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Phenytoin metabolism is saturable within its normal therapeutic range and, therefore, small changes in the activity of the enzyme can lead to marked changes in serum phenytoin concentrations. The anticonvulsant drugs sulthiame and pheneturide both inhibit the metabolism of phenytoin. The mechanism of this interaction appears to be different for these two drugs. Nortriptyline produces a small increase in serum phenytoin concentrations, but this is unlikely to be of clinical importance. Case reports suggest that both chlorpromazine and chloramphenicol inhibit phenytoin metabolism to a significant degree.  相似文献   

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76例癫痫患者苯妥英血药浓度监测   总被引:3,自引:0,他引:3  
目的:分析苯妥英治疗癫痫血药浓度与剂量、疗效的关系。方法:以荧光偏振免疫法(FPIA)对171例次癫痫患者进行苯妥英血药浓度监测。结果:有效控制癫痫发作的浓度为(12.9±6.5)μg·ml-1,其中10~20μg·ml-1范围内的占54.72%。剂量0.3g·d-1时,平均血药浓度为(13.6±7.0)μg·ml-1,约60%的病例癫痫得到有效控制,2.4%发生中毒。结论:苯妥英血药浓度监测具有重要的临床意义  相似文献   

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The plasma protein binding of phenytoin was investigated in 100 epileptic patients, using equilibrium dialysis at 37 degrees C. The unbound fractions of phenytoin in plasma formed a skewed distribution, with a range of 9.7 to 24.7% and a median value of 12.3%. Most (80%) patients appeared to form one group with free phenytoin fractions from 9.7 to 14.5%, while the remainder formed a group with elevated free fractions (greater than 14.5%). Total and unbound plasma concentrations of phenytoin were strongly correlated (r=0.95, P less than 0.0001). There was a weak correlation between increasing age and the unbound phenytoin fraction (r=0.28, P less than 0.01). The results indicate that measurement of the total phenytoin concentration in plasma should usually provide a reliable index of anticonvulsant effect. However, determination of the unbound phenytoin fraction would be beneficial in the management of those patients in whom this fraction may be elevated, due to interacting drugs or biochemical abnormalities.  相似文献   

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Summary Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10–14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.  相似文献   

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1 Serum phenytoin concentration, the serum half-life of a tracer dose of carbon-labelled phenytoin, and the ratio of the major metabolite of phenytoin to unchanged drug in urine (p-HPPH: DPH ratio) were measured in epileptic patients on chronic anticonvulsant therapy.

2 A significant correlation was found between serum phenytoin concentration and half-life, the slope of the regression line being dose dependent.

3 A significant negative correlation was found between serum phenytoin concentration and p-HPPH: DPH ratio.

4 Increasing the daily dose of phenytoin lead to a lengthening of the half-life and a reduction in the p-HPPH: DPH ratio. The reverse occurred on lowering the dose.

5 These changes indicate that phenytoin hydroxylation is saturable.

6 Difficulty in achieving a stable serum phenytoin concentration within the therapeutic range may result.

  相似文献   

8.
目的:研究氟桂利嗪对苯妥英钠耐药癫(癎)(drug resistant epilepsy)小鼠癫(癎)发作的逆转作用,初步探讨其作用机制.方法:采用戊四氮制作小鼠癫(癎)模型,灌胃给予苯妥英钠40 mg/(kg·d),共14 d,制作耐药癫(癎)小鼠模型.造模成功的耐药癫(癎)小鼠30只,按随机数字表法分为3组,分别为模型组、维拉帕米组和氟桂利嗪组.在给予苯妥英钠后30 min,分别腹腔注射生理盐水、维拉帕米20mg/(kg·d)和氟桂利嗪8 mg/(kg·d),连续给药4d,在第4天(d 4)观察给药后30 min内小鼠癫(癎)发作的严重程度.然后处死小鼠,取脑.采用蛋白质印迹法(Western blot)检测P-糖蛋白(P-gp)表达情况;用免疫组化法测定半胱氨酸蛋白酶-3(caspase-3)的表达情况.结果:给药d4,氟桂利嗪组小鼠癫(癎)发作严重程度较模型组显著减轻(P<0.01).维拉帕米组和氟桂利嗪组小鼠脑内P-gp的表达量显著减少(P<0.01),且氟桂利嗪的效果优于维拉帕米(P<0.05);维拉帕米组和氟桂利嗪组小鼠皮层和海马半胱氨酸蛋白酶-3表达量也显著减少(P<0.01),氟桂利嗪的作用优于维拉帕米(P<0.05).结论:氟桂利嗪能够有效降低苯妥英钠耐药小鼠的癫(癎)发作严重程度,其主要机制可能与降低小鼠脑组织P-gp的表达有关,同时氟桂利嗪也能降低耐药小鼠脑内半胱氨酸蛋白酶-3的表达,对脑组织可能有保护作用.  相似文献   

