Drug Effects In Models Research Articles

Simulations showed that validation of database-derived diagnostic criteria based on a small subsample reduced bias

Objective To evaluate alternative approaches to correct for bias due to inaccurate diagnostic criteria in database studies of associations. Study Design and Settings A simulation study of a hypothetical cohort of 10,000 subjects selected based on database-derived diagnostic criteria with positive predictive value (PPV) of either 53% or 80%. Analyses focus on the putative association between a drug and the time to a negative outcome. The association is confounded for “false positive” subjects, where the drug acts as a marker for unobserved frailty. First, we estimate the conventional multivariable Cox's Model 1. We then assume having in-depth evaluation of a fraction of subjects, which permits estimating the probabilities of having the disease for all subjects in the cohort. Alternative correction methods use the estimated probability as a confounder (Model 2), a modifier of the drug effect (Model 3), or an importance weight (Model 4). Results With a PPV of 53%, Models 1 and 2 induced about 50% underestimation bias for the drug effect. Interaction-based Model 3 yielded the least biased estimates (25% bias), whereas weighting by probability (Model 4) resulted in slightly more biased (33%), but more stable estimates. Conclusion Proposed methods help reducing bias due to sample contamination.

Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC‐PAMM‐NDDG

Introduction: The paclitaxel/carboplatin doublet is standard treatment in advanced ovarian cancer and usually applied following cytoreductive surgery. Paclitaxel displays nonlinear PK, and the exposure‐toxicity relationship has been described by threshold‐models, whereas the time above a paclitaxel plasma concentration of 0.05–0.2 μmol/L (T>C0.05‐T>C0.2) was correlated with hematological toxicity. A semimechanistic PKPD model has recently been described for paclitaxel‐induced myelosuppression. The aim of this study was to investigate the population PKPD of paclitaxel and carboplatin in ovarian cancer patients.Methods: 139 ovarian cancer patients received paclitaxel 175 mg/m2 over three hours, followed by carboplatin AUC 5 mg*min/mL over 30 min, after cytoreductive surgery. Plasma concentration‐time data of paclitaxel and carboplatin were measured, and the relationship between PK, hematological toxicity and drug response was evaluated using nonlinear mixed‐effect modelling. Data were analysed according to a semiphysiological model, including proliferation –, transit – and circulation compartments for neutrophils and thrombocytes. Linear and sigmoidal maximum response models were tested for the influence of paclitaxel and carboplatin on the proliferation rate of neutrophils or thrombocytes. Toxicity and clinical outcome data were analysed by previously established threshold models.Results: 105 patients had complete PK and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Hematological toxicity was adequately described by an inhibitory linear drug effect model. Mean paclitaxel T>C0.1 was 16.4 hrs, mean T>C0.05 61.4 hrs. Patients with a complete response to paclitaxel/carboplatin had a higher T>C0.05 as compared to patients with progressive disease (91.9 vs 31.5 hrs, p=0.02). Similarly, T>C0.05 was higher in patients with at least stable as compared to progressive disease (78.3 vs 31.5 hrs, p=0.05). Patients with T>C0.05 > 61.4 hrs (mean value) had a longer time‐to‐disease‐progression compared to patients with T>C0.05 < 61.4 hours (89.0 vs 61.9 weeks, p=0.05). T>C0.05 was also a good predictor for neutropenia, in that patients with absent or mild (WHO grade 1 or 2) neutropenia had a lower T>C0.05 as compared to patients with severe (WHO grade 3 or 4) neutropenia (50.3 vs 74.1 hrs, p=0.01). Carboplatin drug exposure was the best predictor for thrombocytopenia, in that patients with absent thrombopenia had lower values for Cmax and AUC as compared to patients experiencing mild or severe thrombopenia (82.6 vs 132 μmol/L for Cmax, 1.24 vs 1.79 mg*min/mL for AUC, p < 10−4 for both comparisons).Conclusions: Paclitaxel T>C0.05 was useful to predict neutropenia and clinical outcome in ovarian cancer patients receiving paclitaxel/carboplatin, while carboplatin exposure was useful to predict thrombocytopenia. Prospective studies should assess the value of therapeutic drug monitoring in this patient group.

