Prolongación del tiempo QT
Eventos adversos de medicamentos
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de metanfetamina y lorcaserin. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No detectamos ningún cambio en la exposición a la metanfetamina. Actualmente no podemos estimar la influencia de la lorcaserin. No detectamos ningún cambio en la exposición a la lorcaserin. Actualmente no podemos estimar la influencia de la metanfetamina.
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La metanfetamina tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es de 17.5 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 70 horas. Se desconoce la unión a proteínas [ Pb ]. El metabolismo tiene lugar principalmente a través de CYP2D6.
Se desconoce la biodisponibilidad de la lorcaserin. La vida media terminal [ t12 ] es de 11 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 44 horas. La unión a proteínas [ Pb ] es relativamente débil al 100 %. El metabolismo tiene lugar a través de CYP1A2, CYP2B6, CYP2C19, CYP2D6 y CYP3A4, entre otros.
|Efectos serotoninérgicos a||4||++||++|
Recomendación: El riesgo de un síndrome serotoninérgico aumenta, pero sin una respuesta exacta a las preguntas sobre los síntomas cognitivos, vegetativos y neuromusculares no podemos hacer recomendaciones de acción.
Clasificación: Metanfetamina y lorcaserin modulan el sistema serotoninérgico en un grado moderado.
|Kiesel & Durán b||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la metanfetamina ni la lorcaserin aumentan la actividad anticolinérgica.
Prolongación del tiempo QT
No conocemos ningún potencial de prolongación del intervalo QT de la metanfetamina y lorcaserin.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||met||lor|
|Dolor de cabeza||15.7 %||n.a.||15.7|
|Infarto de miocardio||0.0 %||0.0||n.a.|
Muerte cardíaca súbita: metanfetamina
Accidente cerebrovascular: metanfetamina
Enfermedad de Raynaud: metanfetamina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: (+)- 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.
Abstract: The genetic basis for drug dependence has focused on genes that encode receptors involved in the reinforcing properties of drugs of abuse or that determine drug-taking behavior (e.g. impulsivity, etc.). Pharmacogenetic variations in the patterns of metabolism among individuals can also importantly modulate the risk of drug dependence. Cytochrome P450 drug metabolizing enzymes (CYPs), can activate (e.g. codeine to morphine) or deactivate (e.g. nicotine to cotinine) drugs of abuse. Some CYPs are polymorphic, that is, there are gene mutations which result in individuals with no (null mutations) or decreased enzyme activity (e.g. CYP2D6*10). Individuals with two null mutations appear in the population as phenotypic poor metabolizers. Using in vitro studies, we have identified drugs of abuse that are substrates of the polymorphic enzymes CYP2D6 (codeine, amphetamines, dextromethorphan), CYP2A6 (nicotine) and CYP2C19 (flunitrazepam). In human experimental studies, we have shown that CYP phenotype and genotype affect abuse liability of CYP2D6 metabolized drugs of abuse. In addition, we inhibited CYP2D6 and decreased individuals' risk of dependence experimentally (codeine, dextromethorphan) and treated codeine dependence. In epidemiologic studies CYP2D6 and CYP2A6 null mutations protect individuals from becoming codeine and tobacco dependent, respectively. With respect to CYP2A6, individuals with mutations, smoke fewer cigarettes and can quit more easily. Inhibiting CYP2A6 (e.g. tranylcypromine, methoxsalen) decreases smoking and the activation of procarcinogens. By mimicking these gene defects the risk of dependence can be decreased in individuals and new treatments developed.
Abstract: Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "soft-nucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.
Abstract: INTRODUCTION: Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drug's toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication. AIM: The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management. METHODS: A summary of the literature on metamfetamine was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis. Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic monoamines results in an increased activation of central and peripheral α±- and β-adrenergic postsynaptic receptors. This can cause detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from ∼5 to 30 h. Clinical features. The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for sympathomimetic effects and their associated complications. CONCLUSION: Metamfetamine may cause severe sympathomimetic effects in the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery.
Abstract: Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes, was examined in vitro to identify the enzymes involved in the generation of its primary oxidative metabolites, N-hydroxylorcaserin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hydroxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6, 5-hydroxylorcaserin was correlated with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin was correlated with CYP3A4 activity at 10.0 μM lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1.0 μM lorcaserin. N-Hydroxylorcaserin formation was not inhibited by CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 inhibitors at the highest concentration tested. Furafylline, quinidine, and ketoconazole, selective inhibitors of CYP1A2, CYP2D6, and CYP3A4, respectively, inhibited 5-hydroxylorcaserin (IC(50) = 1.914 μM), 7-hydroxylorcaserin (IC(50) = 0.213 μM), and 1-hydroxylorcaserin formation (IC(50) = 0.281 μM), respectively. N-Hydroxylorcaserin showed low and high K(m) components in HLM and 7-hydroxylorcaserin showed lower K(m) than 5-hydroxylorcaserin and 1-hydroxylorcaserin in HLM. The highest intrinsic clearance was observed for N-hydroxylorcaserin, followed by 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin in HLM. Multiple human P450 and FMO enzymes catalyze the formation of four primary oxidative metabolites of lorcaserin, suggesting that lorcaserin has a low probability of drug-drug interactions by concomitant medications.
Abstract: Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide. Under conditions of abuse, which involve the administration of high repetitive doses, methamphetamine can produce considerable neurotoxic effects. However, recent evidence from our laboratory indicates that low doses of methamphetamine can produce robust neuroprotection when administered within 12h after severe traumatic brain injury (TBI) in rodents. Thus, it appears that methamphetamine under certain circumstances and correct dosing can produce a neuroprotective effect. This review addresses the neuroprotective potential of methamphetamine and focuses on the potential beneficial application for TBI.