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1.
Environ Sci Pollut Res Int ; 19(6): 2096-106, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22227832

RESUMO

PURPOSE: Psychoactive compounds-meprobamate, pyrithyldione, primidone, and its metabolites, phenobarbital, and phenylethylmalonamide-were detected in groundwater within the catchment area of a drinking water treatment plant located downgradient of a former sewage farm in Berlin, Germany. The aim of this study was to investigate the distribution of the psychoactive compounds in anoxic groundwater and to assess the risk of drinking water contamination. Groundwater age was determined to achieve a better understanding of present hydrogeological conditions. METHODS: A large number of observation and production wells were sampled. Samples were analyzed using solid-phase extraction and ultrahigh-performance liquid chromatography-tandem mass spectrometry. Groundwater age was estimated using the helium-tritium ((3)He-(3)H) dating method. RESULTS: Concentrations of psychoactive compounds up to 1 µg/L were encountered in the contamination plume. Generally, concentrations of phenobarbital and meprobamate were the highest. Elevated concentrations of the analytes were also detected in raw water from abstraction wells located approximately 2.5 km downgradient of the former sewage farm. Concentrations in the final drinking water were below the limit of quantification owing to dilution. The age of shallow groundwater samples ranged from years to a decade, whereas groundwater was up to four decades old at 40 m below ground. Concentrations of the compounds increased with groundwater age. CONCLUSIONS: Elevated concentrations of psychoactive drugs indicate a strong persistence of these compounds in the environment under anoxic aquifer conditions. Results suggest that the heritage of sewage irrigation will affect raw water quality in the area for decades. Therefore, further monitoring of raw and final drinking water is recommended to ensure that contaminant concentrations remain below the health-based precautionary value.


Assuntos
Água Subterrânea/análise , Psicotrópicos/análise , Esgotos/análise , Poluentes da Água/análise , Berlim , Cromatografia Gasosa-Espectrometria de Massas , Meprobamato/análise , Fenobarbital/análise , Feniletilmalonamida/análise , Primidona/análise , Piridonas/análise
2.
Anal Bioanal Chem ; 386(2): 256-63, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16896629

RESUMO

Simple, sensitive, and reproducible off-line solid-phase microextraction and liquid chromatography (SPME/LC) methods are described for the determination of seven anticonvulsants and tricyclic antidepressants in human plasma. Factorial design and simplex methodology were applied in the optimization of the SPME procedure for tricyclic antidepressants analyses. Important factors in the SPME efficiency are discussed, such as the fiber coatings (both lab-made and commercial), extraction time, pH, ionic strength, influence of plasma proteins, and desorption conditions. The development of the lab-made fiber coatings, namely, octadecylsilane, aminosilane, and polyurethane, are further described and applied to anticonvulsants analyses. The investigated plasmatic range for the evaluated anticonvulsants, using CW-TPR fiber, were the following: phenylethylmalonamide (3.00-40.0 microg mL(-1)), phenobarbital (5.00-40.0 microg mL(-1)), primidone (3.00-40.0 microg mL(-1)), carbamazepine and carbamazepine-epoxide (2.00-24.0 microg mL(-1)), phenytoin (2.00-40.0 microg mL(-1)), and lamotrigine (0.50-12.0 microg mL(-1)). The antidepressants' linear plasmatic concentration ranged from 75.0 to 500 ng mL(-1) for imipramine, amitriptyline, and desipramine, and from 50.0 to 500 ng mL(-1) for nortriptyline, being in all cases, the limit of quantification represented by the lowest value. The precision (interassays) for all investigated drugs in plasma sample spiked with different concentrations of each analyte and submitted to the described procedures were lower than 15%. The off-line SPME/LC methodologies developed allow anticonvulsants and antidepressants analyses from therapeutic to toxic levels for therapeutic drug monitoring.


