RESUMEN

MDL 74,721 (I), sumatriptan(II) and naratriptan(III) are new 5-HT1-like agonists that have potential as a novel treatment for migraine. Liquid chromatographic-electrospray-mass spectrometric (LC-ESI-MS) assay have been developed to compare the pharmacokinetics of these three antimigraine compounds. The concentration of each parent drug was determined using a solid-phase extraction method and LC-ESI-MS analysis demonstrating the high sensitivity and specificity of the methods down to subnanogram levels in rabbit plasma samples. Pharmacokinetic parameters evaluated after administration of single intravenous and oral doses were very similar and the ANOVA analysis did not show any statistically significant differences for t1/2, Cmax, V or AUC (normalised). The pharmacokinetic parameters showed short t1/2 (range 1.14-1.9 h) either after intravenous (i.v.) or oral (p.o.) administration and high total body clearance (CL) after the p.o. dose both probably due to extensive and rapid metabolism of the parent drugs as suggested by the low values for bioavailability (range 13.4-22.8%).

Asunto(s)

Agonistas de Receptores de Serotonina/sangre , Agonistas de Receptores de Serotonina/farmacocinética , Vasoconstrictores/sangre , Vasoconstrictores/farmacocinética , Administración Oral , Animales , Cromatografía Liquida , Indoles/administración & dosificación , Indoles/sangre , Indoles/farmacocinética , Inyecciones Intravenosas , Masculino , Espectrometría de Masas , Piperidinas/administración & dosificación , Piperidinas/sangre , Piperidinas/farmacocinética , Conejos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Agonistas de Receptores de Serotonina/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sumatriptán/administración & dosificación , Sumatriptán/sangre , Sumatriptán/farmacocinética , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/farmacocinética , Triptaminas , Vasoconstrictores/administración & dosificación

RESUMEN

An analytical method has been developed based on cation-exchange liquid chromatography for the measurement of 2-difluoromethyl-DT-ornithine (DFMO) in human plasma, cerebrospinal fluid (CSF) and urine. Fluorescence detection at excitation/emission wavelengths of 340/440 nm is followed by postcolumn derivatization with o-phthalaldehyde-2,mercaptoethanol. All calibration ranges yielded linear relationships with correlation coefficients better than 0.999. In each case the limit of quantitation was equal to the lowest value of the standard curve. The variability of the assay, expressed as relative standard deviations, was less than 7.1%, 15.3% and 7.1% for plasma, CSF and urine, respectively. The accuracy of the assay (expressed as relative errors) ranged between 4.3% and 2.0% for plasma analysis, between -0.1% and 14.0% for CSF analysis and between -8.0% and 2.0% for urine analysis. Plasma, CSF and urinary DFMO concentrations were measured in samples obtained from patients undergoing treatment for trypanosomiasis. The method was found to be applicable for the measurement of DFMO levels in human body fluids for the determination of pharmacokinetic parameters in clinical studies.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Eflornitina/análisis , Inhibidores Enzimáticos/análisis , Ritmo Circadiano , Eflornitina/química , Inhibidores Enzimáticos/química , Colorantes Fluorescentes/química , Humanos , Modelos Lineales , Mercaptoetanol/análogos & derivados , Mercaptoetanol/química , Reproducibilidad de los Resultados , Espectrometría de Fluorescencia , o-Ftalaldehído/análogos & derivados , o-Ftalaldehído/química

RESUMEN

A selective and sensitive analytical method for the simultaneous measurement of dolasetron (I) and its major metabolite, MDL 74,156 (II), in human plasma and urine samples has been developed using a structural analogue. MDL 101,858, as internal standard (I.S.). The compounds were extracted from plasma and urine using solvent extraction after the addition of the I.S. Chromatographic separation was carried out on a reversed-phase HPLC column and detection and quantification was by fluorescence with excitation and emission wavelengths of 285 and 345 nm, respectively. Linear responses were obtained over concentration ranges of 5 to 1000 pmol/ml for plasma samples and 20 to 1000 pmol/ml for urine samples with correlation coefficients for the calibration curves exceeding 0.999 in all cases. Intra-day and inter-day reproducibility yielded limits of quantification of 10 pmol/ml for I and 5 pmol/ml for II plasma and 50 pmol/ml for I and II in urine. The method has been applied to the simultaneous analysis of both compounds in plasma and urine samples coming from clinical pharmacokinetic studies.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Indoles/análisis , Indoles/metabolismo , Quinolizinas/análisis , Quinolizinas/metabolismo , Antagonistas de la Serotonina/análisis , Antagonistas de la Serotonina/metabolismo , Alcoholes/química , Ritmo Circadiano , Fluorometría , Humanos , Indoles/administración & dosificación , Indoles/sangre , Indoles/química , Indoles/orina , Inyecciones Intravenosas , Modelos Lineales , Concentración Osmolar , Quinolizinas/administración & dosificación , Quinolizinas/sangre , Quinolizinas/química , Quinolizinas/orina , Reproducibilidad de los Resultados , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/química , Factores de Tiempo