9.
This study was performed to determine the effect of omeprazole, given in therapeutically recommended doses, on the steady-state plasma levels of phenytoin in epileptic patients. Five men and three women of median age 34 years participated in the study. Steady-state plasma levels of phenytoin were measured once a week for 2 weeks before and after, respectively, and during 3 weeks of concomitant omeprazole treatment with 20 mg daily. Urinary excretion of phenytoin and its metabolite [5-(p-hydroxyphenyl)-5-phenyl-hydantoin] were determined before and at the end of the omeprazole treatment period. The steady-state plasma phenytoin levels as well as urinary excretion of phenytoin and its main metabolite were unchanged during omeprazole treatment. The results from this study suggest that concomitant omeprazole treatment in therapeutically recommended doses (20 mg daily) will not significantly affect the steady-state plasma levels of phenytoin in epileptic patients.  相似文献   

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The effects of thyrotropin-releasing hormone (TRH) were investigated on absence-like seizures, which are characterized by the sudden appearance of 5-7 Hz spike-wave-like complexes in the cortical and hippocampal EEG, and on tonic convulsions of spontaneously epileptic rats (SER; zi/zi, tm/tm), a double mutant obtained by mating zitter homozygote (zi/zi) with tremor heterozygote rats (tm/+). TRH (5 and 10 mg/kg i.v.) inhibited the appearance of both absence-like seizures and tonic convulsions of SER without inducing obvious changes in the background EEG. The inhibitory effects were seen 5-20 min after injection of 10 mg/kg TRH and were antagonized by pretreatment with haloperidol (0.5 and 1.0/kg i.p.), although haloperidol alone did not affect the seizures. These results suggest that TRH has an antiepileptic effect in the genetically defined animal model, SER, and that the effect is mediated by the central dopaminergic system.  相似文献   

12.
Summary This cross-over study was conducted to compare serum phenytoin levels after chronic ingestion of phenytoin tablets with or without previous chewing. The phenytoin therapy was administered as 50 mg chewable Infatabs® tablets in a single morning dose of 200 mg. There was no significant difference between the two modes of ingestion as regards serum phenytoin levels measured at various times after ingestion of the phenytoin tablets. Moreover, the area under the curve did not differ significantly during the 24 h interval. Minor changes between two Dilantin® formulations, however, could influence drug availability.  相似文献   

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Nafimidone and other 1-imidazoles were shown to be potent inhibitors of phenytoin p-hydroxylation in rat hepatic microsomes, being very effective even at submicromolar concentrations. The inhibitory potency of these 1-imidazoles was similar to that of SKF 525-A and considerably greater than that observed for other imidazoles (4,5-diphenylimidazole, cimetidine, metronidazole), metyrapone, or other anticonvulsants. The effects of structural modification on the inhibitory activity were examined. Except at the 2-position on the imidazole, alkyl substitution increased the inhibitory potency, probably because of increased lipophilicity. Substitution at the 2-position caused marked diminution in inhibitory activity, possibly due to steric hindrance. The hydroxy analogs of nafimidone exhibited greater inhibitory activity than the corresponding keto compounds. Furthermore, pretreatment of the rats with nafimidone resulted in greater Vmax values for both low affinity and high affinity metabolic sites.  相似文献   

15.
Sixty-two serum samples from 28 pediatric epileptic patients under treatment with phenytoin [diphenylhydantoin (DPH)] were obtained to study the correlation between total and free serum DPH concentrations. The effect of coadministered antiepileptic drugs on DPH protein binding was also studied. Binding of DPH to serum protein was assessed by ultrafiltration, and total and free DPH concentrations were determined by fluorescence polarization immunoassay. A strong correlation existed between the total and free concentrations [r = 0.958, p less than 0.001, standard error of estimate (+/- 1 SY) = 0.214]. The mean value for the DPH free fraction was 8.9% (range 5.7-16.3%). The samples obtained from patients on combination therapy with valproic acid (VPA) showed a larger DPH free fraction and greater variation. Exclusion of the 16 samples from patients concomitantly taking DPH and VPA yielded a better correlation (n = 46, r = 0.983, p less than 0.001, +/- 1 SY = 0.145). The mean free fraction in the patients not taking VPA was 7.7% (range 5.7-9.0%). The effect of VPA on the protein binding of DPH was also studied by addition of the same antiepileptic drugs to normal human plasma; the results were similar to those obtained for epileptic patients. These findings suggest that the free DPH fraction can be predicted from the total concentration, even when the drug is coadministered with other antiepileptic drugs, the sole exception being VPA.  相似文献   