Assuntos
Anticonvulsivantes/sangue , Antidepressivos Tricíclicos/sangue , Cromatografia Líquida/métodos , Amitriptilina/sangue , Carbamazepina/sangue , Desipramina/sangue , Compostos de Epóxi/sangue , Humanos , Concentração de Íons de Hidrogênio , Imipramina/sangue , Lamotrigina , Nortriptilina/sangue , Fenobarbital/sangue , Feniletilmalonamida/sangue , Poliuretanos/química , Primidona/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Silanos/química , Fatores de Tempo , Triazinas/sangue
3.
J Anal Toxicol ; 27(5): 304-8, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12908944

RESUMO

The determination of lamotrigine (LTG) simultaneously with carbamazepine (CBZ), carbamazepine 10,11 epoxide (CBZ-E), primidone (PRM), phenytoin (PHT), phenobarbital (PB), and 2-phenyl-2-ethyl-malonamide (PEMA) in human plasma was developed using micellar electrokinetic capillary chromatography (MECC) with a diode-array detector. The reproducibility of both separation and quantitation with MECC analysis were appropriate for the intra- and interassay coefficients. The evaluated drugs concentration intervals of LTG, 0.5-10.0 micro g/mL; CBZ, 1.0-16.0 micro g/mL; PEMA, 1.0-20.0 micro g/mL; PB, 1.0-60.0 micro g/mL; PRM, 1.0-20.0 micro g/mL; PHT, 0.7-40.0 micro g/mL; and CBZ-E, 1.0-14.0 micro g/mL were linear with correlation coefficients higher than 0.987 and coefficients of the variation of the points of the calibration curve lower than 10%. The limit of quantitation of the investigated drugs in plasma varied from 0.5 to 1.0 micro g/mL, depending upon the drug. The MECC technique was sensitive enough to work with microsamples into the subtherapeutic, therapeutic, and toxic concentrations, as well as showed to be simple and efficient when applied to monitoring therapeutic drugs in patients treated with a combination of lamotrigine and other antiepileptic drugs such as hepatic enzyme-inducing agents.


Assuntos
Anticonvulsivantes/sangue , Carbamazepina/análogos & derivados , Carbamazepina/sangue , Triazinas/sangue , Cromatografia Capilar Eletrocinética Micelar/métodos , Humanos , Lamotrigina , Fenobarbital/sangue , Feniletilmalonamida/sangue , Fenitoína/sangue , Primidona/sangue , Fatores de Tempo
4.
Drug Metabol Drug Interact ; 18(3-4): 191-208, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11791884

RESUMO

The aim of this study was to evaluate the influence of primidone (PRM) nanoencapsulation on its metabolism. Suspensions of PRM powder and PRM-loaded poly-epsilon-caprolactone nanocapsules were administered orally in the same way to rats. Primidone-loaded poly-epsilon-caprolactone nanocapsules were prepared according to the interfacial deposition technique. Free PRM suspensions were obtained by addition of PRM powder to a suspension of 0.212% carboxymethylcellulose CMC 12H in water. The dose was 20 mg/kg, n = 6, for each experiment. Urinary and faecal levels of PRM and of its three major metabolites, phenylethylmalonamide (PEMA), phenobarbital (PB), and p-hydroxyphenobarbital (p-HO-PB), were determined. Concentrations were evaluated by high-performance liquid chromatography (HPLC) according to a validated analytical method. After PRM nanocapsule administration, non-metabolised PRM urinary levels were increased compared to those observed after administration of a suspension of primidone powder (43.7+/-8.8% after PRM-loaded nanocapsule and 37.7+/-8.1% after free PRM administration). For phenylethylmalonamide, no difference was observed in urinary excretion in the two cases. For two of the oxidised metabolites, PB and p-HO-PB, excretion was delayed and shortened. The amount of these oxidised metabolites was lowered from 0.95% after free PRM administration to 0.25% after PRM-loaded nanocapsule administration. No difference was noted in non-metabolised primidone excretion in faeces. These results suggest that primidone-loaded nanocapsules could be used as a vehicle for oral primidone administration in order to minimise the phenobarbital metabolic pathway.