RESUMEN

An isocratic reversed-phase high-performance liquid chromatographic (HPLC) method using an Ultrasphere IP column has been developed for the determination of testosterone and its metabolites after incubation of 4-14C-labelled or unlabelled testosterone with rat liver microsomes. Compounds were eluted with methanol-water-tetrahydrofuran (35:55:10, v/v, pH 4.0) and detected by ultraviolet (UV) absorption at 245 nm. UV or on-line radioactivity detection can be used although, due to differences in detector cell volumes, peak resolution is slightly better with UV detection. Selectivity was validated by collecting HPLC peaks and verifying their identity by gas chromatography-mass spectrometry after derivatization by N,O-bis(trimethylsilyl)trifluoroacetamide-trimethylchlorosilane. A three-day validation was performed to determine the linearity, repeatability, reproducibility and accuracy of the method, using corticosterone as internal standard. The method is applicable to the measurement of cytochrome P-450 isoenzyme activities in rat liver.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Microsomas Hepáticos/metabolismo , Testosterona/aislamiento & purificación , Testosterona/metabolismo , Animales , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Cromatografía de Gases y Espectrometría de Masas , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

Plasma concentrations of 3,4-dihydroxyphenylethylglycol (DOPEG), noradrenaline (NA), adrenaline (A), 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA) and phenylethylamine (PEA) were analyzed in samples taken prior to, during and following the administration of single, daily doses of 12 or 24 mg MDL 72,974A to healthy male volunteers. No effects on the concentrations of DOPA, A, DA or DOPAC were seen during the administration of either dose over 10 days. No treatment-related changes in the concentration of NA were evident at either dose. No changes in DOPEG or PEA concentrations were seen with the 12 mg dose; however, small but significant decreases in plasma DOPEG concentrations and a significant increase in PEA were seen during the administration of the 24 mg dose. This would suggest that at the 24 mg dose some intraneuronal inhibition of MAO-A may be occurring although the lack of increases in NA and A concentrations indicates no accompanying change in sympatho-adrenal activity. Plasma PEA concentrations do not provide a more sensitive or functional indication of MAO-B inhibition. The increase in PEA concentrations at the higher dose may suggest that the inhibition of both forms of the enzyme is necessary to increase its plasma concentration.

Asunto(s)

Compuestos Alílicos/farmacología , Butilaminas/farmacología , Catecolaminas/sangre , Inhibidores de la Monoaminooxidasa/farmacología , Adulto , Análisis de Varianza , Humanos , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/sangre , Norepinefrina/sangre

RESUMEN

A method based on solid-phase extraction and high-performance liquid chromatography (HPLC) has been developed for the simultaneous quantitation of the principal active metabolites of dolasetron mesilate [i.e. MDL 74,156 (II), MDL 102,382 (III) and MDL 73,492 (IV)] in human urine. The method has been validated over the concentration range of 200-5000 pmol/ml for all three metabolites. Within-day and day-to-day coefficients of variation were less than 9 and 14%, respectively, for the three metabolites. The method allowed the simultaneous quantitation of III, IV and II and the evaluation of the urinary excretion of these metabolites in human urine following the administration of dolasetron mesilate.

