Effect of propranolol on ventricular repolarization and refractoriness: Role of beta-blockade versus direct membrane effects

Summary The purpose of this study was to define the role of beta-adrenergic blockade and direct membrane effects in the ability of dl-propranolol to alter ventricular repolarization and refractoriness in the intact heart. The effective refractory period (ERP) and the local Q-T interval were measured at an epicardial site in the left ventricle in 14 open-chest dogs anesthetized with alpha-chloralose. Beta-adrenergic influences were eliminated in seven dogs (group 1) by stellate transection and nadolol (0.5 mg/kg IV), and enhanced in seven dogs (group 2) by stellate transection and stimulation of the left ansae subclavia. Each dog received an initial beta-blocking dose of propranolol (0.5 mg/kg) followed by a second, cumulative dose of 5.0 mg/kg. In group 1 dogs, there was no significant change in either the ERP or local Q-T interval in response to the first dose of propranolol. In group 2 dogs, left stellate stimulation significantly shortened the ERP (20±2 msec) and the local Q-T interval (17±4 msec). The first dose of propranolol prolonged these parameters to values not different from prestimulation control values. There was no change in the H-V interval, QRS complex duration, or diastolic threshold (DT) in either group after the initial propranolol dose. The second dose of propranolol significantly shortened the ERP (5±1 msec) and the local Q-T interval (11±2 msec) in both groups. This dose also significantly increased the DT, H-V interval, and QRS complex duration. In three additional nadolol-treated dogs, a single 5 mg/kg dose of propranolol shifted the entire strength-interval curve 4 to 7 msec earlier into electrical diastole. The data indicate that a beta-blocking dose of propranolol prolongs repolarization and refractoriness only when adrenergic input is elevated. In the absence of beta-adrenergic influences, high doses of propranolol shorten repolarization and refractoriness. This latter effect may be due to a direct membrane effect of the drug.     

Ventricular monophasic action potential changes associated with neurogenic T wave abnormalities and isoproterenol administration in dogs

Changes in the duration of monophasic action potentials on the anterior and posterior walls of the dog ventricle were correlated with changes in T wave polarity and duration of the Q-T interval after (1) left stellate ganglion transection, (2) right stellate ganglion stimulation, and (3) administration of isoproterenol before or after these procedures. Left stellate ganglion transection and right stellate ganglion stimulation produced similar changes in T wave polarity, but the former prolonged and the latter shortened the Q-T interval. All procedures changed the duration of the monophasic action potential and the Q-T interval in the same direction. The reversal of T wave polarity induced by left stellate ganglion transection, right stellate ganglion stimulation or administration of isoproterenol after left stellate ganglion transection was associated with an average change of 13 to 17 msec in the difference between the monophasic action potential durations on the anterior and posterior ventricular walls.Isoproterenol restored to normal the neurogenic T wave abnormalities produced by left stellate ganglion transection and right stellate ganglion stimulation. The drug shortened the previously prolonged monophasic action potential more than the normal monophasic action potential, and the normal monophasic action potential more than the previously shortened monophasic action potential. This study confirms that the T wave is a sensitive indicator of relatively small changes (less than 20 msec) in the sequence of ventricular repolarization and explains the mechanism by which isoproterenol “normalizes” the primary T wave abnormalities.     

Acute electrophysiologic effects of an HT2-serotonin antagonist,ketanserin, in humans

Summary The acute electrophysiologic effects of an intravenous bolus of ketanserin, a 5HT₂ serotonin blocker, were studied in ten patients (four females, six males) during invasive electrophysiology. Following baseline electrophysiologic measurements during sinus rhythm and fixed-rate atrial pacing at 600 ms, a bolus of 0.2 mg/kg ketanserin was given over a 3-minute period. After 30 minutes all measurements were repeated. Systemic blood pressure was measured at regular intervals throughout. During sinus rhythm, there was no significant change in the basic cycle length or in the PA, AH, HV, QRS, QT, and QTc intervals. During atrial pacing there was a nonsignificant increase in the QT interval, from 342±13 ms to 366±16 ms, and a significant increase in the QTc interval, from 422±27 ms to 449±29 ms (p<0.05). There was no reduction in blood pressure. Thus ketanserin produced a significant prolongation of the QTc interval, in the absence of hypokalemia, in humans.     