Assuntos
Anticonvulsivantes/metabolismo , Fenobarbital/análogos & derivados , Primidona/metabolismo , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/urina , Fenômenos Químicos , Físico-Química , Composição de Medicamentos , Fezes/química , Feminino , Nanotecnologia/métodos , Oxirredução , Fenobarbital/metabolismo , Fenobarbital/urina , Feniletilmalonamida/metabolismo , Feniletilmalonamida/urina , Poliésteres , Primidona/administração & dosagem , Primidona/urina , Ratos , Ratos Sprague-Dawley
5.
Eur J Drug Metab Pharmacokinet ; 24(3): 255-64, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10716065

RESUMO

Primidone is a clinically useful antiepileptic drug that is metabolised to two pharmacologically active metabolites phenobarbital and phenylethylmalonamide. As data on the inter-relationship between the systemic and central nervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely behaving rat model which allows repeated sampling of blood (100 microl) and cerebrospinal fluid (CSF; 20 microl). After administration, by intraperitoneal injection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (Tmax mean range 1.5-2.5 h) and CSF (Tmax mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier. This was also the case for phenylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose linearly and dose-dependently in both serum and CSF. The mean free fraction (free/total concentration ratio) for primidone, phenylethylmalonamide and phenobarbital was 0.86, 0.97 and 0.88, respectively, and, as their respective mean CSF/serum ratio values were 0.73, 1.06 and 0.65, it would suggest that equilibration between the blood and CSF compartments is rapid. CSF mean t(1/2) values for primidone, phenylethylmalonamide and phenobarbital were similar to those of sera and essentially paralleled the pattern seen in sera.


Assuntos
Fenobarbital/farmacocinética , Feniletilmalonamida/farmacocinética , Primidona/farmacocinética , Animais , Meia-Vida , Masculino , Fenobarbital/líquido cefalorraquidiano , Feniletilmalonamida/líquido cefalorraquidiano , Primidona/líquido cefalorraquidiano , Ratos , Ratos Sprague-Dawley
6.
J Chromatogr B Biomed Sci Appl ; 718(1): 199-204, 1998 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-9832377

RESUMO

A new high-performance liquid chromatographic method for simultaneous determination of primidone (PRM) and of its three major metabolites, phenobarbital (PB), p-hydroxyphenobarbital (p-HO-PB) and phenylethylmalonamide (PEMA), in rat urine, was developed. After acid hydrolysis, these compounds were extracted from urine by means of a Bond Elut Certify LRC column with good clean-up. The extracts were chromatographed on a C18 reversed-phase column using isocratic elution at 40 degrees C, with UV detection at 227 nm. The limit of detection was 0.5 mg/ml for the four compounds. Good linearity (r2>0.99) was observed within the calibration ranges studied: 37.4-299.3 microg/ml for PRM, 26.4-211.2 microg/ml for PB, 12.5-100.2 microg/ml for p-HO-PB and 12.1-97.0 microg/ml for PEMA. Repeatability was in the range 3.1-6.8%. This method constitutes a useful tool for studies on the influence of various parameters on primidone metabolism.


Assuntos
Anticonvulsivantes/urina , Cromatografia Líquida de Alta Pressão/métodos , Primidona/urina , Animais , Anticonvulsivantes/metabolismo , Estudos de Avaliação como Assunto , Fenobarbital/análogos & derivados , Fenobarbital/urina , Feniletilmalonamida/urina , Primidona/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
7.
Drug Metab Dispos ; 26(6): 585-94, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9616196

RESUMO

Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies. Estimated primidone metabolism, as expressed by the maximal velocity Vmax, ranged from 0 to 0.24 mg. min-1.kg-1 for the production of phenobarbital and from 0.003 to 0. 02 mg.min-1.kg-1 for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays. This result was in agreement with a recently finished National Toxicology Program (NTP) carcinogenicity study of primidone in rats and mice.


Assuntos
Anticonvulsivantes/farmacocinética , Fenobarbital/farmacocinética , Feniletilmalonamida/farmacocinética , Primidona/farmacocinética , Animais , Humanos , Camundongos , Modelos Biológicos , Ratos , Especificidade da Espécie
8.
J Pharm Sci ; 83(12): 1751-3, 1994 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7891306

