Effective refractory period studies

The Pfizer group in the United Kingdom has been actively involved in the search for new Class III antiarrhythmic agents. It has patented a variety of structural types that make extensive use of the methylsulphonylamino moiety. These include indanes [173,174], pyridines [175,176], piperazines [177-179], benzazepines [180], bisarylalkylamines [181] and diazabicyclic compounds [182], From this extensive work, two compounds, UK-66914 (65) and UK-68798 (66), have entered clinical trials. Compound (65) increases the effective refractory period (ERP) of ferret papillary muscle by 25% at a concentration of 0.5 //M [183]. Whole-cell patch-clamp studies... 

Inhibitors of the slow component Iks were developed in order to circumvent the negative rate dependence of IKr blockers on the effective refractory period (Busch et al. 1996 Suessbrich et al. 1996, 1997 Bosch et al. 1998). Gogelein et al. (2000) studied the effects of a potent inhibitor of Iks channels in Xenopus oocytes and guinea pig ventricular myocytes. 

Standard microelectrode techniques were used to study the effects of isocorydine on potential characteristics of canine cardiac Purkinje fibers and ventricular myocardium in vitro. In the Purkinje fibers, the action potential durations APDjj and APD were prolonged at 3 pmol/1 but shortened at 30 pmol/1 by isocorydine. The action potential amplitude and maximal upstroke velocity were decreased at 100 pmol/1. In the ventricular myocardium, the action potential characteristics were changed by isocorydine at concentrations above 30 pmol/1. The APDJ0 was shortened, the APD90 was prolonged, and the maximal upstroke velocity was decreased at 30 pmol/1. The effective refractory period was prolonged by the alkaloid in Purkinje fibers and ventricular myocardium. These results indicated that the alkaloid may interfere with K+, Na+, and Ca+2 currents in myocardial cell membranes at different concentrations [287]. 

Intracellular microelectrodes were used to study the effects of isocorydine on the action potentials of the rabbit sinoatrial node and guinea pig ventricular muscle, in addition to the spontaneous electrical activity induced by barium ion in the ventricular muscle. Exposure of rabbit sinoatrial node cells to a 30 pM and 300 pM solutions of isocorydine resulted in a decrease in the APA, SP0, and SP4, and slowed the rate of spontaneous impulse initiation by the sinoatrial node. The duration of the action potential (APDS0, APD ) and the effective refractory period... 

The use of propranolol (Inderal) as an antiarrhythmic is useful in the treatment of atrial tachyarrhythmias. Its mechanism is somewhat controversial. Since propranolol is a (3-adrenergic blocking agent, it seems logical to study this feature. The drug can be shown to block the cardiac effects of catecholamines. The effective refractory period of the AV node has been shown to increase. However, some quinidinelike properties have also been observed. The suggestion has been made that the antiarrhythmic action is caused by interference with the cellular transport of Ca2+. 

In an in vitro study, ginsenoside Re (4.7 lO8 M) prolonged the effective refractory period of the left guinea pig atria and dose-dependently decreased the contractile force and frequency of the isolated atria [181]. The correlation between concentrations and effects was significant and these effects may concern the inner Ca2+ current blokage... 

While most -blocking agents on acute administration have little direct electrophysiological effects, studies in rabbits [94] and man [95] have shown that chronic administration of y -blockers increases APD. This increase in APD (and hence refractory period) has been postulated to contribute to the effectiveness of -receptor blocking agents in the prevention of sudden cardiac death [94]. Direct Class III action has been claimed for the y -blockers oxprenolol (30) [96,97], nadolol (31) [96] and atenolol (10) [98] in addition... 

