摘要:

Rational drug therapy requires knowledge about the ratio of risk (adverse drug reaction) to benefit (therapeutic efficacy) for all drugs to be used in humans. However, with newly marketed drugs, the risk/benefit ratio is usually not sufficiently known. Safety is often less well defined than efficacy. This is the result of the present mode of drug development. Premarketing studies are conducted in comparatively small, homogenous populations over relatively short time intervals and under standardized conditions. Only after marketing are larger, more diversified populations exposed over prolonged times, often under uncontrolled conditions. Adverse drug reactions (ADRs) are the result of either overdosage, or allergic or idiosyncratic reactions. They can be life-threatening or mild. Some of the ADRs are common (>1:10): others are very rare (< 1:1000). The overall rate of ADR occurrence in ambulatory and hospitalized patients is high enough to have significant socioeconomic consequences. Some of the risk populations can be suspected a priori: elderly, multimorbid patients and patients with compromised drug elimination who may be overdosed if the regimens are not appropriately modified. Some problem drugs may be recognized if they display one or more of the following characteristics: narrow therapeutic index, steep dose-effect relationship nonlinear kinetics, variable bioavailability, and pharmacogenetically determined kinetics. Other individuals at risk, however, may not be readily identifiable. They develop allergic and idiosyncratic reactions after drug exposure without exhibiting easily recognizable predisposing factors. In order to determine the number of individuals so affected, and the associated drugs as quickly as possible during the developmental process, specific ADR surveillance measures are taken. These include spontaneous reporting by physicians, setting up of registries, performance of specific cohort and case control studies, and implementation of surveillance programs. There is clearly a need for improvement and innovation in order to reduce risks associated with present drug use. Appropriate measures and strategies include the reduction of drug intake by a drug-consuming society; avoidance of polypharmacy by physicians: performance of specific safety, efficacy, and kinetic studies in identifiable risk populations during Phase 3; increased efficiency of the surveillance activities in Phase 4; and intensified research identifying host factors in individuals who react with allergic and idiosyncratic manifestations after exposure to certain drugs.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Single oral doses of 40 mg of the nonsteroidal antiinflammatory drug, tenoxicam, were given to four patients (three with rheumatoid arthritis, one with osteoarthritis). The concentrations of the drug in synovial fluid and plasma were measured by a specific high-performance liquid chromatography method. The unbound fractions of the drug in both fluids were determined at pH 7.4 and 37dGC by equilibrium dialysis. The possible influence of the pH on the protein binding was also assessed. The total concentration time curves in plasma and synovial fluid were fitted to linear oral 1 and 2 compartment body models with an additional synovial fluid compartment connected to the central compartment. The unbound fractions of drug in synovial fluid and plasma were on average 0.015 and 0.011, respectively: not significantly different from each other. The protein binding of tenoxicam was pH dependent with increased free fractions at pH values <7.4. The average peak concentrations of tenoxicam in plasma and synovial fluid were 4.3 and 1.4 mUg/ml, respectively. The mean ratio of the areas under the total concentration time curves in synovial fluid and plasma was 0.42, which corresponded to the steady state of equilibrium ratio of the total drug concentrations in the two body fluids. Two hypotheses were tested: hypothesis I assuming that equilibration across the synovial tissue takes place between the unbound, unionized tenoxicam molecules; hypothesis II assuming that equilibration across the synovial tissue is established between the unbound (unionized + ionized) tenoxicam molecules. Based on the available evidence hypothesis II was rejected.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Impaired binding of anionic drugs to serum albumin in patients with uremia is thought to be due to the accumulation of endogenous substances that bind to albumin. In this study the displacement by the anionic drugs diazepam. warfarin, and salicylic acid, which are known to be representative drugs for the binding sites on the albumin molecule, of several endogenous ligands that bind to albumin in uremic serum was examined. The free fractions of the ligands bound to albumin were separated by ultrafiltration in the presence and the absence of test drugs and assayed by high-performance liquid chromatography. Diazepam displaced indoxyl sulfate (IS), hippuric acid (HA), and indole-3-acetic acid (IAA), and warfarin displaced IS. HA. IAA. and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid from serum albumin. However, salicylic acid did not displace the substance examined. The methods reported here are useful for determining the binding sites of the endogenous ligands on albumin and to clarify the drug-ligand interaction on albumin molecule in uremic serum.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

One tablet containing 755 mg of lithium tryptophanate (10.8 mEq of lithium) was administered to eight healthy volunteers. The main pharmacokinetic parameters for the group of subjects were estimated. Pharmacokinetic parameters (mean \pm SD) from plasma and saliva were respectively: half life (t1/2) 17 \pm 6 vs. 21.8 \pm 14 h; mean residence time 23.7 \pm 7.4 vs. 24.4 \pm 15.3 h; total clearance 30.6 \pm 9.3 vs. 28.6 \pm 6.2 ml/h/kg; and apparent volume of distribution 0.71 \pm 0.20 vs. 0.84 \pm 0.37 L/kg. Although the mean pharmacokinetic parameters in plasma and saliva were similar, there was no significant correlation between the calculated parameters in the individual subject (p > 0.05). The usefulness of monitoring salivary levels of lithium is questionable.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

