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Biomedical subjects

P Dorian

Publications and source records attributed to P Dorian.

At least 109 records · Page 6Linked to original sources
PubMed1989

DL and D sotalol decrease defibrillation energy requirements.

We examined the acute effects of intravenous DL and D sotalol on the energy requirements for internal defibrillation (DF) in 44 dogs anesthetized with pentobarbital (n = 18), enflurane (n = 8), and fentanyl (n = 18). Multiple shocks of varying energies were applied through left and right ventricular epicardial patch electrodes to relate delivered energy to percent success in DF. The energies required for 50% success in DF (E) were estimated by logistic regression. DL or D sotalol was administered in a loading (4 mg/kg over 10 min) and maintenance (1.5 mg/kg/hr) infusion and the energy--success curve was again measured 30 minutes after drug administration. The effect of DL and D sotalol on E50 was compared to controls given saline. Both DL and D sotalol significantly lowered E50 by 16% +/- 14% (P less than 0.05) and 24.5% +/- 8.2% (P less than 0.05), respectively, in fentanyl anesthetized animals; this was accompanied by a 22% +/- 8% (P less than 0.05) and 16% +/- 5% (P less than 0.01) increase in ventricular effective refractory period (VERP), respectively. In pentobarbital anesthetized dogs, DL and D sotalol decreased E50 by 16% +/- 27% (P = ns) and 11% +/- 16% (P less than 0.05), respectively, and were associated with a 23% +/- 5% (P less than 0.01) and 12 +/- 4% (P less than 0.05) prolongation of VERP. DL and D sotalol decrease defibrillation energy requirements, possibly as a result of their Class III antiarrhythmic drug action.

Animals↗
PubMed1988

Effects of magnesium on ischemic and reperfusion arrhythmias in the rat heart and electrophysiologic effects of hypermagnesemia in the anesthetized dog.

Magnesium sulfate, reportedly clinically effective against some ventricular arrhythmias, has not been extensively studied for its effects on experimental ischemic and reperfusion arrhythmias. We evaluated the effects of three high extracellular concentrations of magnesium (Mg2+) 1.19, 2.38, and 4.76 mM in 70 isolated perfused rat hearts following coronary artery ligation and reperfusion, at each of three different perfusate ionized calcium (Ca2+) concentrations (0.9, 1.25, and, 2.5 mM), where 1.25 mM is close to physiologic. At 0.9 mM Ca2+, higher concentrations of Mg2+ increased the sinus node cycle length (p less than 0.02) and virtually abolished ischemic ventricular tachycardia (VT) and reperfusion ventricular fibrillation (VF) (p less than 0.01), otherwise consistently found in this model. At 1.25 and 2.5 mM Ca2+ increasing Mg2+ had no effect on the incidence of ischemic or reperfusion arrhythmias, although at 1.25 mM Ca2+ ischemic VT had longer cycle lengths and VT appeared after a longer delay (p less than 0.01). In the nonischemic dog heart, marked increases of serum Mg2+ progressively prolonged the A-H, H-V, and QR S intervals, the ventricular effective refractory period, and the sinus cycle length, while the arterial blood pressure fell. Because of its relatively modest electrophysiologic and hemodynamic effects, it is inferred that intravenous magnesium may be given therapeutically with relative safety.

Anesthesia↗
PubMed1988

Defibrillation current and impedance are determinants of defibrillation energy requirements.

The relationship between various electrical descriptors of shocks for cardiac defibrillation is incompletely understood. Defibrillating energy, current, impedance and pulse duration were measured in 18 dogs. They were subject to repeated fibrillation--defibrillation through epicardial patches, with shocks of preset energy and voltage and variable pulse duration, impedance and peak current. Current and energy requirements for defibrillation were calculated. Energy requirements were positively correlated with pulse duration and interelectrode impedance (r = .70, P less than 0.01). Correcting for heart weight, these correlations were no longer present. However, peak current was correlated with energy requirements both before (r = -0.62, P less than 0.05) and after (r = 0.76, P less than 0.01) correcting for heart weight, with energy requirement decreasing as peak current/g heart increased. Current requirements were significantly less variable between animals than energy requirements (.027 +/- .012 joules/g vs .016 +/- .003 Amps/g), suggesting that current per unit heart weight may be a better descriptor than energy for the ability to defibrillate.

