摘要:

W studied the pharmacodynamics of warfarin in chronically treated patients. Two methods were used to estimate the pharmacodynamic parameters M/Kdand Cmax(mg/L). In Method 1 the prothrombin time response was modeled directly without use of warfarin concentrations and Method 2 used warfarin concentrations and prothrombin time response to estimate M/Kdand Cmax. The mean Cmaxand M/Kdfor Method 1 (n = 88) were 5.5 ± 2.3 mg/L and 51 ± 46 and for Method 2 (n = 27) 6.3 ± 2.8 mg/L and 35.4 ± 13. When Method 1 was applied to the same 27 patients in Method 2, the mean Cmaxand M/Kdwere 5.7 ± 3.3 mg/L and 36.1 ± 14.9. These differences were not significant. Multiple regression analysis revealed that the value of Cmaxand M/Kdvaried between medical centers. No other patient characteristics were found to be significant. We conclude that modeling steady-state prothrombin time response directly adequately describes pharmacodynamic response to warfarin.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The serum concentrations of amitriptyline (AMI) and its metabolite nortriptyline (NT) were determined in 54 Saudi patients treated for long durations with a daily oral dose (0.111 to 4.167 mg/kg) of AMI. Ten of these patients were concomitantly treated with neuroleptic drugs. The mean (SEM) of the dose-normalized steady-state serum concentration (Css) of AMI in patients who received AMI alone (Group I) was [46.1 (6.5) ng.ml−1/mg.kg−1] with mean NT/AMI Cssratio of 0.962 (0.122). A significantly higher mean of Cssof AMI [82.3 (18.8 ng.ml−1/mg.kg−1] was acquired for patients who concomitantly received AMI and neuroleptic drugs (Group II). However, the difference in the mean NT/AMI Cssratio between Group I and Group II [0.929 (0.197)] was not significant. Also, the results of this study indicate that Cssof AMI and the NT/AMI Cssratio in Saudi patients treated for depression with AMI alone are not significantly different from those reported for subjects from Western populations.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

For assessing the clinical impact of nonlinearity in theophylline elimination, we examined the incidence of individuals with an apparent Michaelis-Menten kinetics (percent change in plasma concentration exceeding that in dose by at least 50%) among asthmatic children (n = 122) and adults (n = 50) screened through a two-step chart review. Forty-nine children and 21 adults had the apparent nonlinearity. When compared overall between the two groups, the maximum elimination rate (Vmax) differed significantly (mean ± SD, 32.2 ± 11.5 versus 21.8 ± 6.7 mg/kg/day, p < 0.001). The Vmaxinversely correlated with age (r= −0.459, p < 0.001). Such a trend as found in Vmaxwas not observed inKm. Our results imply that (a) a disproportionate relationship between dose and concentration of theophylline appears to be relatively common in asthmatic children and adults; (b) the metabolic capacity in children is greater than in adults, if the nonlinearity could occur; and (c) caution is needed with these certain susceptible individuals when using linear kinetics for the dosage modification of theophylline.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

By intrapatient comparison atconstant phenytoin (PUT) dose, the effect of increased carbamazepine (CBZ) dose was studied in 32 epileptic outpatients treated with a combination of PHT and CBZ. The mean PHT plasma concentration, as well as the concentration/dose ratio for PHT, became significantly higher secondary to increased doses of CBZ (14.1 ± 3.5 vs. 19.3 ± 3.6 μg/ml and 2.8 ± 1.0 vs. 3.9 ± 1.4 μg/ml plasma per milligram/kilogram daily dose, respectively; p < 0.001). Concomitantly, in spite of CBZ dose higher by 17.6%, the CBZ concentration increased by only 6.4%, and the CBZ concentration/dose ratio actually decreased by 10%. In contrast, by intrapatient comparison atconstant CBZ dose, the effect of reduced PHT dose on CBZ was studied in 22 patients. The mean CBZ plasma concentration as well as the concentration/dose ratio for CBZ appeared significantly higher, with a concomitant reduction of PHT (6.7 ± 1.6 vs. 8.6 ± 1.6 μg/ml and 0.37 ± 0.1 vs. 0.49 ± 0.2 μg/ml plasma per milligram/kilogram daily dose, respectively; p < 0.001). This simultaneous dual effect—inhibition of PHT metabolism by CBZ and induction of CBZ metabolism by PHT—can result in PHT intoxication along with a fall in CBZ plasma concentration to a subtherapeutic range. This effect may be avoided or reduced if the PHT concentration is adjusted to ∼13 μg/ml before CBZ is added or increased.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

