Physostigmine in coma due to drug overdose.
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Adult↗
Biomedical subjects
S Nattel
Publications and source records attributed to S Nattel.
Mechanism of propranolol withdrawal phenomena.
Nine patients on chronic treatment with propranolol for essential hypertension for 3 months or longer were studied after abrupt discontinuation of the drug. Each patient demonstrated transient supersensitivity to the chronotropic effects of isoproterenol, beginning 2--6 days (median 4 days) after propranolol withdrawal, lasting for 3--13 days (median 6 days), with the maximum sensitivity on day 6. A significantly lower dose of isoproterenol was necessary to increase heart rate 25 beats/min on day 6 (median dose 1.2 microgram, range 0.3--3.4 microgram) compared with after day 14, when sensitivity had stabilized (median dose 2.3 microgram, range 1.4--7.6 microgram). Six patients had transient symptoms (headache, chest pain, palpitations and sweating) after abrupt propranolol withdrawal, coinciding with supersensitivity to isoproterenol in five. Transient increases in plasma catecholamines and blood pressures and sustained increases in heart rate occurred during the period of isoproterenol supersensitivity in most patients, and may have contributed to symptoms noted. The delayed onset and potentially long duration of beta-adrenergic supersensitivity after abrupt propranolol withdrawal have important clinical implications.
Adult↗
Procainamide acetylation and disposition in dialysis patients.
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Acetylation↗
Safety of dipyridamole testing in 73,806 patients: the Multicenter Dipyridamole Safety Study.
BACKGROUND: Dipyridamole imaging is widely used as an alternative to exercise testing to identify and risk stratify patients with coronary artery disease. Safety data on intravenous dipyridamole stress testing has been derived largely from individual institutional data. METHODS AND RESULTS: Data were collected retrospectively by 85 coinvestigators from 73,806 patients who underwent intravenous dipyridamole stress imaging in 59 hospitals and 19 countries to determine the incidence of major adverse reactions during testing. The dose of dipyridamole infused was 0.56 mg/kg in 64,740 patients, 0.74 mg/kg in 6551 patients, and 0.84 mg/kg in 2515 patients. Combined major adverse events among the entire 73,806 patients included seven cardiac deaths (0.95 per 10,000), 13 nonfatal myocardial infarctions (1.76 per 10,000), six nonfatal sustained ventricular arrhythmias (0.81 per 10,000) (ventricular tachycardia in two and ventricular fibrillation in four), nine transient cerebral ischemic attacks (1.22 per 10,000), (with speech or motor deficit), one stroke, and nine severe bronchospasms (1.22 per 10,000) (one intubation and eight near intubations). In addition to the safety data, detailed demographic, peripheral hemodynamic, side effect, and concomitant drug data were examined in a subgroup of 3751 patients. End points from subsets of patients were compared with those of the group as a whole. Multivariate analysis revealed that dipyridamole-induced chest pain was more common in patients less than 70 years old (p = 0.0017), those with a history of coronary revascularization (p = 0.002), or patients taking aspirin (p = 0.0001). Minor noncardiac side effects were less frequent among the elderly (p = 0.0053) and more frequent in women (p = 0.0001) and patients taking maintenance aspirin (p = 0.0034). When a patient was judged on the basis of the adequacy of hemodynamic response to be a dipyridamole "nonresponder" (< 10 mm Hg drop in systolic blood pressure and 10 beats/min increase in heart rate), the only significant predictor was angiotensin-converting enzyme inhibitor intake (p = 0.0025). Inferoposterior hypoperfusion was significantly more frequent in patients with dipyridamole-induced hypotension: 57% (44/77) (p < 0.0001) of those who had hypotension and 89% (8/9) (p = 0.0076) who had severe symptomatic bradyarrhythmias displayed inferoposterior defects on thallium scanning. Caffeine levels were determined in 391 consecutive patients: levels greater than 5 mg/L were observed in only eight patients (2%), suggesting that methylxanthine levels sufficient to alter the hemodynamic response to dipyridamole resulting in suboptimal hyperemic stress are unlikely when patients take nothing by mouth after midnight. CONCLUSION: The risk of serious dipyridamole-induced side effects is very low and is comparable to that reported for exercise testing in a similar patient population.
Adult↗
Relationship between an arrhythmogenic action of lidocaine and its effects on excitation patterns in acutely ischemic porcine myocardium.