Electrophysiologic effects of cibenzoline in humans related to dose and plasma concentration

The electrophysiologic effects of a new antiarrhythmic agent, cibenzoline, were investigated in 25 patients with an average age of 62 years. The compound was administered intravenously, as a bolus given over 2 minutes, then as a slow infusion over 40 minutes. Each subject was randomly allocated to receive one of the following four doses: 1.55 mg/kg (six patients), 1.8 mg/kg (six patients), 2.2 mg/kg (six patients), or 2.6 mg/kg (seven patients). Plasma cibenzoline concentrations at these doses were 378 +/- 80,525 +/- 194, 618 +/- 72, and 731 +/- 196 ng/ml, respectively. Administration of 1.55 mg/kg cibenzoline significantly shortened the sinus cycle (60 msec on average; p less than 0.025) and increased intraatrial (+8 msec; p less than 0.05) and His-Purkinje conduction times (HV interval + 13 msec; p less than 0.001). At 1.80 mg/kg, prolongation occurred in the HV interval (+9 msec; p less than 0.02), the duration of the QRS complex (+20 msec; p greater than 0.05), and the QT interval (+18 msec; p less than 0.025). At the higher doses these changes became more marked (maximum increase: HV = +16 msec, p less than 0.001; QRS + 25 msec; p less than 0.001; QT + 26 msec, p less than 0.05), and additional effects on atrioventricular nodal conduction time (AH interval + 17 msec; p less than 0.05) and atrial (+20 msec; p less than 0.05) and ventricular (+10 msec; p greater than 0.05) effective refractory periods were observed. Prolongation of the QRS duration was the effect that correlated best with plasma cibenzoline levels (r = 0.47; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Intravenous Enoxaparin and Intravenous Inogatran in an Electrolytic Injury Model of Venous Thrombosis in the Dog

The objective of this study was to compare the effectiveness of the low molecular weight heparin, enoxaparin (Lovenox®), and inogatran (a direct thrombin inhibitor) in a canine electrolytic injury model of venous thrombosis. Effectiveness was defined as the ability of either drug to prolong the following parameters: activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombin time (PT), and time to formation of an occlusive thrombus in the vein. There were 5 dogs and 10 vessels for each group (the right and left femoral veins were used in each dog to measure time to occlusion). Dogs were randomly assigned to one of six groups: (1) saline controls; (2) low-dose inogatran (0.075 mg/kg IV bolus followed by a 5 g/kg/min infusion); (3) mid-dose inogatran (0.25 mg/kg IV bolus followed by a 20 g/kg/min infusion); (4) high-dose inogatran (0.75 mg/kg IV bolus followed by a 50 g/kg/min infusion); (5) low-dose enoxaparin (100 units/kg IV bolus followed by a 50 U/kg/h infusion); and (6) high-dose enoxaparin (200 U/kg IV bolus followed by a 100 U/kg/h infusion). Administration of inogatran resulted in dose-dependent increases in aPTT, TT, and PT, and administration of enoxaparin resulted in dose-dependent increases in aPTT and TT. There were no changes in hemodynamics. The time to occlusion in the control group averaged 81.7 ± 9.9 minutes compared with 141.8 ± 12.7, 185.8 ± 17.6, and 226.9 ± 8.8 minutes with the low, mid, and high doses of inogatran, and 131 ± 20.3, and 183.0 ± 19.0 minutes with the low and high doses of enoxaparin. Bleeding times were elevated by inogatran and enoxaparin, but no appreciable differences were detected between the two compounds. In summary, the direct thrombin inhibitor inogatran, administered intravenously, was as effective as the low molecular weight heparin enoxaparin in a canine model of venous thrombosis induced by electrolytic injury, supporting the conclusion that direct antithrombins may prove useful for prevention and treatment of deep venous thrombosis.     

