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PubMed1978

Heroin abuse and a gas chromatographic method for determining illicit heroin samples in Singapore.

The abuse of heroin (diacetylmorphine) in Singapore escalated sharply in 1975 and 1976, as indicated by the 35-fold increase in the number of heroin seizures and the 20-fold increase in the urine samples containing morphine since 1974. A rapid and simple GC method has been described to estimate diacetylmorphine (and caffeine). Monoacetylmorphine and acetylcodeine may be ascertained by an additional step involving acetylation. All gas chromatograms of a large number of samples analyzed consistently had the same pattern, indicating that they possibly had a common origin. This GC "fingerprint," together with the quantitative data, appears to be characteristic of the illicit Asian or Chinese type of heroin found in Singapore. The proportions of the four major ingredients in some twelve typical samples have been tabulated. Statistical data confirming the accuracy and reproducibility of the analytical method have also been presented.

Calibration↗

PubMed1978

Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver.

Hepatic extraction of the long-acting narcotic, methadone, was compared to that of the short-acting narcotics, morphine, diacetylmorphine, and meperidine, using an isolated perfused rabbit liver preparation. Methadone was avidly extracted from portal venous blood (86.1 +/- 0.81%) in a single pass through the liver after a bolus injection (1.5 mg) into a nonrecirculating perfusion system. Hepatic extraction of methadone was independent of rate of hepatic blood flow (0.59 to 1.53 ml per g of liver per min) but was altered by increasing the total amount of methadone injected. After a bolus injection of 15.0 and 75.0 mg, the proportions of methadone extracted were reduced to 75 and 56%, respectively. The hepatic extraction of morphine (1.5 mg) was 25%, of diacetylmorphine (1.5 mg) 59%, and of meperidine (1.5 mg) 66% in a single pass, all significantly lower (P less than 0.01) than that of methadone. Subcellular fractionation of whole liver homogenates after a single pass of drug showed that methadone and its metabolites were localized primarily in the fractions containing nuclei, mitochondria, microsomes, and other membranes, whereas morphine was primarily localized in the supernatant cytosol. Unchanged methadone was shown to be slowly released from the liver into hepatic effluent blood along with small amounts of the inactive pyrrolidine and pyrroline metabolites (identified by gas chromatography and mass spectrometry). These findings suggest that the liver may serve not only as a site of biotransformation of methadone, but also as a major reservoir for storage and subsequent release of unchanged compound.

Animals↗

PubMed1979

Sensitive fluorescence assay for d,l-methadone.

d,l-Methadone forms a fluorophore when reacted with paraformaldehyde in concentrated sulfuric acid. Based on this reaction, a fluorescence assay suitable for quantitative d,l-methadone analysis from plasma and other tissues was developed. d,l-Methadone was extracted at pH 9.2 from the deproteinized filtrate of plasma or of aqueous tissue homogenate into an organic phase of 25% isobutanol in ethylene dichloride. After an aliquot of the organic phase was evaporated to dryness at 50--55 degrees with an air jet, paraformaldehyde (0.1%, in concentrated sulfuric acid) was added, and fluorescence was read at 450 nm with excitation at 275 nm. By this method, d,l-methadone can be assayed in the presence of its metabolites, morphine, diacetylmorphine (heroin), codeine, and cocaine; however, amphetamine, meperidine, and quinine interfere.

Animals↗

PubMed1990

Antinociceptive activity of propionyl esters of morphine: a reevaluation.

The antinociceptive activity of the propionyl homologues of 3-O- and 6-O-acetyl- and 3,6-O-diacetylmorphine was re-investigated using materials of unequivocally established structure. Testing was in male Wistar rats at 60 min following subcutaneous administration by the rat tail-flick method. Results indicate that the antinociceptive activity of 3-O-propionylmorphine was similar to that of 3-O-acetylmorphine. 6-O-Propionylmorphine and 3,6-O-dipropionylmorphine had similar antinociceptive activity and, like 6-O-acetylmorphine, 6-O-propionylmorphine may be the pharmacologically active principle responsible for the antinociceptive activity of its disubstituted homologue.

Analgesics↗

PubMed1983

Drug reinstatement of heroin-reinforced responding in the rat.

