ABSTRACT
A method of producing semichronic diarrhea is presented. It has been shown that, when fed a combination diet of 50% lactose and 50% commercially available feed, rats are subjected to continuous diarrhea, which lasts for 96 hr or more. The relative lack of the enzyme lactase in the rat results in the accumulation of lactose in the gut and probably by an osmotic effect, sets up conditions for the passage of a watery diarrhea. Various combinations of lactose and commercially available feed were tried and it was observed that rats function without any ill effects (e.g., body-weight loss) and produce consistent watery diarrhea with the above-mentioned combination.
Subject(s)
Diarrhea/chemically induced , Disease Models, Animal , Animals , Chronic Disease , Diarrhea/drug therapy , Dietary Carbohydrates , Diphenoxylate/therapeutic use , Female , Lactose/administration & dosage , Loperamide/therapeutic use , Male , Morphine/therapeutic use , Rats , Rats, Inbred Strains , Sex Factors , Species SpecificityABSTRACT
A number of aryl substituted amidinoureas have been prepared and examined for their gastrointestinal spasmolytic, antimotility, antidiarrheal and antisecretory effects. In general, antisecretory and antimotility effects have been found to be associated with each other in these compounds. The structure-activity relationships found show that substitution of the aromatic ring in positions other than 2 and 6 correlates poorly with potency, and potency of such compounds is low. In contrast to this, 2,6-disubstitution confers high potency. The potency of 2,6-disubstituted compounds declines sharply with increasing weight of substitution of the amidinourea chain, with the important exception of the N-alkoxyamidinoureas. Increasing the molecular weight of an N-alkoxy substituent has a much less profound effect than the corresponding increase has in an N-alkyl substituent. High potency in an amidinourea may well be related to low basicity (or a high pKa value for its conjugate salt) but there is insufficient data to support this hypothesis fully. The actual tautomeric structure of an amidinourea probably affects its potency and this is discussed briefly.
Subject(s)
Amidines/pharmacology , Antidiarrheals , Gastric Juice/metabolism , Gastrointestinal Motility/drug effects , Amidines/toxicity , Animals , Charcoal/metabolism , Chemical Phenomena , Chemistry , Depression, Chemical , Isomerism , Lethal Dose 50 , Male , Mice , Molecular Conformation , Rats , Stomach/drug effects , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amidines/pharmacology , Antidiarrheals , Diphenoxylate/pharmacology , Gastrointestinal Motility/drug effects , Isonipecotic Acids/pharmacology , Loperamide/pharmacology , Piperidines/pharmacology , Animals , Carbachol/pharmacology , Charcoal , Cholera Toxin/pharmacology , Diarrhea/chemically induced , Feces , Male , Prostaglandins E/pharmacology , Rats , Serotonin/pharmacology , Stomach/drug effectsABSTRACT
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.
Subject(s)
Amidines/pharmacology , Antidiarrheals/pharmacology , Central Nervous System/drug effects , Hemodynamics/drug effects , Amphetamine/toxicity , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Dogs , Ethanol/pharmacology , Flurazepam/pharmacology , Guinea Pigs , Heart Rate/drug effects , Hexobarbital/pharmacology , In Vitro Techniques , Male , Mice , Myocardial Contraction/drug effects , Pentylenetetrazole/antagonists & inhibitors , Vascular Resistance/drug effectsABSTRACT
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.
