Quantitative Assessment of the Physiological Parameters Influencing QT Interval Response to Medication: Application of Computational Intelligence Tools.

Human heart electrophysiology is complex biological phenomenon, which is indirectly assessed by the measured ECG signal. ECG trace is further analyzed to derive interpretable surrogates including QT interval, QRS complex, PR interval, and T wave morphology. QT interval and its modification are the most commonly used surrogates of the drug triggered arrhythmia, but it is known that the QT interval itself is determined by other nondrug related parameters, physiological and pathological. In the current study, we used the computational intelligence algorithms to analyze correlations between various simulated physiological parameters and QT interval. Terfenadine given concomitantly with 8 enzymatic inhibitors was used as an example. The equation developed with the use of genetic programming technique leads to general reasoning about the changes in the prolonged QT. For small changes of the QT interval, the drug-related IKr and ICa currents inhibition potentials have major impact. The physiological parameters such as body surface area, potassium, sodium, and calcium ions concentrations are negligible. The influence of the physiological variables increases gradually with the more pronounced changes in QT. As the significant QT prolongation is associated with the drugs triggered arrhythmia risk, analysis of the role of physiological parameters influencing ECG seems to be advisable.

Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded Cmax values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction.

Comparison of efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine in patients of allergic rhinitis: A randomized, double-blind clinical trial.

OBJECTIVES: Allergic rhinitis (AR) is a global health problem. Almost 10%-25% of population worldwide is affected by AR. Oral/intranasal H1-antihistamine, decongestants, leukotriene receptor antagonists, and intranasal corticosteroids are the pillars in the management of AR. The combination therapy of montelukast with antihistaminic provides enhancing and complimentary effects, thereby reducing the symptoms effectively, but there are scanty data regarding the comparisons of combinations. Therefore, we aimed to compare the efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine combination in patients of AR. MATERIALS AND METHODS: Seventy patients with AR participated in a prospective, randomized, double-blind, parallel, active-controlled, comparative 4-week trial. The patients between the age group of 18-65 years of either gender having moderate-severe intermittent or mild persistent AR were included in the study. The study inclusion criteria required the patients with total nasal symptom score (TNSS) of 5 or higher. The patients were randomly divided into two treatment groups with montelukast-levocetirizine (10 mg and 5 mg) in one group and montelukast-fexofenadine (10 mg and 120 mg) in another group. TNSS parameter was the main effectiveness parameter. RESULTS: Evaluation of TNSS revealed significant difference (P < 0.05) when compared from baseline to 4th week in both groups. The mean change of TNSS, i.e., 9.46 was significant (P < 0.05) in montelukast-fexofenadine group. The cost-effectiveness ratio was less in montelukast-levocetirizine group than in montelukast-fexofenadine group. CONCLUSION: The decrease in TNSS was more in montelukast-fexofenadine group, but the cost-effectiveness is more with montelukast-levocetirizine combination.

Assessment of the antiobstructive effect of fexofenadine on nasal allergy challenge in patients with seasonal allergic rhinitis.

The oral administration of fexofenadine 120 mg daily is a common treatment of seasonal allergic rhinitis (SAR). It reduces the H1 receptor-mediated symptoms, such as sneezing, pruritus, and nasal secretion as well as non-nasal symptoms such as conjunctivitis. The objective was to assess the effect of fexofenadine on nasal symptoms (such as nasal obstruction) in seasonal allergic rhinitis. A placebo-controlled, double-blind, randomized, cross-over study was performed which yielded evidence that two-week therapy with fexofenadine 120 mg daily in patients with SAR also relieves nasal obstruction and congestion. The parameters of nasal obstruction were evaluated by means of rhinoscopy, a subjective symptom score, and active anterior rhinomanometry. The subjective evaluation of nasal obstruction/congestion as recorded by the patient every 15 minutes for 4.5 hours after nasal allergen provocation showed a significant difference of the AUC (p = 0.025) between fexofenadine and placebo with a 12.8% lower obstruction after fexofenadine. The swelling of the nasal mucosa, which was assessed by rhinoscopy for 4.5 hours after nasal allergen provocation, was 21% lower after treatment with fexofenadine (p = 0.041). In this double-blind, placebo-controlled trial, subjective patient ratings as well as objective investigator assessments demonstrate the anti-obstructive effect of fexofenadine in nasal allergen challenge.

