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At least 19 recordsLinked to original sources
PubMed1986

Epinephrine reduces systemic absorption of extradural diacetylmorphine.

The effect of epinephrine on the vascular absorption of morphine from the extradural space is uncertain; this study examined the effect of epinephrine on the related but more lipophilic opiate diacetylmorphine (diamorphine, heroin) because any effects of vasoconstriction on diacetylmorphine absorption should be maximally apparent. With this experiment, we hoped to resolve whether epinephrine does or does not alter vascular absorption of extradurally injected opiates. Thirty patients undergoing lumbar laminectomy were given either extradural diacetylmorphine, 5 mg, extradural diacetylmorphine, 5 mg with 1:200,000 epinephrine, or 1:200,000 epinephrine followed 5 min later by 5 mg extradural diacetylmorphine. Plasma morphine concentrations were measured by radioimmunoassay because of the rapid conversion of diacetylmorphine to morphine in plasma; repeated blood samples were obtained the first 30 min after injection into the epidural space. Significantly lower plasma morphine levels occurred between 3 and 20 min when epinephrine was added to diacetylmorphine. Peak plasma morphine levels (mean +/- SEM) were 179 +/- 37 nmol/L with diacetylmorphine alone, 87 +/- 16 nmol/L with diacetylmorphine and epinephrine given together and 44 +/- 11 nmol/L with epinephrine pretreatment, all significantly different from one another. The mean peak plasma morphine concentration was 8.7 +/- 1.1 min for diacetylmorphine alone, but addition of epinephrine (together or sequentially) meant that 15 of 20 patients had no peak level before 120 min. Epinephrine reduced absorption of diacetylmorphine from the extradural site by at least 55% over the first 30 min. The incidence of patients with more than 9 hr analgesic duration was significantly (P = 0.033) greater in patients who had diacetylmorphine and epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed2002

Diacetylmorphine degradation to 6-monoacetylmorphine and morphine in cell culture: implications for in vitro studies.

Diacetylmorphine deacetylates rapidly to 6-monoacetylmorphine and then to morphine. The immunomodulatory effects of diacetylmorphine are under investigation by several groups utilising various methods including in vitro cell culture; however, diacetylmorphine stability under these conditions is unknown. The aim of this study was to quantify diacetylmorphine degradation under cell culture conditions and to determine the mechanism by which this occurs. Diacetylmorphine degradation in a mouse splenocyte mitogenesis assay was investigated. Morphine and 6-monoacetylmorphine were quantified using HPLC with UV detection. After 6 h, approximately 73% of diacetylmorphine had been hydrolysed in the presence of cells. The half-life of diacetylmorphine was 1.4 h in cell media alone and 1.2-2.2 h in incubations containing cells, while the half-life of 6-monoacetylmorphine was 3.1 h in cell media alone and 0.99-1.2 h in incubations containing cells. 6-Monoacetylmorphine and morphine formation were found to be dependent on incubation time and diacetylmorphine concentration, and were not dependent on esterase activity, mitogen concentration, presence of erythrocytes and cell media evaporation. Only morphine formation was dependent on lymphocyte concentration. 6-Monoacetylmorphine formation was independent of cells and appeared to be due to the conditions of the cell culture (pH and temperature), while morphine formation was dependent to a greater extent on cells, but independent of esterase activity. The study highlights the limitations of conclusions made in previous studies which have not recognised diacetylmorphine instability.

Animals↗
PubMed2006

Volatilisation of diacetylmorphine: in vitro simulation of 'chasing the dragon'.

