RESUMEN
PURPOSE: The prevalence of comorbid depression and chronic kidney disease (CKD) is high. The aim of this brief report was to review 2 cases of treatment with tranylcypromine (TCP) in patients with treatment-resistant depression (TRD) and CKD. Tests of the plasma concentration of TCP were included. METHODS: Medical and psychiatric notes of the 2 patients were reviewed with plasma concentrations of TCP as a key aspect of the discussion. The data are evaluated in the context of relevant medical and pharmacokinetic literature. FINDINGS: Plasma concentrations of TCP are highly variable both in patients with and without CKD. Plasma concentrations of TCP were not increased in the 2 cases with CKD as compared with literature data of patients without CKD. No signs of intoxication were detected in 2 cases with CKD that impaired continuous treatment of depression with TCP. IMPLICATIONS: TCP may be considered in selected cases of TRD with concomitant CKD. More clinical data and tests of plasma concentrations of TCP are needed in patients with CKD.
Asunto(s)
Trastorno Depresivo Resistente al Tratamiento , Insuficiencia Renal Crónica , Tranilcipromina , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/sangre , Inhibidores de la Monoaminooxidasa/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicacionesRESUMEN
A ,,sine qua non" requirement for a generic formulation to be admitted for a medical use is to provide bioavailability studies in healthy subjects. Therefore, those studies were performed for 150 mg moclobemide tablets (Jelfa, Poland) versus 150 mg Aurorix (Hoffmann la Roche) reference tablets. An open-label, two-phase crossover study was conducted with 10 healthy subjects. Pharmacokinetic parameters (AUC, ke, t1/2, Cmax, tmax, tlag, V/f, Cl/f) obtained at the same time for moclobemide were supposed to be confronted with the literature data available for healthy volunteers. The plasma moclobemide levels as a function of time were calculated according to either an open one-compartment body model with lag time of absorption or non-compartmental method for calculation of bioavailability using Phoenix WinNonlin 8.0 software. For those reasons a suitable HPLC method was worked out. Carbamazepine was proposed as an internal standard and ammonia as well as Na2HPO4 as alkalizing agents for the mobile phase and the liquid-liquid extraction of moclobemide from human blood plasma, respectively. Basic pharmacokinetic parameters of moclobemide obtained in the paper are essentially equal to the literature data for the healthy subjects. However, bioavailability parameters (AUC0ât, AUC0â∞, Cmax, tmax) were greater for moclobemide tablets (Jelfa) if compared to Aurorix tablets (Roche) by more than 20 %. Furthermore, the extent of bioavailability (110.6 %) for the generic moclobemide tablets if compared to Aurorix tablets is not significantly different. It seems to us that the number of subjects should be increased from 10 to 24 to help to clarify that inconsequence.
Asunto(s)
Moclobemida/administración & dosificación , Moclobemida/farmacocinética , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Estudios Cruzados , Femenino , Humanos , Masculino , Moclobemida/sangre , Inhibidores de la Monoaminooxidasa/sangre , Comprimidos , Equivalencia Terapéutica , Adulto JovenAsunto(s)
Azul de Metileno/efectos adversos , Inhibidores de la Monoaminooxidasa/efectos adversos , Seguridad del Paciente , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Síndrome de la Serotonina/inducido químicamente , Índice de Severidad de la Enfermedad , Interacciones Farmacológicas/fisiología , Fluoxetina/efectos adversos , Fluoxetina/sangre , Humanos , Azul de Metileno/metabolismo , Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/sangre , Seguridad del Paciente/normas , Síndrome de la Serotonina/sangre , Síndrome de la Serotonina/diagnóstico , Inhibidores Selectivos de la Recaptación de Serotonina/sangreRESUMEN
Neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) is still controversially discussed. Formation of reactive oxygen species e.g. based on elevated dopamine (DA) concentrations and DA quinone formation is discussed among others. Inhibition potential of MDMA metabolites regarding neurotransmitter degradation by catechol-O-methyltransferase and sulfotransferase was described previously. Their influence on monoamine oxidase (MAO) - the major DA degradation pathway-has not yet been studied in humans. Therefore the inhibition potential of MDMA and its metabolites on the deamination of the neurotransmitters DA and serotonin (5-HT) by MAO-A and B using recombinant human enzymes in vitro should be investigated. In initial studies, MDMA and MDA showed relevant inhibition (>30%) toward MAO A for 5-HT and DA. No relevant effects toward MAO B were observed. Further investigation on MAO-A revealed MDMA as a competitive inhibitor of 5-HT and DA deamination with Ki 24.5±7.1 µM and 18.6±4.3 µM respectively and MDA as a mixed-type inhibitor with Ki 7.8±2.6 µM and 8.4±3.2 µM respectively. Although prediction of in vivo relevance needs to be done with care, relevant inhibitory effects at expected plasma concentrations after recreational MDMA consumption seems unlikely based on the obtained data.