Current assessment of risk-benefit by regulators: is it time to introduce decision analyses?

Regulatory risk-benefit assessments may overweight small but serious risks relative to benefits. Using terfenadine and torsade de pointes as an exemplar, we illustrate how a different decision may result when outcomes are assessed using quality-adjusted life-years within a decision-analytical framework. The adoption of common measures of health outcome and the use of decision analyses, which will allow uncertainty to be characterized and evidence to be compiled from disparate sources, may inform complex risk-benefit decisions and should be used in conjunction with qualitative assessments.

[Risk of drug interactions. Combinations of drugs associated with ventricular arrhythmias]. / Riesgo de interacciones medicamentosas. Combinaciones de medicamentos asociados a arritmia ventricular.

OBJECTIVE: To determine the frequency of concurrent use of cisapride, astemizole and terfenadine with macrolides and azole antimitotics, drug combinations that have been reported in the literature as producing a pharmacological interaction associated with potentially fatal ventricular arrhythmias. MATERIAL AND METHODS: A retrospective analysis of a total of 72,444 prescriptions generated by 611 physicians during a 6 months period for ambulatory patients, was performed. The database included a register of automatic alerts produced every time a predetermined drug combination was detected. RESULTS: 145 potentially risk situations were detected, with an incidence rate to 2.1 cases per 1,000 prescriptions, which increases to 6.2% when prescriptions for terfenadine, astemizole, and cisapride were included, with 12, 9 y 5%, respectively. Only 36 physicians (6%) wrote prescriptions producing alerts, and about half (45%) were pediatricians. The same physician prescribed both drugs in 31% of the cases. CONCLUSION: The use of drug combinations associated with a high risk of potentially fatal ventricular arrhythmias is relatively high in Mexico. An electronic online detecting system showed to be useful in preventing this kind of potential pharmacological interactions.

Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator.

BACKGROUND: Sedating antihistamines may impair driving performance as seriously as alcohol. OBJECTIVE: To compare the effects of fexofenadine, diphenhydramine, alcohol, and placebo on driving performance. DESIGN: Randomized, double-blind, double-dummy, four-treatment, four-period crossover trial. SETTING: The Iowa Driving Simulator. PARTICIPANTS: 40 licensed drivers with seasonal allergic rhinitis who were 25 to 44 years of age. INTERVENTION: One dose of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (approximately 0.1% blood alcohol concentration), or placebo, given at weekly intervals before participants drove for 1 hour in the Iowa Driving Simulator. MEASUREMENTS: The primary end point was coherence, a continuous measure of participants' ability to match the varying speed of a vehicle that they were following. Secondary end points were drowsiness and other driving measures, including lane keeping and response to a vehicle that unexpectedly blocked the lane ahead. RESULTS: Participants had significantly better coherence after taking alcohol or fexofenadine than after taking diphenhydramine. Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use. Mean response time to the blocking vehicle was slowest after alcohol use (2.21 seconds) compared with fexofenadine use (1.95 seconds). Self-reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and leftlane excursion. CONCLUSIONS: Participants had similar performance when treated with fexofenadine or placebo. After alcohol use, participants performed the primary task well but not the secondary tasks; as a result, overall driving performance was poorer. After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did. Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive.

Model for outcomes assessment of antihistamine use for seasonal allergic rhinitis.

BACKGROUND: Drug selection for optimal treatment of common medical conditions may be difficult and involve many diverse factors. OBJECTIVE: The efficacy, safety, quality of life, and cost of treatment of seasonal allergic rhinitis with cetirizine, chlorpheniramine, or terfenadine were compared in a prospective, two-phase, randomized, single-blind clinical trial conducted in a managed care setting. METHODS: In phase I, which lasted 2 weeks, patients were randomized to receive one of the study drugs. In phase II, which lasted 4 weeks, the initial treatment was continued unless patients were dissatisfied, in which case they could be randomly assigned to receive another study drug. In both phases pseudoephedrine could be taken as needed. Patients kept daily diaries of symptoms and costs, and study drugs were evaluated at the end of each phase for efficacy, safety, and effect on quality of life by means of a validated questionnaire. A multiattribute outcomes assessment model for formulary decision making was used to rank the antihistamines. RESULTS: Physicians' and patients' assessments in phases I and II indicated that cetirizine and chlorpheniramine were significantly more effective than terfenadine (p < 0.05). Incidence of sedation in phase I and phase II was 40.5% and 16.7% for chlorpheniramine, 11.6% and 9.8% for cetirizine, and 6.7% and 5.1% for terfenadine, respectively. At the end of phase I, 28.9% of the patients treated with chlorpheniramine, 50% of the patients treated with terfenadine, and 69.4% of the patients treated with cetirizine were satisfied with their therapy and chose not to switch their medication. Quality of life scores improved most after treatment with cetirizine and least after treatment with terfenadine. CONCLUSION: The result of this trial indicate that antihistamine selection is best made with the use of a multiattribute evaluation that includes quality of life. In this study cetirizine was favored by patients and physicians most often, followed by chlorpheniramine and then terfenadine.