RESUMO

Primidone (PRM) and its active metabolites, phenylethylmalonamide (PEMA) and phenobarbital (PB), in rat plasma were simultaneously determined using a solid-phase extraction technique followed by high-performance liquid chromatography (HPLC). Twenty microliters of plasma was applied to a Bond-Elut C-18 cartridge column with 0.1 microgram of acetanilide (internal standard, IS). After the column was washed, PRM, PEMA, PB, and IS were eluted with methanol and injected into the HPLC system. Calibrations for these substances were linear in the range of 0-20 micrograms/mL. The coefficients of variation were 1.5-7.9% and 3.4-9.1% in the within-day and between-day assays, respectively. The recovery rates were 96.8-101.8%. The pharmacokinetics of these substances were examined after oral administration of PRM (50 mg/kg) to rats. The Tmax values for PRM, PEMA, and PB were 1.4, 5.7, and 6.6 h, respectively, and the Cmax values were 18.2, 8.1, and 9.6 micrograms/mL, respectively. This method is useful for pharmacokinetic studies of PRM and its active metabolites.


Assuntos
Fenobarbital/sangue , Feniletilmalonamida/sangue , Primidona/sangue , Administração Oral , Animais , Calibragem , Fenômenos Químicos , Técnicas de Química Analítica , Físico-Química , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Wistar
9.
J Pharmacobiodyn ; 15(9): 467-72, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1287181

RESUMO

Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4 +/- 2.2 (mean +/- S.E.) to 10.2 +/- 5.1 h (p < 0.05) and the total body clearance was increased from 24.6 +/- 3.1 to 45.1 +/- 5.1 ml/h/kg (p < 0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (> or = 0.1 mumol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 mumol/l; PEMA 1.7 mumol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 mumol/l; PEMA 11.0 mumol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Fenobarbital/farmacocinética , Feniletilmalonamida/farmacocinética , Fenitoína/farmacologia , Primidona/farmacocinética , Adulto , Biotransformação , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade
10.
Br J Clin Pharmacol ; 30(4): 607-11, 1990 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2291873

RESUMO

1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 h and 34.8 +/- 9.0 vs 33.2 +/- 7.2 ml h-1 kg-1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.


Assuntos
Envelhecimento/metabolismo , Primidona/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biotransformação , Cromatografia Líquida de Alta Pressão , Epilepsia/tratamento farmacológico , Feminino , Meia-Vida , Humanos , Masculino , Fenobarbital/sangue , Fenobarbital/urina , Feniletilmalonamida/sangue , Feniletilmalonamida/urina , Primidona/metabolismo , Primidona/uso terapêutico , Tremor/tratamento farmacológico
11.
Ther Drug Monit ; 12(3): 281-3, 1990 May.
Artigo em Inglês | MEDLINE | ID: mdl-2349613

RESUMO

Information is presented for the serum concentrations during haemodialysis of primidone, phenobarbitone, and phenylethylmalonamide (PEMA) in a patient with renal failure receiving chronic primidone therapy. The concentrations of drug and metabolites fell during haemodialysis, but PEMA concentrations were above normal at all times. The average renal clearance of PEMA during 6 h of dialysis was found to be 84.7 +/- 4.6 ml min-1.


Assuntos
Falência Renal Crônica/sangue , Malonatos/farmacocinética , Feniletilmalonamida/farmacocinética , Diálise Renal , Humanos , Masculino , Pessoa de Meia-Idade , Fenobarbital/sangue , Fenobarbital/farmacocinética , Feniletilmalonamida/sangue , Primidona/sangue , Primidona/farmacocinética , Fatores de Tempo
12.
J Neurol ; 235(3): 168-70, 1988 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-3367165

RESUMO

To clarify whether primidone itself, and not only its metabolite phenobarbitone, suppresses essential tremor, the effect of a high single dose of primidone was tested. Of 11 patients, 8 showed a reduction of their tremor by 54%-69% for up to 28 h. The serum concentration of primidone was as expected, whereas those of the metabolites phenyl-ethyl-malonamide and phenobarbitone were very low. The tremor suppression can thus be considered to be an effect of primidone. Three of the 11 patients did not show a reduction of tremor.