Non-contingent, 'priming' IV drug injections led to reinstatement of heroin-reinforced responding after a period of extinction. Rats implanted with IV catheters were trained to self-administer heroin (100 micrograms/kg/infusion diacetylmorphine HCl) and were given test sessions consisting of a period of self-administration followed by extinction conditions. 'Priming' infusions of heroin and other drugs were presented during extinction and lever pressing following the injection was observed. Priming injections of 50, 100 and 200 micrograms/kg heroin effectively restored responding after a period of extinction. Morphine and, to a lesser extent, amphetamine and apomorphine also reinstated heroin-reinforced responding whereas cocaine and clonidine did not. These results may help our understanding of 'relapse of drug-taking' behavior.

Animals↗

PubMed1996

Effects of haloperidol in a response-reinstatement model of heroin relapse.

The present study employed an animal model of drug relapse in which previously extinguished heroin self-administration behavior was reinstated following a single reinforced trial. Male albino rats were trained to traverse a straight-alley for a reinforcer consisting of a single IV injection of 0.06 mg/kg diacetylmorphine (heroin). Once the alley-running had been established, the heroin reinforcer was removed and the operant behavior permitted to extinguish over trials. On treatment day, animals were injected 45 min prior to testing with 0.0, 0.075, 0.10, 0.15 or 0.3 mg/kg of the dopamine receptor antagonist, haloperidol. A single trial was then conducted during which some animals continued to experience extinction conditions while others were injected with the heroin reinforcer upon entry into the goal box. The effects of these manipulations were determined during an additional single test trial conducted 24 h later when the subjects were no longer drugged. While heroin produced a reliable reinstatement in operant responding, this effect was dose-dependently prevented by pretreatment with haloperidol. These data suggest that dopamine receptor antagonism alters the reinforcing consequences of heroin administration as measured by heroin's ability to reinstate operant behavior following a prolonged period of nonreinforced responding.

Animals↗

PubMed2002

Heroin-associated environmental stimuli modulate the expression of inducible nitric oxide synthase in the rat.

RATIONALE: Heroin (diacetylmorphine) administration has been shown to alter the induction of nitric oxide, a molecule known to play a critical role in the regulation of immune responses and resistance to infectious challenges. There is evidence that the physiological and behavioral effects of opioids can be conditioned to environmental stimuli associated with drug administration. OBJECTIVES: The present study tests whether environmental stimuli paired with the administration of heroin alter the expression of inducible nitric oxide synthase (iNOS), one of the isoforms of the enzyme responsible for nitric oxide production. METHODS: The experimental group of rats received three conditioning sessions each involving a subcutaneous injection of heroin (1.0 mg/kg) immediately upon being placed in a chamber that served as the conditioned stimulus. Following the conditioning sessions, the rats remained in their home cages for 6 days to recover from the effects of heroin per se. The rats then were re-exposed to the conditioning chamber in the absence of heroin and immediately following the session were injected subcutaneously with lipopolysaccharide (LPS) to induce iNOS expression. Six hours later, the expression of iNOS messenger ribonucleic acid (mRNA) and protein was determined in spleen, lung, and liver using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting, respectively. Control procedures were used to determine whether the alterations in iNOS expression were due to conditioning processes. RESULTS: The results showed that exposure to the conditioned stimulus produced a pronounced reduction in the expression of iNOS mRNA and protein in spleen, lung, and liver tissue. Control procedures showed that this effect was due to conditioning processes. CONCLUSIONS: This study provides the first evidence that heroin-induced alteration of iNOS expression can be conditioned to environmental stimuli, and suggest that environmental stimuli associated with drug use may contribute to the alteration in susceptibility to infection.

Animals↗

PubMed1976

Effects of acute and chronic methadone treatment of the uptake of 3H-5-hydroxytryptamine in rat hypothalamus slices.

Effects of in vitro methadone and several other narcotics were investigated on 3H-5-HT uptake in rat hypothalamus slices. The results indicated that d, l-methadone and levorphanol had slightly greater inhibitory action on the uptake than the isomers, d-methadone and dextrorphan, respectively. Morphine, diacetylmorphine and the narcotic antagonist naloxone produced a considerably weaker inhibitory effect. After an acute injection of methadone, but not morphine, the uptake of 5-HT by hypothalamic slices of treated animals was inhibited. The chronic treatment of rats with methadone for 18 days had no significant effect on the uptake, but following the withdrawal of this treatment for 2 weeks the 5-HT uptake was significantly elevated. The inhibitory effects of in vitro methadone in the hypothalamus slices were not modified by the chronic drug treatment.