Acute Hemodynamic Effects of Amlodipine 15 Days After a Myocardial Infarction in Normotensive Patients Treated with Atenolol

The acute hemodynamic effects of 20 mg iv amlodipine were evaluated in a placebo-controlled study in 16 normotensive patients 15 ± 1 days after an acute myocardial infarction by covariance analysis. Atenolol was given orally for at least 1 week before the study to maintain the heart rate between 50 and 60 beats/min. All patients were given two doses of 10 mg of amlodipine, or 10 ml of a placebo twice, in iv infusion lasting 2 minutes each. Hemodynamic data were collected during the control period and 15 minutes after each of the two amlodipine or placebo infusions. At the time of the last measurements, 15 minutes after the second amlodipine or placebo infusion, the plasma amlodipine level was 31 ± 16 g/l and the plasma atenolol level was 773 ± 564 /l in the amlodipine group versus 795 ± 916 g/l in the placebo group. There were no chronotropic, dromotropic, or inotropic effects. The main hemodynamic effect was a fall in systemic vascular resistance (1548 ± 591 dynes.sec.cm^-5to 1176 ± 526 dynes.sec.cm^-5, p = 0.045) with decreases in aortic pressure and in the left ventricular stroke work index. The left ventricular ejection fraction was 51 ± 12% in the placebo group and 56 ± 15% in the amlodipine group (ns) during the control period, and did not change after infusion of placebo or amlodipine. Left ventricular compliance seemed to be enhanced by amlodipine, because the end-diastolic left ventricular volume index rose from 82 ± 11 ml/m² to 87 ± 11 ml/m² (p = 0.026) 15 minutes after the beginning of the second infusion of 10 mg of amlodipine, without any change in end-diastolic left ventricular pressure. Intravenous infusion of 20 mg of amlodipine is well tolerated 15 days after acute myocardial infarction in normotensive patients without deeply depressed left ventricular systolic function and chronically treated with atenolol. The main hemodynamic effects observed are potentially useful for such patients.     

Prolongation of the human cardiac monophasic action potential by sotalol

Sotalol and propranolol are nonselective beta-adrenergic blocking agents. Sotalol at low concentration, unlike propranolol, prolongs the duration of the transmembrane action potential. In a double-blind study, the electrophysiologic effects of intravenous sotalol (0.30 or 0.60 mg/kg; n = 9) were compared with intravenous propranolol (0.15 or 0.20 mg/kg; n = 8) in 17 patients with use of bipolar suction electrodes in the right atrium and right ventricle to determine whether sotalol prolongs the monophasic action potential duration in man. After administration of sotalol, there were significant increases (paired t test) in the Q-T interval (p less than 0.001), right atrial effective refractory period (p less than 0.05), right ventricular effective refractory period (p less than 0.005), right atrial monophasic action potential duration at 90% repolarization (p less than 0.01), and right ventricular monophasic action potential duration at 90% repolarization (p less than 0.005). Prolongation of the monophasic action potential duration was dependent on plasma sotalol concentration. There were no significant changes in these variables after propranolol. The spontaneous cycle length and Wenckebach cycle length increased significantly in both groups, and the mean blood pressure decreased in both, although not significantly after propranolol. In summary, sotalol but not propranolol prolonged atrial and ventricular effective refractory periods and lengthened the monophasic action potential and the Q-T interval of human myocardium after intravenous infusion. The ability to acutely prolong repolarization at therapeutic plasma concentration is unique among known competitive beta-adrenergic receptor antagonists.     

Atrial Electrical Remodeling by Rapid Pacing in the Isolated Rabbit Heart: Effects of Ca++ and K+ Channel Blockade

