Renal excretion of metolazone, a new diuretic.

1. Metolazone, a new diuretic, was found to be excreted by glomerular filtration and renal tubular secretion.2. The secretory mechanism was antagonized by probenecid but this did not affect the diuretic action of metolazone.

Use of droperidol and fentanyl for analgesia and sedation in primates.

A combination of droperidol and fentanyl produces qualitatively similar pharmacologic effects in dogs and primates. Unlike the dog, however, primates did not appear to respond to auditory stimuli. As a result of the analgesic and sedative or tranquil state produced in primates, the animals were easily handled and tolerant of painful stimuli. The principal desirable features of the combination were high analgesic and sedative potency and a rapid onset of action following intramuscular administration. High doses produced respiratory depression. However, this effect was easily reversed by administering nalorphine hydrochloride.

Toxicity studies on lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent.

The acute oral LD50 of 1-(2,6-dimethylphenyl)-3-amidinourea hydrochloride (WHR-1142A, lidamidine hyrochloride) was 260 (208, 328) mg/kg in male mice, 267 (212, 336) mg/kg in male rats and 160 (130, 197) mg/kg in female rats. A daily oral dose of 10 mg/kg for 30 days was well tolerated in the rat and monkey. Histologic changes were reversible and for the most part could be explained on the basis of one or more of the several pharmacologic effects of WHR-1142A. A short-lived hyperglycemic effect was a prominent effect in mice and rats. This effect was seen occasionally in high doses in the monkey, suggesting a species difference.

Mechanism of action studies of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent.

1-(2,6-Dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142A), lidamidine hydrochloride), a novel antidiarrheal agent, inhibited contractile activity in isolated guinea pig ileum stimulated by acetylcholine, histamine, serotonin, dimethylphenylpiperazinium, prostaglandin E2, BaCl2 and KCl. WHR-1142A also blocked spontaneous and stimulated contractile activity measured with extraluminal strain gauges in the duodenum, ileum and colon of dogs. Studies on the autonomic effects of WHR-1142A indicated little, if any, peripheral adrenergic stimulatory or cholinergic blocking activity. Inhibition of intestinal motility by WHR-1142A was not antagonized by naloxone. WHR-1142A also showed no morphine-like analgesic effects and was devoid of any H1-antihistamine activity. WHR-1142A appears to be a pharmacologically unique antidiarrheal agent.

In vivo antimotility and antidiarrheal activity of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent. Comparison with diphenoxylate and loperamide.

1-(2,6-Dimethylphenyl)-3-methyl-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) was shown to have potent antimotility, antidiarrheal and intestinal antisecretory activity in mice, rats and dogs. Antimotility activity was demonstrated in charcoal intestinal motility, gastric emptying and gastric and intestinal intraluminal pressure studies. Antidiarrheal activity was evaluated in castor oil-, prostaglandin E2-, carbachol-, and serotonin-induced diarrhea. Intestinal secretion induced by cholera toxin was inhibited by WHR-1142A. In general, WHR-1142A was more potent than diphenoxylate and loperamide although species differences were noted. The ED50 for inhibition of castor oil-induced diarrhea was 1.8 mg/kg p.o. and the duration of action at 16 mg/kg p.o. was at least 6 h. Unlike diphenoxylate, WHR-1142A showed no tolerance.

Effects of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent on the cardiovascular and central nervous systems.

1-(2,6-Dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) has been reported to be a potent antidiarrheal agent in laboratory animals. This study defines its effects on the cardiovascular and central nervous systems. At doses greater than 1 mg/kg i.v., WHR-1142A reduced cardiac output in the anesthetized dog primarily by depressing heart rate; the blood pressure was slightly elevated due to an increase in peripheral resistance. WHR-1142A was effective in reverting ouabain-induced ventricular arrhythmias to a sinus rhythm. Unlike diphenoxylate, WHR-1142A did not potentiate the CNS depressant effects of hexobarbital or ethanol. WHR-1142A did not block pentetrazole-induced convulsions, electroshock seizures or amphetamine aggregate toxicity. At high doses WHR-1142A caused a general CNS depressant effect was not related to a neuroleptic- or barbiturate-like action.

Pharmacological properties of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent.

1-(2',6'-Dimethylphenyl)-3-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride), a potent, unique antidiarrheal agent, was tested for other pharmacological properties. It inhibited gastric acid secretion in both 4-h and 22-h pylorus-ligated rats and reduced mortality and gastric ulcer severity in the latter test. WHR-1142A also exhibited local anesthetic activity in the rabbit corneal reflex and guinea pig intradermal wheal tests and reverisbly blocked conduction in isolated frog nerves. Low doses of WHR-1142A increased plasma glucose concentration in fasted mice and rats and prolonged the hyperglycemia in response to a glucose meal. WHR-1142A showed mild diuretic activity but had no anti-inflammatory or antibacterial activity. The acute oral LD50 of WHR-1142A was 260 (208,328) mg/kg in male mice, 267 (212,336) mg/kg in male rats and 160 130,197) mg/kg in female rats.