Asunto(s)
Dopamina/análogos & derivados , Inhibidores de la Monoaminooxidasa/toxicidad , Monoaminooxidasa/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotonina/metabolismo , Catecol O-Metiltransferasa/metabolismo , Cromatografía Liquida , Desaminación , Dopamina/metabolismo , Humanos , Concentración 50 Inhibidora , Inhibidores de la Monoaminooxidasa/sangre , N-Metil-3,4-metilenodioxianfetamina/sangre , Neurotransmisores/metabolismo , Especies Reactivas de Oxígeno , Espectrometría de Masas en TándemRESUMEN
Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2 mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25 mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (Cmax) and elimination half life (t1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co-administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level.
Asunto(s)
Flavanonas/farmacología , Hesperidina/farmacología , Indanos/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Encéfalo/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Interacciones Farmacológicas , Flavanonas/administración & dosificación , Hesperidina/administración & dosificación , Indanos/administración & dosificación , Indanos/sangre , Masculino , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/sangre , Ratas Wistar , Médula Espinal/metabolismo , Distribución TisularRESUMEN
We investigated [(18)F]fluoroethyl-harmol ([(18)F]FEH) as a reversible and selective ligand for positron emission tomography (PET) studies of monoamine oxidase A (MAO-A). Binding of [(18)F]FEH in rat brain cryostat sections indicated high affinity (KD = 3 nM), and density (Bmax; 600 pmol/g). The plasma free fraction was 45%, and untransformed parent constituted only 13% of plasma radioactivity at 10 min after injection. Compartmental analysis of PET recordings in pargyline-treated rats showed high permeability to brain (K1; 0.32 mL/g/min) and slow washout (k2; 0.024/min), resulting in a uniformly high equilibrium distribution volume (VD; 20 mL/g). Using this VD to estimate unbound ligand in brain of untreated rats, the binding potential ranged from 4.2 in cerebellum to 7.2 in thalamus. We also calculated maps of rats receiving [(18)F]FEH at a range of specific activities, and then estimated saturation binding parameters in the living brain. In thalamus, striatum and frontal cortex KD was globally close to 300 nM and Bmax was close to 1600 pmol/g; the 100-fold discrepancy in affinity suggests a very low free fraction for [(18)F]FEH in the living brain. Based on a synthesis of findings, we calculate the endogenous dopamine concentration to be 0.4 µM in the striatal compartment containing MAO-A, thus unlikely to exert competition against [(18)F]FEH binding in vivo. In summary, [(18)F]FEH has good properties for the detection of MAO-A in the rat brain by PET, and may present logistic advantages for clinical research at centers lacking a medical cyclotron. We made a compartmental analysis of [(18)F]fluoroethylharmol ([(18)F]FEH) binding to monoamine oxidase A (MAO-A) in living rat brain and estimated the saturation binding parameters from the binding potential (BPND). The Bmax was of comparable magnitude to that in vitro, but with apparent affinity (300 nM), it was 100-fold lower in vivo. PET imaging with [(18) F]FEH is well suited for quantitation of MAO-A in living brain.