In preparation for a trial on co-prescription of heroin to chronic treatment-resistant addicts, a pharmaceutical dosage form for smokable heroin was developed. During development of this product (a mixture of diacetylmorphine and caffeine), in vitro experiments were performed simulating 'chasing the dragon': the technique used by addicts for inhalation of heroin after volatilisation. Samples were heated on aluminium foil using a heating device and the vapours were collected and analysed using a HPLC-UV method. The recovery of diacetylmorphine and caffeine in vapours was studied after volatilisation of different powder mixtures at temperatures between 200 and 350 degrees C. Furthermore, the volatilisation set-up was combined with an Andersen sampler to determine the sizes of aerosol particles. Only small differences in recovery of diacetylmorphine and caffeine were found between temperatures and between powder mixtures: 46-62% of diacetylmorphine from the sample was recovered in vapour and 65-83% of caffeine. The only degradation product detected in vapour was 6-acetylmorphine (4.1-7.1%). In the temperature range studied, temperature mainly influenced the volatilisation rate. Mass median aerodynamic diameters of aerosols from diacetylmorphine-containing samples ranged from 1.8-4.1 microm; 45-60% of each sample was recovered as aerosol particles <5 microm. Volatilising pharmaceutical smokable heroin resulted in sufficient amounts of diacetylmorphine in vapour and in particles suitable for effective deposition in the lungs.

Aerosols↗
PubMed2006

Morphine and 6-acetylmorphine concentrations in blood, brain, spinal cord, bone marrow and bone after lethal acute or chronic diacetylmorphine administration to mice.

The aim of this study was to evaluate postmortem incorporation of opiates in bone and bone marrow after diacetylmorphine (heroin) administration to mice. Mice were given acute (lethal dose of 300 mg/kg) or chronic (10 and 20 mg/kg/24 h for 20 days) intraperitoneal administration of diacetylmorphine. The two metabolites of diacetylmorphine, 6-acetylmorphine (6-AM) and morphine, were extracted from whole blood, brain, spinal cord, bone marrow and bone (after hydrolysis) using a liquid/liquid method. Quantification was performed by gas chromatography-mass spectrometry (GC/MS). Results showed that after acute administration, opiates were present in all studied tissues. Morphine concentrations appeared to be higher than those of 6-AM in blood (52.4 microg/mL versus 27.7 microg/mL, n=12), bone marrow (87.8 ng/mg versus 8.9 ng/mg, n=6) and bone (0.85 ng/mg versus 0.43 ng/mg, n=6), but 6-AM concentrations were higher than those of morphine in brain (14.0 ng/mg versus 7.4 ng/mg, n=12) and spinal cord (27.8 ng/mg versus 20.8 ng/mg, n=12). No correlation was found for both compounds between blood concentrations and either brain, spinal cord, bone or bone marrow concentrations while a significant one was found between brain and spinal cord concentrations either for morphine (r=0.89, n=12, p<0.001) or 6-AM (r=0.93, n=12, p<0.001), the concentration being higher in spinal cord than in brain. When bones were stored for 2 months, only 6-AM remained in bone marrow but not in bone. After chronic administration, mice being sacrificed by cervical dislocation 24 h after the last injection, no opiate was detected in any studied tissues. Further studies are required, in particular in human bones, but these results seem to show that 6-AM could be detect in bone marrow several weeks after the death and could be an alternative tissue for forensic toxicologist to detect a fatal diacetylmorphine overdose, even if no correlation between blood and bone marrow was observed. On the other hand, neither bone tissue nor bone marrow will allow the confirmation of a chronic diacetylmorphine use.

Analgesics, Opioid↗
PubMed2006

A rapid test for heroin (3,6-diacetylmorphine) based on two chemiluminescence reactions.

A rapid method for screening drug seizure samples for 3,6-diacetylmorphine (heroin), which consists of a simple hydrolysis procedure and flow-injection analysis with two chemiluminescence reagents, is described. Before hydrolysis, 3,6-diacetylmorphine evokes an intense response with a tris(2,2'-bipyridyl)ruthenium(III) reagent (prepared by dissolving the perchlorate salt in acetonitrile), and a relatively weak chemiluminescence response with a second reagent: potassium permanganate in an aqueous acidic polyphosphate solution. However, the permanganate reagent is extremely sensitive toward the hydrolysis products of 3,6-diacetylmorphine (i.e., 6-monoacetylmorphine and morphine). Some compounds commonly found in drug laboratories may cause false positives with tris(2,2'-bipyridyl)ruthenium(III), but do not produce the markedly increased response with the permanganate reagent after the hydrolysis procedure. The combination of these two tests therefore provides an effective presumptive test for the presence of 3,6-diacetylmorphine, which we have verified with 14 samples obtained from a forensic science laboratory.

