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A significant central-to-peripheral arterial pressure gradient may exist during and after cardiopulmonary bypass (CPB). The etiology and mechanisms of this phenomenon remain controversial. We studied the pressure gradient between aorta, brachial artery and radial artery in 68 patients, scheduled for elective coronary artery bypass surgery. We evaluated whether choice of cardioprotection during CPB (use of cold cardioplegic solution or use of intermittent crossclamping under protection with lidoflazine), and choice of pulsatile or nonpulsatile flow during the course of CPB, affected the magnitude and duration of the systolic pressure gradient. We also studied whether central-to-peripheral pressure gradient was influenced by administration on CPB of different vasoactive drugs with different mode of action: sodium nitroprusside (direct action on the vessels), droperidol (alpha-adrenergic blocking action), ketanserin (5-hydroxytryptamine antagonist) and phenylephrine (selective alpha 1-agonist). It appeared that central-to-peripheral gradient occurred early during CPB and remained constant throughout the course of CPB. The gradient disappeared within 60 min after weaning from CPB. We found the main pressure gradient to occur between the brachial and the radial artery. There was no relation between magnitude of the gradient and sex, weight, length or age of the patient. There was also no relation between magnitude of the pressure gradient and type of cardioprotection, choice of pulsatile vs nonpulsatile flow on CPB and duration of CPB. We also found no relation between pressure gradients and changes in temperature, haematocrit and systemic vascular resistance. The pressure gradient was not affected by any of the vasoactive drugs.

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The concept of pretreatment of the myocardium with a pharmacological agent protecting the cell against ischemic and reperfusion injury is very attractive. Lidoflazine, a calcium overload blocker, predominantly membrane stabilizing, is able to prevent cell damage during ischemic arrest and reperfusion. The purpose of this study was to determine whether the combination of lidoflazine pretreatment and St. Thomas' Hospital cardioplegia can provide, in clinical practice, better myocardial protection in aorto-coronary bypass grafting than St. Thomas' Hospital cardioplegia alone. As indices for myocardial protection, recovery of cardiac function, enzyme release, and clinical outcome were registered. Ninety-three patients undergoing aorto-coronary bypass surgery were studied. These patients were randomized into two groups in a double blind fashion. Patients in group A (n = 48) received lidoflazine 1 mg/kg intravenously over a period of 20 min before initiation of cardiopulmonary bypass. Group B (n = 45) receiving placebo, acted as a control group. Myocardial protection consisted of intermittent infusion of cold 4 degrees C St. Thomas' Hospital cardioplegia, topical slush ice, and systemic hypothermia (28 degrees C rectal). No significant differences between the two groups were noted in terms of recovery of cardiac function, enzyme release, incidence of myocardial infarction, low cardiac output, rhythm, and conduction disturbances. In conclusion, our data suggest that the combination of intravenous pretreatment with lidoflazine and St. Thomas' Hospital cardioplegia did not provide significant additional myocardial protection in the clinical situation.

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BACKGROUND: Abnormalities of cellular calcium homeostasis have been implicated in the pathophysiology of postischemic encephalopathy. Calcium-entry-blocking drugs inhibit the influx of calcium into cells and have been shown to mitigate postischemic encephalopathy in animal models. METHODS: Five hundred twenty patients with cardiac arrest who remained comatose after the restoration of spontaneous circulation were randomly assigned to receive three doses of lidoflazine, an experimental calcium-entry blocker, or a placebo and were followed for six months. Four patients were lost to follow-up. Treated patients received an intravenous loading dose (1 mg per kilogram of body weight) of lidoflazine and two subsequent doses (0.25 mg per kilogram) 8 and 16 hours after resuscitation. The investigators were blinded to treatment assignment. RESULTS: There was no statistically significant difference between the lidoflazine group (n = 259) and the placebo group (n = 257) in the proportion of patients who died during the six-month follow-up (82 vs. 83 percent), who survived with good cerebral recovery (15 vs. 13 percent), or who survived with severe neurologic deficit (1.2 vs. 1.9 percent). Analysis of the best level of recovery achieved at any time during follow-up also did not show a difference between the treatment groups: 24 percent of those given lidoflazine and 23 percent of those given placebo recovered good cerebral function (normal or only moderately disabled cerebral performance) at some time. CONCLUSIONS: The administration of lidoflazine after cardiac arrest was not found to be beneficial. Our data do not support the routine use of this calcium-entry-blocking drug in comatose survivors of cardiac arrest.

