RESUMEN
Chirality is a key subject in modern drug research as well as in the pharmaceutical industry and drug development. Almost all second-generation modern antidepressants are chiral substances; however in therapy some are used as racemic mixtures while others are used as pure enantiomers. The development of enantioseparation methods of chiral antidepressants and their metabolites is one of the keys in understanding their enantioselective drug action. For this purpose, efficient and reliable analytical methods are needed, and capillary electrophoresis has proved to be an interesting and advantageous alternative to the more frequently used chromatographic techniques. In this review electrodriven methods available for the chiral discrimination of selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline) and selective serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) are presented and discussed.
Asunto(s)
Antidepresivos , Electroforesis Capilar , Inhibidores de la Captación de Neurotransmisores , Antidepresivos/análisis , Antidepresivos/química , Antidepresivos/aislamiento & purificación , Inhibidores de la Captación de Neurotransmisores/análisis , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/aislamiento & purificación , EstereoisomerismoRESUMEN
No disponible
Asunto(s)
Humanos , Neurofisiología/historia , Neurofisiología/métodos , Dolor/epidemiología , Dolor/historia , Inhibidores de la Captación de Neurotransmisores/análisis , Inhibidores de la Captación de Neurotransmisores/historia , Receptores de Neurotransmisores/análisis , Neurotransmisores/análisisRESUMEN
The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 3² full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t(50%) = 5.92 h, t(75%) = 11.9 h, t(90%) = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.
Asunto(s)
Antidepresivos/química , Ciclopropanos/química , Sistemas de Liberación de Medicamentos , Inhibidores de la Captación de Neurotransmisores/química , Administración Oral , Antidepresivos/administración & dosificación , Antidepresivos/análisis , Fenómenos Químicos , Ciclopropanos/administración & dosificación , Ciclopropanos/análisis , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/análisis , Preparaciones de Acción Retardada/química , Composición de Medicamentos , Estabilidad de Medicamentos , Excipientes/química , Dureza , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Lepidium sativum/química , Fenómenos Mecánicos , Microscopía Electrónica de Rastreo , Milnaciprán , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Inhibidores de la Captación de Neurotransmisores/análisis , Mucílago de Planta/química , Semillas/química , Solubilidad , ComprimidosRESUMEN
Postmortem distribution concentrations of the pain medication tapentadol and its metabolite N-desmethyltapentadol are reported. Tapentadol (Nucynta®) is a synthetic mu-opioid receptor agonist that also has norepinephrine reuptake inhibitor action. The laboratory received two cases. Case 1: a 19-year-old, morbidly obese male with sudden unexpected death. Toxicology results revealed tapentadol (femoral blood: 0.77 mg/L, liver: 1.65 mg/kg), N-desmethyltapentadol (femoral blood: 0.07 mg/L, liver: 0.19 mg/kg), diazepam (femoral blood: 0.04 mg/L), nordiazepam (femoral blood: 0.06 mg/L) and amiodarone (femoral blood: 5.30 mg/L). Case 2: a 60-year-old female who died from complications following hip replacement. Only tapentadol (femoral blood: 0.26 mg/L, liver: 0.52 mg/kg) was found in the toxicology results. Quantitative results of tapentadol/N-desmethyltapentadol were achieved using liquid chromatography-tandem mass spectrometry in multiple reactions monitoring mode. This is the first known distribution study of tapentadol and N-desmethyltapentadol values in postmortem cases.