Asunto(s)

Antieméticos/orina , Cromatografía Líquida de Alta Presión/métodos , Indoles/orina , Quinolizinas/orina , Antagonistas de la Serotonina/orina , Antieméticos/metabolismo , Humanos , Indoles/metabolismo , Masculino , Quinolizinas/metabolismo , Antagonistas de la Serotonina/metabolismo

RESUMEN

The effects of monoamine oxidase B (MAO-B) inhibition by mofegiline on the pharmacokinetics of p-tyramine and its major metabolite, p-hydroxyphenylacetic acid, were investigated in 24 healthy male volunteers. p-Tyramine doses were administered before and after a 14-day treatment period of 1, 12, or 24 mg mofegiline or placebo. Normalized p-tyramine for area under the plasma concentration-time curve after treatment were not significantly different from their respective before-treatment values for any of the dose groups. The relative bioavailability of p-tyramine after treatment was not significantly different from before treatment, although a tendency to a greater bioavailability was seen with the 12 and 24 mg doses. There were no significant differences between pharmacokinetic parameters for p-hydroxyphenylacetic acid. The data suggest that mofegiline maintains its selectivity for MAO-B in the intestine and liver at doses up to and including 24 mg. Therefore these doses would not be expected to be associated with the hypertensive crises normally associated with the "cheese effect."

Asunto(s)

Compuestos Alílicos/farmacología , Butilaminas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Fenilacetatos/farmacocinética , Tiramina/farmacocinética , Adulto , Disponibilidad Biológica , Método Doble Ciego , Humanos , Masculino , Fenilacetatos/sangre , Tiramina/sangre , Tiramina/metabolismo

RESUMEN

A sensitive and specific analytical method has been developed for the measurement of beta-phenylethylamine (PEA) in human plasma and rat brain extracts. The method involves solvent extraction of PEA with cyclohexane in the presence of amphetamine or phenylpropylamine (PPA) as internal standards. Automated precolumn derivatization with o-phthalaldehyde and 2-mercaptoethanol followed by reverse-phase HPLC separated PEA and PPA from endogenous interferences. Detection and quantification were carried out by amperometric detection at +0.75 V relative to a Ag/AgCl reference electrode or by coulometric detection with analytical cell potentials set at +0.29 and +0.50 V. The limit of detection for PEA was 10 pg and the limit of quantification in plasma was 60 pg/ml. The within-day and day-to-day coefficients of variation were 16.1% (n = 3) and 40.6% (n = 8), respectively, at a plasma concentration of 154 pg/ml and 15.2% (n = 5) and 28% (n = 10) at a brain extract concentration of 110 pg/ml. Basal endogenous plasma PEA concentrations of 335 +/- 255 pg/ml (n = 12, range 127-1002 pg/ml) were found for normal volunteers and single, daily doses of 24 mg but not 12 mg of the MAO-B inhibitor, mofegiline, were shown to increase plasma PEA significantly. Basal whole brain and striatal concentrations were 0.584 +/- 0.243 ng/g wet wt (n = 3) and 2.89 +/- 1.03 ng/g wet wt (n = 4), respectively. Statistically significant increases (5.7-fold) in rat whole brain PEA concentrations were seen 3 and 6 h following the administration of a single dose of 0.3 mg/kg mofegiline to rats.

Asunto(s)

Química Encefálica , Fenetilaminas/análisis , Adulto , Animales , Cromatografía Líquida de Alta Presión , Humanos , Fenetilaminas/sangre , Ratas

RESUMEN

MDL 72974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine HCl salt, CAS 120635-25-8) is a new irreversible inhibitor of the B form of monoamine oxidase (MAO-B). MDL 72974A's pharmacokinetic parameters were evaluated after administration of a single oral dose and after multiple oral doses. The concentration of parent drug was determined in plasma using a solid-liquid extraction method and gas chromatographic-mass spectrometric analysis. MDL 72974A produced significant inhibition of platelet MAO-B activity at all of the doses > or = 0.5 mg (> 95% after 1 h). The pharmacokinetic parameters showed a short plasma half-life (1 h) and a high total body clearance (Cltot) both probably due to extensive and rapid metabolism as suggested by the low urinary excretion of unchanged drug (< 1% of the administered dose). After the administration of multiple doses of MDL 72974A, a decrease in Cltot and a concomitant increase in the AUC and t1/2, was observed, probably due to a change in the elimination rate of MDL 72974A. Due to the once-a-day dosing schedule and the short plasma t1/2, no drug accumulation occurred.