Introduction: Electrical remodeling describes atrial electrophysiologic changes that occur following atrial fibrillation. The mechanism(s) responsible for this phenomenon is not well understood. The purpose of this study was to examine the effects of rapid atrial pacing on atrial action potential duration, conduction time and refractoriness in the isolated rabbit heart. The effects of Ca⁺⁺ and K⁺ blockade in this model were also studied.Methods and Results: Monophasic action potential recordings were made from 12 epicardial atrial sites in 50 isolated perfused rabbit heart preparations. These recordings were analyzed for activation time (AT), 90% action potential duration (APD) and conduction times (CT) measured at a 250 msec cycle length. Atrial effective refractory periods (ERP) were determined at a 200 msec cycle length. All measurements were made at baseline and repeated after 2 hours of biatrial pacing at 250 msec (control group, n = 10) or 2 hours of rapid biatrial pacing (80 msec) in 4 groups: rapid pacing alone (rapid pacing group); rapid pacing in the presence of 0.1mM verapamil (verapamil group) for L-type Ca⁺⁺ channel blockade; rapid pacing with 1 mM 4-aminopyridine (4-AP group) for K⁺ channel blockade; and rapid pacing with 50 M nickel chloride (Ni⁺⁺ group) for T-type Ca⁺⁺ channel blockade (n = 10 each group). All baseline and post pacing measurements were taken in the presence of Ca⁺⁺ or K⁺ blockers for the respective groups.After rapid atrial pacing alone the average APD shortened by 8.2±10.4 msec compared to 3.6±12.5 msec shortening for control group (p = 0.002). The shortening of APD was uniform at all recording sites. For the rapid pacing group, CT was unchanged for right to left atrial conduction but shortened significantly for left to right atrial conduction (26.8±1.9 msec at baseline to 22.3±4.1 msec post pacing, p = 0.005). Conduction times were unchanged in the control group. The dispersion of repolarization was unchanged by rapid pacing alone. The decrease in APD from baseline to post rapid pacing was similar to the control group for those hearts treated with verapamil and 4-AP (1.5±12.3 and 4.7±10.4 msec, respectively, both p 0.18 vs control group). The decrease in APD was significantly greater for the Ni⁺⁺ group (11.8± 14.3 msec) than for either the control group or rapid pacing group (both p 0.023). The dispersion of repolarization was increased only in the 4-AP group post rapid pacing (41.7±6.2 msec at baseline to 53.5±9.6 msec post pacing, p = 0.01). ERPs were unchanged in any of the 5 groups except for a decrease in left atrial ERP in the Ni⁺⁺ group after rapid pacing (98±14 msec at baseline to 88±8 msec post rapid pacing, p = 0.005).Conclusions: In the isolated rabbit heart model: 1) atrial APD is shortened after rapid pacing; 2) the shortening of APD is attenuated by verapamil and 4-AP but exaggerated by Ni⁺⁺ 3) atrial conduction times are shortened in a direction specific manner after rapid pacing; and 4) shortening of ERP in this model is measured only in the presence of Ni⁺⁺. These findings suggest that both L-type Ca⁺⁺ and 4-AP sensitive channels may participate in atrial electrical remodeling.     

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

Summary We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs)300/hr and Lown class 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200±189 ng/ml vs. 492±530 ng/ml; p<0.05) and for 5-hydroxy-propafenone (82±40 ng/ml vs. 149±80 ng/ml; p<0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r=0.91) or after chronic administration (r=0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations. In conclusion, a) the lower efficacy and delayed electrophysiologic effects of propafenone after intravenous administration suggest that longer infusion times are necessary for complete antiarrhythmic efficacy; b) the differences observed in the minimal effective concentrations of acute versus chronic oral therapy suggest the development of partial tolerance to propafenone during chronic treatment.     

Electrophysiologic Effects of Endothelin Receptor–A Blockade in Patients with Coronary Artery Disease

Selective endothelin receptor-A antagonists are a promising new treatment in patients with heart failure and/or pulmonary hypertension. Animal studies have suggested that these agents may have additional cardiac electrophysiologic actions, however, no data exist in man. We examined the effects of acute endothelin receptor-A blockade on the sinus node, the atrioventricular node and on the ventricular myocardium, in patients with single-vessel coronary artery disease and preserved left ventricular function. The selective endothelin receptor-A antagonist BQ-123 was administered by the intracoronary route, in order to achieve maximum local cardiac effects.After endothelin receptor-A blockade, QT interval increased from 373 ± 30 msec (mean ± SD) to 395 ± 20 msec (p < 0.01) and QTc interval increased from 394 ± 36 msec to 421 ± 28 msec (p < 0.01). QT-dispersion, calculated from 12-lead ECG, decreased from 40 ± 18 msec to 24 ± 8 msec (p < 0.01) and QTc-dispersion decreased from 44 ± 20 msec to 26 ± 9 msec (p < 0.05). These changes were evident only after infusion in the left, but not in the right coronary artery. No effect was found on the sinus node, the atrioventricular node, or the ventricular effective refractory periods.We conclude that selective endothelin receptor A blockade lengthens ventricular repolarization and decreases its inhomogeneity. Further studies are needed to evaluate possible antiarrhythmic actions of this class of agent.     