16.
The effect of valproic acid (VPA) on the disposition of carbamazepine-10,11-epoxide (epoxide) was studied in five epileptic patients on chronic carbamazepine (CBZ) therapy. The individual pharmacokinetic parameters influencing epoxide disposition were determined in the presence and absence of VPA. VPA significantly decreased the clearance of unbound epoxide (an in vivo index of epoxide hydrolase activity), but did not appear to affect epoxide formation. VPA also increased the free concentrations of both CBZ and epoxide.  相似文献   

17.
1. The bioavailability of a brand of phenytoin tablets used in Finland was improved in 1976. In the present retrospective study serum concentrations of phenytoin, measured before and after the change of bioavailability, are compared in 50 epileptic out-patients, who for various reasons used exactly the same dose of phenytoin tablets and of other drugs despite the increased bioavailability of phenytoin. 2. The mean increase of serum phenytoin steady-state concentration was about 70% after the change of bioavailability but there were considerable interindividual differences in the response. The mean increase in serum phenytoin was only 28% in patients with serum phenytoin concentrations 5 microgram/ml or less but the mean increase was 100% in patients with serum phenytoin between 5 and 10 microgram/ml. In patients with serum phenytoin concentrations more than 10 microgram/ml the mean increase in concentration was 60-80% after the improvement of bioavailability. However, in these groups of patients some clinically manifested phenytoin intoxications enforced the patients to the control and to dose reduction obviously before the steady-state concentration of phenytoin was reached. 3. On the basis of our experiences and those reported in the literature some proposals are presented to be considered when the bioavailability of phenytoin or of another drug with a narrow therapeutic range and a dose-dependent kinetics has to be changed.  相似文献   

18.
An evaluation of serum protein and immunoglobulins with regard to valproic acid (VPA) and phenytoin (phen) serum levels was performed in 28 epileptic patients. Serum antiepileptic levels were measured in fasting conditions. All patients were classified into the following groups: A (VPA below 50 micrograms/ml), B (VPA 50-89 micrograms/ml), C (VPA above 89 micrograms/ml), D (VPA 50-89 micrograms/ml and phen below 10 micrograms/ml). Patients of group C showed higher serum protein values than groups A (P less than 0.02), B and D (P less than 0.001). The alpha 2 and beta-globulin fractions were higher in group C than the remaining groups (P less than 0.05). Immunoglobulin A, G and M remained unaltered in all patients.  相似文献   

19.
The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.  相似文献   

20.
OBJECTIVE: The antiepileptic drugs phenobarbital, phenytoin and carbamazepine are widely used for the treatment of partial and tonic-clonic seizures. Large inter-individual differences in pharmacokinetics of these drugs, and the intermittent nature of epileptic attacks, increase the need for therapeutic drug level monitoring of these drugs. MATERIAL AND METHODS: In this study, data from the therapeutic drug monitoring of phenobarbital, carbamazepine and phenytoin in 328 epileptic patients were evaluated. Serum levels of drugs were determined in a University Department of Pharmacology by high-performance liquid chromatography. RESULTS: In this study, approximately 56% of patients were treated with 1; 30% with 2; and 14% with 3 antiepileptic drugs. In patients receiving 1 antiepileptic drug, the percentages treated with phenobarbital, carbamazepine and phenytoin were 41, 38 and 21%, respectively. In patients who received carbamazepine, serum levels in 40% of the patients were in the range of 4-8 microg/ml and more than in the range 4-12 microg/ml in 74% of the patients. In phenobarbital-treated patients, serum levels in 73% of the patients were in therapeutic range of 10-40 microg/ml, and about 44% of phenytoin-treated patients had serum levels in therapeutic range of 10-20 microg/ml. Approximately 50% of carbamazepine- and phenytoin-treated patients and approximately 70% of phenobarbital-treated patients were completely controlled. The frequency of concentrations within the therapeutic ranges decreased in patients using more than 1 antiepileptic drug. In patients who received both phenobarbital and sodium valproate, serum levels of phenobarbital were significantly (p < 0.05) greater than in patients who were taking this drug in combination with carbamazepine or phenytoin. CONCLUSION: Our results indicate that serum levels of antiepileptic drugs, and the percentage of patients with complete seizure control are comparable with results obtained in other populations in previous studies.  相似文献   

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