Prolongation of procaine's and procainamide's actions by binding to acryloyl polymers.

Procaine and procainamide were covalently bound to acryloyl monomers and polymers. The dose-response and time-action parameters of the cardiac antiarrhythmic protection afforded by the prototype drugs and their acryloyl derivatives against chloroform-hypoxia-induced cardiac arrhythmias in unanesthetized mice and epinephrine-induced arrhythmias in alpha-chloralose anesthetized cats were determined. Similarly, the pharmacological parameters which characterized their acute toxic responses in unanesthetized male albino mice were also determined. The similar pharmacological spectra of their activity and the parallelism of their lethal dose-response curves indicate that the active constituents of the polymer derivatives are the local anesthetic moieties. Compared to the prototype drugs, the polymer derivatives were more potent on a molar basis and their pharmacological effects were prolonged. The increased potency and duration of action reinforce the idea that the local anesthetic moieties are pharmacologically active while still bound to the polymer backbones.

Acute toxic effects in mice of an extract from the marine algae Gonyaulax monilata.

Unialgal cultures of Gonyaulax monilata were cultured and harvested. A modified Westphall procedure was used to prepare an extract which did not contain saxitoxin, the gonyautoxins and structurally related toxins. The extract was administered i.p. to young adult, male CD-1 mice and produced: sedation, abdominal constriction, fecal clumping in the perianal area, ataxia, tremors, cyanosis, loss of reflexes, convulsions and death (LD50 = 2.28 mg/kg). Gross and microscopic pathology in the treated mice included: acute active hyperemia of the viscera, multifocal areas of necrosis of the musculature of the intestinal wall and diaphragm and the presence of cytoplasmic vacuoles in the peripheral margins of the acinar portion of the pancreas. Clinical pathology of the mice which survived 24 hr included significant elevation in the levels of serum lactic dehydrogenase, glutamic pyruvic and glutamic oxaloacetic transaminases. Some of these mice also had significantly decreased white blood cell counts. The extract administered orally produced similar signs without the abdominal constriction and convulsions (median lethal oral dose = 6.73 mg/kg). Gross pathology findings included extensive and severe congestion of the abdominal visceral organs. Vehicle control mice were normal. In conclusion, G. monilata, previously reported as nontoxic in homeotherms, yields an extract which contains a water soluble glycosidic substance(s) which is lethal to mice.

Development of a cardiac antiarrhythmic screening test utilizing theophylline in the rat.

Cardiac arrhythmias were produced in Sprague-Dawley-derived rats by chloroform challenge. The incidence of cardiac arrhythmias so induced increased with age and as a function of dose after pretreatment with theophylline. The dose-response and time-action parameters of theophylline's predisposing action to chloroform-hypoxia-induced cardiac arrhythmias were determined. This information has been utilized to develop a cardiac antiarrhythmic screening test in unanesthetized rats which is presented in the following paper.

A cardiac antiarrhythmic screening test in the rat: the effects of lidocaine, propranolol and quinidine.

The dose-response and time-action parameters for the prototype antiarrhythmic drugs lidocaine, propranolol and quinidine were established using a cardiac antiarrhythmic screening procedure in the rat. This simple screening procedure produces severe cardiac arrhythmias, primarily ventricular fibrillation, in young post-weaning rats which have been pretreated with a single intramuscular injection of theophylline (20 mg/kg) 15 to 45 min prior to their inhalation of chloroform vapors.

The site and the mechanism of phenoxy-benzamine potentiation of the pressor response to oxytocin and vasopressin: in vivo and isolated aortic strips studies.

In intact rats, alpha adrenergic receptor blocking agents, phenoxybenzamine (PBZ) and phentolamine potentiated the pressor response to oxytocin and vasopressin (VP). In the presence of PBZ or phentolamine blockade, the dose-response curves of oxytocin and VP were shifted to the left, resulting in an apparent doubling of the pressor potency of the neurohypophysial peptides. The beta adrenergic blocking agent, propranolol had no significant effect on the pressor response to oxytocin or VP. Combined PBZ and propranolol blockade did not alter the potentiating activity of PBZ. The PBZ-potentiating effect seems to be specific to the neurohypophysial peptides, since the pressor response to angiotensin was not potentiated by PBZ. The potentiating effect of PBZ on VP could be demonstrated in isolated rat aortic strips. This clearly indicated that the site of action of PBZ is directly on the vascular smooth muscle. However, in aortic strips, the effect of PBZ was seen only if norepinephrine (NE) was also added to the bathing medium. NE alone had no significant effect on the contractile response to VP. The requirement of both PBZ and NE for the potentiating effect suggests that an interaction between these two agents is involved in the PBZ potentiation of VP response. The possibility that NE and not PBZ is the direct agent causing the potentiation of VP response is discussed.