Coprescription of terfenadine and erythromycin or ketaconazole: an assessment of potential harm.

PURPOSE: In a retrospective study, the authors used a pharmacy claims database to analyze the rate of coprescription of terfenadine and erythromycin or ketaconazole. STUDY PERIOD: The investigators reviewed claims filed for these drugs between January 1, 1990, and June 30, 1993. The time period allowed for comparison of coprescription rates before and after the Food and Drug Administration (FDA) required the manufacturer of terfenadine to inform the medical community of potentially serious adverse interactions. RESULTS: There were 5,802 coprescription events for terfenadine and erythromycin and 150 coprescription events for terfenadine and ketaconazole. Rates per 100,000 terfenadine users demonstrated large declines about 18 months after initial regulatory action. Coprescription events of terfenadine with either erythromycin or ketaconazole continued to occur despite regulatory action. CONCLUSIONS: Results of this study suggest important roles for the pharmacist as a risk manager, disseminating information about newly published drug interactions. Both health providers and patients are audiences for the pharmacist's drug expertise. The delay in physician reaction to new information from pharmaceutical companies and the federal government suggests an early, strong role for the pharmacist in changing prescribing behavior.

An assessment of cognitive function and mood in chronic fatigue syndrome.

Data were gathered regarding the associates of chronic fatigue syndrome (CFS) with: (1) speed of cognitive processing, (2) motor speed, (3) ability to sustain attention, and (4) mood. Patients were given a brief neuropsychological test battery before and after double-blind treatment with terfenadine or placebo and completed a daily mood rating scale (Positive and Negative Affect Schedule) during the study. CFS patients exhibited slower cognitive processing and motor speed and lower positive affect, as compared to data reported from previous studies of healthy subjects and other patient groups; however, CFS patients did not exhibit deficits in sustained attention in comparison to other groups. The CFS patients' ability to attend to verbal versus figural stimuli and mood ratings were different from those reported in studies of patients with depression. Because of methodological limitations, these findings are preliminary, but they encourage further assessment of cognitive dysfunction and mood in CFS.

Terfenadine-associated ventricular arrhythmias and QTc interval prolongation. A retrospective cohort comparison with other antihistamines among members of a health maintenance organization.

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

Comparative study of terfenadine and cetirizine in hay fever: assessment of efficacy and central nervous system effects.

A daily dose of either terfenadine 120 mg or cetirizine 10 mg was compared in two parallel groups of patients suffering from hay fever. According to a double-blind, double-dummy, randomized design, 28 patients were treated with one of the two drugs once daily in the morning for 2 weeks during the 1990 grass pollen season. The severity of nasal congestion, rhinorrhea, sneezing, nasopharyngeal itching and itchy, watery, red eyes was evaluated by the investigator after a 1-week run-in period and at the end of the treatment. The patients made a daily record of the severity of symptoms on a diary card. In addition, drug-related central nervous system (CNS) effects were assessed at baseline and at the end of the treatment by neuropsychological tests aimed at investigating selective and sustained attention, visuomotor abilities and anxiety, and by quantitative, bit-mapped EEG. Both terfenadine and cetirizine produced a significant improvement in symptoms at endpoint without any significant difference between the two drugs. Drowsiness was referred by one patient in each treatment group. No significant impairment of psychomotor performance occurred with either drug. Quantitative EEG showed a significant power increase in the relative (%) delta band in both groups of treated patients. Although the difference was not statistically significant, a tendency towards greater involvement of the CNS was observed with the use of cetirizine. In conclusion, the results of this study confirm that terfenadine and cetirizine are equally effective in the management of hay fever. Some differentiated untoward EEG changes were also observed in relation to the drugs used, without any variation in neuropsychological performance.