Journal Article↗
PubMedDate not supplied

Analysis of diacetylmorphine, caffeine, and degradation products after volatilization of pharmaceutical heroin for inhalation.

Pharmaceutical smokable heroin was developed for a clinical trial on medical co-prescription of heroin and methadone. This product, consisting of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate, was intended for use via "chasing the dragon", that is, inhalation after volatilization. This procedure involves heating the powder mixture, which may lead to formation of degradation products that could subsequently be inhaled. We developed a method that used a high-performance liquid chromatography system that was compatible with photodiode-array detection and mass spectrometric detection to separate diacetylmorphine- and caffeine-related compounds in a wide polarity range for analysis of the vapor. This method was used to analyze the contents of the plastic drinking straws that were used by patients to inhale the vapors from pharmaceutical heroin used via chasing the dragon, which were considered to be representative of the vapors the patients inhaled. They contained primarily unchanged diacetylmorphine, its main metabolite 6-acetylmorphine, caffeine, and some morphine. Several unidentified peaks were observed in the straw chromatograms. Chemical structures were proposed for nine degradation products: morphine derivatives with different substitution patterns of the C(3), C(6), and/or N(17) positions, which comprised 0.4-9.7% of the straw sample residue weight. Activity and toxicity of most of these compounds are unknown and require further investigation.

Caffeine↗
PubMed2005

Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Administration, Inhalation↗
PubMed2005

Rapid comparison of diacetylmorphine on banknotes by tandem mass spectrometry.

A procedure is described for the determination of the distribution of the contamination of banknotes with controlled drugs using tandem mass spectrometry. The method is illustrated using diacetylmorphine, which is the major active component of heroin. A series of banknotes is introduced into the mass spectrometer and the intensities of two product ions (m/z 328 and 268) derived from the precursor protonated molecule (m/z 370) are recorded. A banknote is considered contaminated if it shows a significant peak for both product ions, and if the ratio of intensities of these two peaks falls within accepted limits. The distribution of diacetylmorphine on sterling banknotes taken from general circulation within the UK can be modelled by an arcsin (square root) transformation of the data or by a log transformation of the data with a higher proportion of contamination. The two models were found to be in close agreement, predicting an upper limit (at 99.9% confidence) of contamination on banknotes from general circulation between 9 and 10%. The percentage contamination in a case study was calculated and compared to the background distribution using the two models proposed. This comparison revealed that the contamination present in the case study was inconsistent with that present on banknotes in general circulation.

Forensic Sciences↗
PubMed1975

Rapid and sensitive gas chromatographic determination of diacetylmorphine and its metabolite monoacetylmorphine in blood using a nitrogen detector.

A quantitative gas chromatographic method for the determination of plasma concentrations of diacetylmorphine and its metabolite monacetylmorphine using an alkali flane detector (nitrogen detector) is described. Plasma samples (pH 9.0) containing ethylmorphine acetate as internal standard are extracted with benzene. The dried benzene extracts are analysed as their corresponding acetylated derivatives following treatment with trifluoroacetic anhydride-benzent (1:5). The nitrogen detector permits quantitation of narcotic levels down to 100ng/ml with detection as low as 20 ng/ml. The higher sensitivity and selectivity of the nitrogen detector are compared to those obtained in flame ionization detection. Species differences in the rate of conversion of diacetylmorphine to monacetylmorphine in vitro in blood are also presented.

Animals↗
PubMed2002

GC/MS determination of pyrolysis products from diacetylmorphine and adulterants of street heroin samples.

The inhalation of heroin vapors after heating on aluminium foil ("chasing the dragon") is gaining popularity nowadays among heroin users seeking to avoid the risks of parenteral drug administration. The heroin-smoking procedure was simulated under laboratory conditions by heating the samples on aluminium foil at 250 to 400 degrees C and collecting the vapors in a condenser trap. A total of 72 pyrolysis products of diacetylmorphine, street heroin, residues from aluminium foils used to smoke street heroin, typical by-products, and adulterants were detected by gas chromatography/mass spectrometry (GC/MS). About half of these compounds could be identified. Diacetylmorphine (base and salt) undergoes substantial to complete degradation. Some typical street heroin constituents, like morphine, codeine, acetylcodeine, papaverine, and caffeine, are rather heat-stable. Other compounds, like noscapine and paracetamol, are pyrolyzed to a greater extent. The principal chemical reactions leading to the formation of pyrolysis products are desacetylation, transacetylation, N-demethylation, O-methylation, ring cleavage and oxydation.

