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PubMed1997

High-performance liquid chromatographic monitoring of intravenously administered diacetylmorphine and morphine and their metabolites in human plasma.

A rapid and selective reversed-phase high-performance liquid chromatographic assay with gradient elution and diode-array detection for diacetylmorphine, morphine, codeine, and their free and glucuronidated metabolites in plasma, was developed. After addition of ethylmorphine as internal standard the plasma samples were extracted using C18 ODS-2 solid-phase columns with a recovery better than 80%. The limit of quantitation using an injection volume of 2 microl was 25 ng/ml for each compound. The intra- and inter-day precision was better than 5%. The described method cannot only be used for pharmacokinetic studies but also for intoxication cases to monitor a wide range of opiates.

Chromatography, High Pressure Liquid↗
PubMed2006

Contact allergy and respiratory/mucosal complaints from heroin (diacetylmorphine).

After the start of heroin (diacetylmorphine)-assisted treatment to a selected group of chronic treatment-resistant heroin-dependent patients in the Netherlands, we reported about work-related eczema and positive patch tests to heroin in some nurses and nasal and respiratory complaints. To investigate the prevalence of heroin contact allergy, we started a questionnaire-based study with follow-up by allergological examinations. Of 120 questionnaires sent, 101 (84%) was returned: 67 from nurses and 34 from other employees. Of 101 workers, 38 (38%) had reported work-related complaints: 33 of 67 (49%) nurses and 5 of 34 (15%) other employees. Patch tests to heroin were performed in 24 nurses and were positive in 8 (33%). All the 8 had eyelid or facial eczema and, in 6, accompanied by mucosal or respiratory complaints. The prevalence of heroin contact allergy in this study was 8% (8/101) among all employees and 12% (8/67) among nurses. Respiratory and mucosal complaints could not be ascribed to a contact allergy, and in these cases, serum was analysed for specific immunoglobulin E to heroin. A type 1 allergy to heroin could not be shown. These complaints are possibly due to the histamine-liberating effect of heroin, to atopic constitution, to a combination of these factors or - less likely - to other non-allergic factors.

Allergens↗
PubMed1983

Diacetylmorphine (heroin) hydrolases in human blood.

Human blood esterases responsible for diacetylmorphine (DAM, heroin) metabolism were examined by means of an HPLC assay system for DAM, 6-monoacetylmorphine (MAM), and morphine. Four kinetically distinct enzymes capable of hydrolyzing DAM to MAM were observed in the plasma, erythrocyte (RBC) cytosol, and RBC membrane fractions of human blood. Under physiological conditions (pH 7.4, 37 degrees C), the Km (micromolar) and Vmax (micromolar per minute) values, respectively, for these enzymes were as follows: plasma, 200 and 210; RBC cytosol, 710 and 815; RBC membranes, 2000 and 748, and 38 and 80. For DAM blood concentrations less than or equal to 100 ng/mL, RBC associated esterases are responsible for the majority (76%) of DAM hydrolysis in blood.

Adult↗
PubMed1983

Central nervous system site of action for the respiratory depressant effect of diacetylmorphine (heroin) in the cat.

The purpose of our study was to identify central nervous system sites involved in the respiratory depressant effect of drugs that stimulate opioid receptors. Diacetylmorphine (heroin) was administered into several cerebroventricular regions of chloralose-anesthetized cats, while monitoring pulmonary ventilation with a Fleisch pneumotachograph. Administration of heroin (17, 50, 150, and 450 micrograms) into the forebrain ventricles, which was restricted to these ventricles, resulted in no significant respiratory effects. In contrast, administration of heroin into either the fourth ventricle or the cisterna magna resulted in a significant (P less than 0.05) decrease in respiratory minute volume (VE). In the fourth ventricle this was because of a decrease in frequency (f) and in the cisterna magna, to a decrease in tidal volume (VT). Intravenous administration of heroin in the same dose-range produced a decrease in VE, which was primarily due to a decrease in f. Bilateral application of heroin (70 micrograms/side) to each of three ventral medullary surface sites (Mitchell's, Schlaefke's, and Loeschcke's areas) known to influence respiration elicited a decrease in VE only at Mitchell's area. This decrease was due to decreases in f and VT. The role of this site in the action of intravenously administered heroin was tested by topical application of naloxone to this area in animals with respiratory depression evoked by intravenous heroin. Bilateral application of naloxone (15 micrograms/side) to Mitchell's area restored breathing to normal. These results lead us to suggest that the site of heroin-induced respiratory depression is a specific area (Mitchell's area) on the ventral surface of the medulla.

Administration, Topical↗
PubMed2000

Pharmacodynamics and pharmacokinetics of intravenously, orally and rectally administered diacetylmorphine in opioid dependents, a two-patient pilot study within a heroin-assisted treatment program.

