Interspecies allometric scaling in pharmacokinetics of drugs

Cytomegalovirus infections and their sequelae are the most serious complications in patients after allogenic bone marrow transplantations. Therefore in recent years quite rightly attention is paid to new diagnostic methods which make earlier and more sensitive detection of incipient CMV infection possible. The method of the two-stage polymerase chain reaction (PCR) was used for early detection of CMV infection and its possible further monitoring in 38 recipients of allogenic bone marrow. A positive result was recorded in 15 (39%) patients whereby in 10 (13%) repeated positivity was involved. In three in this group of patients (8%) CMV disease developed, always preceded by PCR positivity. Sensitivity, specificity, positive and negative predictive CMV PCR values were 100, 66, 20 and 100%. Concomitant comparison with serological examination (antibody titre class IgM/seroconversion) revealed the small contribution of serology (corresponding values are 67, 54, 11 and 95%) in patients after bone marrow transplantations. The presented results provide evidence of the contribution of PCR in the diagnosis of CMV in those patients where due to their high sensitivity and excellent predictive value it is possible to avoid the toxicity of unnecessary antiviral treatment.     

Interspecies scaling of cimetidine-theophylline pharmacokinetic interaction: interspecies scaling in pharmacokinetic interactions

The aim of the present study was the use of an interspecies scaling approach to predict drug interactions during preclinical drug disposition studies. Theophylline and cimetidine were selected because of their documented interaction. The literature was searched for pharmacokinetic data of intravenously administered theophylline alone and in the presence of cimetidine in humans, dogs and rats. Further, we determined the theophylline-cimetidine drug interaction in rabbits. Application of allometric equations to the pharmacokinetic parameters and the conversion of chronological time into pharmacokinetic time allowed us to obtain the complex Dedrick plot for theophylline when administered alone or in combination with cimetidine. A superimposable kinetic profile was obtained for the plasma levels of theophylline in all species studied, both with and without cimetidine. From the terminal phase of the curves it is possible to calculate the elimination half-life: 2.69 apolisychrons for theophylline when it is administered alone and 3.86 apolisychrons when it is administered in combination with cimetidine. This 43% increase in t1/2 is similar to the increase in the elimination half-life of theophylline in humans when it is administered after pretreatment with cimetidine. These results show that an interspecies scaling approach may be useful to predict the effect of interactions in humans from the results obtained in preclinical research with new drugs.     

The application of population pharmacokinetics to the drug development process

Population pharmacokinetics is playing an increasing role in clinical drug development. An overview of the population approach, including software and the advantages and limitations of the approach compared to the traditional approach to pharmacokinetic studies, is given. This paper also documents how the area has evolved over the past 15 years and addresses some of the issues that have arisen over the design and conduct of population studies. Finally, some alternative applications of the population approach are given for areas other than clinical drug development.     

Macrotransport-solidification kinetics modeling of equiaxed dendritic growth: Part I. Model development and discussion

An analytical model that describes solidification of equiaxed dendrites has been developed for use in solidification kinetics-macrotransport modeling. It relaxes some of the assumptions made in previous models, such as the Dustin-Kurz, Rappaz-Thevoz, and Kanetkar-Stefanescu models. It is assumed that nuclei grow as unperturbed spheres until the radius of the sphere becomes larger than the minimum radius of instability. Then, growth of the dendrites is related to morphological instability and is calculated as a function of melt undercooling around the dendrite tips, which is controlled by the bulk temperature and the intrinsic volume average concentration of the liquid phase. When the general morphology of equiaxed dendrites is considered, the evolution of the fraction of solid is related to the interdendritic branching and dynamic coarsening (through the evolution of the specific interfacial areas) and to the topology and movement of the dendrite envelope (through the tip growth velocity and dendrite shape factor). The particular case of this model is the model for globulitic dendrite. The intrinsic volume average liquid concentration and bulk temperature are obtained from an overall solute and thermal balance around a growing equiaxed dendritic grain within a spherical closed system. Overall solute balance in the integral form is obtained by a complete analytical solution of the diffusion field in both liquid and solid phases. The bulk temperature is obtained from the solution of the macrotrasport-solidification kinetics problem.     