Drug Contamination↗
PubMedDate not supplied

Pharmaceutical development of an intravenous dosage form of diacetylmorphine hydrochloride.

A solid dosage form for multiple use was developed for parenteral administration of diacetylmorphine in a clinical trial on co-prescription of heroin to heroin addicts. A 300-mg/mL diacetylmorphine hydrochloride solution was lyophilised as 10-mL aliquots in 30-mL glass vials, to be reconstituted to 150 mg/mL with water for injection before use. Addition of bulking agents for improvement of the cake structure of the lyophilised product appeared unnecessary. Stability studies indicated good stability of the lyophilised product under prescribed storage conditions (25 degrees C, 60% relative humidity) and under more extreme conditions (40 degrees C, 75% relative humidity). The reconstituted product was found to be stable for six days at room temperature. Suitability of the product for multiple use was supported by the fact that the reconstituted product was found to be antimicrobially active.

Chemistry, Pharmaceutical↗
PubMed1997

[Detection of diacetylmorphine (heroin) use by thin-chromatography analysis of urine].

The proof of diacetylmorphine (heroin) application is based on the identification of its specific metabolite 6-monoacetylmorphine simultaneously detected with the main metabolite morphine in human urine. Codeine is another morphine derivative appearing in cases of diacetylmorphine abuse; it can be considered a metabolite of 6-acetylcodeine, a typical impurity found in raw heroin. An analytical procedure for detection of the mentioned morphine basesin urine is presented, including a screening method. A careful extraction method is required for 6-monoacetylmorphine. To classify it into the code system of the screening, its properties are expressed by a threecomponent code. Subsequent identity confirmation of the mentioned bases by means of thin layer chromatography uses mobile phases, in which optimal separation effects are achieved, even in the presence of nicotine or caffeine and its metabolites theobromine and theophylline. Circumstances of 6-monoacetylmorphine discovery in urine are discussed.

Chromatography, Thin Layer↗
PubMed1977

Identification of diacetylmorphine metabolites in humans.

With the techniques of column chromatography, TLC, and GLC, morphine, 6-acetylmorphine, normorphine, morphine 3-glucuronide, 6-acetylmorphine 3-glucuronide, and normorphine glucuronide were identified as metabolites of diacetylmorphine (heroin) in the urine of humans administered 10 mg iv/70 kg body weight.

Adult↗
PubMed1980

Stability of Brompton mixtures: determination of heroin (diacetylmorphine) and cocaine in presence of their hydrolysis products.

The application of a rapid, selective, and sensitive reversed-phase high-performance liquid chromatographic method to the separation of the hydrochloride salts of heroin (diacetylmorphine) and cocaine and their hydrolysis products is described. The method was used to study the stability of heroin and cocaine in Brompton mixtures in pharmaceutically useful pH range and vehicles at different temperatures. The pH range of optimal stability for both heroin and cocaine was 3.0-3.5. The disappearance of heroin and cocaine in Brompton mixtures followed pseudo-first-order kinetics in buffered solutions. Increased alcohol and decreased syrup concentrations diminished heroin hydrolysis but did not influence cocaine stability. Substitution of morphine for heroin in Brompton mixtures markedly increased the rate of cocaine hydrolysis.

Chemistry, Pharmaceutical↗
PubMed1984

Evaluation of 3,6-dibutanoylmorphine as an analgesic in vivo: comparison with morphine and 3,6-diacetylmorphine.

