ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

In spite of the fact that therapeutic and toxic ranges of phenytoin are well defined, it is still often difficult to calculate an optimal dosage regimen because of the nonlinear saturable kinetics of the drug. Predictions are much more complicated when impaired bioavailability exists. We estimated individual Michaelis-Menten pharmacokinetic parameters from two reliable steady-state serum concentrations of phenytoin following two different drug dosages in 13 epileptic children treated with a preparation that has been shown to be poorly absorbed. Their calculated average V. (the maximal rate of elimination) was significantly higher than the average for their age (12.21 and 9.28 mg/kg/day, respectively) (p < 0.05). The impaired bioavailability did not affect the values ofKm.In the six children who needed a third adjustment of dosage, the observed steady-state serum levels of phenytoin with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with the predicted levels (r = 0.97, p < 0.01). Our data suggest that Michaelis-Menten kinetics can be used to predict phenytoin levels even when impaired bioavailability exists, providing that the fraction of absorption is constant.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Elevations of serum β-glucuronidase (GRS) enzyme activity can occur under a variety of pathological conditions. Using phenolphthalein glucuronic acid as the substrate, 158 epileptic patients were randomly screened for GRS. GRS was distinctly elevated (65.9 ± 30.0 phenolphthalein/ml serum) in patients, compared with the normal group (27.0 ± 10.0). No difference in GRS levels were found when seizure-free (>1 year) patients (n = 61; GRS, 62.6 ± 32.7 μg) were compared with patients who had seizure episodes within 1 week (n = 26; GRS, 73.2 ± 24.9 μg), and there were no differences when intermediate groups were examined. GRS elevations were found to be linearly and directly correlated with free phenytoin ultrafiltrate levels (n = 35, r = 0.7692, p < 0.0001) when patients were co-medicated with valproic acid, with serum phenobarbital levels (n = 58, r = 0.5361, p < 0.05), with serum valproic acid levels (n = 43, r = 0.3173, p < 0.05), and with the sum of serum phenobarbital and valproic acid levels (n = 16, r = 0.8657, p < 0.0001). The findings indicate that GRS elevations are probably due to anticonvulsant medications rather than to the frequency of seizures. There is no evidence that GRS determinations can be used for the diagnosis or prognosis of patients with epilepsy.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Five adult epileptic patients received 1,000 mg of valproic acid (Depakene™) in both the regular and the enteric-coated form. Serum valproic acid levels were determined at suitable intervals after drug administration. Pharmacokinetic parameters were equivalent for both preparations except for an absorption lag with the enteric-coated form. The relative bioavailability of the two compounds was similar across the group of patients, although there were marked differences between individual subjects. Close supervision of valproic acid serum levels is suggested after a change in drug formulation.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

The mechanism underlying the impaired serum protein binding of valproic acid (VPA) in pregnancy was examined in samples collected from 24 healthy women in the last 3 weeks of gestation and 15 age-matched nonpregnant female controls. Experiments were performedin vitrousing a rapid equilibrium dialysis technique free fromin vitroalterations in free fatty acids (FFA). At a total drug concentration of approximately 420 μmol/L, the free VPA fraction was 10.2 ± 2.9% (SD) in pregnant women and 4.8 ± 1.0% in controls (p < 0.001). Pregnancy was associated with a marked reduction in serum albumin levels but with only a slight, nonsignificant elevation in FFA. Free VPA fraction was negatively correlated with serum albumin levels. A positive correlation between free VPA fraction and FFA was observed in the pregnant group but not in the controls. The only sample collected during labour showed a striking elevation of both free VPA fraction and FFA, in spite of a normal albumin concentration. Scatchard's plots showed VPA bound to two classes of binding sites on the albumin molecule. The number of primary (ni) and secondary (n2) binding sites in pregnant women (n1=2.0; n2= 10.7) was virtually identical to that observed in the controls (n1= 1.9;n2= 9.8). The association constants of the primary (k1) and secondary (k2) sites were lower in pregnant women (15.9 × 103and 0.19 × 103L/mol, respectively, vs. 22.6 × 103and 0.33 × 103L/mol in controls) but the difference was not significant. These results suggest that, contrary to findings in animal studies, the defective binding of acidic drugs in sera of pregnant women is largely (although probably not entirely) due to a reduction in albumin concentration. The same may not be true in the perinatal period when marked elevation in maternal FFA can result in drug displacement from binding sites on the albumin molecule.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