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Lidoflazine, a piperazine derivative with known selectivity for vascular smooth muscle, was evaluated as a possible agent for prophylaxis of cerebral vascular contraction induced by subarachnoid perfusion with serotonin. The animals treated with serotonin (5 X 10(-6) M), had a 60% reduction in the diameter of basilar artery but when pretreated with Lidoflazine (1 mg/kg) intravenously, only had a 20% reduction in diameter (p less than 0.01). Lidoflazine, when administered intravenously at a slow rate will not adversely lower systemic blood pressure and can prevent the contraction of cerebral vessels when the stimulus for contraction is in the subarachnoid space.

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The short-term (1 month) and long-term (6 months) safety of combination lidoflazine-propranolol therapy was investigated in an open trial of 15 patients with stable angina of effort. The possible advantages of adding lidoflazine (titrated to 360 mg daily) to patients having a therapeutic response to propranolol (80-400 mg daily) was also evaluated. Effects on non-invasive indexes of left ventricular function (echocardiography, systolic time intervals, radionuclide ventriculography) and exercise tolerance (treadmill exercise testing) were determined. There was no change in mean resting heart rate with the combination therapy, although one patient developed sinus bradycardia at a rate of 44 and had to have his propranolol dose reduced. Electrocardiographic analysis showed significant prolongation of the QTc intervals on lidoflazine-propranolol therapy compared to propranolol alone, with 3 patients having QTc interval prolongation to above .53 seconds, but there was no evidence of increased arrhythmogenesis with the combination therapy compared to propranolol alone. Left ventricular end-diastolic volume index tended to rise with combination therapy. However, lidoflazine-propranolol therapy did not produce any significant effects on resting ejection fraction determined by M-mode echocardiography or by radionuclide ventriculography. Radionuclide ventriculography determined peak exercise ejection fractions were also not significantly changed with combination therapy compared to propranolol alone. There were only small, insignificant improvements in exercise tolerance with the lidoflazine-propranolol combination treatment compared to propranolol alone. It is concluded that lidoflazine-propranolol combination therapy is generally safe but has the potential of causing serious adverse effects in certain patients, i.e. those with sick sinus disease, prolonged QTc intervals, and severe baseline left ventricular dysfunction, and that caution must be exercised in its use. Furthermore, it would appear that combination therapy provides only slight, if any, improvements in exercise tolerance in patients with chronic stable angina having a therapeutic response to oral propranolol.

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Lidoflazine is a calcium channel blocking agent that is effective and safe in the treatment of angina pectoris, but has been reported to be associated with sudden death when administered for the treatment of supraventricular arrhythmias. Studies were performed in dogs to determine if lidoflazine caused a rise in serum digoxin concentration that could cause arrhythmias or if it was directly arrhythmogenic. Dogs received chronic injections of digoxin and then digoxin in combination with lidoflazine. No increase in digoxin concentration was found. Dogs also underwent programmed electrical stimulation while not receiving medications and then after incremental doses of lidoflazine administered intravenously. Lidoflazine did not cause spontaneous ventricular tachycardia and did not lower the threshold of ventricular tachycardia induction. Combined administration of lidoflazine and digoxin did not facilitate arrhythmia induction. These studies do not support a digoxin-lidoflazine interaction or a direct arrhythmogenic action of lidoflazine.