Dibutanoylmorphine (DBM), a synthetic diester of morphine, was compared with morphine (M) and diacetylmorphine (DAM) for analgesic efficacy, potency and duration of action following I.V. administration in rats. Analgesia was assessed in groups of eight animals using both tail-flick and hot-plate testing methods following random administration of five different doses of each drug. DBM was found to be substantially more potent than M, but less potent than DAM in both tail-Flick and hot-plate tests of nociception. Similarly, assessment of duration of action at the ED50 for each drug revealed that DBM has a duration of analgesia which is intermediate between the durations of M and DAM. Thus, in rats in vivo, DBM is an effective analgesic and has a reasonable duration of action release to other opioids.

Analgesics↗
PubMed1995

Direct cellular immunomodulation produced by diacetylmorphine (heroin) or methadone.

1. Abuse of the narcotic drug diacetylmorphine (heroin), as well as methadone, a drug for treating heroin addiction, has been associated with alterations in immune function in humans. The current study was performed to assess the direct (in vitro) immunomodulatory effect of exposure to these drugs, in view of the very limited studies reported thus far on this effect. 2. Murine splenocytes or peritoneal macrophages were cultured in vitro at concentrations of 0.0001-100 microM heroin or methadone. B-cell function was assessed by quantitating cellular proliferation in response to stimulation with an antigen analog; T-cell regulatory function was assessed by culturing splenocytes with or without drugs in the presence of anti-CD3 antibody and subsequently quantitating cytokine production; and T-cell effector function was evaluated by culturing lymphocytes with or without drugs during a 5-day induction culture followed by assessment of specific cytotoxic T-lymphocyte (CTL) activity. Natural immunity was assessed by quantitating basal and IL-2 augmented natural killer (NK) cell function, and macrophage function was assessed by cytokine production. 3. In vitro exposure to heroin resulted in decreased B-cell proliferation at concentrations of 1-100 microM, and methadone had a similar effect at concentrations of 0.1-100 microM. 4. Production of IL-2 was suppressed by 0.1-100 microM of heroin, whereas exposure to methadone appeared to result in a generalized modulation, with suppression of IL-2 at most concentrations. In contrast, IL-4 production was only affected at the 100 microM concentration of both drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Complaints of heroin-maintained patients: A survey of symptoms ascribed to diacetylmorphine.

Prescribing of injectable diacetylmorphine (DAM) for heroin dependence has raised concerns about its safety. In light of various reports by heroin-maintained patients of DAM-related adverse events, and previously established unwanted effects of opioids in pain management, we undertook a survey in February 2001 of a random sample of 132 (127 participated) of 1061 patients prescribed DAM in Switzerland at that time. The purpose was to document the prevalence rates of a list of unintended symptoms experienced and attributed to DAM by patients. To assess symptom complaints and other data, staff administered a six-page self-report questionnaire. The patients ascribed numerous symptoms to DAM, with the best-known being the most frequently reported (e.g. skin itching, sweating, constipation). Among potentially more problematic complaints ranged irregular menses, cognitive deficits, muscle twitches, labored breathing, pains in the cardiac region, and temporary paralysis of limbs. In the absence of a control group, however, these may also be due to other factors, such as expectation, co-medication, concomitant substance use or co-morbidity. This pilot study emphasizes the necessity of rigorous assessment of the true rates, types, severity and preventability of such complications, especially given the current efforts to establish heroin maintenance as an optional treatment for heroin dependence.

Adult↗
PubMed1979

Simple high-performance liquid chromatographic method for the separation of 3,6-diacetylmorphine hydrochloride (heroin) and hydrolysis products.

The application of reversed-phase high-performance liquid chromatography to the measurement of 3,6-diacetylmorphine (DAM) hydrochloride and its degradation products is described. This method has been applied to study the kinetics of the DAM hydrolysis at 26 +/- 0.1 degrees and 48 +/- 0.1 degrees. The hydrolysis of DAM involved a two-step first-order sequential mechanism between pH 3 and 8.6. The first-order rate constants of each step at all pH levels have been determined. The pH rate profile was constructed from kinetic measurements and demonstrated that stability of DAM hydrochloride solutions was optimal at pH 4.3. This information is being applied to the development of parenteral dosage forms of DAM hydrochloride.

Chromatography, High Pressure Liquid↗