To investigate the relationship between the effects of lidocaine on excitation patterns and its effects on the incidence of arrhythmias, the left anterior descending coronary artery was occluded for 6-min periods separated by 30 min of reperfusion, under control conditions and after injection of lidocaine, at a dose of either 2.5, 5.0, or 10.0 mg/kg i.v., in 29 open-chest anesthetized pigs. Sixty-three unipolar electrograms and a surface lead electrocardiogram were continuously recorded during atrial pacing and spontaneous ventricular arrhythmias. Ventricular fibrillation (VF) occurred only in four of a total of 45 control occlusions. VF occurred in two of five pigs following injection of lidocaine 2.5 mg/kg, in 15 or 17 pigs following injection of a 5 mg/kg dose, and in all three preparations following injection of a 10 mg/kg dose. Just prior to VF during occlusions preceded by injections of lidocaine 5 mg/kg, activation time of ischemic myocardium in atrial-paced beats was delayed by only 30 +/- 17 ms beyond preocclusion values, compared with 18 +/- 11 ms at a similar time during control occlusions and 33 +/- 18 ms at the end of control occlusions (mean +/- SD; n = 8). As ventricular tachycardia (VT) developed in the presence of lidocaine, conduction was further slowed or blocked in ischemic areas, and slowed in nonischemic regions; at the transition from VT to VF, excitation patterns displayed circus movement involving nonischemic regions.
Animals↗
Effects of probucol on vascular remodeling after coronary angioplasty. Multivitamins and Protocol Study Group.
BACKGROUND: We have shown that probucol reduces restenosis after balloon angioplasty. Whether probucol acted via prevention of neointimal formation or improvement in vascular remodeling could not be addressed by angiography and required the use of intravascular ultrasound (IVUS). METHODS AND RESULTS: Beginning 30 days before angioplasty, 317 patients were randomly assigned to receive probucol, multivitamins, combined treatment, or placebo. Patients were then treated for 6 months after angioplasty. IVUS examination was performed immediately after angioplasty and at follow-up in 94 patients (111 segments). The cross section selected for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. In the placebo group, lumen area decreased by -1. 21+/-1.88 mm2 at follow-up, and wall area and external elastic membrane (EEM) area increased by 1.50+/-2.50 and 0.29+/-2.93 mm2, respectively. Change in lumen area, however, correlated more strongly with the change in EEM area (r=0.53, P=0.002) than with the change in wall area (r=-0.13, P=0.49). Lumen loss was -1.21+/-1.88 mm2 for placebo, -0.83+/-1.22 mm2 for vitamins, -0.25+/-1.17 mm2 for combined treatment, and -0.15+/-1.70 mm2 for probucol alone (P=0.002 for probucol, P=0.84 for vitamins). Change in wall area was similar for all groups. EEM area increased by 0.29+/-2.93 mm2 for placebo, 0. 09+/-2.33 mm2 for vitamins only, 1.17+/-1.61 mm2 for combined treatment, and 1.74+/-1.80 mm2 for probucol only (P=0.005 for probucol). CONCLUSIONS: Lumen loss after balloon angioplasty is due to inadequate vessel remodeling in response to neointimal formation. Probucol exerts its antirestenotic effects by improving vascular remodeling after angioplasty.
Angioplasty, Balloon, Coronary↗
Pharmacodynamic studies of amiodarone and its active N-desethyl metabolite.
Electrophysiologic effects of the N-desethyl metabolite of amiodarone have been postulated to explain differences between the effects of acute and chronic amiodarone administration. To compare the effects of amiodarone and desethylamiodarone, each agent was administered to Sprague-Dawley rats, and the relationship between plasma drug concentrations, measured by high-pressure liquid chromatography (HPLC), and changes in electrocardiographic intervals was observed. Both drugs produced concentration-related increases in QRS, QT, and QTc intervals. Desethylamiodarone altered these variables with a potency significantly greater than that of amiodarone after both single-dose and chronic (for 1 or 4 weeks) therapy. In contrast, chronic administration of amiodarone (but not of desethylamiodarone) produced concentration-related increases in RR and PR intervals. Some of the potency differences between these agents may have been due to greater myocardial concentration of desethylamiodarone as compared to amiodarone. These experiments suggest that desethylamiodarone has potentially important electrophysiologic effects, differing in some respects from those of the parent compound. The accumulation of desethylamiodarone in patients chronically treated with amiodarone may result in significant electrophysiologic changes.
Adipose Tissue↗
Experimental amitriptyline intoxication: electrophysiologic manifestations and management.
Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.
Amitriptyline↗