Asunto(s)
Analgésicos Opioides/análisis , Inhibidores de la Captación de Neurotransmisores/análisis , Fenoles/análisis , Receptores Opioides mu/agonistas , Adulto , Analgésicos Opioides/sangre , Analgésicos Opioides/farmacocinética , Biotransformación , Femenino , Humanos , Hígado/química , Masculino , Persona de Mediana Edad , Inhibidores de la Captación de Neurotransmisores/sangre , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Fenoles/sangre , Fenoles/farmacocinética , Tapentadol , Distribución Tisular , Adulto JovenRESUMEN
OBJECTIVE: Venlafaxine use during pregnancy has increased over the past decade in concert with accumulating reproductive safety data; however, systematic data on venlafaxine during lactation remain sparse. The current study characterizes the level and determinants of venlafaxine and desvenlafaxine concentrations in breast milk and in nursing infant plasma. METHOD: Women participating in a prospective investigation of perinatal pharmacokinetics from January 2001 through July 2006 who were treated with venlafaxine and who chose to continue venlafaxine during lactation were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient, and serial samples were collected over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Venlafaxine and desvenlafaxine concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. RESULTS: Thirteen women and their nursing infants participated, providing 106 breast milk samples. The mean milk/plasma ratio was 275.3% (95% CI = 144.8% to 405.7%). There were statistically significant time courses of excretion for venlafaxine (R = 0.36, F = 6.82, P < .02), desvenlafaxine (R = 0.48, F = 4.41, P < .009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < .004), with the highest venlafaxine and desvenlafaxine concentrations in the breast milk occurring 8 hours after maternal ingestion. Infant plasma concentrations for combined venlafaxine/desvenlafaxine were 37.1% of maternal plasma concentrations. The theoretical infant venlafaxine/desvenlafaxine dose was 0.208 mg/kg/d, and the relative infant venlafaxine/desvenlafaxine dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 197% and 224% higher, respectively, than those for venlafaxine. No adverse events were observed or reported in the nursing infants. CONCLUSIONS: Consistent with previous investigations of medications in breast milk, the venlafaxine and desvenlafaxine milk/plasma ratios were highly variable. The rate of venlafaxine/desvenlafaxine excretion into human breast milk is relatively higher than that observed for other antidepressants, largely due to higher desvenlafaxine excretion. These data expand the extant literature on venlafaxine and desvenlafaxine in lactation.
Asunto(s)
Lactancia Materna , Ciclohexanoles/metabolismo , Ciclohexanoles/farmacocinética , Lactancia/metabolismo , Leche Humana/química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Adulto , Cromatografía Líquida de Alta Presión , Ciclohexanoles/análisis , Ciclohexanoles/sangre , Preparaciones de Acción Retardada , Succinato de Desvenlafaxina , Femenino , Humanos , Lactante , Recién Nacido , Lactancia/sangre , Leche Humana/metabolismo , Inhibidores de la Captación de Neurotransmisores/análisis , Inhibidores de la Captación de Neurotransmisores/sangre , Embarazo , Inhibidores Selectivos de la Recaptación de Serotonina/análisis , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Clorhidrato de VenlafaxinaRESUMEN
The reuptake blockade of biogenic amines by antidepressants is related not only to their therapeutics effects, but also to their side effects and potential drug-drug interactions. As an alternative to classical quantitative structure-activity relationships studies, in this work we propose different quantitative retention-activity relationships (QRAR) models that are able to describe the monoamine reuptake inhibition by antidepressants. The retention of compounds is measured using a biopartitioning micellar chromatography (BMC) system that can simulate the same hydrophobic, electronic and steric molecular interactions as those that condition drug activity. Since all the compounds considered in this work are structurally related because all of them share the same molecular features as the corresponding basic pharmacophore, the results obtained show that there is a retention range in which antidepressants present the highest monoamine reuptake inhibitor potency.
Asunto(s)
Antidepresivos/uso terapéutico , Monoaminas Biogénicas/metabolismo , Cromatografía Liquida/métodos , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Antidepresivos/análisis , Micelas , Inhibidores de la Captación de Neurotransmisores/análisis , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
A case study is described of a patient who was intoxicated after the intake of so-called herbal stimulants. A visit to a physician after the intoxication prompted to this investigation and the case was examined for its direct cause. An interview with the patient revealed that the source of the herbal stimulants was a so-called 'S-5 tablet'. Information provided on the packings of the tablet only indicated the presence of natural alkaloids and vitamins. Toxicological analysis however proved that the 'S-5 tablet' contained para-methylthioamphetamine (MTA), mainly. MTA is a relative unknown amphetamine designer drug, which has only been studied as a model compound in some structure-activity relationship studies. The fact that MTA appeared in tablets was therefore completely unexpected. Not only the potential abuse of this new amphetamine designer drug is a serious matter of concern, but also the misleading information provided with the tablet.
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Anfetaminas/envenenamiento , Drogas de Diseño/envenenamiento , Inhibidores de la Captación de Neurotransmisores/envenenamiento , Adulto , Anfetaminas/análisis , Drogas de Diseño/análisis , Etiquetado de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Inmunoensayo de Polarización Fluorescente , Humanos , Masculino , Inhibidores de la Captación de Neurotransmisores/análisis , Psicosis Inducidas por Sustancias/psicologíaRESUMEN
A method is described for the determination of cocaine, benzoylecgonine and cocaethylene in the human brain using Clean Screen solid phase extraction cartridges and gas chromatography/ion trap mass spectrometry with electron impact and full scan analysis. The procedure uses deuterated internal standards. Run-to-run and within-run coefficients of variation are < 7% and the sensitivity proved to be 50 ng/g from 1 g of sample. The procedure has been applied to a number of forensic cases involving cocaine intoxication. Cocaine was relatively unstable in brain tissue stored at 4 degrees C when compared to storage at -80 degrees C.
