neural processes which hinder the research on the mechanisms involved. Therefore, in order to be able to ascertain the mechanism we have established an animal (mouse) model for the teratogenicity induced by opioid abuse, which focused on behaviours related to specific brain area and innervation. Diacetylmorphine (heroin) and not morphine was applied because heroin exerts a unique action, distinguished from that of morphine. Pregnant mice were exposed to heroin (10 mg/kg per day) and the offspring were tested for behavioural deficits and biochemical alterations related to the septohippocampal cholinergic innervation. Some studies employing the chick embryo were concomitantly added as a control for the confounding indirect variables. Prenatal exposure to heroin in mice induced global hyperactivation both pre- and post-synaptic along the septohippocampal cholinergic innervation, including basal protein kinase C (PKC) activity accompanied by a desensitization of PKC activity in response to cholinergic agonist. Functionally, the heroin-exposed offspring displayed deficits in hippocampus-related behaviours, suggesting deficits in the net output of the septohippocampal cholinergic innervation. Grafting of cholinergic cells to the impaired hippocampus reversed both pre- and post-synaptic hyperactivity, resensitized PKC activity, and restored the associated behaviours to normality. Consistently, correlation studies point to the relative importance of PKC to the behavioural deficits. The chick model, which dealt with imprinting related to a different brain region, confirmed that the effect of heroin is direct. Taken together with studies by others on the effect of prenatal exposure to opioids on the opioidergic innervation and with what is known on the opioid regulation of the cholinergic innervation, it appears that heroin exerts its neuroteratogenicity by inducing alterations in the opioidergic innervation, which by means of its regulatory action, attenuates the functional output of the cholinergic innervation. In our model, there was hyperactivity mostly of the post-synaptic components of the cholinergic innervation. However, the net cholinergic output is decreased because PKC is desensitized to the effect of the cholinergic agonist, and this is further evidenced by the extensive deficits in the related behaviours.

Animals↗
PubMed1998

Opiate analgesics' dual role in firefly luciferase activity.

The effects of three opiate analgesics, isolated from opium, on the firefly luciferase enzyme have been studied. Morphine (MN), 6-acetylmorphine (MAM), and diacetylmorphine (DAM) inhibited the enzyme activity at different levels. At lower concentrations, MN and MAM enhanced enzyme activity, effecting inhibition at higher concentrations. However, DAM inhibited the enzyme activity at all concentrations investigated. The stimulating activity of MN and MAM is attributed to the hydrophilic interaction of the proton donor-acceptor type with the polar regions of the luciferase located outside the binding pocket of the active site. The inhibition at higher concentrations of MN and MAM and at all concentrations of DAM is found to be competitive in nature, with the analgesics competing for the binding of the enzyme's natural substrate luciferin. The binding site of the luciferase could accommodate only one analgesic molecule. Binding constants determined from bioluminescence studies showed that the inhibitor binding site is hydrophobic in nature. The inhibition constants of analgesics are in the order MN > MAM > DAM. The greater binding of DAM to luciferase is attributed to its ability to form a ground state complex with ATP and greater hydrophobicity. At higher concentrations of ATP, the binding constants increased. The results obtained are explained assuming that the firefly luciferase acts as a subtype mu-opioid receptor model.

Adenosine Triphosphate↗
PubMed2000

Quality of heroin and heroin-related deaths from 1987 to 1995 in Vienna, Austria.

AIMS: To investigate the quality of heroin seized in Vienna between 1987 and 1995 and to examine whether there was a relationship between the quality of heroin and the rate of drug-related deaths. DESIGN: Reports of heroin seizure analysis and post-mortem reports of heroin-related deaths in Vienna from 1987 to 1995 were analysed. RESULTS: There were 386 seizures of heroin comprising a total weight of 25 640.12 g heroin. All the seizures were in the base form. All seizures also contained a diluent, mainly lactose. Additionally, in 95 seizures caffeine, in four seizures paracetamol and in three seizures metaqualon were detected. Of a total of 764 drug-related deaths 506 cases were classified as heroin-related deaths. In 336 cases other central nervous system-depressant drugs and/or alcohol could be detected in the blood in addition to morphine (polydrug heroin-related deaths). There was evidence of a trend towards greater polydrug involvement during the study period. The age of victims of polydrug heroin-related deaths remained unchanged over time while the age of victims of pure heroin-related deaths decreased significantly. The morphine concentration in the medulla oblongata in heroin-related deaths decreased significantly. Finally, there was no statistically significant relationship between the rate of heroin-related deaths per year and the diacetylmorphine concentration of heroin seizures in that year. CONCLUSION: The results did not substantiate the widely held belief that increases in heroin-related deaths could be explained by an increase in the quality of heroin.

Adolescent↗
PubMed2003

Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice.