Asunto(s)
Encéfalo , Harmina/análogos & derivados , Inhibidores de la Monoaminooxidasa/farmacocinética , Monoaminooxidasa/metabolismo , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Harmina/sangre , Harmina/farmacocinética , Técnicas In Vitro , Ligandos , Masculino , Inhibidores de la Monoaminooxidasa/sangre , Tomografía de Emisión de Positrones , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
AIM: A sensitive and selective method was developed and validated to study the pharmacokinetics of isatin. METHODS: The blood samples were pretreated by protein precipitation method using methanol. Quetiapine was used as an internal standard. After pretreatment, the samples were assayed by LC/MS/MS method and the pharmacokinetic parameters were calculated by WinNonlin 5.2 using non-compartment model. The separation was performed on a Venusil XBP PH column (5 µm, 2.0×100 mm) with an isocratic mobile phase consisted of methanol-water (containing 50 mM ammonium formate) (65:35, v/v) at a flow rate of 0.3 mL/min. The Agilent G6410B triple quadrupole LC/MS system was operated under the multiple reactions monitoring mode (MRM) using the electrospray ionization technique in positive mode. RESULTS: The lower limits of quantification (LLOQ) of the analyte of the method was 10 ng/mL. The method was linear with correlation coefficient >0.995. The intraday and interday accuracy and precision of the assay were acceptable. CONCLUSION: This method has been applied successfully to a pharmacokinetic study involving the oral and intravenous administration of isatin to beagle dogs.
Asunto(s)
Cromatografía Liquida/métodos , Isatina/sangre , Inhibidores de la Monoaminooxidasa/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Calibración , Perros , Femenino , Isatina/farmacocinética , Límite de Detección , Masculino , Inhibidores de la Monoaminooxidasa/farmacocinética , Reproducibilidad de los ResultadosRESUMEN
Equol (EQ), a metabolite of the soy isoflavone daidzein, has well known estrogenic properties. Data from animal studies suggested that EQ may act also as an anti-androgen. However, data regarding how EQ may affect brain functions like the regulation of neuroendocrine activity and reproductive outcomes in adult male rats are still lacking. We therefore investigated the effects of EQ on sex-steroid regulated gene expression in the brain [medial preoptic area/anterior hypothalamus (MPOA/AH) and medial basal hypothalamus/median eminence (MBH/ME)], pituitary, and prostate as a reference androgen-dependent organ. Furthermore reproductive outcomes were evaluated. The anti-androgen flutamide (FLUT) served as reference compound. Male rats (n=12 per group) were treated by gavage for 5 days with either EQ (100 or 250 mg/kgBW/day), or FLUT 100 mg/kgBW/day. All vehicle- and EQ-treated males showed successful reproductive outcomes, whereas FLUT-exposed males had severe reproductive impairments resulted in infertility. FLUT decreased relative weights of prostate, seminal vesicles and epididymides, and increased serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone and 5α-dihydrotestosterone without altering prolactin levels, whereas EQ exerted opposite effects. Both EQ and FLUT decreased gonadotropin releasing hormone (GnRH) expression in the MPOA/AH. Only FLUT upregulated levels of GnRH receptor expression both in the MBH/ME and pituitary. While EQ downregulated the hypothalamic ERα and ERß expressions, but FLUT did not. In the prostate, only FLUT upregulated both ERα and AR mRNA expression levels. Taken together, our findings are the first data that EQ did not induce anti-androgenic effects on brain, prostate and male reproductive parameters, however, estrogenic neuroendocrine and reproductive effects of EQ were observed.
