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Biomedical subjects

D C Harrison

Publications and source records attributed to D C Harrison.

At least 73 records · Page 4Linked to original sources
PubMed1984

Telemetry of electrophysiologic variables from conscious dogs: system design, validation, and serial studies.

The necessity for conscious animal models in the study of cardiac physiology has been established for hemodynamics. The characterization of the electrophysiologic properties of the heart has not been performed in a serial fashion in a conscious animal model. Implanted telemetry sensing devices for recording atrial, ventricular, and His electrograms and stimulation systems for both atrium and ventricle allowed serial evaluation of eight dogs for up to 4 months. There were significant fluctuations in some electrophysiologic variables with time, particularly heart rate, sinus node recovery time, and pacing rate for induction of Wenckebach block. This variability did not appear to deviate with time after implantation, and no significant differences in the basal electrophysiologic state were found between the period early after surgery (0 to 2 1/2 weeks) and later (3 to 8 weeks).

Animals↗
PubMed1984

Therapy with investigational antiarrhythmic drugs.

The investigational antiarrhythmic agents available for use in this country are predominantly class I drugs with local anesthetic membrane effects. These drugs are often used successfully to control arrhythmias refractory to treatment with the standard antiarrhythmic drugs. Side effects often limit their use, and particular attention needs to be paid to their cardiac side effects, such as exacerbation of arrhythmia or enhanced conduction defects.

Amiodarone↗
PubMed1984

Propafenone disposition kinetics in cardiac arrhythmia.

Propafenone disposition kinetics were studied after intravenous and oral doses in patients with ventricular arrhythmias. Plasma concentration-time data were fit to a two-compartment model for all but one patient, whose data required fitting to a three-compartment model. The model-independent calculated values of clearance, steady-state volume of distribution, and terminal t1/2 were 11.2 +/- 4.8 ml/min/kg, 3.6 +/- 2.1 l/kg, and 5.0 +/- 3.6 hr. After 5 days on oral propafenone, elimination t1/2 was 6.2 +/- 3.3 hr. The longer t1/2s and the estimates of steady-state bioavailability above 100% suggests that clearance decreases during chronic oral dosing. Considerable intersubject variability was noted in all disposition parameters.

Adult↗
PubMed1984

Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.

Action Potentials↗
PubMed1983

Methods for documenting antiarrhythmic efficacy.

Methods of documenting the efficacy of antiarrhythmic drugs are controversial because of wide inter- and intrasubject variability of the arrhythmias treated. In patients with symptomatic arrhythmias, clinical benefit can be inferred when symptoms are reduced or abolished, but the response cannot be quantitated. Multiple ambulatory monitoring periods before and during treatment permit determination of reductions of arrhythmia to levels of statistical significance but are costly and time-consuming. Programmed electrophysiologic induction study may be helpful in determining efficacy of some antiarrhythmic agents because of its high specificity, but its use is limited because of a low sensitivity. Titrating patients with multiple dosing into accepted plasma level therapeutic ranges may be helpful for individual patient care but does not allow quantitation. Recently, a statistical model based on linear regression analysis with established 95 and 99% confidence intervals has been used to compare efficacy of quinidine and encainide with success. Wider application of this model is suggested for determining antiarrhythmic drug efficacy.

Ambulatory Care↗
PubMed1983

Calcium overload, "injury" current, and early ischaemic cardiac arrhythmias--a direct connection.

Intracellular calcium ions induce a depolarising inward current by reacting with specific sites on the inner surface of cardiac muscle cell membranes. Since intracellular calcium overload invariably occurs with myocardial ischaemia, it may be that the early electrophysiological manifestations of ischaemia, including cellular depolarisation, diastolic current flow, and early ischaemic arrhythmias, are directly mediated by calcium. A simple explanation for the effects of many drugs upon the electrical behaviour of ischaemic myocardium is proposed.

Adrenergic beta-Antagonists↗
PubMed1983

Study of the normal and failing isolated human heart: decreased response of failing heart to isoproterenol.

We evaluated the effects of isoproterenol in right ventricular papillary muscles derived from normal and failing isolated human hearts. Basal values for the peak force developed, rate of force development (dF/dt), and time to peak tension (TPT) were similar in both groups. Isoproterenol produced a significantly smaller (p less than 0.05) increase in peak force developed and dF/dt in failing papillary muscles. The half equivalent dose (ED50) of isoproterenol was fivefold higher in failing muscle as compared to normal muscle. We conclude that failing cardiac muscle demonstrates decreased responsiveness to beta-receptor mediated stimulation.

Adolescent↗
PubMed1983

Possible contribution of encainide metabolites to the long-term antiarrhythmic efficacy of encainide.

To establish long-term efficacy and the relation between drug plasma concentration and antiarrhythmic response, 12 patients with encainide-responsive frequent complex ventricular ectopic activity underwent 1 year of therapy with encainide. Twenty-four hour ambulatory electrocardiograms were obtained at baseline and every 2 months. Drug withdrawal with concomitant plasma sampling and electrocardiographic monitoring was performed at 6 and 12 months. Average group premature ventricular contraction (PVC) suppression during the year was 97 to 99%, with nearly total suppression of pairs and salvos. The most common adverse effects were transient visual disturbances and dizziness or lightheadedness. During a dose interval (6 to 12 hours) the concentration of encainide metabolites exceeded that of encainide by several-fold. The median time of arrhythmia return after drug withdrawal was 12 to 14 hours. At the time of arrhythmia return encainide was generally no longer detectable but the average concentration of O-demethylencainide and 3 methoxy-O-demethylencainide was 72 +/- 49 and 172 +/- 74 ng/ml, respectively. It is concluded that encainide therapy is extremely effective for continuous long-term suppression of complex ventricular arrhythmias and its metabolites contribute significantly to its antiarrhythmic action during chronic oral therapy.

Adult↗
PubMed1983

Clinical pharmacology of propafenone.

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.

Adult↗
PubMed1983

Beneficial effects of beta blockers: a class action or individual pharmacologic spectrum?

Beta-adrenergic blockers have several physiologic and pharmacologic actions that are due to a class action resulting from competitive blockade of cellular receptors. However, they have other actions that are due to an individual spectrum of pharmacologic activity. These may be due to pharmacologic differences, such as cardioselectivity, membrane-stabilizing activity, and intrinsic sympathomimetic activity, or to disease-specific responses of patients.

Adrenergic beta-Antagonists↗
PubMed1982

Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts.

To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.

Adenylyl Cyclases↗