Assuntos
Primidona/uso terapêutico , Tremor/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenobarbital/sangue , Feniletilmalonamida/sangue , Primidona/sangue , Primidona/metabolismo
13.
J Chromatogr ; 416(2): 281-91, 1987 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-3611260

RESUMO

A method is described for the analysis of phenylethylmalonamide in human plasma. Analysis of plasma requires only 200 microliter of sample which is extracted with dichloroethane. After filtration and evaporation of the solvent the residue is reconstituted in 50 microliter of chloroform and 5 microliter are injected onto the gas chromatograph. The column used is a mixture of CDMS/WG11 coated on Chromosorb W HP 100-120 mesh. The method is suitable for use in single-dose pharmacokinetic studies.


Assuntos
Malonatos/sangue , Feniletilmalonamida/sangue , Anticonvulsivantes/sangue , Cromatografia Gasosa , Humanos , Indicadores e Reagentes , Primidona/sangue , Controle de Qualidade
14.
Eur J Clin Pharmacol ; 33(4): 431-4, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3443150

RESUMO

The pharmacokinetics of phenylethylmalonamide (PEMA) were studied in 6 elderly men after oral administration of a single 400 mg dose. Peak PEMA serum levels were obtained within 4 h of intake, half-life values ranged from 30.7-57.9 h in these elderly men. The elimination half-life was twice as long when compared to a study previously performed in young volunteers.


Assuntos
Malonatos/farmacocinética , Feniletilmalonamida/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Cromatografia Gasosa , Humanos , Masculino
15.
Br J Hosp Med ; 35(6): 388, 390-2, 1986 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3719206

RESUMO

Essential tremor is a common disorder whose aetiology is unknown. Characteristically it is present on maintaining posture, absent at rest, and not made significantly worse with movement.


Assuntos
Tremor , Diagnóstico Diferencial , Humanos , Doença de Parkinson/diagnóstico , Fenobarbital/uso terapêutico , Feniletilmalonamida/uso terapêutico , Primidona/uso terapêutico , Propranolol/uso terapêutico , Tremor/diagnóstico , Tremor/tratamento farmacológico , Tremor/fisiopatologia
16.
Ther Drug Monit ; 8(2): 161-5, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3088778

RESUMO

Data are presented for the serum levels of 2-ethyl-2-phenylmalonamide (PEMA) in patients receiving anticonvulsant medication. Statistical analysis of these data indicates that the serum level of PEMA, which is a metabolite of primidone, is affected not only by the dose of primidone but also by the serum levels of other prescribed anticonvulsant drugs. In particular, phenobarbitone is shown to be a major perturbation upon the PEMA serum level.


Assuntos
Anticonvulsivantes/farmacologia , Malonatos/sangue , Feniletilmalonamida/sangue , Primidona/metabolismo , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Humanos , Fenobarbital/farmacologia , Fenitoína/farmacologia , Primidona/uso terapêutico , Ácido Valproico/farmacologia
17.
Biochem Pharmacol ; 33(11): 1753-6, 1984 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-6732842

RESUMO

Primidone and phenobarbital (each 85 nmoles/ml were separately perfused through the isolated brain of the rat. After 5 min of perfusion similar amounts of primidone and phenobarbital were taken up into the brain; for both drugs the concentration ratio between brain and perfusion medium was about 0.2. However, after 2 hr of perfusion the mean concentration ratio for primidone was about 0.55; for phenobarbital it was about 0.9 thus indicating a better uptake of phenobarbital. In two regions (hypophysis, mesencephalon) the concentration of phenobarbital was significantly higher than in perfusion medium. During 2 hr of perfusion of primidone, substantial quantities of phenobarbital and PEMA were formed amounting to 1400 pmoles for each metabolite. The highest concentration of the metabolites was found in septum, hypothalamus, hypophysis and mesencephalon. The in situ metabolism of primidone in the intact brain was demonstrated for the first time.