Pharmacokinetics and Hemostatic Effects of Saruplase in Patients with Acute Myocardial Infarction: Comparison of Infusion,Single-Bolus,and Split-Bolus Administration

Saruplase, or unglycosylated, single-chain urokinase-type plasminogen activator (scu-PA) selectively activates fibrin-bound plasminogen, and is subsequently converted to its two-chain derivative tcu-PA (urokinase) by plasmin. The efficacy of a 20 mg IV bolus followed by an infusion of 60 mg over 1 hour (standard regimen) has been demonstrated in acute myocardial infarction (AMI). The Bolus Administration of Saruplase in Europe (BASE) study compared the efficacy of standard therapy, single bolus (80 mg), and split bolus (2 × 40 mg at 30-minute intervals) in AMI. In a substudy of BASE, the pharmacokinetics of total u-PA activity (amidolytic activity after plasmin treatment), high molecular weight (HMW) u-PA antigen, and tcu-PA activity were compared in patients receiving standard therapy (n = 4), single bolus (n = 4), or split bolus (n = 5). Total u-PA activity and HMW u-PA antigen were similar. The maximum concentration (C_max,, mean ± SD) of total u-PA activity was 2.2 ± 0.3 µg/mL after standard therapy, 16.3 ± 3.9 µg/mL after single bolus, and 8.2 ± 1.6 ug/mL after split bolus. The area under the concentration versus time curve (AUC) values of total u-PA activity were 1.7 ± 0.1 µg/mL*h (standard therapy), 4.0 ± 0.9 µg/mL*h (bolus), and 3.0 ± 0.7 µg/mL*h (split bolus). The dominant initial half-lives (t^1/2 ) were 7.1 ± 1.1 minutes (standard), 8.8 ± 0.8 minutes (bolus), and 5.1 ± 2.1 minutes (split bolus). Maximum plasma concentrations of of tcu-PA activity were observed at 5.2 ± 7 minutes (standard), 21 ± 10 minutes (bolus), and 42 ± 2 minutes (split bolus). C_max was lowest after standard therapy (0.6 ± 0.3 µg/mL), highest after bolus (4.2 ± 2.2 µg/mL), and approximately twice as high as standard therapy after split bolus (1.3 ± 0.8 µg/mL). After standard therapy the mean fibrinogen concentration decreased gradually from approximately 300 mg/dL to 70 mg/dL at 90 and 120 minutes. After a single bolus the fibrinogen concentration decreased below the limit of quantification within 30 minutes and remained there for at least 120 minutes. Directly after the second 40 mg dose of the split bolus, the fibrinogen levels had an accelerated and more pronounced decrease to approximately 65 mg/dL at 90 and 120 minutes. A single bolus results in very high early total u-PA activity, which accelerates the appearance of tcu-PA activity and fibrinogen consumption. The pharmacokinetics and hemostatic effects of the split-bolus regimen are more comparable with those of standard therapy.     

Paget's disease of bone: Five regimens of pamidronate treatment

Summary The efficacy of five therapeutic regimens using (3-amino-1-hydro-xypropylidene)-1,1-bisphosphonate (APD or pamidronate) was assessed in patients with Paget's disease of bone. These regimens were as follows: (a) pamidronate 600 mg/day given orally during six months; (b) iv infusion of 20 mg daily for 10 days; (c) iv infusion of 40 mg daily for 5 days; (d) iv infusion of 10 mg daily for 4 days and (e) a single iv infusion of 10 mg. Six months after the initiation of therapy, urinary excretion of hydroxyproline and serum alkaline phosphatase activity (expressed as percent of their initial value) were: Group a: 30±10 (mean±SE) and 30±6, Group b: 55±8 and 46±6, Group c: 54±7 and 57±6, Group d: 53±7 and 69±4, and Group e: 85±10 and 98±4 respectively. Oral route was accompanied by digestive intolerance. On the contrary, except for rare and transient flu-like syndromes, the iv treatment was not associated with any serious secondary effect. Intravenous infusion of pamidronate, 20 mg for 10 days or 40 mg for 5 days, appears as an interesting alternative to the oral route in the treatment of Paget's disease of bone.     