Heroin treatment or abusive drug addiction influences many physiological functions, including the reactions of the immune system. Although suppression of various manifestations of the immune system after heroin (or morphine) administration has been reported, we show here that production of proinflammatory cytokines and nitric oxide (NO) was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated recipients. Mice were treated by a subcutaneous administration of heroin (diacetylmorphine) given in one or repeated daily doses. The ability of spleen cells from treated mice to respond in vitro to alloantigens and to produce IL-2, IL-4, IL-10 and IFN-gamma, and the production of IL-1beta, IL-12 and NO by peritoneal macrophages, were tested. Within 2 h after heroin administration, proliferative responses to alloantigens and the production of IL-1beta, IFN-gamma, IL-12 and NO were enhanced significantly. In contrast, the production of anti-inflammatory cytokines IL-4 and IL-10 was at the same time rather decreased. As a consequence, skin allografts in heroin-treated mice were rejected more promptly than in untreated or vehicle-treated recipients. Similarly, the growth of allogeneic tumours induced by high doses of tumour cells was suppressed significantly in heroin-treated mice. The enhancing effects of heroin on the production of proinflammatory cytokines were antagonized by naltrexone, a specific inhibitor of classic opioid receptors. These results show that heroin treatment augments production of proinflammatory cytokines and accelerates allotransplantation reactions. The observations thus illustrate the complexity of the effects of heroin on the immune system and should be taken into account during medical treatment of opiate addicts and in the use of morphine to decrease pain in various clinical situations.

Animals↗
PubMed1996

The mu opioid receptor: from molecular cloning to functional studies.

Opioids have been used and abused by humans for centuries. The mu opioid receptor represents the high affinity binding site for opioid narcotics with high abuse liability such as morphine, codeine and fentanyl. Heroin (diacetylmorphine), a semi-synthetic derivative of morphine, crosses the blood-brain barrier more readily than morphine due to its increased hydrophobicity. Once in the brain heroin is hydrolyzed to morphine, which acts at the mu opioid receptor and results in euphoria, thus conferring the reinforcing properties of heroin. Using molecular biology techniques, the mu opioid receptors from several species have been cloned. This article reviews recent progress in this area, with respect to the two major cellular functions of the mu opioid receptor: reduction of intracellular cAMP concentration by inhibiting adenylyl cyclase activity, and inhibition of neuronal firing by modulating membrane ion channels.

Journal Article↗
PubMed2004

Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via 'chasing the dragon' by heroin addicts.

In 1998, two clinical trials were started in The Netherlands to evaluate the effect of coprescription of heroin and methadone on the mental and physical health and social functioning of chronic, treatment-resistant, heroin-dependent patients. Since 75-85% of the heroin addicts in The Netherlands use their heroin by "chasing the dragon," one of the two study arms concerned the coprescription of inhalable heroin. A pharmaceutical dosage form for inhalable heroin was developed for this trial, consisting of a 3:1 powder mixture of diacetylmorphine base and caffeine anhydrate. We describe the manufacturing process that was developed for filling sachets with this mixture in four dosages using a micro dose auger filler. In order to control product quality, in-process controls were developed to monitor the filling process and quality control tests were performed on the finished product. In-process control results have shown the filling process to be accurate and precise. The diacetylmorphine/caffeine sachets were shown to comply with the specifications for content and uniformity of mass. The finished product was found to be stable for 2 years when stored at 25 degrees C, 60% relative humidity and for 6 months when stored at 40 degrees C, 75% relative humidity.

Administration, Inhalation↗
PubMed2003

Adherence to heroin dependence therapies and human immunodeficiency virus/acquired immunodeficiency syndrome infection rates among drug abusers.

Adherence is a primary determinant of treatment effectiveness; thus, poor adherence attenuates optimum clinical benefit. A bibliographic review was conducted to evaluate the impact of adherence to heroin dependence treatment on human immunodeficiency virus (HIV) transmission and to identify interventions proven to be effective in improving adherence. The best adherence rates were achieved by methadone and diacetylmorphine, both of which are comparable in promoting significant reduction in heroin use. Methadone adjusted-dose studies with daily doses ranging from 100 to 200 mg and multiple support interventions achieved the highest adherence rates. Studies of methadone maintenance that examined changes in HIV prevalence of infection have found that higher treatment adherence is correlated with a reduction in HIV transmission. These data suggest that patients who adhere continuously to methadone treatment are less likely to continue injecting illicit drugs and sharing contaminated injection equipment than are those who interrupt treatment, thus preventing the spread of HIV via drug injection.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Is the clinical efficacy of epidural diamorphine concentration-dependent when used as analgesia for labour?

BACKGROUND: The physicochemical properties of diamorphine (3,6-diacetylmorphine) enhance its bioavailability compared with more lipid-soluble opioids when administered into the epidural space. However, the influence of concentration, volume or mass on the clinical efficacy of diamorphine is not known. METHOD: In this double-blind, randomized, prospective study, 62 women in active labour and </=5 cm cervical dilatation were recruited to determine whether the mode of action of diamorphine in the epidural space is concentration-dependent. After insertion of a lumbar epidural catheter, patients received epidural diamorphine 3 mg either as a high-volume, low-concentration solution (group A) or a low-volume, high-concentration solution (group B). The concentration of diamorphine was determined by the response of the previous patient in the same group using up-down sequential allocation. Pain corresponding to the previous contraction was assessed using a 100-mm visual analogue score and effective analgesia was defined as </=10 mm within 30 min of epidural injection. RESULTS: There was no significant difference in EC50 for diamorphine between the groups: the difference was 15.0 microg ml(-1) (95% CI -40.3 to 10.3). The EC50 for group A was 237.5 microg ml(-1) (95% CI 221.2 to 253.8) and the EC50 for group B was 252.5 microg ml(-1) (95% CI 232.2 to 272.8). The EC50 ratio was 0.95 (95% CI 0.87 to 1.06). The groups exhibited parallelism (P=0.98). The overall EC50 for all data was 244.2 microg ml(-1) (95% CI 230.8 to 257.2). CONCLUSION: We conclude that diamorphine provides analgesia in labour by a concentration-dependent effect.

Adult↗