Neuroprotection of Cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window

All attempts to reduce neuronal damage after acute brain ischemia by the use of neuroprotective compounds have failed to prove efficacy in clinical trials so far. One of the main reasons might be the relatively narrow time window for intervention. In this study 2 different tissue culture models of ischemia, excitotoxic lesion by the use of glutamate and oxygen-glucose deprivation (OGD), were used to investigate the effects of delayed application of Cerebrolysin (Cere) on neuronal survival. This drug consists of low molecular weight peptides with neuroprotective and neurotrophic properties similar to naturally occurring growth factors. After both types of lesion, acute as well as delayed treatment with Cere resulted in a dose dependent and significant rescue of neurons. In the model of excitotoxic cell death significant drug effects were found even when the treatment started with a delay of 96 hours after addition of glutamate. In the OGD model pronounced effects were found after 48 hours delay of treatment, and even after 72 hours a small but significant rescue of neurons was detected. The neuroprotective effects of a single addition of Cerebrolysin to the culture medium resulted in significant protection until end of the experiments which was up to 2 weeks after the initial lesion. A shift of the efficacious dosages from low to high concentrations indicates that most likely active compounds are used up, indicating that multiple dosing might even increase the effect size. In conclusion the results indicate that Cere displays a relatively wide therapeutic time window which might be explained by a combination of acute neuroprotective properties and neurotrophic efficacy.

Comparable Effects of Nicotine in Smokers and Nonsmokers on a Prospective Memory Task

In a double-blind placebo-controlled study, we examined the effect of nicotine, a cholinergic agonist, on performance of a prospective memory (ProM) task in young adult volunteers. Volunteers were required to complete an ongoing lexical decision task while maintaining the ProM task (responding with a different button press to items containing particular target letters). Half of the volunteers were smokers, half were nonsmokers. Half of each group received a single dose (1 mg) of nicotine nasal spray before completing the task; the remaining volunteers received a matched inactive placebo spray. Nicotine improved performance on the ProM task when volunteers were able to devote resources to that task. Under a variant procedure, where volunteers completed a concurrent auditory monitoring task, ProM performance was impaired under nicotine. Results are discussed in terms of the resource model of ProM, and the arousal model of drug effects. The data suggest that ProM under the conditions tested here is a resource-needy process, and that nicotine can improve performance by increasing available resources. Increased working memory demands that encourage redirection of resources may impair ProM performance, but the conditions under which these deficits emerge depend upon the subjective allocation of resources across tasks, rather than resource availability per se.

Cost-Effectiveness Analysis of Extended-Release Formulations of Oxybutynin and Tolterodine for the Management of Urge Incontinence

Oxybutynin and tolterodine are two drugs widely used for the management of overactive bladder and urge urinary incontinence. The once-daily, extended-release formulations benefit from being well tolerated and efficacious. However, their costs, compared with generic immediate-release (IR) oxybutynin, are significantly greater. This study compared the cost effectiveness of oxybutynin extended-release (Oxy-XL), tolterodine extended-release (Tol-ER), tolterodine immediate-release (Tol-IR) and oxybutynin immediate-release (Oxy-IR). A cost-effectiveness model. A systematic review that identified appropriate randomised clinical trials provided evidence on efficacy. Empirical models of drug effects (number of incontinent-free weeks) and persistence (proportion of patients still on therapy) were constructed in order to determine clinical effectiveness which was combined with cost data (direct medical costs to the UK NHS, year 2001 values) to calculate the drugs' cost-effectiveness from the perspective of the NHS. Univariate sensitivity analyses were conducted to test the robustness of the results. Hypothetical cohort of patients with urge incontinence associated with overactive bladder. The incremental cost per incontinent-free week for Oxy-IR (versus no treatment) ranged from pound sterling 2.58 to pound sterling 16.59. Oxy-XL and Tol-ER were more effective than Oxy-IR but at additional costs per incontinent-free week. Tol-IR did not appear to be a cost-effective option as it was less effective and more costly than the extended-release formulations. Uncertainty surrounding the health and cost consequences of early discontinuation affected these results, although the model results were robust to parameter uncertainty. Oxy-IR, Oxy-XL and Tol-ER appear to be cost-effective options for the management of urge incontinence from the NHS perspective. A decision among the treatments depends on the acceptable cost per additional incontinent-free week.

A Model for Drug Effects on Intracranial Pressure at Altitude

A Model for Drug Effects on Intracranial Pressure at Altitude

Improved multiparameter models of drug effects on response rate under multiple variable interval schedules: evidence from rat studies.