Asunto(s)
Antagonistas de Andrógenos , Equol/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Sistemas Neurosecretores/efectos de los fármacos , Animales , Encéfalo/anatomía & histología , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Equol/sangre , Femenino , Flutamida/farmacología , Genitales Masculinos/patología , Hormonas Esteroides Gonadales/sangre , Hormonas Esteroides Gonadales/fisiología , Masculino , Inhibidores de la Monoaminooxidasa/sangre , Tamaño de los Órganos , ARN/biosíntesis , ARN/aislamiento & purificación , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Conducta Sexual Animal/efectos de los fármacosRESUMEN
The most frequently described drugs in the treatment of mood disorders are selective serotonin reuptake and monoamine oxidase (MAO) inhibitors, enhancing serotonin levels in the brain. However, side-effects have been reported for these drugs. Because serotonin levels in the brain are dependent on the availability of the food-derived precursor tryptophan, foods such as chicken, soyabeans, cereals, tuna, nuts and bananas may serve as an alternative to improve mood and cognition. Here we discuss the effects of high- or low-tryptophan-containing food, as well as plant extracts with a modest monoamine reuptake and MAO-A inhibition functional profile, on mood and cognition in healthy and vulnerable human subjects and rodents. Together the studies suggest that there is an inverted U-shaped curve for plasma tryptophan levels, with low and too high tryptophan levels impairing cognition, and moderate to high tryptophan levels improving cognition. This relationship is found for both healthy and vulnerable subjects. Whereas this relationship may also exist for mood, the inverted U-shaped curve for plasma tryptophan levels and mood may be based on different tryptophan concentrations in healthy v. vulnerable individuals. Animal studies are emerging and allow further understanding of effects and the mode of action of food-derived serotonergic components on mood, cognition and mechanisms. Ultimately, insight into the concentrations of tryptophan and other serotonergic components in food having beneficial effects on mood and cognition in healthy, but particularly vulnerable, subjects may support well-being in our highly demanding society.
Asunto(s)
Afecto/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Dieta , Serotoninérgicos/farmacología , Serotonina/metabolismo , Triptófano/farmacología , Animales , Antidepresivos de Segunda Generación/sangre , Antidepresivos de Segunda Generación/farmacología , Encéfalo/metabolismo , Humanos , Inhibidores de la Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/farmacología , Extractos Vegetales/sangre , Extractos Vegetales/farmacología , Serotoninérgicos/sangre , Triptófano/sangreRESUMEN
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.
Asunto(s)
Citocromo P-450 CYP2D6/metabolismo , Harmalina/farmacocinética , Metoxidimetiltriptaminas/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Animales , Catálisis , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2D6/genética , Relación Dosis-Respuesta a Droga , Harmalina/sangre , Ratones , Ratones Transgénicos , Monoaminooxidasa/efectos de los fármacos , Inhibidores de la Monoaminooxidasa/sangre , Espectrometría de Masas en TándemRESUMEN
BACKGROUND/AIMS: Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth. MATERIALS AND METHODS: Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival. Over a 21-day period, animals were administered daily oral gavage (15 mg/kg) or one or two rasagiline mesylate transdermal patches every 3 days. After the last dose administration, blood samples were collected to confirm drug exposure. RESULTS: All animals from the untreated, vehicle and rasagiline groups survived to the end of the study; however, 7 out of the 10 cisplatin-treated animals died before the end of the study. Rasagiline mesylate dosed either via the oral or transdermal routes had comparable plasma exposure and, unexpectedly, significantly reduced absolute tumor volumes and tumor growth rates in the nude mouse SKMEL28 xenograft model. CONCLUSION: Transdermal delivery of melanin-binding rasagiline does not increase melanoma growth in the xenograft model. Because rasagiline decreases melanoma growth, it may be candidate for combination therapy for melanoma.