Comparison of the pharmacokinetics and effects on the hemostatic system of saruplase and urokinase in patients with acute myocardial infarction

The aim of the study was to compare in a single trial, using identical methodology, the pharmacokinetic properties and the effect on the hemostatic system of saruplase (unglycosylated scu-PA) and urokinase (glycosylated tcu-PA). Twenty-four patients with an acute myocardial infarction were either treated with saruplase (n = 12; 20 mg IV bolus followed by a 60 mg infusion for 60 minutes) or urokinase (n = 12; 1.5 million IU IV bolus followed by 1.5 million IU infusion for 60 minutes). Blood samples from saruplase-treated patients were analyzed for u-PA antigen and total u-PA and tcu-PA activities; those from urokinase-treated patients for u-PA antigen and tcu-PA activity. The effect of treatment on, including recovery of, plasma ₂-antiplasmin, fibrinogen, and plasminogen was examined in both groups. The total clearance of urokinase (179 ± 55 ml/ min) is about half that of saruplase (406 ± 154 ml/min), and the mean residence time of urokinase (59.1 ± 22.5 minutes) is nearly twice that of saruplase (28.3 ± 7.8 minutes), which results in a slower elimination of urokinase from plasma. Whether differences in the pharmacokinetic behavior of the unglycosylated saruplase and the glycosylated urokinase observed in this study are due to the difference in glycosylation or to other factors is not resolved. The systemic effect of saruplase on ₂,-antiplasmin, fibrinogen, and plasminogen is similar to that of urokinase, although retarded.     

Effects of Sodium Channel Blockade on Ibutilide Induced Prolongation of Repolarization in the Isolated Rabbit Ventricle

Introduction: Ibutilide fumarate is indicated for the termination of atrial fibrillation and atrial flutter. It's mechanism of action is unclear but may involve activation of a late inward Na⁺ current. Methods and Results: Twenty seven experiments were performed using an isolated perfused rabbit right ventricle preparation. In each experiment effective refractory periods (ERP) and transmembrane 90% action potential durations (APD) were measured. In 8 experiments ERP and APD were measured at baseline, in the presence of ibutilide (0.1[emsp4 ]uM), and in the presence of both ibutilide and tetrodotoxin (TTX, 2[emsp4 ]uM). In 8 experiments lidocaine (10[emsp4 ]uM) was used in place of TTX. Measures were made at 200, 400, and 800[emsp4 ]msec paced cycle lengths under each condition. The baseline values for APD at 200, 400 and 800[emsp4 ]msec cycle lengths for the experiments treated with ibutilide and TTX were 111±8, 140±14 and 159±22[emsp4 ]msec, respectively. In the presence of ibutilide, APD increased to 130±19, 192±26 and 217±35[emsp4 ]msec at 200, 400 and 800[emsp4 ]msec cycle lengths, respectively (all p0.03). After the addition of TTX there was no shortening of APD or ERP compared to treatment with ibutilide alone at any cycle length (all p0.062). Similarly, in the presence of ibutilide and lidocaine there were no changes in APD or ERP compared to treatment with ibutilide alone (all p0.41). In 11 control experiments, there were no changes in APD or ERP on serial measures after placebo and TTX or lidocaine. Conclusion: Ibutilide induced prolongation of ventricular repolarization is not affected by Na⁺ channel blockade with lidocaine or TTX in the isolated rabbit heart. These findings suggest that the effects of ibutilide are not mediated by a Na⁺ channel dependent late current or that this mechanism contributes minimally to its action in this model.     

Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): Potent dose-dependent inhibition of platelet function

Summary The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPIIb/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20–0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25–0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (±SE) GPIIb/IIIa receptor blockade was 81±3%, ex vivo platelet aggregation in response to 20 µM ADP was 14±6% of baseline, and the median bleeding time was >20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.     

