摘要:

An index of desipramine (DMI) hydroxylation, calculated as the ratio between the amounts of DMI and 2-hydroxydesipramine (2-OH-DMI) excreted in urine after 25 mg orally, was determined in 16 depressed patients. The index varied almost 100-fold between the patients and correlated significantly to the steady-state plasma concentrations of DMI (rs= 0.85; p < 0.01) but not to the plasma levels of imipramine (IMI) when the patients were treated with 75 mg of IMI daily. Eleven of the 16 patients were subsequently treated with DMI and a significant relationship was again found between the plasma levels of DMI and the urinary DMI-hydroxylation index (rs= 0.87; p < 0.01). The latter may be utilized in therapeutic drug monitoring to identify individuals with unusually rapid or slow hydroxylation of DMI.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Guidelines for measuring free drug concentrations in serum have become necessary due to the easy availability of these assays as a result of the introduction of commercial kits. The present study was performed to identify patients or groups of patients in whom the serum free phenytoin fraction varied from normal, such that they might benefit from measurement of serum free phenytoin. Three hundred fourteen samples submitted for routine phenytoin analysis were studied by enzyme-modified immunoassay technique (EMIT). Thirty-eight patients on phenytoin monotherapy and without other factors thought to affect protein binding of this drug had a mean (PT SD) free phenytoin fraction of 9.8 ± 1.8% of total concentration (mean serum albumin concentration 43.4 ± 3.9 g/L). The free fraction was elevated by administration of comedications which are themselves highly protein bound, and in those patients who were hypoalbuminaemic (serum albumin < 30 g/L). The groups studied were not mutually exclusive, but stepwise regression analysis showed that other factors known to affect serum albumin (e.g., age > 65 years, liver or renal disease, or pregnancy) did not, in themselves, produce a significant effect on free phenytoin fraction. Similarly, an elevated total serum phenytoin concentration was not a significant factor in producing an elevation in free phenytoin fraction. In most situations, total serum phenytoin measurement is adequate pharmacologically, but monitoring of free phenytoin levels may be useful in those patients with a low serum albumin and in those who take comedications that are themselves highly protein bound (e.g., sodium valproate, aspirin, or diazepam).

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The serum kinetics of an intravenous bolus of a combination of ticarcillin (TIC) (3 g) and clavulanic acid (CLAV) (0.2 g) have been determined in a number of patients with different degrees of renal failure as characterized by creatinine clearance. The volume of distribution for both drags was unaffected by renal failure. Indices of serum and renal drug clearance were related to the degree of renal failure. TIC was cleared more slowly than CLAV. Anephric patients may have a higher serum clearance of CLAV than patients categorized by creatinine clearance as having severe renal failure; this could be due to an increase in metabolic clearance. Haemodialysis effectively clears both drugs. “Rebound” serum concentrations were consistently observed for TIC, but were observed in only one patient for CLAV. Continuous ambulatory peritoneal dialysis results in significant recovery of both drugs. The dosing requirements for the combination of TIC and CLAV in patients with renal failure are considered.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

In patients with normal renal function, defined peak (5–10 mg/L) and trough levels (

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Our study was designed to determine the population pharmacokinetic parameters of amikacin in intensive care unit patients and to develop a Bayesian method allowing individual estimation of pharrmacokinetic parameters. A two-stage method was used for estimating the population characteristics of the pharmacokinetic parameters. Calculations of optimum doses and dosing intervals were based on individual parameters. Our results indicate that the Bayesian method is capable of estimating the individual pharmacokinetic parameters with no significant bias and good precision. Individualization of amikacin dosage was assessed 70 times in 51 patients. To determine the predictive performance of the method, observed peak and trough levels were compared with predicted values by computing precision, bias, and correlation. The amikacin dosing method was unbiased and showed a high correlation coefficient (r = 0.962) between measured and predicted drug serum concentrations. No significant differences were found between the predicted and observed peak (17.3 PT 3.5 and 17.3 PT 3.8 mg/ml, respectively) and trough (2.86 PT 0.93 and 3.08 PT 1.41 mg/ml, respectively) amikacin serum concentrations. Among the 52 patients, wide variations were observed in the pharmacokinetic parameters (Vd= 0.21–0.50 L/kg; tv2= 1.1–22 h) and the daily doses (2.8–42 mg/kg/day).

