Interspecies scaling: predicting pharmacokinetic parameters of antiepileptic drugs in humans from animals with special emphasis on clearance

A method for benzoic acid determination in soft drinks by liquid chromatography using UV detector is presented. The method makes the possibility of benzoic acid determination with recovery about 95% and with variability index about 2.6%.     

Synthesis of pharmacokinetic parameters of vancomycin via bootstrap methods

OBJECTIVE: For the adjustment of individual vancomycin dosages, we estimate the important pharmacokinetic quantities half-life, clearance, and volume of distribution. MATERIAL: To obtain reliable information 293 observations from 244 patients were extracted from 23 published studies on vancomycin. Information about vancomycin's pharmacokinetics out of different sources represents an increase in sample size and, therefore, interpretive power. METHODS: Once the whole of the data had been stratified into a small number of homogeneous clusters based on cofactors, different (robust) estimators (mean, median, Winsorized, and trimmed mean) were calculated for the expected value of the pharmacokinetic parameters of vancomycin within the clusters. Measures of the statistical accuracy such as standard error, bias, mean square error, and confidence interval were estimated via bootstrap methods from large bootstrap sample sizes to compare the quality of the estimators. RESULTS: Due to the homogenization of the data all individual estimator functions yield very similar results and the empirical mean works fairly well as an estimate. The most frequently used estimator with the smallest estimated mean square error was the Winsorized mean.     

The estimation of population pharmacokinetic parameters using an EM algorithm

A questionnaire was mailed to locally trained Division One dental surgeons. The questionnaire was designed to assess the practice of orthodontics, the undergraduate orthodontic curriculum in relation to the dental practitioner and continuing orthodontic education. The results showed that the undergraduate orthodontic curriculum was of limited use to the practitioner and that there was a need for a continuing orthodontic education programme. Information pertaining to various aspects of orthodontic practice was presented.     

Effect of sodium methyl arsinate and imidocarb dipropionate antiprotozoal drugs on the pharmacokinetic of gentamicin in equines

The pharmacokinetic behaviour of gentamicin sulphate (3.4 mg/kg bwt) was studied following its intramuscular injection to a group of horses and to another group of horses premedicated with sodium methyl arsinate (2 mg/kg bwt) or imidocarb dipropionate (4.8 mg/kg bwt). Considerable differences were observed in the pharmacokinetics of gentamicin in pre-medicated horses and in horses which had received the antibiotic alone. Peak serum concentration of gentamicin (9.85 +/- 0.05 and 11.15 +/- 0.15 micrograms/ml) were attained within 1.45 +/- 0.05 and 0.92 +/- 0.04 h in arsinate and imidocarb-medicated horses, respectively, but reached a level of 9.18 +/- 0.07 micrograms/ml at 1.87 +/- 0.12 h in non-medicated animals. Gentamicin elimination half-life (+/- 0.5(el)) was faster in arsinate (7.82 +/- 0.31 h) and imidocarb (6.12 +/- 0.14 h) pre-medicated horses than in non medicated horses (9.88 +/- 0.19 h). In addition, the interval between doses (lbd) necessary to maintain a therapeutic level were shorter in the pre-medicated animals. In summary, the hypothesis that the pharmacokinetics of gentamicin are altered by concomitant therapy with antiprotozoal drugs was confirmed by this study.     

Interpretation of simulation studies for efficient estimation of population pharmacokinetic parameters

OBJECTIVE: To develop new approaches for evaluating results obtained from simulation studies used to determine sampling strategies for efficient estimation of population pharmacokinetic parameters. METHODS: One-compartment kinetics with intravenous bolus injection was assumed and the simulated data (one observation made on each experimental unit [human subject or animal]), were analyzed using NONMEM. Several approaches were used to judge the efficiency of parameter estimation. These included: (1) individual and joint confidence intervals (CIs) coverage for parameter estimates that were computed in a manner that would reveal the influence of bias and standard error (SE) on interval estimates; (2) percent prediction error (%PE) approach; (3) the incidence of high pair-wise correlations; and (4) a design number approach. The design number (phi) is a new statistic that provides a composite measure of accuracy and precision (using SE). RESULTS: The %PE approach is useful only in examining the efficiency of estimation of a parameter considered independently. The joint CI coverage approach permitted assessment of the accuracy and reliability of all model parameter estimates. The phi approach is an efficient method of achieving an accurate estimate of parameter(s) with good precision. Both the phi for individual parameter estimation and the overall phi for the estimation of model parameters led to optimal experimental design. CONCLUSIONS: Application of these approaches to the analyses of the results of the study was found useful in determining the best sampling design (from a series of two sampling times designs within a study) for efficient estimation of population pharmacokinetic parameters.     

Effects of repeated clarithromycin administration on the pharmacokinetic properties of pindolol in rats

The goal of the present work was to determine the effect of clarithromycin (CAM) administration on the pharmacokinetic properties of pindolol in rats. The binding of pindolol to serum components increases proportionally with increasing alpha1-acid glycoprotein (AGP) concentration, indicating that AGP might play a major role in the binding of pindolol. After intravenous administration of pindolol to rats, the CAM-treated group showed a decrease in the volume of distribution, an increase in AUC and no change in the half-life as compared to the control group. Treatment with CAM increased the AGP concentration only. The serum concentration of albumin and creatinine, as well as the metabolic activity of hepatic microsomes towards pindolol, were not altered. Good correlation was observed between the AUC of pindolol in rats and the AGP concentration in serum. Moreover, at 5 min after the administration of an intravenous bolus dose of pindolol to CAM-treated rats, the free concentration of pindolol was lower but the total concentration was higher, compared with the control rats. These results suggested that the influence of CAM on the pharmacokinetic properties of pindolol in CAM-treated rats can be explained by protein binding which, in turn, may be associated with variations in AGP concentration.     

Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients

BACKGROUND: Airway obstruction after anesthesia may be caused or exaggerated by residual neuromuscular block, with loss of muscle support for collapsible upper airway structures. METHODS: Six male volunteers were studied before treatment, during stable partial neuromuscular block with vecuronium at a mean train-of-four (TOF) ratio of 50% (95% CI, 36-61%), and after reversal by neostigmine. Catheter-mounted transducers were placed in the pharynx and esophagus to estimate, respectively, the upper airway resistance, and the work of breathing (calculated as the time integral of the inspiratory pressure developed by the respiratory muscles, esophageal pressure time product) during quiet breathing, during breathing 5% carbon dioxide, and while breathing with an inspiratory resistor. Breathing with pressure at the airway opening held at pressures from -5 to 40 cm H2O were also tested to assess airway collapsibility. RESULTS: Although breathing through a resistor increased upper airway resistance from 1.2 (0.67, 1.72) cm H2O x l(-1) x s to 2.5 (1.32, 3.38) cm H2O x l(-1) x s, and carbon dioxide stimulation reduced resistance to 0.8 (0.46, 1.33) cm H2O x l(-1) x s, no effect of partial neuromuscular block (mean TOF ratio, 52%) on upper airway properties could be shown. CONCLUSIONS: Neuromuscular block with a TOF ratio of 50% can be present yet clinically difficult to detect in patients recovering from anesthesia. This degree of block has no effect on airway patency in volunteers, even during challenge. Airway obstruction during recovery from anesthesia thus is more likely to be caused by residual effects of general anesthetic agents or centrally acting analgesics, either alone or perhaps in concert with residual neuromuscular block.     

Effects of spaceflight on rat erythroid parameters

This paper describes a simple and more sensitive reversed-phase HPLC method for the quantification of phenol, 4-nitrophenol and beta-naphthol and some of their glucuronide and sulphate conjugates in aqueous solution and liver perfusate buffer. Methanol-water mobile phases with ion-pairing agents for each phenolic group are detailed. The assay showed good recovery, accuracy and precision and is suitable for the quantification of these phenolic compounds in liver perfusion experiments.     

Effects of anticonvulsant drugs on the cerebral enzymes metabolizing GABA

The effect of anticonvulsant drugs on the activity of enzymes responsible for the further metabolism of GABA has been studied in mouse brain homogenates. Slight inhibition (5 to 20%) of GABA-T activity was seen with chlordiazepoxide (0.1 mM), ethosuximide (0.1 mM) and di-n-propylacetate (0.1 mM). No anticonvulsant drug (even at a concentration of 10 mM) produced inhibition comparable to that seen with amino-oxyacetic acid (65% at 0.01 mM). Succinic semialdehyde dehydrogenase activity was inhibited by 10 to 20% at low concentrations (0.01 to 0.1 mM) of diazepam, carbamazepine, beclamide, acetazolamide, and di-n-propylacetate, and by 40% or more at high concentrations (2.5 to 10.0 mM) of diazepam, phenobarbital, carbamazepine, beclamide, and di-n-propylacetate. Interference with the further metabolism of GABA may contribute to the antiepileptic action of drugs or to the acute neurological toxicity of anticonvulsant agents.     

Effects of sinus surgery on speech

The human 4 hour patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. The protocol is designed to avoid the production of more than mild irritant reactions and meets the highest ethical standards. This paper provides the background to the development of the method and comments on its performance in the light of recent intra- and inter-laboratory investigations. In particular, the value of the method in providing 'gold standard' data for the identification of those substances (or preparations) which should, or should not, be classified as irritant to skin in European legislation is discussed. On the basis of the published data and supplementary investigations, recommendations are made on both the conduct and interpretation of the human 4 hour patch test. Finally, the lack of any necessity for formal validation of this assay is addressed.     

Effects of vasoactive drugs on gastric intramucosal pH

The peptidergic neurohormone somatostatin (SRIF) derives from a precursor called preprosomatostatin (PPS) by proteolysis. We have isolated by RT-PCR and sequenced a partial cDNA coding for the ovine PPS. It contains a 348 base pairs coding sequence that shares strong similarities with previously cloned mammalian cDNAs. The ovine cDNA was used to synthesize radiolabeled cRNA to probe the PPS mRNA in the ewe hypothalamus by in situ hybridization. The PPS mRNA-containing cells are widely distributed in the hypothalamus. According to the number of silver grains over a cell, they show various staining intensities. The distribution of the PPS mRNA is in good agreement with that of the peptide previously determined using immunohistochemistry. The strongest labeled areas include the periventricular region of the paraventricular nucleus and the lateral division of the ventromedial nucleus. The difference in labeling intensity observed in the diverse populations of labeled neurons could reflect various levels of neuronal activity.     

Effects of abused drugs on psychomotor performance.

Some abused drugs have been reported to alter performance on naturalistic tasks such as driving and also on laboratory tasks. The performance effects of several drug classes were examined using a repeated measures design. Eight volunteers were administered 2 doses of ethanol, marijuana, amphetamine, hydromorphone, pentobarbital, or placebo on separate days. The larger dose of each increased subjective drug strength; however, only ethanol and pentobarbital impaired performance on circular lights, digit symbol substitution, and serial math tasks. Both ethanol and pentobarbital impaired performance on card-sorting tasks; impairment was evident at lower doses as the cognitive load increased. Results illustrate differences among drugs in producing performance impairment at doses that cause subjective effects. Increasing cognitive requirements uncovered performance impairment at lower doses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data

We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.