Asunto(s)
Antineoplásicos/administración & dosificación , Indanos/administración & dosificación , Melanoma/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Administración Oral , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Modelos Animales de Enfermedad , Femenino , Humanos , Indanos/sangre , Indanos/farmacocinética , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Desnudos , Inhibidores de la Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/farmacocinética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Distribución Tisular , Parche Transdérmico , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Because moclobemide pharmacokinetics vary considerably among individuals, monitoring of plasma concentrations lends insight into its pharmacokinetic behavior and enhances its rational use in clinical practice. The aim of this study was to evaluate whether single concentration-time points could adequately predict moclobemide systemic exposure. Pharmacokinetic data (full 7-point pharmacokinetic profiles), obtained from 21 depressive inpatients receiving moclobemide (150 mg 3 times daily), were randomly split into development (n = 18) and validation (n = 16) sets. Correlations between the single concentration-time points and the area under the concentration-time curve within a 6-hour dosing interval at steady-state (AUC(0-6)) were assessed by linear regression analyses. The predictive performance of single-point sampling strategies was evaluated in the validation set by mean prediction error, mean absolute error, and root mean square error. Plasma concentrations in the absorption phase yielded unsatisfactory predictions of moclobemide AUC(0-6). The best estimation of AUC(0-6) was achieved from concentrations at 4 and 6 hours following dosing. As the most reliable surrogate for moclobemide systemic exposure, concentrations at 4 and 6 hours should be used instead of predose trough concentrations as an indicator of between-patient variability and a guide for dose adjustments in specific clinical situations.
Asunto(s)
Antidepresivos/farmacocinética , Depresión/tratamiento farmacológico , Monitoreo de Drogas/métodos , Moclobemida/farmacocinética , Modelos Biológicos , Inhibidores de la Monoaminooxidasa/farmacocinética , Adulto , Antidepresivos/administración & dosificación , Antidepresivos/sangre , Área Bajo la Curva , Depresión/sangre , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Pacientes Internos , Modelos Lineales , Masculino , Persona de Mediana Edad , Moclobemida/administración & dosificación , Moclobemida/sangre , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/sangre , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , SerbiaRESUMEN
Antidepressants are of great interest to clinical and forensic toxicologists as they are frequently used in suicidal gestures; they can be the source of drug interactions and some have narrow therapeutic indices making the potential for toxicity more likely. There are five categories of antidepressants based on function and/or structure. These are monoamine oxidase inhibitors (MAOI), cyclic antidepressants including tricyclic and tetracyclic compounds (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and atypical compounds. This method is designed to detect the presence of antidepressant drugs in blood/serum, urine, and tissue specimens using gas chromatography/mass spectrometry (GC/MS) following liquid-liquid extraction (LLE) and identified by relative retention times and mass spectra.
Asunto(s)
Antidepresivos/sangre , Antidepresivos/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Antidepresivos/uso terapéutico , Antidepresivos Tricíclicos/sangre , Antidepresivos Tricíclicos/uso terapéutico , Antidepresivos Tricíclicos/orina , Humanos , Inhibidores de la Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/uso terapéutico , Inhibidores de la Monoaminooxidasa/orina , Reproducibilidad de los Resultados , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/orinaRESUMEN
OBJECTIVE: Intoxication with antidepressants, frequently encountered in pediatric emergency medicine, can often lead to life threatening situations. While hyperthermia, hypertonicity and rigidity are symptoms indicative of a serotonin syndrome triggered by an intoxication with serotonin reuptake inhibitors or monoamine oxidase inhibitors, cardiotoxicity, coma and ECG changes are typical of an intoxication with tricyclic antidepressants. CASE REPORT: Hypothermia (instead of the expected hyperthermia) is described for the first time as a persistent symptom during the course of a combined moclobemide-doxepin intoxication in an attempted suicide of a 16-year-old adolescent. DISCUSSION: The administration of serotonin reuptake inhibitors alone or in combination with other medication which increases the level of 5-hydroxytryptamine, i.e. serotonin, in the synaptic cleft mainly leads to hyperthermia. According to a recent study, however, the application of a selective 5-HT(1a) agonist to transgenic mice with a prominent overexpression of the 5-HT(1a) receptor lead to immobility and hypothermia. These findings might help to explain the hypothermia observed in the case of the intoxicated 16-year-old. CONCLUSION: Intoxication with antidepressants should not be excluded a priori in a hypothermic patient who displays other clinical signs of the said intoxication.