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The effect of trimethuprim (TMP) on serum creatinine concentration (SCr) was studied in 10 healthy (H) subjects and nine subjects with chronic renal failure (CRF). Each volunteer was given TMP 100 mg perorally every 12 h for 10 days followed by a 7-day washout period. SCr was measured colorimetrically immediately before the study (baseline), on day 10 of TMP, and 7 days after TMP had been discontinued. SCr increased an average of 14.8% from baseline during TMP administration in the H volunteers, but this increase was not statistically significant. During TMP administration to the CRF volunteers, a pronounced elevation (34.6%) of mean SCr from baseline was observed (p < 0.05). SCr returned to baseline values in both groups following the 7-day washout period. These results are consistent with the hypothesis that TMP competitively inhibits the renal tubular secretion of creatinine.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

This study evaluated a nomogram designed to identify a subgroup of the patients whose serum phenytoin concentrations are near steady state at a given time after initiation of therapy. A sample of 95 adult subjects with reported values ofVmaxandKmwas pooled from the literature, and computer simulations of phenytoin accumulation for 15 days after initiation of phenytoin acid at 300 mg/day were performed. Simulated serum concentrations on days 5, 10, and 15 were used to identify subjects who were predicted by the nomogram to be at >83% of steady state, and these results were compared with those expected from the Michaelis-Menten model. In the simulations, 42, 62, and 66 subjects reached >83% of steady state by days 5, 10, and 15, respectively. The nomogram correctly identified 13 (31.0%), 33 (53.2%), and 43 (65.2%) of these individuals, respectively. The frequence of erroneous predictions was low, even in subjects whoseKmand volume of distribution were outside the limits set in the development of the nomogram. Use of a nomogram such as this would help a subgroup of patients to attain a desired serum phenytoin concentration earlier in therapy and with, fewer seram phenytoin determinations than would otherwise be required. It would also prevent premature increases in phenytoin dose in patients whose serum concentration is still rising.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Steady-state serum phenytoin concentration (C35) is known to increase nonlinearly with dose, but it is less well recognized that the rate of phenytoin accumulation is also dose dependent. This simulation study estimated the extent and rate of phenytoin accumulation in a sample of 95 adult subjects, with known values ofVmaxandKm, pooled from the literature. Simulations were done using a Michaelis-Menten model and phenytoin sodium doses of 200, 300, and 400 mg/day. The distributions of C35and the time required to reach 90% of steady state (T90) became increasingly positively skewed as dose was increased. TheT90and C35were positively correlated (r> 0.8880, p > 0.00001) and subjects reached 90% or more of C35more slowly as the initial phenytoin dose was increased. At an initial dose of 300 mg/day of phenytoin sodium, mean C35was 11.0 PT 9.10 mg/ml (median, 7.62 mg/ml), and meanT90was 12.2 PT 15.4 days (median, 5.98 days). Only 25.3% of the subjects would be expected to achieve therapeutic serum concentrations (10–20 mg/ml) on this dose, and 88.4% would reach 0.9 C35within 30 days. Phenytoin dosage must be individualized to achieve concentrations of 10–20 mg/ml. Multiple serum phenytom determinations during the first 30 days or more are required to determine that steady state has been reached, but these need not be done more often than once a week.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

In an 11-year-old child with juvenile rheumatoid arthritis (JRA), the addition of prednisone caused a significant decrease in salicylate serum con-centrations. A pharmacokinetic assessment suggested that these changes were not the result of altered compliance or impaired absorption of salicylate but rather an increase in salicylate clearance induced by the corticosieroid.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

This paper deals with our experiences in drug metabolism in the Parke-Davis Research Laboratories at a time when good analytical procedures were just starting to make their appearance and pharmacokinetics was an undiscovered territory. Some of our groping efforts to understand the factors influencing absorption are described. These included formulation differences in generic products and their effect upon absorption. Compounds such as paminosalicylic acid, chloramphenicol, phenytoin and acedapsone are used as examples. Our intent is to show how our knowledge of drag metabolism developed during this period, and to describe some areas that still need additional investigation.

ISSN:0163-4356    

出版商:OVID    

年代:1987

数据来源: OVID