The effect of an electric field on self-sustaining combustion synthesis: Part I. modeling studies

An analysis of the effect of an electric field on self-propagating high-temperature synthesis (SHS) reactions is presented. Using the synthesis of SiC as a model, the analysis showed that the imposition of a field results in a highly localized distribution of the current density. It was shown that the current is primarily restricted to the region just ahead of the combustion zone. Thus, in addition to the chemical heat release, this zone also includes heat release from an electric source, a value equivalent to σE₂ where σ is the conductivity andE is the field. From the dependence of the degree of conversion to the product on the applied voltage, it is shown that the velocity of the combustion wave is linearly proportional to the field.     

Influence of cholestasis on drug elimination: pharmacokinetics

A two-compartment model representing the body and the GI tract, with elimination occurring in each compartment, was used to study, in theory, the influence of impaired biliary excretion on drug disposition. The results suggest that cholestasis can either increase or decrease a drug's half-life, depending upon the relative values of the two elimination rate constants, In all cases, however, impaired biliary excretion reduced the initial elimination of drug from the body and increased the half-life of the alpha-phase of drug disposition.     

Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation: midazolam neonatal pharmacokinetics

BACKGROUND: Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. METHODS: Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. RESULTS: Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL CONCLUSIONS: Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.     

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%.     

Empirical modeling of an alcohol expectancy memory network using multidimensional scaling.

Risk-related antecedent variables can be linked to later alcohol consumption by memory processes, and alcohol expectancies may be one relevant memory content. To advance research in this area, it would be useful to apply current memory models such as semantic network theory to explain drinking decision processes. Multidimensional scaling (MDS) was used to empirically model a preliminary alcohol expectancy semantic network, from which a theoretical account of drinking decision making was generated. Subanalyses showed how individuals with differing alcohol consumption histories may have had different association pathways within the expectancy network. These pathways may have in turn influenced future drinking levels and behaviors while the person was under the influence of alcohol. All individuals associated positive/prosocial effects with drinking, but heavier drinkers indicated arousing effects as their highest probability associates, whereas light drinkers expected sedation. An important early step in this MDS modeling process is the determination of iso-meaning expectancy adjective groups, which correspond to theoretical network nodes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fundamental studies of copper anode passivation during electrorefining: Part I. development of techniques

Anode passivation is an extremely important phenomenon in commercial copper electrorefining operations. Due to the electrochemical nature of the refining process, various electrochemical techniques have been applied to examine anode passivation behavior. In this investigation, cyclic voltammetry, linear potential sweep, and chronopotentiometry measurements were carried out on several commercial copper anodes, as well as on pure electrowon (EW) copper cathode, in synthetic electrolytes simulating the primary constituents for industrial operations. The important parameters associated with anode passivation were identified and compared for the three electrochemical techniques. Chronopotentiometry is an extremely sensitive technique and proved to be the most suitable for analyzing and characterizing copper anode passivation.     

Interface morphology development during stress corrosion cracking: Part I. Via surface diffusion

The initiation of a crack in a specimen under tensile or compressive stresses is treated from the point of view of perturbation analysis. A surface distortion is Fourier analyzed into a series of waves and the amplitude response of a single component of varying frequency is theoretically investigated. The response of the individual components yields a Griffith-type criterion for wave amplitude growth. The model is applied to alloy systems undergoing stress corrosion cracking via surface diffusion.     

Drug discrimination training during chronic drug treatment affects the development of tolerance.