Animals↗

PubMed1982

Heroin: analgesia, toxicity and disposition in the mouse.

The acute toxicity of heroin (3,6-diacetylmorphine, DAM) and its metabolites 6-acetylmorphine (AM) and morphine (M) following intravenous (i.v.) and intracerebroventricular (i.c.v.) administration and their tailflick-test analgesic activity following i.c.v. administration were studied in mice. After i.c.v. administration, M was 2.5-3 times more potent as a naloxone-reversible analgesic than either DAM or AM. DAM and AM provoked a naloxone-sensitive respiratory depressant lethality (i.c.v.) while M (i.c.v.), and all three drugs given i.v., caused convulsions prior to death. The dose-response and naloxone antagonism studies suggest that the receptor mechanisms which may subserve opiate convulsions differ from those mediating either analgesia or depressant lethality. Studies of DAM's disposition in vivo and in vitro suggest that unhydrolyzed DAM may contribute to its own pharmacodynamic profile after i.v., but not subcutaneous (s.c.) administration to mice.

Analgesia↗

PubMed1992

Alterations in septohippocampal cholinergic innervations and related behaviors after early exposure to heroin and phencyclidine.

Mice were exposed to diacetylmorphine (heroin) or phencyclidine (PCP) prenatally or neonatally. At a later age, they were tested for hippocampus-related behavioral deficits and concomitant alterations in the septohippocampal cholinergic innervations. Actually, this is an application of the previously established phenobarbital neuroteratogenicity model to heroin and PCP. Prenatal exposure was accomplished transplacentally by injecting the mother 10 mg/kg heroin or PCP on gestation days 9-18. Neonatal administrations were applied directly by injections of 10 mg/kg of either drug to the pups between neonatal days 2-21. At the age of 50 days, mice exposed to heroin and PCP prenatally exhibited a 107% and 159% increase in their muscarinic cholinergic receptors Bmax, respectively. Neonatal exposure to heroin or PCP caused an 83% and 76% increase in the receptors respectively. On the behavioral level, both prenatal and neonatal exposure to heroin or PCP reduced performance in the hippocampus related eight-arm maze and Morris mazes. Depending on the drug, the test and the period of drug administration, the reduction ranged between 10% and 75%. The results suggest that heroin and PCP induce alterations in the septohippocampal cholinergic innervations and in related behavioral performance. Further studies are necessary in order to connect the biochemical and behavioral events in causal relationships.

Aging↗

PubMed1977

Choice of strong analgesic in terminal cancer: diamorphine or morphine?

A controlled trial of diamorphine (diacetylmorphine, heroin) and morphine is reported in which the two drugs were administered regularly by mouth in individually determined effective analgesic doses. Elixirs contained cocaine hydrochloride 10 mg/dose; other drugs were prescribed when indicated clinically. 699 patients entered the trial and, of these, 146 crossed from diamorphine to morphine, or vice versa, after about two weeks using an oral potency ratio of 1.5/1 determined in a pilot trial. Additional medication and survival were closely similar in both treatment groups. In the female crossover patients, no difference was noted in relation either to pain or the other symptoms evaluated. On the other hand, male crossover patients experienced more pain, and were more depressed, while receiving diamorphine. In these, the potency ratio of diamorphine to morphine appeared to be less than 1.5/1. If this is allowed for, then the difference in mood is probably not significant. Compared with male patients, fewer females required a dose of 10 mg or more, but more were prescribed an anxiolytic. The ability to do without a 2 a.m. dose appeared to be related more to the size of the dose than to gender or treatment. It is concluded that, provided allowance is made for the difference in potency, morphine is a satisfactory substitute for orally administered diamorphine. However, when injections are necessary, the greater solubility of its hydrochloride gives diamorphine an important practical advantage over morphine, especially when large doses are required.

Administration, Oral↗

PubMed1996

Inositol phosphate formation in mice prenatally exposed to drugs: relation to muscarinic receptors and postreceptor effects.