Asunto(s)
Antidepresivos Tricíclicos/efectos adversos , Doxepina/efectos adversos , Hipotermia/inducido químicamente , Moclobemida/efectos adversos , Inhibidores de la Monoaminooxidasa/efectos adversos , Lesión Renal Aguda/inducido químicamente , Adolescente , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/sangre , Cromatografía Liquida , Coma/inducido químicamente , Doxepina/administración & dosificación , Doxepina/sangre , Femenino , Toxicología Forense , Cromatografía de Gases y Espectrometría de Masas , Humanos , Moclobemida/administración & dosificación , Moclobemida/sangre , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/sangre , Hipotonía Muscular/inducido químicamente , Rabdomiólisis/inducido químicamente , Intento de SuicidioRESUMEN
OBJECTIVES: To evaluate the potential of pharmacodynamic and pharmacokinetic interactions of a concomitantly administered monoamine oxidase (MAO) type B inhibitor rasagiline and a selective serotonin reuptake inhibitor (SSRI) escitalopram. METHODS: Twelve healthy male volunteers received a 10-day regimen of rasagiline 1mg daily, followed by concomitant rasagiline 1mg and escitalopram 10mg daily for 7 days. RESULTS: We found that the drug combination was generally well tolerated, and there were no signs of central nervous system hyperexcitation or changes in the subjects' vital signs. The reported adverse effects were mainly mild or moderate, and typical for SSRIs. The MAO-A-dependent catecholamine metabolite DHPG levels did not change significantly during the study suggesting that rasagiline's MAO-B selectivity was preserved. The plasma monoamine concentrations indicated no subclinical signs of interaction. As expected, the whole blood serotonin was significantly reduced by escitalopram but unaffected by rasagiline. Rasagiline AUC was increased by 42% (p<0.0001) and the weight-adjusted apparent oral clearance was reduced by 35% (p=0.0009) after 7 days' concomitant escitalopram treatment. Escitalopram reduced the ratio of the AUC values of the main metabolite 1-aminoindan and rasagiline by about 23% (p=0.0079). There were no significant changes in the elimination half-life, t(max) and C(max) of rasagiline. CONCLUSIONS: These results suggest good tolerability of concomitant administration of rasagiline and escitalopram. However, other medications, diseases and aging may change the individual drug response and tolerability of concomitant rasagiline and escitalopram, e.g. in Parkinsonian patients, and thus careful monitoring is recommended when combining rasagiline and escitalopram.
Asunto(s)
Citalopram/administración & dosificación , Indanos/administración & dosificación , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Adulto , Área Bajo la Curva , Monoaminas Biogénicas/sangre , Sangre/efectos de los fármacos , Citalopram/efectos adversos , Citalopram/sangre , Citalopram/farmacocinética , Esquema de Medicación , Interacciones Farmacológicas , Humanos , Indanos/efectos adversos , Indanos/sangre , Indanos/farmacocinética , Masculino , Inhibidores de la Monoaminooxidasa/efectos adversos , Inhibidores de la Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/farmacocinética , Prolactina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are uncommonly used due to their high frequency of adverse effects, including tachycardia and hypertension. Recently, there has been renewed interest in the role of this class of drugs in treating a variety of psychiatric disorders. The clinical features of MAOI overdose are poorly characterised. This paper describes a novel cardiac complication of phenelzine toxicity in a previously healthy young adult with no history of cardiovascular disease. METHODS: A 23-year-old woman presented to hospital after massive phenelzine overdose, and the clinical features and pathological findings are discussed in light of existing literature. RESULTS: Clinical features of phenelzine toxicity included reduced consciousness level, seizures, and tachycardia, in keeping with previous reports. Unexpectedly, the patient developed severe and unexplained hypotension and impaired left ventricular function, and died 3 days after initial presentation. Post-mortem examination confirmed high serum phenelzine concentrations (4.1 mg/L) and histopathological features that were consistent with drug-induced acute myocarditis. CONCLUSION: Acute myocarditis was attributed to phenelzine in the absence of any plausible alternative explanation. This possible complication should be considered in patients who develop unexplained hypotension after phenelzine overdose.
