Therapeutic drug monitoring
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Driving under the influence of drugs is an issue of growing concern in the industrialized countries as a risk and a cause for road accidents. In forensic toxicology, the increasing number of samples for determination of drugs in blood is mainly due to zero-tolerance laws in several countries and well-trained police officers who can better recognize drivers under the influence of drugs of abuse. This review describes procedures for detection of the following drugs of abuse in whole blood, plasma, and serum: amphetamine, methamphetamine, 3,4-methylenedioxy methamphetamine (MDMA), N-ethyl-3, 4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxyamphetamine (MDA), cannabinoids (delta-9-tetrahydrocannabinol [THC], 11-hydroxy-delta-9-THC, 11-nor-9-carboxy-delta-9-THC), cocaine, benzoylecgonine, ecgonine methyl ester, cocaethylene, the opiates (heroin, 6-monoacetylmorphine, morphine, or codeine), and methadone as well as gamma-hydroxybutyric acid (GHB), lysergic acid diethylamide (LSD), phencyclidine (PCP), and psilocybin/psilocin. ⋯ Gas chromatography-mass spectrometry (GC-MS) is still the state-of-the-art method for confirmatory analysis or for screening and confirmation in one step. Liquid chromatography-mass spectrometry (LC-MS) procedures for such purposes are also included in this review. Basic data about the biosample assayed, internal standard, workup, GC or LC column and mobile phase, detection mode, reference data, and validation data of each procedure are summarized in two tables.
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The authors examined the effect of mild therapeutic hypothermia on phenytoin pharmacokinetics in 14 patients with brain damage. Each patient was given phenytoin during and after mild therapeutic hypothermia. Plasma concentrations of total phenytoin, unbound phenytoin, and 5-(p-hydroxyphenyl)-5-phenylhydantoin (5-p-HPPH), the major metabolite of phenytoin, were measured. ⋯ Moreover, the elimination constant (ke) was decreased by 50% and elimination clearance of phenytoin was decreased by 67% during hypothermia compared with the corresponding values after hypothermia. The plasma concentration of 5-p-HPPH was significantly lower during hypothermia than after hypothermia. These findings suggest that phenytoin metabolism is inhibited by mild therapeutic hypothermia.
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Clinical Trial
Analytical validation for a series of marker compounds used to assess renal drug elimination processes.
Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. ⋯ For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.
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Randomized Controlled Trial Clinical Trial
Relationships between psychotropic drug dosage, plasma drug concentration, and prolactin levels in nursing home residents.
This study aimed to characterize the relationships between administered dosages of psychotropic drugs, plasma drug concentration, and prolactin levels in a group of elderly nursing home residents. In a randomized, placebo-controlled, double-blind crossover design study, blood samples were drawn from 47 nursing home residents at least 6 hours after taking either haloperidol, thioridazine, or lorazepam. Correlations between drug dosage and plasma drug levels were significant for haloperidol and thioridazine, but not for lorazepam. ⋯ For those taking haloperidol or thioridazine, prolactin levels decreased when participants were on placebo. When an older person is taken off lorazepam, the possibility of residual drug in their bodies even 6 weeks after termination of drug use should be considered. Haloperidol may be clinically active in the brain despite no currently detectable plasma drug concentration.
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Comparative Study
Population pharmacokinetics of flucytosine: comparison and validation of three models using STS, NPEM, and NONMEM.
The objective of this study is to compare and validate three models of flucytosine (5-FC) population pharmacokinetics using three methods of analysis to elucidate which model describes 5-FC pharmacokinetics most accurately and which method is the most suitable for this purpose. Retrospectively, demographic and clinical data of two similar sets of a total of 88 intensive care unit (ICU) patients were gathered for calculation and validation of 5-FC pharmacokinetics respectively. Three pharmacokinetic models were analyzed: a one-compartment with renal elimination (renal model), a one-compartment with renal and metabolic elimination (mixed model), and a two-compartment with renal elimination (two-compartment model). ⋯ Based upon AIC values, bias and precision, the best results are obtained using a two-compartment model with renal elimination (k(elr) = 0.000858 +/- 0.000143 l/h per mL per min, k12 = 0.0313 +/- 0.0168 h(-1), k21 = 0.0353 +/- 0.0145 h(-1), and Vd = 0.541 +/- 0.084 L/kg; bias = -13.16; 95% CI = -16.77; -9.55; precision = 30.50; 95% CI = 27.47; 33.26) or a two-compartment covariate model as built by NONMEM [Vd (L) = 0.572 x WT, Cl(5FC) (L/h) = 1.69 + 0.0273 x (Cl(cr) (mL/min) - 52.5), k12 = 0.0235 +/- 0.0107 h(-1), and k21 = 0.0375 +/- 0.0147 h(-1); bias = -8.29; 95% CI = -11.63; -4.95; precision = 26.77; 95% CI = 24.24; 29.07]. In conclusion, this study shows that a two-compartment model with renal elimination best describes 5-FC population pharmacokinetics and NONMEM is able to build a two-compartment covariate model that predicts 5-FC levels equally well in our population of ICU patients. Furthermore, NONMEM appeared to be the most suitable method of population pharmacokinetics in our population and for this purpose it offers more reliable and accurate results than NPEM or the STS method.