This study compared the accuracy of the one-point method (OPM) of Cooper et al., the repeated one-point method (ROPM) using a 12 h initial dosage interval (ROPM-12), and the ROPM using a 24 h initial dosage interval (ROPM-24) for predicting lithium steady-state concentrations after lithium carbonate 600 mg every 12 h. Pharmacokinetic values for elimination rate constant (k), volume of distribution (V), and absorption rate constant (ka) were generated randomly for 950 subjects to produce normally distributed values of the parameters with target means and standard deviations in accordance with values reported in the literature. Errors with a mean of zero and a standard deviation of ±5% (SD5%) and ±10% (SD10%) were added to the calculated lithium concentrations used in the prediction methods to simulate assay and timing errors. The mean (±SD) values generated fork, ka‘andVwere 0.035 ± 0.008 (h-1), 0.897 ± 0.059 (h-1), and 40.97 ± 5.27 (L), respectively. Prediction errors were smallest with the OPM (SD5%, SD10%) and ROPM-24 (SD5%). There was a significant correlation betweenkand the prediction error for the OPM (SD5%, SD10%) and the ROPM-24 (SD5%). The OPM was the most accurate of the methods studied; however, it tended to underpredict actual concentrations in subjects with long half-lives.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

A population base of 6,367 in-patients from 28 general hospital wards was included in a nation-wide project aimed at documenting the extension and criteria of therapeutic drug monitoring (TDM). On randomly selected index days over a 3-month period details of age. clinical status, renal and liver function, diseases, drug therapies, and drug monitoring of all in-patients of eight different clinical specialties were recorded and analyzed. A total of 648 requests for 387 patients (16.3% of the population given drugs for which TDM was available in the hospital) was traced. Digoxin was the most frequently monitored drug (481 requests for 289 patients), accounting for 74% of the overall requests. This finding is consistent with the yearly activity of the laboratories of the same hospitals, which documented that 63% of the whole in-hospital analytical work (29.396 out of 46.692 requests) concerned digoxin. From a more qualitative point of view, data are provided that document a largely inappropriate use of TDM. which was employed only for 20% of patients who might have benefited from it.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Dosage prediction methods for optimization of aminoglycoside therapy were evaluated in 19 critically ill patients. Two different three-point methods and a novel Bayesian method were used. The predictive accuracy and precision of all tested methods were clinically satisfactory. The time needed for the necessary calculations was 10–15 min. After administration of predicted dosages. 90% of the observed peak and trough aminoglycoside serum concentrations fell within the therapeutic range. Without systematic use of these prediction methods, only 40% of tobramycin peak serum concentrations and 80% of trough serum concentrations were within the therapeutic range. Daily dosage adjustments particularly in patients with rapid changes of aminoglycoside clearance are greatly facilitated by use of these prediction methods. These findings suggest that all of the dosage prediction methods tested are well suited for optimization of aminoglycoside dosage regimens.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

A prospective study was carried out in 50 adult patients to determine the extent and quality of aminoglycoside serum concentration monitoring and dosage adjustment in a U.K. teaching hospital. Data were collected concerning prescription details, assay results, and subsequent dosage adjustment, methods of dosage determination, and timing of samples. Thirty-three patients received aminoglycosides without a positive culture. The mean ± SD initial doses were 1.75 ± 0.45 mg/kg for gentamicin and 2.33 ± 0.55 mg/kg for netil-micin. Doses were derived from physicians' personal experience for 35 patients and using nomograms for 11 patients. Prescribed and actual administration times were observed on 218 occasions. The difference between these times were significantly different (p < 0.005). Fifty-six trough, 61 peak, and 61 random assays were carried out, of which 48% of troughs and 56% of peaks were in the therapeutic range. Dosage regimens were calculated based on actual serum concentration assay results using the Sawchuk-Zaske method. These calculated doses were compared to actual prescribed doses for each patient. The calculated doses were > 120% of the prescribed doses in 78% of patients. There was a significant tendency to underdose (p = 0.001). It is concluded that the service might benefit from an individualised approach to dosage determination.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The calculations of pharmacokinetic parameters for each dosing at unequal doses and dosing intervals were proposed. Systemic clearance of a drug following one-compartment open model can be determined by the product of the apparent first-order elimination rate constant and the apparent volume of distribution. The determination of maximum plasma concentration (Cmax) and the time required for theCmaxat each dosing were also presented here. These theoretical considerations are applicable to multicompartment open model.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Pharmacokinetic parameters for theophylline were determined in 33 patients (3 women), mean age 61.2 years and weight 74.6 kg using the following three methods: (a) standard one-compartmental model calculations, assuming 100% bioavailability. after a single dose of theophylline syrup (mean dose 413 mg): (b) drug nomogram; and (c) Bayesian analysis. Patients entered a randomised study of three two-monthly dosage regimens using low, medium, and high theophylline twice daily doses. These doses produced mean (±SE) steady-state serum theophylline concentrations of 6.3 (±0.4), 12.1 (±0.3) and 18.3 (±0.5) mg/L, respectively. A fourth period of placebo (2-month duration) was also included. At the end of each treatment period the measured serum theophylline concentration of each patient was compared with those predicted by each of the above three methods. The revised estimates derived from Bayesian analysis produced the least biased [mean prediction error (ME)] and most precise (mean squared prediction error) predictions for all three dosage periods. Statistical analysis of relative performance demonstrated that the difference in precision between the revised estimates and those of the other two methods was significant (p < 0.05) with the magnitude of the difference increasing with dose. The revised estimates were also found to be less biased (p < 0.05) than those of the nomogram. The ME (±SE) of the revised estimates for the low, medium, and high dosage periods was 0.34 (±0.30), −0.02 (±0.22) and −0.48 (±0.31) mg/L, respectively.

ISSN:0163-4356    

出版商:OVID    

年代:1988

数据来源: OVID