1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties.

1',1'-Dimethylheptyl-Delta-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin's test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55 degrees C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED(50) values; 5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.

Mucosal protective activity of activated aluminum complex.

The antacid ES Riopan was acidified ex vivo to pH 2.5 to completely eliminate its buffering capacity and was then tested as a mucosal protective agent. The pH 2.5 acidified antacid solution was named activated aluminum complex. Activated aluminum complex was 8.2 times more potent than its parent antacid in protecting against acidified aspirin-induced gastric lesions in the rat. Activated aluminum complex had a duration of action greater than 10 h in the ethanol-induced gastric lesion model, while ES Riopan was active for 6 h. Activated aluminum complex was able to inhibit both acid- and nonacid-mediated ulcers in the stomach and intestine. Its mucosal protective activity was not blocked by pretreatment with indomethacin. These results demonstrate that the nonbuffering antacid activated aluminum complex exerted a more potent and longer-lasting mucosal protective activity than its parent antacid. The activity was probably due to the presence of a hexaaquoaluminum cation and supports the argument that antacids possess mucosal protective effects independent of their acid-neutralizing capacity.

N-phenyl-2-pyridinecarbothioamides as gastric mucosal protectants.

A series of substituted 2-pyridinecarbothioamides was synthesized and evaluated for gastric mucosal protectant activity in the rat. Out of this investigation N-(3,5-difluorophenyl)-2- pyridinecarbothioamide (23, AY-31,574) was identified. This compound was much more potent than sucralfate and ranitidine against ethanol-induced lesions. Compound 23 was equipotent with ranitidine against gastric injury caused by stress. Unlike ranitidine, 23 was found to be devoid of antisecretory activity in the pylorus-ligated rat model, making it a selective mucosal protectant. Such a potent selective mucosal protectant may provide a novel clinical approach in treating ulcers.

Cytoprotective and antiulcer activities of the antacid magaldrate in the rat.

The cytoprotective and antiulcer activities of the antacid magaldrate (ES Riopan) as well as its effects on gastric mucosal blood flow and mucus secretions, were determined in the rat. Magaldrate afforded protection against gastric necrotic lesions induced by absolute ethanol (ED50, as magaldrate, 419 mg/kg); gastric ulcers induced by acidified acetylsalicylic acid (ED50 540 mg/kg), stress (cold restraint, ED50 388 mg/kg), indometacin (ED50 281 mg/kg), and pylorus ligation; and intestinal ulcers induced by cysteamine (ED50 243 mg/kg) and indometacin (ED50 184 mg/kg). At a dose of 8 ml/kg (1728 mg/kg magaldrate), the cytoprotective effect of magaldrate against ethanol was evident 1 min after oral administration and lasted more than 8 h. The cytoprotection induced by magaldrate was decreased by pretreatments with the depletor of endogenous thiols, n-ethylmaleimide, or with the cyclooxygenase inhibitor, indometacin. Magaldrate did not affect gastric mucosal blood flow, but it increased gastric mucus secretion. This later effect may be a factor responsible for the cytoprotective activity of the agent. The efficacy of magaldrate may be due not only to its antacid, bile sequestering, and antipeptic activities, but also to its cytoprotective activity. The present results suggest that magaldrate could be effective in preventing gastric damage caused by alcohol and antiinflammatory drugs.

Activated aluminum complex derived from solubilized antacids exhibits enhanced cytoprotective activity in the rat.

Removing the buffering capacity of aluminum-containing antacids by acidification greatly increased their cytoprotective activity over the parent antacid. Commercially available antacids were acidified with 6 N HCl. Peak mucosal protective activity occurred at pH 2.5, and declined at lower pH. At pH 2.5, the antacid suspensions became solubilized and no acid-neutralizing capacity remained. This solution was named activated aluminum complex. Based on aluminum ion content, each aluminum-containing antacid suspension tested demonstrated a comparable increase in potency on acidification against ethanol-induced lesions. HCl (pH 2.5) was inactive against ethanol-induced lesions. At cytoprotective doses, activated aluminum complex did not cause gastric lesions when orally administered by itself, demonstrating that it is not acting as a local mucosal irritant. The data suggest that solubilization of aluminum-containing antacids in acidic medium enhances their mucosal protective activity, probably by releasing an activated species of aluminum ion reported to be a hexaaquoaluminum cation.