The neurotoxic effects after 10 years or more of long-term, low-level occupational exposure to carbon disulfide in workers at a viscose rayon plant were examined by assessing markers of the peripheral and autonomic nervous system (Ruijten et al. 1990, 1993). Reinvestigation of 44 of 45 exposed and 31 of 37 matched control workers revealed changes in the motor nerve conduction velocity (Ruijten et al. 1993). The exposure concentration in the two studies varied from 1 to 30 ppm. For peripheral nerves, a decrease in the conduction velocity in both fast and slow motor nerve fibers (peroneal nerve) was observed in exposed workers. Sensory conduction velocities were reduced and the refractory period of the sural nerve was increased. The effects on the sural nerve were pronounced. A small decrease in conduction velocities in the absence of symptoms of neuropathy and decreased response amplitudes suggest a mild presymptomatic nerve impairment. 

Papaverine (Fig. 26.8) is a benzoisoquinoline vasodilator that produces generalized, nonspecific arteriolar dilatation and smooth muscle relaxation. Its oral bioavailability ranges from 30 to 50%, suggesting first-pass metabolism. Increased levels of intracellular cAMP secondary to inhibition of phosphodiesterase may contribute to its vasodilatation and relaxation effects without involving nerve supply. Large doses of papaverine can cause hypotension and tachycardia. Other studies suggest that it also depresses cardiac conduction and prolongs the refractory period. 

The antianhythmic activity was evaluated in vitro according to the extent to which the compounds affected the prolongation of the myocardial absolute refractory period in an isolated rat atrium of the heart stimulated by electric impulses [3, 138]. This method does not allow for the identification of all of the antiarrhythnuc effects of new substances, but the technique is valid at the stage of primaiy screening. MEC, the minimum effective concentration of a substance (mol/L) preventing the atrium from adopting the rhythm forced on it, served as a measure of the antiarrhythmic activity. Moricizine (CAS 31883-05-3) was studied as the drag for comparison its MEC was found to be 5.10-10 M. 

The efficacy, safety, tolerability, and optimal dose of ciclosporin eye-drops have been studied in a randomized, double-masked, vehicle-controlled multicenter trial in 162 patients with keratoconjunctivitis sicca with or without Sjogren s disease and refractory to conventional treatment (48). Ciclosporin ophthalmic emulsion 0.05, 0.1, 0.2, or 0.4%, or the vehicle alone was instilled twice daily into both eyes for 12 weeks, followed by a 4-week observation period. There was no clear dose-response relation ciclosporin 0.1% emulsion produced the most consistent improvement in objective and subjective endpoints and ciclosporin 0.05% gave the most consistent improvement in sjmptoms. The vehicle also performed well, perhaps because of its long residence time on the ocular surface. There were no significant adverse effects, no microbial overgrowth, and no residence time of the vehicle emulsion on the ocular surface. AH treatments were well tolerated and the highest ciclosporin blood concentration detected was 0.16 ng/ml. 

The effects of tiagabine have been studied in a 4-month, single-blind study in 52 children over the age of 2 years with different syndromes of refractory epilepsy (5). Adverse events, mostly mild to moderate, were reported by 39% of the children during the single-blind placebo period and by 83% of the children during tiagabine treatment. The events predominantly affected the nervous system weakness (19%), nervousness (19%), dizziness (17%), and somnolence (17%) were the most common. One child had hallucinations that responded to dosage reduction. Only three children withdrew because of adverse events. 

In humans, spironolactone is absorbed readily and is metabolized in the liver to active compounds called canrenones. It is these metabolites that compete with aldosterone for its cytosolic receptor therefore, the maximal natriuretic effect is not observed until 24-48 h after treatment has been initiated. Spironolactone is indicated for the treatment of primary hyperaldosteronism but is also used in refractory edema and in secondary hyperaldosteronism consequent to use of loop or thiazide-type diuretics (Martinez-Maldonado Cordova 1990, Rose 1989, 1991, Wilcox 1991). In one study, the administration of spironolactone via nasogastric tube (1 and 2mg/kg) to ponies more than doubled the urinary excretion of sodium and reduced the urinary excretion of potassium for a period of 72 h, although there was no difference in the volume of urine produced (Alexander 1982). This suggests that spironolactone is a potassium-sparing agent in horses however, to date, no pharmacokinetic studies have been published. 

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