Asunto(s)

Compuestos Alílicos , Butilaminas/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Monoaminooxidasa/metabolismo , Plaquetas/enzimología , Método Doble Ciego , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Indicadores y Reactivos

RESUMEN

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment. The influence of vigabatrin on the cerebrospinal fluid concentrations of free and total GABA, homocarnosine, homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol, as well as of the drug itself, was assessed. All patients demonstrated a clinical response to vigabatrin, and the drug was well tolerated over the entire observation period. Mean (+/- SD) reduction of seizure frequency was 65% +/- 23% (range, 26% to 100%) when comparing the end of the treatment period to the previgabatrin baseline. The cerebrospinal fluid concentrations of both free and total GABA and of the dipeptide homocarnosine showed approximately 2- to 5-fold increases over baseline values, with free GABA and homocarnosine being the more sensitive variables. Cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were not altered in a significant manner over the observation period. These findings support the concept that the effects of vigabatrin are restricted to an effect on GABA catabolism and do not extend to the neurotransmitters dopamine and norepinephrine. Clinical efficacy and elevation of GABA and homocarnosine concentration were sustained over the period of observation.

Asunto(s)

Aminocaproatos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Epilepsia Parcial Compleja/tratamiento farmacológico , Ácido gamma-Aminobutírico/líquido cefalorraquídeo , Adulto , Aminocaproatos/farmacocinética , Anticonvulsivantes/farmacocinética , Carnosina/análogos & derivados , Carnosina/líquido cefalorraquídeo , Electroencefalografía/efectos de los fármacos , Epilepsia Parcial Compleja/líquido cefalorraquídeo , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Cuidados a Largo Plazo , Masculino , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Persona de Mediana Edad , Vigabatrin

RESUMEN

Lumbar punctures were performed on four occasions over a 5-day period (8:30 a.m. on days 1, 3, and 5; 2:30 p.m. on day 2) on 10 normal volunteers (five of each sex; mean age, 27.7 years) to assess, with repeated sampling, the day-to-day variation of selected CSF parameters. Two subjects abstained from the lumbar puncture on day 5 due to headache after the third puncture. Lumbar CSF was analyzed for concentrations of free and total gamma-aminobutyric acid (GABA), homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), total protein, albumin, and immunoglobulin (Ig)G. No significant concentration differences were found between the afternoon and next morning samples. No differences were found in concentrations of free GABA, total GABA, homocarnosine, 5-HIAA, or albumin across the study. In contrast, HVA concentrations significantly increased by day 5, whereas total protein and IgG decreased during the study. The most likely explanation for these changes involves the known concentration gradients in the CSF column.

Asunto(s)

Carnosina/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/análisis , Dipéptidos/líquido cefalorraquídeo , Ácido Homovanílico/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Ácido gamma-Aminobutírico/líquido cefalorraquídeo , Adulto , Albúminas/líquido cefalorraquídeo , Carnosina/análogos & derivados , Femenino , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Masculino , Valores de Referencia , Punción Espinal/efectos adversos , Punción Espinal/métodos

RESUMEN

1. Vigabatrin, 50 mg kg-1, was administered orally as add-on therapy to 11 patients with drug-resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA-histidine dipeptide), homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre-treatment levels with subsequent dosing schedules. In contrast, 5-HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre-treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.

Asunto(s)

Aminocaproatos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Proteínas del Líquido Cefalorraquídeo/metabolismo , Epilepsia/tratamiento farmacológico , Adulto , Aminocaproatos/efectos adversos , Anticonvulsivantes/efectos adversos , Carnosina/análogos & derivados , Carnosina/sangre , Epilepsia/líquido cefalorraquídeo , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Vigabatrin , Ácido gamma-Aminobutírico/líquido cefalorraquídeo

RESUMEN

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3-fold in the time to reach the maximum concentration, 2.7-fold in the maximum concentration, and 9.8-fold in the AUC; a twofold prolongation of the t1/2; and reduced urinary excretion of the biologically and pharmacologically active S(+)-enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(-)-enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.

Asunto(s)

Envejecimiento/metabolismo , Aminocaproatos/farmacocinética , Creatinina/metabolismo , Riñón/metabolismo , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estereoisomerismo , Vigabatrin

RESUMEN

Vigabatrin, as a single oral dose of 50 mg/kg, was administered to 11 patients with drug-refractory complex partial epilepsy. Serial lumbar punctures were performed prior to and 5 times within the first week following treatment. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vigabatrin were determined as well as blood vigabatrin levels. CSF GABA, homocarnosine, HVA and 5-HIAA concentrations increased by 6 h after the single dose and remained elevated for up to 5-7 days. In contrast, CSF and blood vigabatrin levels were maximal within the first 24 h and were no longer detectable thereafter. Hence, these results are consistent with vigabatrin acting as an irreversible inhibitor of GABA-transaminase and suggest that it may also increase biogenic amine turnover.