The functional analysis of the behavioral effects of drugs has lagged behind more biological research approaches in elucidating how drugs influence behavior. Part of the problem is the scarcity of mathematical models of responding under standardized behavioral procedures. A two-parameter model derived from the matching law to account for response rate as a function of reinforcement rate in single response alternative procedures provides a good description of responding under multi-component multiple variable interval (multVI) schedules of reinforcement, both in the absence of drugs and in the presence of a variety of drugs. This paper explores how well the two-parameter model and its exponentiated variant (three-parameter model) describe drug effects on responding under multVI schedules. Data from seven published papers concerning the effects of drugs on multVI schedules are reanalyzed. The three-parameter model describes the effects of drugs on responding more accurately than does the two-parameter model. The three-parameter model also describes well the type of relation between response rates under drug and no-drug conditions that the rate dependency hypothesis is usually invoked to explain. The three-parameter model can be improved by adding a parameter to account for base response rate, that is, response rate when reinforcement rate is zero. The parameters of the best descriptive model could be used to devise a classification system for the behavioral effects of drugs under multVI schedules. The parameters should be conceptualized by relating the drug-induced changes in parameter value to converging changes in measurements of brain function. This would connect the behavioral and the biological analyses of drug action to the benefit of both research fields.

Cellular mechanism of calcification and its prevention in glutaraldehyde treated vascular tissue.

Prevention of calcification in glutaraldehyde (GA) treated porcine aortic valve fibroblasts and rat aorta with Ca2+ channel blockers (Ca(2+)-CBs). GA causes a massive increase in [Ca2+]i and a many fold increase in [Pi]i followed by calcification of porcine aortic valve fibroblasts. The influx of extracellular Ca2+ into [Pi]i rich cells apparently underlies the mechanism of calcification. Inhibition of Ca2+ influx is likely to prevent calcification in GA-treated cells. [Ca2+]i in GA-treated cells was measured by fluorescence image analysis. [Ca2+]i increase in fibroblasts treated with various Ca(2+)-CBs was compared with the untreated control. To study the role of Ca2+ influx in calcification and to find out the portals of Ca2+ entry, porcine aortic valve fibroblasts and freshly removed rat aorta were treated with verapamil + ryanodine, or verapamil + econazole, fixed with GA and incubated in Hank's balanced salt solution with 2.5 mmol/L calcium. The progress of calcification was monitored by the rate of Ca and Pi depletions from the supernatant. Calcified cells and tissues were identified by calcein fluorescence. Verapamil + ryanodine or econazole inhibited the GA-induced Ca2+ influx and prevented calcification of the cells and rat aorta. The effect of verapamil was additive to that of ryanodine and econazole. Findings further support the influx theory of calcification. Ca2+ enters GA-treated cells mainly through the store operated and the L-type Ca2+ channels. Ca(2+)-CBs may be useful for prevention of calcification in GA-treated vascular bioprostheses. Cell culture serves as a convenient model for screening drug effects on calcification.

Markov Modeling of Allosteric Drug Effects on Ion Channels, with Particular Reference to Neuronal Nicotinic Acetylcholine Receptors

Allosteric mechanisms have been suggested for an increasing number of ion channel drug interactions, but often these ideas are not examined quantitatively through use of Markov models that would allow statistical estimation of proposed coupling effects. In this paper we illustrate, using properties relevant to the neuronal nicotinic acetylcholine receptor, how these models can be used to provide insight into the behavior of cooperative systems. Such models would then provide the basis for inferential studies with experimental data aimed at quantifying the magnitude of drug-induced changes on particular channel parameters. It is shown that even small changes in agonist binding affinity or channel gating are sufficient to produce biphasic modulatory drug effects in an allosteric model of nicotinic receptor activity.

Clinical psychopharmacology of AD/HD: Implications for animal models

A working knowledge of the clinical psychopharmacology of the psychostimulants in AD/HD is essential to the development of valid animal models of the disorder. The clinical pharmacokinetics and pharmacodynamics of d-amphetamine ( d-AMP) and methylphenidate (MPH) have been well-studied. The plasma half-life of these compounds in children is approximately 5 h, with an onset of therapeutic action within a half-hour, and peak action at 1–3 h. The effective dose range for d-AMP in children is 0.2–0.5 mg/kg, and for MPH 0.3–1.0 mg/kg. In humans, psychostimulants bring about reductions in activity level and impulsivity, and improvement in attention span. Enhancement of executive processes mediated in the pre-frontal cortex in humans (especially tolerance for delay) is believed to mediate these therapeutic effects. There are no long-term remedial effects of the drug on behavior—i.e. symptoms return when the drugs are withdrawn. When used in the therapeutic dose range, there is no evidence of the development of significant tolerance or sensitization. These and other clinical findings to be discussed must guide and constrain the development of animal models of stimulant drug effects in AD/HD.

