A model study directed towards the preparation of nucleopeptides via H-phosphonate intermediates.

The monofunctional phosphitylating reagents bis-(N,N-diethylamino)chlorophosphine and salicylchlorophosphine have been applied for the preparation of H-phosphonates of the amino acids serine, threonine and tyrosine. Experimental evidence showed that the latter reagent was less effective for the synthesis of a tyrosine H-phosphonate. The amino acids (peptide) H-phosphonates of serine or threonine proved to be suitable starting compounds for the formation of a phosphate diester bond with the 5'-OH of a d-nucleoside derivative using pivaloyl chloride as the activating reagent.

Mechanism of the repetitive ventricular response in man.

The electrophysiologic characteristics of the repetitive ventricular response that followed an electrically induced single premature ventricular complex were evaluated to determine its mechanism during atrial pacing or sinus rhythm in 30 patients. Seven patients had preexisting bundle branch block. His bundle or right bundle branch deflections did not precede the repetitive complex in 29 of the 30 patients, which implies that the proximal His-Purkinje system was not involved in the reentry circuit. In 24 of 30 patients the QRS axis ot the repetitive complex was divergent 45 degrees or more from the stimulated complex. In 22 of 30 patients the reprtitive complex had a right bundle branch block configuration. In 14 of 18 patients with two or more repetitive complexes, the QRS pattern changed from beat to beat, which implies that either the reentry pathway or conduction was changing. Thus, the repetitive ventricular response, which can be associated with clinically important ventricular arrhythmias, probably represents intraventricular rather than proximal His-Purkinje system reentry.

Prolongation of cardiac conduction times by intravenous aprindine in man.

The acute electrophysiologic effects of intravenous aprindine were evaluated in 48 patients to assess the effect on conduction times and refractoriness in patients with severe cardiac disease and arrhythmias. The patients had not responded to conventional antiarrhythmic medications or had been unable to tolerate effective doses of conventional medications because of side effects. Eleven patients had an abnormal H-V interval, 9 had prolonged QRS duration and 22 had evidence of severe left ventricular dysfunction. Aprindine prolonged conduction transiently in the atria, the atrioventricular (A-V) node, the His-Purkinje system and the ventricles. The refractory times of the atria, the A-V node and the ventricles increased insignificantly, both functionally and statistically. Atrioventricular block did not develop in any patient, and side effects were minor. Thus, aprindine can be safely administered intravenously (10 to 15 mg/min) to severely ill patients with arrhythmias that are refractory to other medications even in the presence of underlying conduction system and myocardial disease.

Suppression of the repetitive ventricular response: an index of long-term antiarrhythmic effectiveness of aprindine for ventricular tachycardia in man.

The repetitive ventricular response, defined as the production of two or more ventricular premature complexes in response to a single ventricular pacing stimulus, is common in patients with serious ventricular arrhythmias. Twenty-seven patients with refractory ventricular tachycardia were studied to determine whether acute suppression of the repetitive ventricular response by aprindine predicts long-term effectiveness of this agent. Twenty-three of the 27 patients had the repetitive ventricular response before intravenous administration of aprindine, whereas only 6 had the response after aprindine. All patients were maintained on a regimen of oral aprindine and evaluated repeatedly for a mean of 12 months. Twenty of the 21 patients who had no repetitive ventricular response after intravenous aprindine manifested clinical improvement compared with only 1 of the 6 in whom the repetitive response was present after aprindine (P less than 0.0005). Aprindine is a useful agent in refractory ventricular tachycardia, and the absence of the repetitive ventricular response after its intravenous administration predicts long-term clinical responsiveness to the oral form.

The repetitive ventricular response in man. A predictor of sudden death.

We examined the value of cardiac pacing for assessing ventricular electrical instability and for predicting ventricular tachycardia and sudden death in 50 patients with refractory symptomatic ventricular tachycardia, 12 normal patients, and 48 survivors of a recent myocardial infarction. The repetitive ventricular response (two or more ventricular premature beats produced by a single ventricular pacing stimulus during control of heart rate with atrial pacing) was absent in all 12 normal patients but was present in 44 of the 50 patients (88 per cent) with recurrent ventricular tachycardia (P less than 0.001). Of the 48 survivors of myocardial infarction, 19 had repetitive ventricular responses. During the next 12 months 15 of these patients (79 per cent) had symptomatic ventricular tachycardia or sudden death, or both, as compared with four of 29 patients (14 per cent) who did not have repetitive ventricular responses (P less than 0.001). The repetitive ventricular response identifies patients with life-threatening ventricular instability, but it is still an investigational technic that should be used only with due precautions.

Mitral-valve prolapse syndrome and recurrent ventricular tachyarrhythmias: a malignant variant refractory to conventional drug therapy.

Of 60 patients referred for management of drug-refractory ventricular tachyarrhythmias, 10 (17%) had mitral-valve prolapse. These 10 patients ranged in age from 19 to 70 years (mean, 47 years); seven were women. All 10 had recurrent ventricular tachycardia, while four had a history of ventricular fibrillation. Nine patients were refractory to propranolol in combination with one or more of the standard antiarrhythmic agents. All showed improvement with aprindine therapy. The results show that refractory malignant ventricular prolapse syndrome; patients with mitral-valve prolapse account for a rather high percentage of those patients referred with recurrent drug-refractory ventricular tachyarrhythmias; in patients with unexplained ventricular arrhythmias, mitral-valve prolapse should be considered; and aprindine may be effective for ventricular tachyarrhythmias associated with mitral-valve prolapse.