Asunto(s)

Aminocaproatos/uso terapéutico , Carnosina/líquido cefalorraquídeo , Dipéptidos/líquido cefalorraquídeo , Epilepsias Parciales/líquido cefalorraquídeo , Ácido Homovanílico/líquido cefalorraquídeo , Serotonina/líquido cefalorraquídeo , Ácido gamma-Aminobutírico/líquido cefalorraquídeo , Administración Oral , Adulto , Aminocaproatos/administración & dosificación , Aminocaproatos/líquido cefalorraquídeo , Carnosina/análogos & derivados , Epilepsias Parciales/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigabatrin

RESUMEN

An analytical method based on solvent extraction and reversed-phase high-performance liquid chromatographic separation with electrochemical detection has been developed for the dihydropyridines, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl) -1,4-dihydropyridine (MDL 72.567) and nifedipine. The analysis includes an internal standard of similar light sensitivity to correct for possible photodegradation during the procedure. The specificity of electrochemical detection precludes interference from oxidized metabolites. Total analysis time was 35 min per sample, and the detection limit for quantification was 1-2 ng/ml. Linear regression analysis gave calibration curves with coefficients or correlation of 0.9992 for MDL 72.567 (1-100 ng) and 0.997 for nifedipine (1-50 ng). Assays for within-run and day-to-day reproducibility gave coefficients of variation of 3.9% and 6.0%, respectively, at concentrations of 50 ng/ml. The method has been applied to the analysis of plasma levels of nifedipine and MDL 72.567 in dogs.

Asunto(s)

Bloqueadores de los Canales de Calcio/análisis , Dihidropiridinas , Ácidos Nicotínicos/análisis , Nifedipino/análisis , Animales , Bloqueadores de los Canales de Calcio/sangre , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión , Perros , Electroquímica , Cinética , Ácidos Nicotínicos/sangre , Nifedipino/sangre

RESUMEN

In a pilot single-blind study, gamma-vinyl GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase (GABA-T), was administered orally to 10 epileptic patients who were refractory to conventional anticonvulsant therapy. Daily doses of 1 g and 2 g for 2 weeks each as add-on therapy were followed by 2 weeks of placebo treatment. CSF obtained from suboccipital and lumbar punctures demonstrated dose-related increases in concentrations of free and total GABA and homocarnosine with treatment, but no changes in 5-hydroxyindoleacetic acid or homovanillic acid levels, indicating effective and selective CNS GABA-T inhibition. These biochemical changes were associated with decreased seizure frequency in seven patients, decreased seizure severity in one, no change in one, and possible worsening in one. gamma-Vinyl GABA may be useful in the therapy of epilepsy.

Asunto(s)

Aminocaproatos/uso terapéutico , Epilepsia/tratamiento farmacológico , Adulto , Sistema Nervioso Central/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Vigabatrin , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

The effects of the irreversible, enzyme-activated, aromatic L-amino acid decarboxylase (AADC) inhibitors alpha-monofluoromethyl-beta-(3,4-dihydroxyphenyl)alanine (MFMD), alpha-difluoromethyl-beta-(3,4-dihydroxyphenyl)alanine (DFMD), and alpha-monofluoromethyl-beta-(2,3-dihydroxyphenyl)alanine (MDL 72. 163) on the serum t1/2 and other pharmacokinetic parameters of co-administered L-3,4-dihydroxyphenylalanine (L-DOPA) were compared to those of the reversible inhibitor, carbidopa in rats. MFMD and MDL 72. 163, administered as their DL-racemic mixtures, produced increases in the t1/2 and bioavailability of co-administered L-DOPA comparable to that produced by a 10-fold larger dose of carbidopa administered as the active L-enantiomer; increasing the dose of MDL 72. 163 did not further increase the t1/2 or bioavailability of L-DOPA. DFMD produced smaller increases of both t1/2 and bioavailability at higher doses. Concomitant decreases in the ClT and aVD were observed with all four inhibitors. Although AADC inhibition reduced the magnitude of the increases in serum dopamine levels following L-DOPA administration, no reduction in serum 3,4-dihydroxyphenylacetic acid levels was observed. The failure of the irreversible inhibitors to produce a larger increase in the t1/2 of L-DOPA than is produced by carbidopa is suggested to reflect the existence of alternative pathways of L-DOPA metabolism.

