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At least 415 records · Page 23Linked to original sources
PubMed2002

Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?

Human variability in the kinetics of CYP2D6 substrates has been quantified using a database of compounds metabolised extensively (>60%) by this polymorphic enzyme. Published pharmacokinetic studies (after oral and intravenous dosing) in non-phenotyped healthy adults, and phenotyped extensive (EMs), intermediate or slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve) and primarily to acute exposure (peak concentration). Similar analyses were performed with the available data for subgroups of the population (age, ethnicity and disease). Interindividual differences in kinetics for markers of oral exposure were large for non-phenotyped individuals and for EMs (coefficients of variation were 67-71% for clearances and 54-63% for C(max)), whereas the intravenous data indicated a lower variability (34-38%). Comparisons between EMs, SEMs and PMs revealed an increase in oral internal dose for SEMs and PMs (ratio compared to EMs=3 and 9-12, respectively) associated with lower variability than that for non-phenotyped individuals (coefficients of variation were 32-38% and 30% for SEMs and PMs, respectively). In relation to the uncertainty factors used for risk assessment, most subgroups would not be covered by the kinetic default of 3.16. CYP2D6-related factors necessary to cover 95-99% of each subpopulation ranged from 2.7 to 4.1 in non-phenotyped healthy adults and EMs to 15-18 in PMs and 22-45 in children. An exponential relationship (R(2)=0.8) was found between the extent of CYP2D6 metabolism and the uncertainty factors. The extent of CYP2D6 involvement in the metabolism of a substrate is critical in the estimation of the CYP2D6-related factor. The 3.16 kinetic default factor would cover PMs for substrates for which CYP2D6 was responsible for up to 25% of the metabolism in EMs.

Adult↗
PubMed1991

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in patients surviving open label titration but not randomized to double-blind therapy.

The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial (CAST) and who were not randomized to double-blind therapy and in 942 patients, who were randomized to double-blind placebo therapy. The patients randomized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate (4% vs. 8.5%). However, at baseline, nonrandomized patients were dissimilar from patients randomized to placebo in the following ways: older; lower left ventricular ejection fraction; greater use of digitalis, diuretic drugs and antihypertensive agents; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems, including runs of ventricular tachycardia and left bundle branch block. A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonrandomized patients and clinically equivalent patients randomized to placebo. Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonrandomized patients: female gender (4.7, p less than 0.05) and electrocardiographic events (ventricular tachycardia, proarrhythmia, widened QRS complex, heart block, bradycardia) during open label titration (7.0, p less than 0.005). However, some potentially important differences between men and women were not included in the Cox regression model. Of the nonrandomized patients, approximately 70% were not randomized because of lack of suppression of ventricular premature depolarizations or adverse events, or both, and the remaining 30% because of patient or private physician request with no indication of another reason.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1981

The treatment of ventricular tachycardia using an automatic tachycardia terminating pacemaker.

Implanted cardiac pacemakers may be used in the management of selected patients with ventricular tachycardia unresponsive to other forms of medical and surgical therapy. We would like to report the successful treatment of such a patient utilizing a new multiprogrammable automatically activating ventricular burst pacemaker. Thorough electrophysiologic study preceded implantation, and was instrumental in choosing an effective terminating technique, in identifying the need for adjunctive drug therapy, and in testing the safety and efficacy of the implanted system.

Aged↗
PubMed1998

ST segment elevation induced by class IC antiarrhythmic agents: underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia.

Three patients in whom Class IC sodium channel blockers induced ST segment elevation in leads V1 through V3 are described. The underlying electrophysiologic mechanism, implications for drug-induced proarrhythmia, and the relationship of the finding to the Brugada syndrome type of idiopathic ventricular fibrillation are discussed.

Anti-Arrhythmia Agents↗
PubMed1985

Antiarrhythmic drug therapy. Recent advances and current status.

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Adrenergic beta-Antagonists↗
PubMed1982

Effects of antiarrhythmic agents on cardiac function.

Many, if not most antiarrhythmic drugs, even with differing pharmacologic properties, are capable of myocardial depression. That this has not occurred commonly with most drugs currently available may reflect several factors. These may include depression of myocardial function which is not clinically overt or which is masked by preexisting cardiac decompensation, limitation of dosages because of the difficulty in accurately determining a therapeutic endpoint, and the lack of physician awareness of the effects of these drugs on myocardial performance. However, as techniques for monitoring and quantifying arrhythmia permit more aggressive drug therapy, and as more drugs become available for clinical use, the incidence of clinically overt myocardial depression from anti-arrhythmic therapy will undoubtedly rise. Hopefully, awareness of the hemodynamic effects of these drugs and applications of new technology permitting accurate, noninvasive assessment of left ventricular function will identify and hence limit the occurrence of toxic hemodynamic effects, as well as permit the usage of maximum dosages of antiarrhythmic drugs when warranted by clinical circumstances.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Reliability of antiarrhythmic drug plasma concentration monitoring.

Measurement of drug levels is becoming increasingly popular to optimise the dosage of various drugs. In the case of antiarrhythmic drugs, the narrow therapeutic margin of most of these agents and a direct relationship between their pharmacological effects and plasma concentrations would justify more widespread use of monitoring. Optimum plasma concentration ranges have been described for lignocaine (lidocaine), procainamide, quinidine and, more recently, also for disopyramide, mexiletine, tocainide and other new antiarrhythmics. A critical analysis of the original data shows, however, that therapeutic and toxic levels are not so well defined as often assumed: small numbers of patients, marked interindividual variability, sometimes inadequate documentation of arrhythmias and lack of standardised blood sampling characterise many of these studies. Uncertainty about the reliability of concentration-effect relationships also arises when active drug metabolites are identified or there are marked concentration-dependent changes of drug protein-binding. In addition, abolition of various types of arrhythmias might require different drug concentrations. Nevertheless, therapeutic monitoring can be of practical value in patients with life-threatening ventricular arrhythmias and can also greatly facilitate dosage adjustment in cases with renal hepatic or severe cardiac failure. For a correct interpretation of drug levels, the time of blood sampling, dosage regimen, duration of treatment, pharmacokinetic principles, and the clinical condition of the patient must be taken into account. Further studies are needed to define the optimum therapeutic range for several drugs and to evaluate the usefulness of plasma concentration measurements in routine antiarrhythmic treatment.

Amiodarone↗