Mice were exposed to phenobarbital or heroin [diacetylmorphine (DAM)] prenatally by feeding the mother phenobarbital on gestation day 9-18; DAM was injected into the mother on gestation days 9-18. At the age of 50 days, mice exposed to phenobarbital or DAM prenatally were examined for long-term biochemical changes in the postsynaptic septohippocampal system as measured by alterations in formation of the second messenger inositol phosphate (i.p.). A significant increase in i.p. formation in response to carbachol was found after prenatal exposure to DAM. An increase in i.p. formation in response to 20 mM KCl alone or in the additional presence of 10 mM carbachol or 1mM physostigmine was found after prenatal exposure to phenobarbital or DAM. In addition, a significant increase in IP formation in response to sodium fluoride was found after prenatal exposure to phenobarbital or DAM. It is suggested that an increase in G-protein activation and in the second messenger formation accompanies the early drug-induced upregulation of the muscarinic receptors found in our previous studies.

Animals↗

PubMedDate not supplied

Illicit drug abuse in the Marmara region of Turkey.

Data on the analysis of 840 illicit drug samples of a total weight of 749.677 kg, confiscated in the Marmara Region, Turkey, from January 1986 to April 1987 is presented. The majority (82.3%) of all cases examined by the Division of Narcotic Drugs Research Laboratories of the Council of Forensic Medicine of Turkey, related to Cannabis products. Heroin represented 16.7% and all other controlled drugs made up the remaining 1%. From the 691 samples analyzed, 43.15% was Cannabis plant material. From the 140 illicit heroin samples analyzed by capillary gas chromatography, 61% had a diacetylmorphine content between 30 and 48%. O-6-monoacetylmorphine was detected in 43% of the samples ranging from 0.4 to 8.6%. Almost half (46.6%) of all heroin samples contained procaine ranging from 0.7 to 22%.

Cannabis↗

PubMed1995

An amperometric opiate assay.

Current techniques for the detection and measurement of diacetylmorphine (heroin), morphine and their principal metabolite morphine-3-glucuronide (M3G) are based mainly on chromatography or immunoassay. No enzymatic method for the detection of these compounds has yet been reported. Two novel microbial enzymes have been isolated and characterized in this laboratory: an acetylmorphine carboxyesterase (heroin esterase) and a morphine dehydrogenase (MDH). These highly specific enzymes have been incorporated in an amperometric assay for heroin and morphine using phenazine methosulphate as a mediator. The assay gives a rapid and sensitive response to heroin and morphine, with a detection limit for morphine of 6.8 micrograms ml-1 (23.7 microM).

Acetylesterase↗

PubMed2005

Automated multiple development thin-layer chromatography for separation of opiate alkaloids and derivatives.

There are three types of opiate alkaloids. First, the poppy alkaloids: morphine, codeine, thebaine, noscapine and papaverine; then, the semi-synthetic and synthetic derivatives used in therapy as antitussives and analgesics, such as pholcodine, ethylmorphine and dextromethorphan; at last narcotic compounds, diacetylmorphine (heroin) and opiates employed as substitutes in treatment of addiction: buprenorphine and methadone. For classical thin-layer chromatography (TLC) of opium alkaloids, it is necessary to use complex eluents with strong alkaline substances to obtain a clean separation between morphinan and isoquinoline compounds. This study purposes the planar chromatographic analysis of these substances by the automated multiple development (AMD) compared with results obtained by classical TLC method. The aim of this work was to achieve the best separation of these opiate alkaloids and derivatives by this modern technique of planar chromatography. The AMD system provided a clean separation for each of three opiates groups studied and the best results have been obtained with universal gradient: methanol 100, methanol-dichloromethane 50/50, dichloromethane 100, dichloromethane 100, hexane 100 for opium alkaloids and with gradient A: 5% of 28% ammonia in methanol 100, acetone 100, acetone 100, ethyl acetate-dichloromethane 50/50, dichloromethane 100 for antitussives and substitutes. Two reagents were used for the detection of alkaloids by spraying: Dragendorff and iodoplatinate reagents. The detection limits with these two reagents were 1 microg for ethylmorphine, thebaine, papaverine, codeine, and 2 microg for morphine and noscapine and other alkaloids.