The purpose of this experiment was to evaluate the extent to which continued drug discrimination training during chronic drug treatment affects the development of tolerance. Rats were trained to discriminate distilled water from 0.75 mg/kg amphetamine in a two-lever drug discrimination task. Two groups were then given a chronic drug regimen of 13 daily injections of either distilled water or 10 mg/kg amphetamine. Drug discrimination training was continued for half of each chronic drug group. Tolerance was apparent only in the group that was not trained during the chronic amphetamine treatment. The data support the conclusion that continued training throughout the chronic drug treatment provides the opportunity for reinforced correct responding as both nondrug- and drug-cue states are gradually shifted by the chronic drug regimen. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The use of dogs as second species in regulatory testing of pesticides. I. Interspecies comparison

The relevance of studies in dogs on regulatory testing of pesticides was examined retrospectively using data of 216 pesticides (acaricides, fungicides, growth regulators and hormones, herbicides, insecticides, molluscicides, nematicides, rodenticides, synergists for insecticides) submitted for regulatory purposes during the past 40 years to the Federal Institute of Health Protection of Consumers and Veterinary Medicine (BgVV), the competent national authority in Germany. At first the relevance of the no-observed-effect levels (NOEL) for safety assessment was evaluated for each chemical in 4-week (subacute), 13-week (subchronic) and 52/104-week (chronic) toxicity studies carried out on dogs, rats and mice. After subchronic and chronic application of fungicides the sensitivity of rats and dogs to the toxic chemicals was quite similar. However, the dog was generally a more sensitive species to toxic effects of insecticides than rat and mouse. On the other hand the NOEL was lower in the rat than the dog in chronic studies on herbicides. When the lowest-observed-effect level (LOEL) was evaluated in animal species, the dog was the most sensitive in approximately 15% of the studies. Mice were found to be the most sensitive species only in approximately 1% of the studies on 216 pesticides. Comparison of organ specific toxicity at the LOEL in subacute studies on fungicides and herbicides revealed a poor correlation of target-specific organ toxicity across species. However, in the subchronic and chronic studies (13 and 52/104 weeks) no significant differences in species-specific organ toxicity were observed in the three species rat, mouse and dog. The only exception were haematoxic effects in chronic studies on herbicides, which were more frequent in dogs (40%) than in rats and mice (20%). The results support the established concept that studies on dogs and rats are important for the safety assessment of pesticides, while studies on mice do not provide further information, except for detection of an oncogenic potential which is a further controversial issue. Further analysis of subacute, subchronic and chronic studies in dogs should reveal if all of the studies are essential for safety assessment of pesticides.     

Atypical antipsychotics. Part I: Pharmacology, pharmacokinetics, and efficacy

OBJECTIVE: To compare the pharmacology, pharmacokinetics, and efficacy of the newer atypical antipsychotics with those of conventional agents and existing atypical agents. DATA SOURCES: Information was retrieved from a MEDLINE English-literature search from July 1986 to June 1998 and by review of references. Indexing terms included neuroleptics, atypical antipsychotics, clozapine, risperidone, olanzapine, sertindole, quetiapine, and ziprasidone. STUDY SELECTION: Comparative studies were selected when possible; placebo-controlled studies were included when data were limited on newer atypical antipsychotics. DATA EXTRACTION: Emphasis was placed on properly designed clinical trials that assessed dosage, expanded efficacy, enhanced adverse effect profile, and cost. DATA SYNTHESIS: Like other atypical antipsychotics, the newer agents have an enhanced 5-hydroxytryptophan/dopaminergic receptors (5-HT2/D2) affinity ratio and undergo extensive biotransformation. Risperidone and olanzapine demonstrate more favorable efficacy/adverse effect ratios than clozapine, sertindole, and conventional antipsychotics in nonrefractory and refractory schizophrenics. Future studies will more clearly define the role of quetiapine and ziprasidone in antipsychotic therapy. CONCLUSIONS: Data from controlled trials on efficacy and extrapyramidal side effects support risperidone or olanzapine as first-line agents for the treatment of schizophrenia. Pharmacologic and pharmacokinetic factors do not distinguish between agents sufficiently for drug selection.     

A multidimensional scaling analysis of the development of animal names.