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Twenty-four patients received either propranolol, lidoflazine (Clinium), or propranolol/lidoflazine combinations in a study designed to evaluate the effect of these drugs in angina pectoris. Five patients developed ventricular tachycardia when receiving either lidoflazine or lidoflazine and propranolol in combination; one of these patients died. In addition, one patient died suddenly while being treated with propranolol alone. Lidoflazine therapy was associated with a significant prolongation of the QT interval of the electrocardiogram. Lidoflazine either alone or in combination with propranolol, appears to induce ventricular tachycardia.

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Forty-seven patients with chronic atrial fibrillation and (or) flutter in whom the clinical picture and the length of arrhythmia indicated that drug-mediated cardioversion should be tried were treated with a combination of lidoflazine and propafenon. The average daily dosage was 600 mg for propafenon and 180 mg for lidoflazine. Duration of treatment was limited to 8 days. Return to sinus rhythm was achieved in 34 patients. In comparison with monotherapy combined use of the drugs thus led to a clear-cut increase of the conversion rate. Dosage reduction of these differently acting substances decreases the risk of toxic side effects, particularly as both substances have different side effects which in part cancel each other out. It can be assumed that ventricular extrasystoles seen during treatment with lidoflazine as precursor of malignant tachycardia can be suppressed or eliminated by propafenon.

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60 patients with chronic atrial fibrillation and flutter were randomly allotted to two groups and treated alternately with two different therapy regimes. 30 patients (group I) received lidoflazine in increasing dosage up to 480 mg/24 h and in cases where there was no conversion to sinus rhythm propafenon in a maximal daily dosage of 1800 mg orally. The duration of treatment was limited to 4 days for each substance. 30 patients (group II) were treated in the reverse order, i.e. propafenon and in cases of ineffectiveness with lidoflazine. Atrial fibrillation could be overcome in 21 patients in group I and in 23 patients in group II. The combined success rate in both groups was 73%. The conversion rates for the individual substances were 41% for propafenon (17 out of 41 patients) and 59% for lidoflazine (27 out of 46 patients). The difference was not statistically significant. Successive use of both substances leads to an increased conversion rate. Dangers arising from therapy are a conduction inhibitory action and depression of sinus node function as far as propafenol is concerned and the risk of ventricular ectopy and tachyarrhythmia in lidoflazine.

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Successful conversion to sinus rhythm was achieved in 20 out of 26 patients (77%) with chronic atrial fibrillation or flutter of various origin, that had existed for about 40 +/- 13 months. There was a significant relation between the converting dose of Lidoflazine and the duration of atrial fibrillation. In those patients with atrial fibrillation, that preexisted no longer than two years, restoration of sinus rhythm was achieved in 12 of 14 cases (86%) with an average dose of 109 +/- 67 mg Lidoflazine a day, whereas in the group with atrial fibrillation known for more than two years therapeutical success was obtained only in 8 of 12 cases (67%). The dose of conversion was 382 +/- 150 mg/day in this group and produced in a few patients toxic side effects. Two patients relapsed to atrial fibrillation. On this reasons conversion with Lidoflazine should only be done in patients with atrial fibrillation within two years. There were no significant changes related to: heart rate, myocardial function and intraventricular conduction process. In the presence of underlying hypokalaemic disturbances and/or additional therapy with digitalis preparations Lidoflazine may be the cause of developing premature beats. Lidoflazine may be regarded as a relatively safe drug even in large doses, if monitoring of heart rhythm and QTc-interval is available.

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Electrocardiographic alterations and onset of angina pectoris during an acute treatment period with lidoflazine -3 to 4 mg/kg b.w. by oral application- was investigated in 20 patients with latent coronary insufficiency under increasing heart rate condition by atrial pacing. Significant changes in the repolarisation phase mainly due to prolongation of the QTc-interval already appeared 90 to 120 min after oral administration. The onset of test-induced agina pectoris and ischaemic ST-segmental depression in the ECG were not influenced by lidoflazine. Exceeding a rate of 140 min-1 produced a delay of atrioventricular conduction time under drug influence whereas significant changes of intraventricular conduction did not appear. Under frequent heart rates bundle branch block developed in a few individuals that might be drug-induced. In addition, there were some signs of digitalis-potentiation by lidoflazine.

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