Antitussive Agents↗

PubMed2004

Heroin profiling: mannitol hexaacetate as an unusual ingredient of some illicit drug seizures.

Mannitol hexaacetate (MHA) has been detected by GC-MS in some brown illicit drug seizures in which diacetylmorphine (DAM) was completely lacking. The presence of MHA as a genuine ingredient of the drug seizures rather than a storage- or an analytical artifact, formed by transacetylation of mannitol with the DAM in the heroin, has been verified. It is argued that MHA was formed as a result of the addition of mannitol, as diluent, before the acetylating step in the process of the heroin preparation. This early dilution in the production and distribution chain of the illicit drug is deemed as peculiar, nonetheless it may be highly indicative of a specific production process of heroin in a trafficking organization.

Acetates↗

PubMed2004

Process characterisation, optimisation and validation of production of diacetylmorphine/caffeine sachets: a design of experiments approach.

Powder filled sachets containing a 3:1 (w/w) powder mixture of diacetylmorphine base and caffeine anhydrate were developed as a dosage form for smokable heroin used for the treatment of chronic, treatment-resistant heroin addicts. The powder mixture was filled into sachets using a micro dose auger filler machine. The goal of this study was to identify the most important process variables that influence precision of dosing. Five variables were tested: auger speed, agitator speed, hopper fill level, dose interval, and dose. An experimental design was used to study the effects of each of these variables, including possible non-linear and interaction effects. A 9-term regression model was constructed, explaining 94% of the observed variation in dose weight variation coefficient. Dose, agitator speed and hopper fill level were the most important variables. The regression model was used to identify optimal settings of the variables for four sachet doses intended for routine manufacture. The results of four test batches manufactured with these optimised settings showed that accurate (accuracy: 99.0-101.0%) and precise (CV: 3.2-5.3%) filling of diacetylmorphine/caffeine sachets is possible using the micro dose auger filler machine.

Administration, Inhalation↗

PubMed2006

Controlled trial of prescribed heroin in the treatment of opioid addiction.

AIM: This study aimed to assess the efficacy of the prescription of intravenous diacetylmorphine (DAM) versus oral methadone with medical and psychosocial support, with a view of improving physical and mental health as well as social integration among socially excluded, opioid-dependent individuals for whom standard treatments have failed. DESIGN: This study used an open, randomized controlled trial. SETTING: This study took place in Granada, Spain. PARTICIPANTS: Sixty-two opioid-dependent participants were randomized, 31 in each treatment group, and 50 of them were analyzed. The participants were recruited directly from the streets, through peer outreach, in well-known meeting places for drug-addicted individuals. INTERVENTIONS: Participants in the experimental group received injected DAM, twice a day, plus oral methadone, once a day, for 9 months. The control group received only oral methadone, once a day. The two groups received an equivalent opioid dosage. The average DAM dosage was 274.5 mg/day (range: 15-600 mg), and an average methadone dosage was 42.6 mg/day (range: 18-124 mg). The daily methadone dosage in the control group was 105 mg/day (range: 40-180 mg). Comprehensive clinical, psychological, social, and legal support was given to both groups. MEASUREMENTS: The following were measured in this study: general health, quality of life, drug-addiction-related problems, nonmedical use of heroin, risk behavior for HIV and HCV, and psychological, family, and social status. FINDINGS: Both groups improved with respect to the total domain assessed. Those in the experimental group showed greater improvement in terms of physical health (the improvement was 2.5 times higher; p = .034) and risk behavior for HIV infection (the improvement was 1.6 times higher; p = .012). In addition, this group decreased its street heroin use from 25 days/month to 8 days/month as seen on the Addiction Severity Index (p = .020), as well as the number of days free from drug-related problems (the improvement was 2.1 times higher; p = .004) or involvement in crime (from 11 days/month to <1 day/month; p = .096 between groups). CONCLUSIONS: These findings support the hypothesis that, under the same conditions, DAM could be safely delivered, in our context. Also, in physical health, HIV risk behavior, street heroin use, and days involved in crime, DAM plus methadone was more efficacious than methadone alone. This implies that this treatment could provide an effective alternative for the treatment of socially excluded, opioid-dependent patients with severe physical and mental health problems because of drug addiction, when all available previous treatments have failed.

Adult↗