Animals↗
PubMed1988

Digoxin-cyclosporine interaction: severe digitalis toxicity after cyclosporine treatment.

Digoxin toxicity developed in two patients awaiting cardiac transplantation upon the initiation of cyclosporine. Toxicity was associated with elevated digoxin concentrations (10.6 and 5.7 nmoles/L), gastrointestinal symptoms, and arrhythmias classic for digoxin toxicity (bidirectional ventricular tachycardia and AV nodal block with accelerated junctional rhythm respectively). A previously unreported drug interaction between cyclosporine and digoxin was suspected and digoxin pharmacokinetics were studied in two additional patients both before and after cyclosporine therapy prior to cardiac transplantation. The study confirmed a significant interaction between cyclosporine and digoxin; the apparent volume of distribution of digoxin decreased by 71% and its plasma clearance decreased by 53%. Until further information regarding the cyclosporine-digoxin interaction is available, this combination should be used with great caution.

Coronary Disease↗
PubMed1987

The relationship between successful defibrillation and delivered energy in open-chest dogs: reappraisal of the "defibrillation threshold" concept.

The traditional assessment of the energy required for successful ventricular defibrillation involves the measurement of a "defibrillation threshold" (DFT), implying a clear-cut distinction between effective and ineffective energies. We examined the relationship between delivered energy and the likelihood of successful defibrillation in 10 open-chest pentobarbital anesthetized dogs, with the use of an internal spring/patch electrode system. An initial DFT was determined by decreasing the energy discharged until a failure first occurred (10.3 +/- 3.4 J). Six energy levels in 1 to 2 J increments were then selected surrounding this value and each was administered eight times in balanced random order (total 48 trials). The relationship between energy and percent success in defibrillation exhibited a shallow slope, with a gradual increase in success from 0% to 100% over several energy increments. The initial DFTs showed actual success rates varying from 25% to 87.5% (mean 71 +/- 26%). The results were fitted to a sigmoidal dose-response curve by logistic regression analysis and the energy associated with 50% success (E50) and 80% success (E80) was determined, as no single value for DFT could be defined in any animal. In 12 other dogs, a defibrillation curve was similarly constructed at baseline and was repeated after 90 minutes. No significant change in E50 (5.0 +/- 2.1 J vs 5.2 +/- 2.7 J) or E80 (6.3 +/- 2.5 J vs 6.6 +/- 3.2 J) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Ethmozine: electrophysiology, hemodynamics, and antiarrhythmic efficacy in patients with life-threatening ventricular arrhythmias.

Thirteen patients with drug-resistant, life-threatening ventricular arrhythmias and inducible sustained ventricular tachycardia (VT) at electrophysiologic study received moricizine HC1 (ethmozine), 10 mg/kg/day orally. Eight patients underwent electrophysiologic study before and after drug administration; the arrhythmia became noninducible in one. In five other patients, spontaneous sustained VT occurred after 1 to 5 days of drug therapy, and one patient had a worsening of arrhythmias on ethmozine. Ethmozine prolonged infranodal conduction time (HV interval) (51.4 +/- 13.8 msec to 69.3 +/- 17.7 msec [mean +/- SD]), PR interval (201 +/- 28.1 msec to 244 +/- 62.2 msec), and QRS interval (123 +/- 27 msec to 147 +/- 32 msec). Ventricular refractory periods were not consistently affected, and only the one patient who became noninducible had an increase in effective ventricular refractory period (280 to 310 msec). The drug had no significant effect on sinus cycle length or sinus node recovery time, atrial conduction or refractoriness, or atrioventricular nodal refractoriness. Ethmozine had no effect on radionuclide ejection fraction (25.5 +/- 12.7% to 28.2 +/- 13.8%) or cardiac index (2.4 +/- 0.7 to 3.0 +/- 0.6 ml/min/m2) and caused no significant changes in mean aortic, right atrial, pulmonary arterial, or pulmonary capillary wedge pressures. Although the drug is well tolerated and produces no untoward hemodynamic effects, ethmozine is relatively ineffective in patients with sustained VT refractory to conventional antiarrhythmic agents.