Asunto(s)

Inhibidores de Descarboxilasas de Aminoácidos Aromáticos , Levodopa/metabolismo , Animales , Carbidopa/farmacología , Dihidroxifenilalanina/análogos & derivados , Dihidroxifenilalanina/farmacología , Semivida , Cinética , Masculino , Metildopa/análogos & derivados , Metildopa/farmacología , Ratas , Ratas Endogámicas

RESUMEN

An analytical procedure, which allows the determination and quantitation of the R(-)- and S(+)-enantiomers of gamma-vinyl-gamma-aminobutyric acid (gamma-vinyl-GABA; MDL 71.754) in body fluids was developed. The method is based on a combined gas chromatographic--mass spectrometric technique. A glass capillary column coated with a chiral phase enabled the separation of the enantiomers of gamma-vinyl-GABA as their N-trifluoroacetyl-O-methyl ester derivatives. This was followed by quantitation using a selected ion monitoring technique in the electron-impact mode of ionization. The internal standard, gamma-acetylenic GABA, was included throughout the work-up of the samples. The assay was shown to be reproducible, specific and sensitive. No interferences were encountered from plasma, urine or cerebrospinal fluid constituents. The method was applied to the analysis of plasma samples obtained from a human volunteer who had received racemic gamma-vinyl-GABA. Significant differences in the plasma concentrations and plasma half-lives of the two enantiomers were seen, clearly illustrating the need for a specific assay technique capable of distinguishing between the enantiomers of this drug.

Asunto(s)

Líquidos Corporales/análisis , Alquinos , Aminocaproatos/análisis , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Masculino , Estereoisomerismo , Factores de Tiempo , Vigabatrin

RESUMEN

The biosynthesis and urinary excretion of the trace amines PE, mTA, pTA and TRYP have been investigated after systemic injection in the rat and ingestion in the human. In the rat the likely precursors phe, tyr, DOPA and PE, radioactively labelled, were injected in tracer and supplemented doses. pTA was shown to be formed from PE and ptyr and in tiny amounts from phe and DOPA. mTA was formed from PE, phe and DOPA. PE was found after phe and PE injections. In the human, after ingestion of the deuterated precursors phe, ptyr, PE and try, only deuterated PE and mTA were located after phe, deuterated pTA after ptyr, deuterated PE after PE and deuterated TRYP after try. These results suggest that in the periphery pTA may be formed by p-hydroxylation of PE as well as by decarboxylation of ptyr while PE and TRYP are formed by decarboxylation of their parent amino acids phe and try respectively. PE is also a possible source of mTA but in this case hydroxylation and decarboxylation of phe and dehydroxylation and decarboxylation (or vice versa) of DOPA are also important.

Asunto(s)

Aminas/biosíntesis , Bencilaminas/biosíntesis , Triptaminas/biosíntesis , Tiramina/biosíntesis , Animales , Deuterio , Humanos , Masculino , Ratas , Ratas Endogámicas

RESUMEN

The urinary excretion of a beta-phenylethylamine (PE), m-tyramine (mTA), p-tyramine (pTA) and tryptamine (TR) in their unconjugated (free) and conjugated (except tryptamine) forms, was examined in a male human subject over a total period of 28 days. The average excretion values were (in microgram per 24 h, mean +/- standard error): PE, free 3.19 +/- 0.21, conjugated 6.85 +/- 0.52, mTA, free 98.0 +/- 2.2, conjugated 106.1 +/- 18.6; pTA, free 427 +/- 12, conjugated 571 +/- 142; and TR, free 79.4 +/- 2.8. This data, when considered along with other published information, permits the suggestion that probably mTA and pTA in the unconjugated form are exclusively formed endogenously; whether or not this also pertains to PE and TR is less clear. In all cases, the conjugated amines derive from both exogenous and endogenous sources.

Asunto(s)

Fenetilaminas/orina , Triptaminas/orina , Tiramina/orina , Humanos , Masculino , Métodos , Factores de Tiempo