Practical Application of Pharmacokinetic-Pharmacodynamic Modeling.

Recently, an increasing number of pharmaceutical scientists and clinical pharmacists have begun to focus on pharmacodynamics, which relates the time course of drug concentration to the time course of pharmacological effects. An integration knowledge of pharmacokinetics and pharmacodynamics is essential for the development of rational pharmacotherapeutics because pharmacodynamics and pharmacokinetics are able to determines the drug concentration required to produce the desired therapeutic effect and the drug dose regimen required to achieve the targeted drug concentration, respectively, by using various models. The general principles of the drug effect model are based on the reversible direct and indirect models. In this review, various models in terms of the time course of drug effects are presented and discussed.

The Situation � Trait Adaptive Response (STAR) Model of Drug Use, Effects, and Craving

This review examines situational and trait factors that influence drug use, craving, and the affect-modulating effects of drugs. Situation- and personality-dependent cognitive, emotional, and biological effects of psychoactive drugs are addressed within the context of the recently developed Situation by Trait Adaptive Response (STAR) model. It is argued that drugs do not have inherent (situation- and trait-independent) effects on emotion and related affective processes. Emotion modulation is accomplished by three overall mechanisms: (1) enhanced goal achievement via cognitive performance enhancement; (2) alteration of cognitive capacity and/or attentional processes; and (3) cognitive-affective information priming/biasing towards positive associations and away from negative schemas. Further, the lateralized neural network hypothesis of the STAR model is extended from previous formulations to provide an integrative framework for understanding relationships of cognitive, affective, and learning mechanisms underlying drug use urges and behaviour. © 1997 John Wiley & Sons, Ltd.

The Situation × Trait Adaptive Response (STAR) Model of Drug Use, Effects, and Craving

The Situation × Trait Adaptive Response (STAR) Model of Drug Use, Effects, and Craving

Pharmacokinetics of pirmenol enantiomers and pharmacodynamics of pirmenol racemate in patients with premature ventricular contractions.

The pharmacokinetics and pharmacodynamics of pirmenol were investigated in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 hours. Holter monitoring was performed and serial blood samples were collected after the seventh doses. Plasma concentrations of pirmenol enantiomer were determined using a stereospecific liquid chromatographic assay. Clearance of total (-)-pirmenol was 20% higher than that of total (+)-pirmenol, and the difference in unbound clearance was 45% between enantiomers. Total pirmenol showed a smaller difference because of stereoselective protein binding, with 25% (100-mg dose) or 27% (200-mg dose) higher fraction unbound for (+)-pirmenol than for (-)-pirmenol. Distribution volume was similar for both enantiomers. Dose-dependent clearance was observed for unbound pirmenol enantiomers, as both enantiomers showed 20% lower unbound clearance at the higher dose. Antiarrhythmic effect (% reduction in PVCs from baseline) was correlated with plasma concentrations of pirmenol using a sigmoid maximum drug effect model, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for minimum effective plasma concentration of racemic pirmenol was 1.5 micrograms/mL.

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Influence of histamine receptor antagonists on the dynamics of the cutaneous hypersensitivity reaction in patients infected with schistosoma haematobium.