Adult↗
PubMed1986

Effect of quinidine and bretylium on defibrillation energy requirements.

We examined the effect of bretylium and quinidine on the energy requirements for internal defibrillation in 14 pentobarbital-anesthetized dogs. Bretylium, 6 or 10 mg/kg (n = 6), did not affect the relation between energy and the likelihood of successful defibrillation. The mean energy required to achieve 50% success (E50) or 90% success (E90) in defibrillation was not significantly altered; E50 was 5.3 +/- 1.9 J (X +/- s.d) before and 6.1 +/- 3.5 J after bretylium (n.s.), and E90 was 7.2 +/- 2.1 J before and 8.6 +/- 3.3 J after drug (n.s.). Quinidine was administered in a series of two loading and maintenance infusions to achieve mean plasma concentrations of 2.4 +/- 0.63 and 2.95 +/- 0.88 microgram/ml, respectively (n = 8). No significant effect on defibrillation energy requirement was observed; mean E50 before and after treatment was 6.3 +/- 3.3 J and 6.2 +/- 2.9 J, respectively, and mean E90 was 8.3 +/- 4.4 J and 8.3 +/- 4.1 J, respectively. Similarly, saline administration to control dogs (n = 12) resulted in no change in E50 or E90. At concentrations or doses similar to those in patients with serious arrhythmias, neither quinidine nor bretylium appears to have consistent effects on the energy requirements for internal defibrillation in our dog model.

Animals↗
PubMed1986

Lidocaine causes a reversible, concentration-dependent increase in defibrillation energy requirements.

To investigate the influence of lidocaine on the energy requirements for internal defibrillation, lidocaine (n = 8) or saline solution (n = 12) was administered by intravenous infusion to 20 pentobarbital-anesthetized dogs, and the likelihood of successful defibrillation was examined at various shock energy levels before and after treatment. After lidocaine administration to a mean steady state concentration of 5.6 +/- 2.7 micrograms/ml, the mean energy required to achieve 50 and 90% success in defibrillation (E50 and E90) increased by 61.1 +/- 34.1% (mean +/- SD, p less than 0.005) and 47.1 +/- 28.6% (p less than 0.005), respectively. The steady state log lidocaine concentration correlated positively with the observed increase in E50 (r = 0.887, p less than 0.01) over a concentration range from 1.95 to 9.8 micrograms/ml. In a related experiment, lidocaine infusion was administered to five dogs and then abruptly discontinued. At energy levels achieving a mean 90.0 +/- 10.0% success in defibrillation before treatment, only 43.3 +/- 23.4% success was achieved after 60 minutes of the lidocaine infusion (p less than 0.01) at a mean plasma concentration of 8.4 +/- 2.1 micrograms/ml. The percent of successful defibrillations returned to baseline value (92.0 +/- 18.0%, p less than 0.01) after drug washout at a time when mean lidocaine concentration had declined to 1.8 +/- 0.5 microgram/ml. Lidocaine causes a reversible, concentration-dependent increase in the energy requirements for successful defibrillation; recommendations to administer lidocaine to patients with ventricular fibrillation resistant to defibrillation may need to be reviewed.

Animals↗
PubMed1986

Effects of encainide and its metabolites on energy requirements for defibrillation.

Encainide, a class IC antiarrhythmic agent, has been associated with proarrhythmic responses of ventricular tachycardia and fibrillation requiring defibrillation in patients. We examined the short-term effects of intravenous encainide and its two major metabolites, O-demethyl-encainide (ODE) and 3-methoxy-ODE (MODE), on the energy requirements for successful defibrillation in 25 pentobarbital-anesthetized, open-chest dogs. Truncated exponential (60% tilt) defibrillation shocks were administered through right atrial spring and left ventricular epicardial patch electrodes identical to those used in man with the automatic implantable defibrillator. At baseline multiple shocks of varying energy were applied to construct curves of percent successful defibrillation as a function of energy (DF curves) for each animal. Encainide, ODE, or MODE was then infused in loading and maintenance doses to achieve QRS widening of 20% to 50%. Saline was administered to animals serving as controls. Determination of the DF curve was repeated, after which the infusion was discontinued. After 1 hr washout period, an additional DF curve was constructed. The data were analyzed by logistic regression, and the energies required for 50% successful defibrillation (E50) were compared. No significant differences existed between the four groups in body or heart weight, extent of QRS widening, or baseline E50 values. After administration of encainide and ODE, the E50 increased by 129 +/- 43% (p less than .001) and 76 +/- 34% (p less than .005), respectively. Return of E50 toward baseline was observed after the washout periods in both groups (p less than .025), demonstrating the reversibility of the drugs' effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1986