In six patients with epilepsy and fibrocystic breast disease the concentration in serum of antiepileptic drugs was obtained before, during, and after danazol therapy. Carbamazepine serum levels increased almost twofold in the presence of danazol. Thus, interaction between carbamazepine and danazol producing acute carbamazepine toxicity is clinically significant. If these drugs are administered concurrently, an awareness of the potential for this drug-drug interaction along with monitoring of carbamazepine levels is required for optimal patient care.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Differences in product formulations have been shown to affect the therapeutic response by altering the relative bioavailability and pharmacoki-netics of a drug. The relative bioavailability and pharmacokinetics of carbamazepine tablets (CBZ) and a chewable tablet formulation were evaluated in 10 normal healthy subjects (five men and five women). The study utilized a randomized, crossover design with a 4-week washout period between doses. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 14, 24, 30, 36, and 48 h following a 200-mg dose. Plasma samples were assayed by fluorescence polarization immunoassay.Ke,Cmax,Tmax, area under the curve (AUC), and relative bioavailability were estimated using traditional pharmacokinetic methods and compared by paired / test. A statistically significant higherCmax(3.81 ± 81 vs. 4.64 ±.80 mg/L) was observed with the chewable tablet formulation but was not thought to be clinically relevant. No significant differences between formulations forKe(0.022 ± 0.007 vs. 0.025 ± 0.008h−1h),Tmax(7.49 ± 2.69 vs. 6.04 ± 2.7 h), AUC 48 h (119 ± 22 vs. 133 ± 13 mg/h/L), or AUCO-∞(221 ± 40 vs. 203 ± 41 mg/h/L) were noted. Absorption was variable for both preparations. The relative bioavailability using the tablet as the standard formulation was (0.92 ± 0.22). Transient, mild side effects were noted in three subjects with the chewable tablet alone, and one subject experienced side effects with both formulations. It was concluded that CBZ tablets and chewable tablets may be used interchangeably; however, considerable intra- and intersubject variability exists, and the need for patient monitoring is emphasized.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Adverse effects and venous blood ammonia concentrations were monitored over a period of 7 months in patients with epilepsy treated with valproate (VPA). During the 1st, 4th, 12th, 20th, and 28th weeks of therapy, blood samples for analysis of ammonia and anticonvulsants were taken immediately before the morning dose of VPA as well as 2 h after dosing. In all, 40 patients completed the follow-up; 16 of these (Group 1) received VPA alone, while the remaining 24 (Group 2) were treated simultaneously with VPA and other anticonvulsants (phenobarbital, phenytoin, and/or carbamazepine). In Group 1 patients, a slight though significant increase in ammonia concentrations was found during long-term VPA treatment; this trend was even more pronounced in Group 2 patients. The difference between postdose and predose ammonia levels in Group 2 patients was significant at each of the five follow-up examinations. In contrast, no such difference was demonstrated in patients of Group 1. VPA concentrations were found to be consistently higher in Group 2 patients than in Group 1. Twenty-three patients complained of various long-term adverse effects, while the other 17 remained symptom-free. The adverse effects reported included drowsiness, tremors, weight gain, hair loss, and gastrointestinal symptoms. Our data confirm the previously suggested hypothesis that changes in venous blood ammonia are particularly evident in patients taking VPA in combination with other antiepileptic drugs, such as phenobarbital and phenytoin.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13–34% decrease in the area under the serum concentration time curve (AUC) for 0–60 h occurred with the administration of the activated charcoal, and a 19–52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 ± 0.019 ml/min/kg to 0.141 ± 0.029 and 0.146 ± 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea: there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Enzyme immunoassay (EIA) and fluorescence polarization immunoassay (FPIA) methods are commercially available for quantitation of serum amikacin concentration. The purpose of this study was to determine if the two assay methods were comparable and would provide the same estimates for pharmacokinetic parameters and dosage recommendations. A total of 73 amikacin serum samples were used to evaluate the two assay techniques. Forty-four of these samples, obtained from 10 patients, were used to evaluate the comparability of pharmacokinetic parameters and dosage regimens. The correlation coefficient between the two assay methods was 0.98 (y= 1.03x+ 0.64). There were substantial differences in assay performance noted in samples < 10 mg/L, 10–20 mg/L, and > 20 mg/L, typical concentration ranges for serum sampling used in pharmacokinetic analysis. A difference of ∼10% was observed in the determination of amikacin half-life, total body clearance, and dosage calculation. A 7% difference was noted in the volume of distribution. A significant difference (p < 0.05) in volume of distribution and dosage recommendations was noted. Although the two methods for determining amikacin serum concentrations appear to be interchangeable on the basis of the in vitro comparison, significant differences were observed between the two assays in pharmacokinetic parameters and dosage recommendations.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The Bratton-Marshall reagent is one of the real land-marks in the development of drug metabolism and pharmacokinetics, coming at a time when highly sensitive and specific analytical procedures were desperately needed for the measurement of drug concentrations in the body. Examples of its applications are taken from early work in the mid-40's and 50's in the Parke-Davis Research Laboratories, extending from primary aromatic amines (e.g., sulfonamides), to p-nitrophenyl compounds that must first be reduced to amines (e.g., chloramphenicol), and to phenyl derivatives that must be nitrated on a microgram scale and then reduced to aryl amines (e.g., phenytoin). The development and use of separation techniques such as liquid/liquid counter-current partition and paper chromatography is described. Emphasis is placed upon continued, progressive improvement in the basic assay procedures over long periods of time.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID