(1/1448) Highly sensitive quantitation of methamphetamine by time-resolved fluoroimmunoassay using a new europium chelate as a label.
A simple and highly sensitive time-resolved fluoroimmunoassay of methamphetamine (MA) using a new fluorescent europium chelate (BHHCT-Eu3+) as a label is described. Two variations of competitive immunoassay were attempted. In the first (one-step) assay, microtiter plates coated with anti-MA were used, and the new label was bound to a conjugate of bovine serum albumin and N-(4-aminobutyl)-MA (MA-BSA). In the second (two-step) assay, instead of the labeled MA-BSA, biotinylated MA-BSA and BHHCT-Eu3+-labeled streptavidin-BSA were used. The lowest measurable concentrations of MA for the one-step and the two-step methods were 1 ng/mL (25 pg/assay) and 1 pg/mL (25 fg/assay), respectively. These were 10 to 1000 times superior to the detection limits of MA in any other immunoassay. Intra-assay coefficient of variation was approximately 2-8% at eight different concentrations (n = 4). Analysis of 34 urine samples with the new method and conventional gas chromatography showed a good correlation (r = 0.954). The high detectability of the present assay also enabled segmental hair analysis with a few centimeters of a hair. (+info)
(2/1448) Determination of pyrolysis products of smoked methamphetamine mixed with tobacco by tandem mass spectrometry.
This study examines the pyrolysis products of smoked methamphetamine mixed with tobacco that was trapped with a C8 adsorbent cartridge and then detected by gas chromatography-tandem mass spectrometry. According to the results, the mainstream smoke contains 2-methylpropyl-benzene, 2-chloropropyl-benzene, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 3-ethyl-phenol, methamphetamine, dimethylamphetamine, hydroquinone, 3-methyl-5-(1-methylethyl)-methylcarbamate phenol, N-methyl-N-(2-phenylethyl)-acetamide, 4-(3-hydroxy-1-butenyl)-3,5,5-trimethyl-2-cyclohexene-1-one, propanoic acid, N-acetylmethamphetamine, phenyl ester, and furfurylmethylamphetamine. In addition, the compounds in sidestream smoke are 2-propenyl benzene, phenylacetone, methamphetamine, dimethylamphetamine, benzyl methyl ketoxime, 3,4-dihydro-2-naphthalenone, N-folmyamphetamine, N-acetylamphetamine, bibenzyl, N-folmylmethamphetamine, N-acetylmethamphetamine, N-propionymethamphetamine, and furfurylmethylamphetamine. Moreover, the presence of methamphetamine promotes the oxidation of the tobacco components. (+info)
(3/1448) Toxicological findings in a fatal ingestion of methamphetamine.
This paper presents the case history of a fatality caused by the complications brought about by the presence of methamphetamine and ethanol. Drug concentrations are reported from samples obtained approximately 15 min after the subject was last observed to be chewing what was then believed to be gum, 3 h after the initial toxic symptoms were displayed, 6, 11, and 22 h later. The subjects conditions deteriorated over the course of this time, and he was declared dead 33 h after the initial display of toxic symptoms. The toxicological findings and concentration levels of the reported biological specimens concurred with the expected findings in a case of methamphetamine toxicity. (+info)
(4/1448) Effects of stimulants of abuse on extrapyramidal and limbic neuropeptide Y systems.
Neuropeptide Y (NPY), an apparent neuromodulating neuropeptide, has been linked to dopamine systems and dopamine-related psychotic disorders. Because of this association, we determined and compared the effects of psychotomimetic drugs on extrapyramidal and limbic NPY systems. We observed that phencyclidine, methamphetamine (METH), (+)methylenedioxymethamphetamine (MDMA), and cocaine, but not (-)MDMA, similarly reduced the striatal content of NPY-like immunoreactivity from 54% (phencyclidine) to 74% [(+) MDMA] of control. The effects of METH on NPY levels in the nucleus accumbens, caudate nucleus, globus pallidus, and substantia nigra were characterized in greater detail. We observed that METH decreased NPY levels in specific regions of the nucleus accumbens and the caudate, but had no effect on NPY in the globus pallidus or the substantia nigra. The dopamine D1 receptor antagonist SCH-23390 blocked these effects of METH, suggesting that NPY levels throughout the nucleus accumbens and the caudate are regulated through D1 pathways. The D2 receptor antagonist eticlopride did not appear to alter the METH effect, but this was difficult to determine because eticlopride decreased NPY levels by itself. A single dose of METH was sufficient to lower NPY levels, in some, but not all, regions examined. The effects on NPY levels after multiple METH administrations were substantially greater and persisted up to 48 h after treatment; this suggests that synthesis of this neuropeptide may be suppressed even after the drug is gone. These findings suggest that NPY systems may contribute to the D1 receptor-mediated effects of the psychostimulants. (+info)
(5/1448) N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication.