Qualitative and quantitative comparison of the cardiac effects of encainide and its three major metabolites in the dog.

We have evaluated the electrophysiologic effect of encainide and its three major metabolites, O-demethyl encainide, 3-methoxy-O-demethyl encainide and N-demethyl encainide in an anesthetized dog model. Our results support previous reports that O-demethyl encainide and 3-methoxy-O-demethyl encainide are both more potent than encainide in the depression of conduction. We also have shown that N-demethyl encainide is of about equal potency to encainide. Whereas the major differences between these compounds is primarily one of potency, there are some qualitative differences. Although O-demethyl encainide did not change the ventricular or atrial effective refractory periods significantly, 3-methoxy-O-demethyl encainide and N-demethyl encainide prolonged both. Encainide increased the atrial effective refractory period but did not produce significant changes in the ventricular refractory period. These data support previous suggestions of an important role for these metabolites as modulators of the clinical efficacy of encainide.

Anilides↗
PubMed1985

Triazolam and ethanol interaction: kinetic and dynamic consequences.

The kinetic and dynamic consequences of the coadministration of triazolam and ethanol were investigated in six normal subjects. Each received three treatments: triazolam, 0.25 mg by mouth, preceded by 1 hour and followed for 7.5 hours by oral ethanol dosed to maintain breath concentrations of 800 to 950 mg/L; placebo and ethanol; and triazolam and orange juice. After ethanol, triazolam total AUC0-infinity increased (mean +/- SD = 21% +/- 18%). Subjects showed greater psychomotor impairment on measures of free recall, postural stability, and hand-eye coordination after the combination than after either drug alone. These dynamic interactions are greater than the kinetic changes.

Administration, Oral↗
PubMed1985

Is there acute tolerance to alcohol at steady state?

Although acute tolerance to the psychomotor impairment caused by alcohol has been documented in single-dose studies, the pharmacodynamic effects of continued alcohol administration in humans have not been well studied. Six nonalcoholic men received alcohol to achieve and maintain breath alcohol levels of 80-100 mg/dl for 6 hr. The men suffered an initial impairment in word recall but improved over the next 6 hr. Measures of standing steadiness and manual tracking did not show evidence of the development of tolerance. This lack of tolerance was reflected in subjects' self-assessments of sedation and intoxication.

Adult↗
PubMed1984

Ethanol-induced inhibition of hepatic uptake of propranolol in perfused rat liver and in man.

Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol (mean = 40.1 mmol/l diminished the clearance of dl-propranolol (1.93 +/- 0.43 to 1.24 +/- 0.22 ml/min/g liver, p less than 0.05); increased its t1/2 (12.8 +/- 1.5 to 20.7 +/- 3.25 min, p less than 0.01); and decreased the proportion metabolized (68.7 +/- 4.7% to 34.3 +/- 10.3%, p less than 0.01). These results suggest that ethanol could substantially increase the oral bioavailability of propranolol in humans. However, in normal human volunteers administered 80 mg of propranolol orally, alone, or preceded and followed by ethanol to maintain breath ethanol concentrations of 800-1000 mg/l, increases in propranolol AUC were smaller than anticipated. Seven subjects had increases in free propranolol AUC0-8h (32%, range: 12-61%) (p less than 0.05), while total propranolol AUC0-8h increased by a mean 22% (range: -4-+49%). Propranolol free fraction varied with time and was higher after ethanol (mean = 0.090 vs 0.084) (p less than 0.077). The extent of the propranolol-induced slowing of heart rate was not influenced by ethanol (mean decrease from baseline of 13 bpm at peak propranolol effect vs 9 bpm without ethanol); mean heart rates following propranolol with ethanol were higher at all times (mean of 7.5 bpm) (p less than 0.001) than after propranolol alone. Ethanol inhibits the hepatic oxidative metabolism of propranolol in vitro; however, any effect on heart rate of higher concentrations of propranolol induced by ethanol in humans is offset by the cardio-acceleratory effect of ethanol.

Animals↗
PubMed1983

Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction.

Amitriptyline has clinically important interactions with ethanol. Five healthy volunteers received 25 mg of amitriptyline orally, preceded by one hour and followed for eight hours by oral ethanol (or juice), dosed to achieve and maintain blood ethanol concentrations of 800 mg/l. In the presence of ethanol, amitriptyline free plasma concentrations were increased by a logarithmic mean of 204%, 186% and 127% at 1.5, 2, and 2.5 h, respectively, and amitriptyline free AUC0-8h was increased by 48% +/- 13% (means +/- SEM) (t = 5.21, p less than 0.01). Nortriptyline total AUC0-8h was increased by 26.6% +/- 12% (means +/- SEM) (t = 2.21, p less than 0.09). At the time of peak amitriptyline plasma concentrations, mean postural sway was increased over baseline by 92% with, and 2% without ethanol; likewise, mean short term memory (word recall) was decreased over baseline by 71% with, and 37% without ethanol. Ethanol increases free amitriptyline plasma concentrations most dramatically during the period of drug absorption; this is due to a decrease in amitriptyline hepatic clearance, resulting in decreased first-pass extraction. Together with the pharmacodynamic interaction, the kinetic changes provide a rationale for the toxicity of this combination and its deleterious effects on psychomotor skills.

Adult↗
PubMed1983

Effect of alcohol on propylthiouracil disposition.

We examined the effect of ethanol on propylthiouracil (PTU) disposition in normal subjects and a rabbit. The drug is metabolized by conjugation. In six normal subjects 19.2 gm oral ethanol, taken either with or two hr after 300 mg PTU, did not change maximum concentration, time to maximum concentration, or total or free AUC of PTU. Pretreatment with ethanol and supplementation to keep blood ethanol concentration above 800 mg/l for 8 hr also did not alter PTU disposition. In the rabbit, the infusion of ethanol (8.81 mg/min) 4 hr after the beginning of an intravenous infusion of PTU 0.05 mg/min did not alter the plasma concentration profile. These results indicate that short-term ethanol dosing does not affect PTU disposition and therefore dosage adjustment is not necessary in patients who drink alcohol.

Administration, Oral↗
PubMed1983

Evaluation of zopiclone physical dependence liability in normal volunteers.

The potential of zopiclone, a non-benzodiazepine sedative hypnotic, to induce physical dependence in normal human volunteers was investigated. 9 male subjects (age range 21-39 years) participated in a 56-day double-blind study with random assignment to initial treatment A or B: (A) zopiclone 7.5 mg p.o. nightly for 21 days followed by placebo for 7 days, and (B) placebo nightly for 21 days followed by placebo for 7 days. Heart rate, blood pressure, hand tremor and auditory-evoked EEG were repeatedly measured during the withdrawal periods. No differences in any of these variables between phases were found (beta = 0.90 for mean differences of 16% between phases). Subjects slept longer (mean 28 min, p less than 0.013) on zopiclone than on placebo. Symptoms of state anxiety were greater on days 2 and 4 after discontinuing zopiclone compared to all other withdrawal days (p less than 0.0021). The mean relative increase on days 2 and 4 was 30%. Sleep depth (self-rating scale) was no deeper on drug than on placebo, but during the withdrawal phases, sleep was less deep on days 2 and 4 of withdrawal from zopiclone compared to all other withdrawal days (p less than 0.0001). Subjects were unable to identify the pattern of drug administration on withdrawal, and none reported important symptoms. Discontinuation of zopiclone (7.5 mg for 21 days) is associated with detectable increase in state anxiety and lighter sleep on days 2 and 4 of withdrawal. Quantitatively, similar changes occur with other hypnotic drugs of relatively low dependence liability.

Adult↗