The binding of valproic acid (VPA) to human serum albumin (HSA) and to pooled human plasma has been investigated by using equilibrium dialysis with three different dialysis solutions: phosphate buffer (solution I), Krebs solution (solution II), and Krebs solution without calcium (solution III). The effect of pH variation from 6.4 to 8.2 has been also investigated. VPA free fraction increased by increasing pH with all the dialysis solutions (from 4.1% at pH 6.4 to 9.4% at pH 8.2 with solution I, from 8.1% to 11.3% with solution II, and from 10.6% to 14.3% with solution III, in plasma). At each pH value, free fraction obtained with solution III was the highest and that obtained with solution I was the lowest. Data in plasma and HSA solution were similar. In a separate experiment we compared (at pH 7.4, with plasma) the three more frequently used dialysis solutions: phosphate buffer, phosphate buffer with NaCl, and Krebs solution. They gave, respectively, a mean VPA free fraction of 7.8, 10.3, and 12.7%. These findings can explain the wide range of VPA free fraction values reported in the literature. Researchers intending to deter-mine VPA free concentration by equilibrium dialysis should take into account these methodological aspects.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

It has previously been shown that saliva phenytoin concentration bears a constant relationship to plasma free concentration whether protein binding of phenytoin is normal or disturbed by other drugs, pregnancy, renal failure, or hypoalbuminaemia. The present work examines the relationship between saliva (S), plasma free (F), and plasma total (P) concentrations of other anticonvulsants in 100 epileptic patients. Mean S/P ratios were for phenobarbitone 0.37 (r = 0.95), primidone 0.95 (r = 0.87), and carbamazepine 0.27 (r = 0.94). A highly significant correlation of S with F was found for these drugs, more significant than the correlation of S with P for carbamazepine in patients receiving multiple anticonvulsant drugs. Saliva valproate, however, had no predictive value for P or F. No binding to saliva proteins was demonstrated for any drug. Data forin vitrobinding to plasma proteins was in good agreement withex vivodata. Saliva is therefore a valid medium for monitoring treatment with phenobarbitone, primidone, and carbamazepine, as well as phenytoin.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

Saliva and serum quinidine concentrations were determined in six cardiac patients after twice-daily dosing with 324 or 648 mg quinidine gluconate and the relationship of these concentrations to the degree of suppression of ventricular premature beats (VPB) was evaluated. Mixed saliva and corresponding serum samples were obtained at various times after the 1st, 9th, and 19th doses. With serum quinidine concentrations ranging from 0.05 to 0.83 μg/ ml after the first dose, the average saliva/serum ratios for quinidine varied between 0.25 and 1.35 (0.54 ± 0.43). At steady state with the serum quinidine concentrations ranging between 0.36 and 3.35 i.g/ml, the average saliva/serum ratios ranged from 0.27 to 1.79 (0.81 ± 0.72) and from 0.19 to 1.84 (0.90 ± 0.85) for the 9th and 19th doses, respectively. The interpatient variations in the saliva/serum ratio were large for the three doses (approximately 90%). On the other hand, the intrapatient variations were smaller and diminished with each succeeding sampled dose (from 31 to 18 to 12% for the 1st, 9th, and 19th doses, respectively). Moreover, the value for the quinidine saliva/serum ratio for a given patient was similar for all three doses. No significant correlation between the extent of VPB suppression and the concentrations of quinidine in the saliva or serum was observed. The data suggest that salivary quinidine concentrations may be clinically useful to monitor serum drug concentrations in a given patient. However, the relationship between saliva and serum quinidine concentrations and suppression of VPB measured by Holter monitoring is not clear-cut.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID

摘要:

An adaptation of a previously published program for nonlinear regression analysis of serum drug concentrations which can utilize data obtained during multiple-dose administration is described. Specific programs have been developed for aminoglycosides, digoxin, and theophylline. The pro-grams provide initial parameter estimates (for a one-compartment linear model) for each drug based on mean population parameters and refined estimates based on observed concentration data. Clinical examples which demonstrate the flexibility of these programs are provided. The programs may also be employed for fitting data for any drug that can be adequately described by a one-compartment linear model.

ISSN:0163-4356    

出版商:OVID    

年代:1984

数据来源: OVID