New antiarrhythmic agents. 1. Primary alpha-amino anilides.

Thirty-two alpha-amino anilides with various substituents in the aromatic ring and in the alpha position are described. Their abilities to protect mice against chloroform-induced fibrillation and to elicit toxicity were determined. Substitution of an alkyl or aryl group in the alpha position enhanced the antifibrillatory activity. In most cases, increased potency was accompanied by increased toxicity. Eleven compounds were tested in dogs with surgically induced myocardial infarction; most showed antiarrhythmic activity. 2-Aminopropiono-2',6'-xylidide, tocainide, was chosen for clinical investigation.

Cardiovascular pharmacology of local anaesthetics.

Although most local anaesthetic drugs are generally regarded as vasodilators at their site of injection, they produce systemic effects characterized by increases in peripheral resistance, cardiac output, arterial pressure heart rate. The direct depressive effects of the drugs are counterbalanced by increased sympathetic activity. There is evidence that many local anaesthetic agents increase the myogenic tone of certain vascular beds. A proper understanding of these phenomena could lead to improvements in the development of new local anaesthetic agents and appropriate vasoconstrictors.

The local anesthetic activity of tetrodotoxin alone and in combination with vasoconstrictors and local anesthetics.

Tetrodotoxin (TTX), alone and in combination with various vasoconstrictors and local anesthetics, was evaluated for its ability to produce peripheral nerve blocks in the rat and central neural blocks in the cat and dog. High frequency and long duration of block can be attained if sufficiently high concentrations of TTX are used, although latency is long and high dosage may produce systemic toxicity. Frequency and mean duration of block can be increased and systemic toxicity reduced if TTX is administered with a vasoconstrictive agent. Conventional local anesthetics also enhance the nerve-blocking activity of TTX. When appropriate concentrations of TTX and local anesthetics are used, a high frequency of blocks characterized by short latency and long duration can be demonstrated. The studies present some indirect evidence that local anesthetics enhance TTX activity by reversibly increasing the permeability of various neural barriers to TTX.

The local anesthetic activity of saxitoxin alone and with vasoconstrictor and local anesthetic agents.

STX (saxitoxin), alone and with various vasoconstrictor and local anesthetic agents, was evaluated for its ability to produce topical anesthesia on the rabbit cornea, peripheral nerve block in the rat, and epidural anesthesia in the dog. High frequency and long duration of block can be attained if sufficiently high concentrations of STX are used, although latency is long and the doses used may produce systemic toxicity. Frequency of satisfactory blocks and mean duration of block can be increased and systemic toxicity reduced if STX is administered with a vasoconstrictor agent. Conventional local anesthetic agents also enhance the nerve blocking activity of STX. When appropriate concentrations of STX, vasoconstrictor and local anesthetic agents are used, systemic toxic effects are not manifested and the blocks produced exhibit the rapid onset and high frequency of block characteristic of the local anesthetic agent and the remarkably long duration of STX.