Investigated developmental changes in semantic structure using the INDSCAL multidimensional scaling procedure. Dissimilarity judgments of all possible parts of 10 animal names were obtained from 39 1st-, 3rd-, 6th-grade, and college students. The overall scaling solution revealed a semantic space consisting of the features of size, domesticity, and predativity. Further analyses revealed that this structure changes with development inasmuch as the perceptual feature of size becomes less salient and the more abstract features of predativity and domesticity becomes more salient. This finding is compared to those from earlier research in which other techniques were used, and it is concluded that multidimensional scaling is a useful tool for determining developmental changes in semantic structure. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

OBJECTIVE: The objective of the study was to determine the major factors that underlie auditory/audiological performance measures in an elderly population, with particular emphasis on finding those factors responsible for speech understanding under specific conditions of interference. DESIGN: Audiological status and auditory performance of a group of elderly (60- to 81-yr-old) and normal-hearing young (18- to 30-yr-old) individuals was determined through a test battery. When present, the hearing loss of elderly subjects was symmetrical in the two ears and, at most, moderate. The battery included tests of speech intelligibility on the word and sentence levels, with and without the presence of interfering speech. In addition to pure-tone and speech reception thresholds, perception of spectrally or temporally distorted speech as well as auditory resolution of frequency, time, and space were tested. Two tests received special consideration: the Speech Perception In Noise Test and the Modified Rhyme Reverberation Test. Taking the overall results as well as various subsets of the results, principal component analyses were conducted to identify major factors underlying auditory performance. RESULTS: The factors extracted by the principal component analyses present a portrayal of the auditory performance profile in which effects of interference, high-frequency hearing, and basic auditory function play a major role. Interference factors include general susceptibility to noise as well as segregation of concurrent speech sounds on the basis of temporal dissimilarities and spatial separation. Comparison of factors extracted from various subsets of tests indicate that factors underlying the decline of the "cocktail party effect" in the elderly are addressed mostly by tests specifically designed to assess speech understanding in spatially distributed babble or in a reverberant environment. CONCLUSIONS: Factor analysis of test measures obtained from a group of elderly individuals with normal hearing or mild-to-moderate hearing loss led to two main findings. First, it portrayed hearing loss as a component of different factors rather than as a factor on its own. Second, the independence of measures of speech understanding in babble or reverberation from other measures suggests that such tests should become an integral part of audiological test batteries designed to assess auditory functions in aging.     

List-strength effect: I. Data and discussion.

Extra items added to a list cause memory for the other items to decrease (the list-length effect). In one of the present studies we show that strengthening (or weakening) some items on a list harms (or helps) free recall of the remaining list items. This is termed the list-strength effect. However, in seven recognition studies the list-strength effect was either absent or negative. This held whether strengthening was accomplished by extra study time or extra repetitions. The seven studies used various means to control rehearsal strategies, thereby providing evidence against the possibility that the findings were due to redistribution of rehearsal or effort from stronger to weaker items with a list. Current models appear unable to predict these results. We suggest that different retrieval operations underlie recall and recognition, as in the SAM model of G. Gillund and R. M. Shiffrin (see record 1984-08340-001), which can be made to fit the results with certain relatively minor modifications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phase I pharmacokinetics and limited sampling strategies for the bioreductive alkylating drug EO9. EORTC Early Clinical Trials Group

EO9 is a synthetic indoloquinone which was designed to undergo redox cycling and formation of alkylating intermediates under bioreductive conditions. As part of a phase I clinical trial, EO9 plasma disposition was evaluated in 20 patients receiving 2.7-15 mg/m2i.v. weekly for 3 weeks. Pharmacokinetic studies were performed with the first and third dose of therapy and nine blood samples were obtained over 30 min postinfusion. Plasma EO9 was detected using HPLC UV and the disposition described by a two-compartment model. Wide variability in EO9 pharmacokinetics was observed. EO9 was rapidly eliminated from plasma with a median systemic clearance of 3.5 l/min/m2 (range 1.2-9.8), apparent volume of distribution of 6.2 l/m2 (1.0-34.9) and t 1/2 beta of 10.1 min (2.2-63.0). Substantial intrapatient variability was observed for all pharmacokinetic parameters. Linear regression and Bayesian methods were developed and validated for estimation of EO9 plasma AUC using up to three samples postinfusion. The use of two or three plasma samples provided precise estimation with acceptable prediction bias. In addition, a Bayesian algorithm offered more robust estimation of AUC and is preferable to linear regression models for future EO9 population pharmacokinetic analysis.