OBJECTIVE: The pharmacokinetics and pharmacodynamics of high-dose intravenous (i.v.), oral and rectal diacetylmorphine (diamorphine, heroin, DAM) preparations were compared. METHOD: Two heroin-dependent patients participating in a heroin-assisted treatment program received single or repeated doses of 200 - 690 mg DAM i.v., orally (capsules, controlled-release tablets) and rectally. Plasma and urine profiles of DAM and metabolites were monitored by high-performance liquid chromatography and gas chromatography mass spectrometry, flash and high effects by visual analog scaling (VAS). RESULTS: DAM was only detectable in plasma after i.v. administration. With a t 1/2 beta of 1.3 - 2.2 min it was rapidly desacetylated to 6-acetylmorphine which was further metabolized to morphine and its 3- and 6-O-glucuronide. Morphine-3-glucuronide was the dominating metabolite in plasma and urine independent of the administration route. Oral and rectal doses and dosage intervals were adequate to produce flash and high effects without any cardiovascular and respiratory side-effects nor withdrawal symptoms. CONCLUSIONS: Oral and rectal DAM should further be tested and validated on a wider patient group for the non-invasive, long-term application of high-dose DAM within heroin-assisted treatment programs as alternative to the harmful i.v. application.

Administration, Oral↗
PubMed1981

Pharmacodynamics of subcutaneously administered diacetylmorphine, 6-acetylmorphine and morphine in mice.

Diacetylmorphine (DAM) and 6-acetylmorphine (AM) exhibit virtually identical dose-response and time-action profiles in studies in antinociceptive, excitatory, antidiarrheal and antidiuretic activity after subcutaneous administration to mice. In antinociceptive (Haffner tail clip, phenylquinone writhing and hot plate) and excitatory (Straub tail) tests, both drugs are 3 to 10 times more potent than morphine (M) and reach their peak effect more rapidly than M. Analysis of these data by graded and quantal methods establishes the comparability of the results obtained, while confirming the greater efficiency of the graded method. The durations of action of DAM and AM are shorter than that of M, yielding significant differences in potency estimates based upon peak vs. total effect. DAM and AM are only twice as potent as M in the suppression of prostaglandin E2-induced diarrhea and in antidiuretic activity. These pharmacodynamic studies, along with prior dispositional studies, suggest that the ability of DAM and AM to rapidly cross the blood-brain barrier determines their potency and time-action differences from M in centrally mediated bioassays. In contrast, DAM and AM are only slightly more potent than M in th antidiarrheal and antidiuretic test. These studies support the concept that the pharmacological effects of DAM are mediated principally by metabolically formed AM.

Analgesics↗
PubMed1980

Hydrolysis of diacetylmorphine (heroin) by human serum cholinesterase.

The enzyme in human serum that rapidly hydrolyzes diacetylmorphine (heroin) to 6-acetylmorphine is identified in this report as serum cholinesterase (EC 3.1.1.8, acylcholine acylhydrolase; also called pseudocholinesterase or butyrylcholine esterase). The rate of heroin hydrolysis was measured spectrophotometrically at 245 nm using highly purified serum cholinesterase. The turnover number was 500 mumol of heroin hydrolyzed per min per mumol active site. The product was identified spectrophotometrically and by thin-layer chromatography to be 6-acetylmorphine. There appeared to be marked product inhibition of heroin hydrolysis, as 6-acetylmorphine (Ki = 0.015 mM) bound 7 times more tightly than heroin (Ki = 0.11 mM). Purified human serum arylesterase did not hydrolyze heroin. Purified serum cholinesterase accounted for all the observed heroin hydrolysis by whole serum. The genetic variants of human serum cholinesterase, silent and atypical cholinesterase, were also tested. Serum from a person identified as having silent cholinesterase did not hydrolyze heroin. Purified atypical cholinestearase hydrolyzed heroin, but the binding was less tight (Km = 0.45 mM) than with usual cholinesterase (Km = 0.11 mM). The possibility that heroin potency may be influenced by serum cholinesterase genotype or activity level remains to be investigated.

Cholinesterase Inhibitors↗
PubMed1977

Chemistry and pharmacology of homologs of 6-acetyl-and 3,6-diacetylmorphine.

3,6-Diformyl- and 3,6-dipropanoylmorphine and 6-formyl- and 6-propanoylmorphine were prepared to obtain longer acting, heroin-like compounds. The 6-acylated compounds were more potent than heroin subcutaneously and were orally effective, and their duration of action was at least two to three times greater than that of heroin in monkey species.

Acetylation↗
PubMed1985

Binding features of diacetylmorphine (heroin) in whole blood and in blood fractions.

Binding features of heroin in whole blood and in blood fractions were delineated by measuring the selective spin-lattice relaxation rates of heroin protons in physiologic conditions. Interaction with some receptor located in the whole human blood or in the human plasma was detected and the apparent binding constant calculated (K = 39 mol-1 dm3). Inferences about molecular dynamics of the bound heroin could be also gained.

Erythrocytes↗
PubMed1984

A study of transacetylation between 3,6-diacetylmorphine and morphine.

Interaction between some of the constituents of illicitly prepared heroin results in the formation of 6-acetylmorphine. Such interactions have been observed during the gas chromatographic examination of heroin. An explanation of these reactions is proposed. Attempts to block the formation of 6-acetylmorphine were not successful, although the problem is minimised by using the lowest temperature consistent with satisfactory chromatography.

Acetylation↗
PubMed1996

A diacetylmorphine polymorph.

The title compound, 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diyl diacetate, C21H23NO5, was crystallized from a solution of its hydrochloride and sodium acetate. Unlike prior reports in which crystals were hexagonal shaped (orthorhombic) and in space group P2(1)2(1)2(1), the crystals in the present determination grew as large prisms (monoclinic) and were in space group P2(1).

Crystallography, X-Ray↗