Oral dosing with ketanserin to control high blood pressure in the elderly

Summary Ketanserin is the prototype of a new class of antihypertensive drugs based on a selective blockade of serotonin S₂ receptors. A number of controlled trials have indicated that ketanserin is more effective in older than in younger subjects and that, in the elderly, ketanserin may be even more effective than other antihypertensive drugs. We set up a large multicenter trial to compare the two most common dosages of ketanserin (20 mg and 40 mg twice daily) in patients of 60 years of age and over. In these patients, blood pressures were elevated systolically (SBP160 mmHg), diastolically (DBP95 mmHg), or both, and any existing antihypertensive medication was continued at a constant dosage. The total duration of the trial was 3 months and monthly control visits were held. Throughout the Netherlands, 252 general practitioners participated in the trial, which included 462 evaluable patients. After 1 month of open treatment with 20 mg ketanserin twice daily, blood pressure was found to be fully normalized in 18% of patients, while the proportion of patients with both systolic and diastolic hypertension was reduced from 89% to 50%. In three out of four patients, an adequate and maximal fall in blood pressure was reached only after 2–3 months of treatment. In such patients, raising the ketanserin dose from 20 mg to 40 mg twice daily did not result in any faster or improved antihypertensive response. A number of symptoms related to peripheral circulatory disturbances, or possibly to hypertension itself, markedly improved during oral treatment with ketanserin.     

Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans

We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57 +/- 14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p less than 0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20, 18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively; p less than 0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tolbutamide does not alter insulin requirement in Type 1 (insulin-dependent) diabetes

Summary We examined whether tolbutamide has any acute or short-term effects on insulin action in Type 1 (insulin-dependent) diabetes. A euglycaemic glucose clamp was performed in seven Type 1 diabetic patients without clinical insulin resistance by infusing glucose at a constant rate of 0.01 mmol·kg^-1·min^-1 for 3 h together with a simultaneous insulin infusion using an artificial pancreas. The insulin infusion rate required to maintain blood glucose at 6.7 mmol/l at a set low glucose infusion rate provides an index of insulin action in vivo. The euglycaemic clamp was performed on 3 separate days in the same patient: (1) in the basal state; (2) during simultaneous intravenous tolbutamide infusion of 0.5 g/h, and (3) after treatment with 2.5 g tolbutamide/day for 6 days in addition to insulin. The insulin infusion rate needed to maintain the set blood glucose level did not differ significantly between the three experimental conditions (1.2±0.2 versus 1.3±0.3 versus 1.2±0.3 U/h). Plasma glucagon, growth hormone, non-esterified fatty acid and glycerol levels did not differ between control or sulphonylurea treatment studies. The results suggest that tolbutamide does not exert any acute or short-term effects on insulin action in vivo in Type 1 diabetes. Our results do not provide support for the idea that this agent is a clinically useful adjunct to insulin in such patients.     

硒对大鼠心电图及心肌细胞动作电位的影响

目的　探讨硒对大鼠心电图及心肌细胞动作电位的影响。方法　对Ｗ ｉｓｔａｒ雄性大鼠腹腔内注射亚硒酸钠（２ｍ ｇ·ｋｇ－１·ｄ－１）,连续９ 周,应用心电图和细胞内玻璃微电极技术,观察正常大鼠和阿霉素致心肌损伤大鼠心电图及心肌细胞动作电位的变化。结果　硒组心电图较实验前及对照组无变化（ Ｐ ＞ ０．０５ ）,心肌细胞复极达峰值电位５０％ 所需时间（ＡＰＤ５０）延长（ Ｐ ＜ ０．０５ ）。ＡＤＭ 组和硒＋ ＡＤＭ 组心电图Ｑ－Ｔ 间期及心肌细胞ＡＰＤ５０、ＡＰＤ９０较对照组及试验前均延长（ Ｐ＜ ０．０１）。心率、静息电位（ＲＰ）、动作电位幅度（ＡＰＡ）及动作电位０ 相最大去极化速率（Ｖｍ ａｘ）无变化（ Ｐ ＞ ０．０５）。结论　硒能延长正常大鼠心肌细胞ＡＰＤ５０,不能逆转阿霉素心肌损伤大鼠ＡＰＤ５０、ＡＰＤ９０及Ｑ—Ｔ 间期延长。此结果对于心肌病的防治具有重要意义。     

Efficacy,safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 μg/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 ± 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.