Asunto(s)
Química Encefálica , Cocaína/análogos & derivados , Cocaína/análisis , Narcóticos/análisis , Inhibidores de la Captación de Neurotransmisores/análisis , Causas de Muerte , Cocaína/sangre , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Narcóticos/sangre , Inhibidores de la Captación de Neurotransmisores/sangreRESUMEN
Drug screening of breast milk in a clinical toxicology laboratory is reported. Findings from three cases include cocaine, ethylbenzoylecgonine (cocaethylene), ethanol, oxycodone, codeine, and nicotine. We believe this to be the first report of ethylbenzoylecgonine in human breast milk. One other specimen submitted for analysis was screened with negative results. Screening and confirmation procedures adapted for use with breast milk are described. Finally, the potential for cocaine intoxication from mother to baby is discussed. Estimates of infant blood cocaine concentration are given which may increase awareness of the need to monitor milk and blood cocaine concentrations in the infant when the situation warrants.
Asunto(s)
Drogas Ilícitas/análisis , Leche Humana/química , Detección de Abuso de Sustancias/métodos , Adulto , Cocaína/análogos & derivados , Cocaína/análisis , Codeína/análisis , Etanol/análisis , Femenino , Humanos , Recién Nacido , Inhibidores de la Captación de Neurotransmisores/análisis , Nicotina/análisis , Oxicodona/análisis , Embarazo , Complicaciones del Embarazo/diagnóstico , Efectos Tardíos de la Exposición Prenatal , Trastornos Relacionados con Sustancias/diagnósticoRESUMEN
GC and GC/MS analysis was used to detect cocaine and cocaethylene in hair extracts of mice injected with 20 mg/kg cocaine hydrochloride or an equivalent dose of cocaethylene fumarate twice daily for 3 weeks. Some mice were fed liquid Lieber-DeCarli diets containing ethanol (26% of total calories) and injected twice daily with the same doses of cocaine or cocaethylene or combination of cocaine and morphine (5 mg/kg). The average concentrations of cocaine in different experimental groups were in the range of 0.9-2.4 ng/mg of hair and for cocaethylene, 2.4-2.8 ng/mg of hair. There were no significant differences in hair concentrations of cocaine among groups receiving cocaine treatment, nor were there significant difference in cocaethylene concentration in hair in the two groups administered cocaethylene. In hair extracts of mice treated with cocaine and ethanol, levels of cocaethylene were below the limit of detection.
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Cocaína/análogos & derivados , Cocaína/análisis , Etanol/análisis , Cabello/química , Inhibidores de la Captación de Neurotransmisores/análisis , Administración Oral , Animales , Cromatografía de Gases , Cocaína/administración & dosificación , Esquema de Medicación , Etanol/administración & dosificación , Cromatografía de Gases y Espectrometría de Masas , Inyecciones Intraperitoneales , Masculino , Ratones , Inhibidores de la Captación de Neurotransmisores/administración & dosificaciónRESUMEN
Cocaethylene is a psychoactive ethyl homologue of cocaine, and is formed exclusively during the coadministration of cocaine and alcohol. Not a natural alkaloid of the coca leaf, cocaethylene can be identified in the urine, blood, hair, and neurological and liver tissue samples of individuals who have consumed both cocaine and alcohol. With a pharmacologic profile similar to cocaine, it can block the dopamine transporter on dopaminergic presynaptic nerve terminals in the brain. It increases dopamine synaptic content, provoking enhanced postsynaptic receptor stimulation, resulting in euphoria, reinforcement, and self-administration. Equipotent to cocaine with regard to dopamine transporter affinity, cocaethylene appears to be far less potent than cocaine with regard to serotonin transporter binding. Lacking the serotonergic-related inhibitory mechanism, cocaethylene appears to be more euphorigenic and rewarding than cocaine. Synthesized and administered cocaethylene has a behavioral stimulation profile similar to cocaine. Cocaethylene has been shown to be less potent and equipotent to cocaine, and alcohol plus cocaine produces more stimulatory locomotor behavior in mice than either drug alone. Equipotent to cocaine with regard to primate reinforcement and self-administration, cocaethylene can substitute for cocaine in drug discrimination studies, and can produce stimulation of operant conditioning in rats. With regard to lethality, cocaethylene has been shown to be more potent than cocaine in mice and rats. The combination of cocaine and alcohol appears to exert more cardiovascular toxicity than either drug alone in humans. Alcohol appears to potentiate cocaine hepatotoxicity in both humans and mice.