Hepatic. The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine.
Methamphetamine is metabolized in the liver by aromatic hydroxylation, N-dealkylation, and deamination; at least 7 metabolites have been identified in urine.
A species difference was found in a study of the metabolism of methamphetamine, (+/-)-2-methylamino-1-phenylpropane. In man, 22% of an oral dose was excreted into urine unchanged, & 15% of the dose was excreted as 4-hydroxymethamphetamine. After ip admin to rat, 4-hydroxymethamphetamine was principal urinary metabolite (31% of dose), together with 4-hydroxynorephedrine (16%) & unchanged drug (11% of dose). In the guinea pig an ip dose was extensively metabolized to benzoic acid & its glycine & glucuronic acid conjugates.
In vivo metab of N-alkylated amphetamines in rat produced 4-hydroxy- & 4-hydroxy-3-methoxy-metabolites. Relative quantities of phenolic metabolites formed were dependent upon the length of the N-alkyl substituent.
IDENTIFICATION AND USE: Methamphetamine is a white solid odorless crystals. Indications: Narcolepsy and hyperkinetic states in children (as an adjunct to psychological, educational and social measures). Its misuse includes performance enhancement and relief of fatigue. It is a Schedule II Controlled Substance. HUMAN EXPOSURE AND TOXICITY: Main risks include: acute central nervous system (CNS) stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse. High risk of dependency and abuse. Cardiovascular effects include: palpitation, chest pain, tachycardia, arrhythmias and hypertension; cardiovascular collapse can occur in severe poisoning. Myocardial ischemia, infarction and ventricular dysfunction are described. CNS effects include: stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia. Stroke and cerebral vasculitis have been observed. Gastrointestinal effects include: vomiting, diarrhea and cramps. Acute transient ischemic colitis has occurred with chronic methamphetamine abuse. Genitourinary effects include: increased bladder sphincter tone which may cause dysuria, hesitancy and acute urinary retention. Renal failure can occur secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Transient hyperthyroxinemia may be noted. Increased metabolic and muscular activity may result in hyperventilation and hyperthermia. Weight loss is common with chronic use. Hypo- and hyperkalemia have been reported. Dehydration is common. Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe amphetamine poisoning. Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are typical. Chronic abuse can cause delusions and paranoia. A withdrawal syndrome occurs after abrupt cessation following chronic use. The ability of methamphetamine to both release dopamine and serotonin as well as to inhibit monoamine oxidase activity leads to the non-enzymatic oxidation of dopamine and serotonin. Methamphetamine induced neuronal damage is mediated by the production of free radicals. This drug causes a long lasting depletion of dopamine and serotonin in the striatum and that pre-treatment alteration of this effect by four different antioxidants, as well as an inhibitor of superoxidase dismutase, indicate that oxygen free radicals have a role in methamphetamine- induced neurotoxicity. In fatal cases of poisoning in human patients, the panic state is followed by convulsions, coma and death from intracranial hemorrhages or cardiac arrhythmias. The use of amphetamine and its congeners for medical indications do not pose a significant risk to the fetus for congenital anomalies. They generally do not appear to be human teratogens. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long-term sequelae. Illicit maternal use or abuse presents a significant risk to the fetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity. These poor outcomes are probably multifactorial in origin, involving multiple drug use, life-styles and poor maternal health. However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines. Sixty-five children were followed whose mothers were addicted during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive. ANIMAL STUDIES: The administration of high dose of methamphetamine causes long lasting damage to central dopaminergic and serotonergic neurons through a mechanism known to involve presynaptic, cytoplasmic stores of those transmitters dependent upon a free radical reaction in experimental animals. Confinement and aggregation markedly increased lethality of methamphetamine in mice. Pregnant sheep given methamphetamine appeared anxious, with quick side to side movements of the head and feet.
Methamphetamine enters the brain and triggers a cascading release of norepinephrine, dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor (MAOI). The mechanism of action involved in producing the beneficial behavioral changes seen in hyperkinetic children receiving methamphetamine is unknown.
Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Moreover, when administered intranasally or as an inhalation, methamphetamine also demonstrates a high degree of absorption. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta.
Excretion occurs primarily in the urine, the rate of which is dependent on urine pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine.
Methamphetamine is readily absorbed from the GI tract and effects persist for 6-12 hours but may continue up to 24 hr after large doses. /Methamphetamine hydrochloride/
Single pharmacological doses of amphetamines (ie, 10-25 mg) given to human volunteers produce peak plasma levels within 1-2 hr & are rapidly absorbed from the GI tract. Amphetamine absorption usually is complete by 4-6 hr. The illicit use of amphetamines ... by insertion into the vagina (termed "balling") before intercourse suggests that these compounds are also absorbed through mucosal surfaces. ... Methamphetamine ... /has/ absorption characteristics similar to those of amphetamines. ... Sustained release prepn are avail as resin-bound rather than soluble salts. These compounds display reduced peak blood levels compared with std amphetamine prepn, but total bioavailability & time to peak levels remain similar. Pharmacokinetics in overdose are not well described.
Methamphetamine is eliminated principally in urine. Urinary excretion of the drug is pH dependent, and excretion is enhanced in acidic urine. Following oral administration of methamphetamine hydrochloride, approximately 62% of the administered dose is excreted in urine within the first 24 hours, with metabolites and unchanged drug accounting for about two-thirds and one-third, respectively, of the recovered drug.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats
作者：Shweta Ganapati、Stephanie D. Grabitz、Steven Murkli、Flora Scheffenbichler、Maíra I. Rudolph、Peter Y. Zavalij、Matthias Eikermann、Lyle Isaacs
DOI：10.1002/cbic.201700289
日期：2017.8.17
of five molecularcontainer compounds (calabadions 1 and 2, CB[7], sulfocalix[4]arene, and HP-β-CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods (1H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (Ka values) spanning from <102 to >108 m−1. We also report X-ray crystal structures of CB[7]⋅methamphetamine and 1⋅methamphetamine
[EN] IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS IMIDAZOPYRIDINE ET LEURS UTILISATIONS
申请人：NEOMED INST
公开号：WO2014117274A1
公开（公告）日：2014-08-07
This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.