Asunto(s)
Inhibidores de la Monoaminooxidasa/envenenamiento , Miocarditis/inducido químicamente , Fenelzina/envenenamiento , Enfermedad Aguda , Adulto , Trastornos de la Conciencia/inducido químicamente , Sobredosis de Droga , Resultado Fatal , Femenino , Humanos , Hipotensión/inducido químicamente , Inhibidores de la Monoaminooxidasa/sangre , Fenelzina/sangre , Convulsiones/inducido químicamente , Índice de Severidad de la Enfermedad , Suicidio , Taquicardia/inducido químicamente , Disfunción Ventricular Izquierda/inducido químicamenteRESUMEN
The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6-mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline.
Asunto(s)
Antidepresivos/administración & dosificación , Antidepresivos/farmacocinética , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/farmacocinética , Selegilina/administración & dosificación , Selegilina/farmacocinética , Administración Cutánea , Administración Oral , Adolescente , Adulto , Antidepresivos/efectos adversos , Antidepresivos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Cápsulas , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/efectos adversos , Inhibidores de la Monoaminooxidasa/sangre , Selegilina/efectos adversos , Selegilina/sangreRESUMEN
Here we describe a liquid chromatography-tandem mass spectrometry method for the blood determination of tricyclic antidepressant drugs (amitriptyline, clomipramine, trimipramine, and imipramine, doxepin, mianserin, maprotyline, dosulepine, amoxapine), their active metabolites (desipramine, nortriptyline, demethylclomipramine, and nordoxepin), and monoamine oxidase inhibitors (toloxatone and moclobemide). A nontricyclic antidepressant (viloxazine) and two other anxiolytic drugs (buspirone and hydroxyzine) that could be encountered in toxicology have been included to this method. After a liquid-liquid extraction from blood, the compounds and their internal standard (methylrisperidone) were eluted on a XTerra RP18 column with a gradient of acetonitrile/ammonium formate buffer 4 mmol/L (pH 3.2). They were then detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 5-100 ng/mL. The limit of quantification was 2 ng/mL for each compound. The bias were lower than 10%. Intraday and interday precisions, expressed as variation coefficient, were lower than 13%. The extraction recoveries were between 60 and 80% except for moclobemide, viloxazine, and toloxatone (10-60%). This specific and sensitive method allows management of intoxication and is suitable for the routine determination of antidepressants in forensic investigation.
Asunto(s)
Antidepresivos Tricíclicos/sangre , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas/métodos , Medicina Legal/métodos , Inhibidores de la Monoaminooxidasa/sangre , Espectrometría de Masa por Ionización de Electrospray , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem , Antidepresivos Tricíclicos/farmacocinética , Biotransformación , Humanos , Inhibidores de la Monoaminooxidasa/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with ultraviolet detection has been developed for the determination of moclobemide and its metabolites, p-chloro-N-(-2-morpholinoethyl)benzamide N'-oxide (Ro 12-5637) and p-chloro-N-[2-(3-oxomorpholino)ethyl]-benzamide (Ro 12-8095), in human plasma. The assay was performed after single liquid-liquid extraction with dichloromethane at alkaline pH using phenacetin as the internal standard. Chromatographic separation was performed on a C(18) column using a mixture of acetonitrile and water (25:75, v/v), adjusted to pH 2.7 with ortho-phosphoric acid, as mobile phase. Spectrophotometric detection was performed at 239 nm. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The quantification limit for moclobemide and Ro 12-8095 was 10 ng/mL, and for Ro 12-5637 was 30 ng/mL. Linearity of the method was confirmed for the range 20-2500 ng/mL for moclobemide (r = 0.9998), 20-1750 ng/mL for Ro 12-8095 (r = 0.9996) and 30-350 ng/mL for Ro 12-5637 (r = 0.9991). Moreover, within-day and between-day precisions and accuracies of the method were established. The described method was successfully applied in pharmacokinetic studies of parent drug and its two metabolites after a single oral administration of 150 mg of moclobemide to 20 healthy volunteers.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Moclobemida/sangre , Inhibidores de la Monoaminooxidasa/sangre , Humanos , Moclobemida/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta/métodosRESUMEN
UNLABELLED: CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. PERSPECTIVE: This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.