Assuntos
Encéfalo/metabolismo , Primidona/metabolismo , Animais , Técnicas In Vitro , Masculino , Perfusão , Fenobarbital/metabolismo , Feniletilmalonamida/metabolismo , Ratos , Ratos Endogâmicos , Distribuição Tecidual
18.
J Pharmacol Exp Ther ; 228(1): 121-7, 1984 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-6607337

RESUMO

The effects of primidone (1.0 mM), phenobarbital (0.2 mM) and phenylethylmalonamide (PEMA) (1.0 mM) on nerve-stimulated transmitter release (quantal content) were determined for extracellular Ca++ concentrations ([Ca++]0) from 0.4 to 0.8 mM at 1.0 Hz nerve stimulation frequency. At these [Ca++]0, the relationship between the log of quantal content vs. the log of [Ca++]0 is linear. Both primidone and phenobarbital increased quantal content to 171% of controls. These drugs, however, caused parallel shifts of the log-log plot of quantal content vs. [Ca++]0 to the left. Thus, drug effects were not modified by varying [Ca++]0. These drugs were also examined on frequency facilitation. During frequency facilitation, the relationship between the log of quantal content vs. nerve-stimulation frequency (0.5-8.0 Hz) is linear. Both primidone and phenobarbital caused parallel shifts of this plot to the left. These drug effects, therefore, were not modified by nerve stimulation frequency. PEMA did not affect quantal content in either series of experiments. Finally, the sciatic nerve was not stimulated and spontaneous transmitter release was measured. Under these conditions, phenobarbital increased transmitter release in high external K+ (7.5 mM) (1.8 mM Ca++, no Mg++) and in normal K+ (2.5 mM) (1.8 mM Ca++, no Mg++) to the same magnitude (130% of control) in contrast to the reported effects of primidone and PEMA. In conclusion, the effects of primidone, phenobarbital and PEMA were different in the stimulated frog neuromuscular junction.


Assuntos
Malonatos/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Fenobarbital/farmacologia , Feniletilmalonamida/farmacologia , Primidona/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cálcio/fisiologia , Estimulação Elétrica , Técnicas In Vitro , Magnésio/fisiologia , Placa Motora/efeitos dos fármacos , Potássio/fisiologia , Rana pipiens , Sinapses/efeitos dos fármacos
19.
Pharmacology ; 28(6): 329-35, 1984.
Artigo em Inglês | MEDLINE | ID: mdl-6728906

RESUMO

The anticonvulsant effect of primidone was determined in gerbils, in which seizures were elicited by a blast of compressed air, over the time range of 30 min to 18 h after oral administration. ED50s remained fairly constant from 1 to 12 h after administration: 46-73 mumol/kg with the minimal value at 6 h. Of the metabolites, phenobarbital was maximally effective at 2 h after administration (ED50 35 mumol/kg), whereas phenylethylmalondiamide (PEMA) only had a weak anticonvulsant effect (ED50 1.55 mmol/kg at 2 h). By determination of primidone and its active metabolites in plasma and brain at 1, 4 and 12 h after administration of the respective ED50s, it could be shown that unchanged primidone is mostly responsible for the anticonvulsant effect of the first hours, but, at 12 h, only phenobarbital could be detected in both tissues. PEMA could not be detected in brain. From the effective brain concentrations at different times it could be calculated that primidone and phenobarbital have the same anticonvulsant potency on a molar base in the gerbil. The concentrations necessary to control seizures in this model were considerably lower than those needed to suppress convulsions in maximal seizure models in mice and rats.


Assuntos
Primidona/uso terapêutico , Convulsões/tratamento farmacológico , Administração Oral , Animais , Encéfalo/metabolismo , Cromatografia Gasosa , Gerbillinae , Fenobarbital/sangue , Fenobarbital/metabolismo , Fenobarbital/uso terapêutico , Feniletilmalonamida/sangue , Feniletilmalonamida/metabolismo , Primidona/sangue , Primidona/metabolismo
20.
J Toxicol Clin Toxicol ; 20(4): 307-18, 1983 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-6655772

RESUMO

The present paper describes a patient who was in danger of dying from a massive primidone overdose. She was comatose, hypotensive and in acute renal failure with crystalluria. Because of her clinical condition and high plasma primidone level (209 mg/l) haemoperfusion was instituted. Both the calculated drug clearances and the remarkable improvement in the patient's clinical condition suggest that haemoperfusion was very effective.


Assuntos
Coma/induzido quimicamente , Hemoperfusão , Primidona/envenenamento , Idoso , Carvão Vegetal/uso terapêutico , Coma/terapia , Feminino , Meia-Vida , Humanos , Cinética , Fenobarbital/sangue , Feniletilmalonamida/sangue , Primidona/metabolismo
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