The biphasic cutaneous hypersensitivity response elicited by intradermal administration of S. haematobium antigen to patients with schistosomiasis may be used as a model for drug effects on cell dynamics. As the effects of H1- and H2-blockade, and the possible involvement of H3-receptors, have not been elucidated, we have examined the effects of combinations of cetirizine, cimetidine and betahistine on the response of patients with confirmed schistosomiasis. The skin blister technique was used. After intradermal administration of antigen, blister fluid containing inflammatory cells was collected on microscope slides at 6 and 24 h, and a differential cell count was done; and the area of induration was measured at 0.25, 1, 6 and 24 h. These baseline tests were repeated after 3 days of pretreatment with cetirizine 20 mg/d, after the addition of cimetidine 1200 mg/d for 3 further days, and finally after adding on betahistine 32 mg/d for 3 days. Simultaneous H1- and H2-blockade with cetirizine plus cimetidine caused a significantly greater reduction in induration than cetirizine (H1-blockade) alone; the reductions from the baseline value were 70%, 78%, 89%, 97%, and 33%, 53%, 43%, 30%, at times 0.25, 1, 6 and 24 h, respectively. The triple combination with the addition of betahistine (H1- and H2-agonist and H3-antagonist) resulted in reductions of 37%, 63%, 95% and 97% at the same times. The most striking changes in cellular dynamics were a significant increase in eosinophil (6 h) and neutrophil (6 h) vacuolation, and enhancement of monocyte (24 h) and basophil (6 h) accumulation, when the betahistine was added.(ABSTRACT TRUNCATED AT 250 WORDS)

Ambient temperature effects on thermoregulation and endurance in anticholinesterase-treated rats

In sedentary animals, physostigmine (PH) administration resulted in a decreased core temperature that is ambient temperature (Ta) dependent. PH administration in rats exercising on a treadmill (26°C, 50% rh, 11m/min, 6° incline) decremented endurance and increased rate of rise of core temperature (heating rate, HR). This study was undertaken to examine the effects of Ta on the endurance and thermoregulatory decrements of PH-treated running rats. Adult male rats (510–530g) were given either 0.2ml saline (C) or 100 ug/kg physostigmine salicylate in 0.2 ml saline via tail vein 15 min prior to the start of running to exhaustion at 10, 15, 26, or 30°C. In both C- and PH-treated groups, endurance decreased and HR increased with increasing Ta from 15 to 30°C. At 15 and 26°C the C rats ran significantly (p<.05) longer and had significantly lower HR than the PH rats: C15 = 90±9 min, 0.022±0.006°C/min; C26 = 67±6, 0.051±0.007; PH15 = 57±5, 0.052±0.008; and PH26 = 43±6, 0.092±0.007. At 10 and 30°C there were no significant differences between C and PH-treated rats. A Ta of 30°C was too high for effective cooling in either group, and at 10°C both groups were able to dissipate heat despite the increased metabolic rate of the PH-treated rats. The PH-treated rat model of cholinergic drug effect is useful at a Ta of 15 and 26°C.

Pharmacodynamic modeling of anesthetic EEG drug effects.

The integration of pharmacokinetics and pharmacodynamics using pharmaco­ dynamic modeling concepts has been advanced by investigative efforts with anesthetic drugs. By simultaneously measuring the drug plasma concentration and the drug effect, it becomes possible to dissect the dose vs response relationship into its pharmacokinetic and pharmacodynamic components (Fig­ ure 1). There are several reasons why anesthetic drugs are ideal compounds for understanding integration of pharmacokinetics and pharmacodynamics. These include the common use of intravenous ( IV) or pulmonary administra­ tion, the relatively rapid blood:biophase equilibration that is necessary for an anesthetic drug to be clinically useful, the rapid dissipation of drug effect from a combination of redistribution and elimination mechanisms, and finally the relatively profound degree of drug effect that anesthetic drugs create. Dl'4g effect that is relatively intense makes pharmacodynamic measurement and quantitation an easier task. Finally, it has been possible to develop surrogate measures of drug effect with many anesthetic dt1.lgs. Surrogate drug effects are secondary drug-induced measurable changes of body physi-

The influence of dosage time of midazolam on its pharmacokinetics and effects in humans

The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.

Mapping and interpreting complex interactions between psychoactive drugs by simple computer-generated models

Drug combinations often yield results not readily predictable from those of their separate constituents. Computer programs have been developed to generate models of dual drug effects to analyse the results of experiments involving drug combinations. Single and combined dose-response results of rat locomotor activity are expressed as three-dimensional models. A manually plotted isobol diagram, showing eqi-active dose combinations of amylobarbitone and dexamphetamine, is compared with isobols constructed by the computer. A simple dose model theory is proposed which assumes that the two drugs have merely additive effects: differences between expectations from this theoretical model and the experimental results actually obtained were found by the computer. This computer approach allows detailed analysis of results. Three-dimensional dose response surfaces can provide a simple visual guide to dose combinations whose effects deviate significantly from those expected if the constituents were simply additive. Areas of special interest can thus be highlighted.