(+)- And (-)-amphetamine and methamphetamine were N-oxygenated by the cDNA expressed adult human flavin-containing monooxygenase form 3 (FMO3), their corresponding hydroxylamines. Two major polymorphic forms of human FMO3 were studied, and the results suggested preferential N-oxygenation by only one of the two enzymes. Chemically synthesized (+/-)-amphetamine hydroxylamine was also a substrate for the human FMO3 and it was converted to phenylpropanone oxime with a stereoselectivity ratio of trans/cis of 5:1. Human FMO3 also N-oxygenated methamphetamine to produce methamphetamine hydroxylamine. Methamphetamine hydroxylamine was also N-oxygenated by human FMO3, and the ultimate product observed was phenylpropanone. For amphetamine hydroxylamine, studies of the biochemical mechanism of product formation were consistent with the production of an N, N-dioxygenated intermediate that lead to phenylpropanone oxime. This was supported by the observation that alpha-deutero (+/-)-amphetamine hydroxylamine gave an inverse kinetic isotope effect on product formation in the presence of human FMO3. For methamphetamine, the data were consistent with a mechanism of human FMO3-mediated N,N-dioxygenation but the immediate product, a nitrone, rapidly hydrolyzed to phenylpropanone. The pharmacological activity of amphetamine hydroxylamine, phenylpropanone oxime, and methamphetamine hydroxylamine were examined for effects at the human dopamine, serotonin, and norepinephrine transporters. Amphetamine hydroxylamine and methamphetamine hydroxylamine were apparent substrates for the human biogenic amine transporters but phenylpropanone oxime was not. Presumably, phenylpropanone oxime or nitrone formation from amphetamine and methamphetamine, respectively, represents a detoxication process. Because of the potential toxic nature of amphetamine hydroxylamine and methamphetamine hydroxylamine metabolites and the polymorphic nature of N-oxygenation, human FMO3-mediated metabolism of amphetamine or methamphetamine may have clinical consequences. (+info)
(6/1448) Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.
Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity. (+info)
(7/1448) Does nicotine modify the psychotoxic effect of methamphetamine? Assessment in terms of locomotor sensitization in mice.
In this study, effects of nicotine on locomotor sensitization to methamphetamine in mice were investigated to assess whether nicotine modified induction and expression of psychotoxic action of methamphetamine. Although nicotine (0.03-1 mg/kg s.c.) had no effect at first administration, 5-time nicotine administrations at 3-day intervals progressively developed a significant locomotor stimulant effect, and caused an enhanced sensitivity (cross-sensitization) to methamphetamine (2 mg/kg s.c.). Five-time administrations of methamphetamine (2 mg/kg) at 3-day intervals produced not only a locomotor sensitization to methamphetamine itself, but also a cross-sensitization to nicotine (0.1-1 mg/kg). Nicotine (0.03-1 mg/kg) did not affect the locomotor stimulant effect of methamphetamine (2 mg/kg) in the drug-naive mice. However, nicotine acted dose-dependently to reduce the progressive enhancement of the locomotor stimulant effect of methamphetamine during 5-time repeated administrations. Mice treated with coadministration of methamphetamine with nicotine (1 mg/kg) showed less sensitization to methamphetamine than mice treated with methamphetamine alone. In addition, nicotine (1 mg/kg) inhibited the locomotor stimulant effect of methamphetamine in mice sensitized to methamphetamine. These results suggest that methamphetamine and nicotine produce a symmetrical cross-sensitization, although nicotine may act to inhibit the induction and expression of locomotor sensitization to methamphetamine in mice. (+info)
(8/1448) Synergistic interactions between ampakines and antipsychotic drugs.
Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia. (+info)