Antisecretory and antiulcer activities of a potent new histamine H2-receptor antagonist with an intermediate duration of action.

The antisecretory activities of 4-(dimethylamino)- N-[2-[3-[3-(1-piperidinyl)methyl]phenoxy]propyl]amino]- 1,2,5-thiadiazol-4-yl]amino]ethyl]-butanamide, S-oxide (AY-29,315) and ranitidine were determined in the rat, dog and monkey. In conscious, chronically cannulated rats, AY-29,315 was 10 and 208 times more potent than ranitidine as an inhibitor of spontaneous gastric acid secretion by the p.o. and i.v. routes, respectively. Tolerance did not develop in the conscious rat with either compound when administered for 8 consecutive days at doses equivalent to 4 times their antisecretory ED50. In lumen-perfused, anesthetized rats, AY-29,315 i.v. was 44 times more potent than ranitidine as an inhibitor of dimaprit-induced acid secretion. In the gastric fistula dog, AY-29,315 was 7.5 times more potent than ranitidine as an inhibitor of dimaprit-induced secretion by the i.v. route but 3 times less potent by the oral route. In the monkey, against dimaprit, AY-29,315 was 3 and 12 times more potent than ranitidine by the oral and i.v. routes, respectively. p.o./i.v. ratios indicate that, relative to ranitidine, the bioavailability of AY-29,315 by the oral route was low, particularly in the dog. In the dog, at 4 times the oral ED50 dose, the antisecretory effect of ranitidine lasted 190 +/- 3 min, while that of AY-29,315 lasted more than 9 h. AY-29,315 was 8 times more potent than ranitidine as an inhibitor of acetylsalicylic acid-induced ulcers in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperglycemic effect of lidamidine in the rat.

Lidamidine, a new antidiarrheal agent, produced a dose-dependent increase in plasma glucose levels in fed rats. The hyperglycemic response was evident 10 min after oral administration of lidamidine and lasted for 4 hr. Lidamidine's effect was absent in alloxanized rats. Insulin administration prevented the hyperglycemia. Pretreatment with the alpha 2-adrenoceptor antagonists yohimbine or RX781094A blocked the hyperglycemic response, while prazosin, propranolol, and hexamethonium pretreatment had no effect. These results indicate that the hyperglycemic effect of lidamidine is primarily due to the activation of peripherally located alpha 2-adrenoceptors that inhibit the release of insulin from pancreatic beta-cells.

Gastric antisecretory and antiulcer effects of WHR1582A, a compound exerting alpha-2 adrenoceptor agonist activity.

The gastric antisecretory and antiulcer effects of a novel compound, [1-(2,-dimethylphenyl)-3-isobutoxyamidinourea]hydrochloride (WHR1582A), are described. WHR1582A was active in preclinical ulcer models induced by 18-hr pylorus ligation, aspirin, indomethacin, reserpine, stress or cysteamine. WHR1582A inhibited acid secretion in the pylorus-ligated rat and in the anesthetized, lumen-perfused rat. The antisecretory effects of WHR1582A were antagonized by yohimbine, RX781094A and phentolamine. Propranolol, prazosin, corynanthine, methysergide, sulpiride and pimozide were unable to block its activity. WHR1582A blocked acid secretion stimulated by 2-deoxy-D-glucose but was inactive against the direct parietal cell stimulants carbachol and dimaprit. WHR1582A also inhibited electrically stimulated contractions that were mediated via the vagus in the isolated rat stomach preparation. The antisecretory activity of WHR1582A was not due to a reduction in gastric mucosal blood flow. These results demonstrate that WHR1582A is an effective antiulcer-antisecretory agent that exerts its gastric effects through the activation of alpha-2 adrenoceptors located presynapitcally on the vagus.

Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach.

Alpha-2 receptor activation mediates the inhibition of a number of gastrointestinal functions including gastric and intestinal secretions. Alpha-2 receptors are located in the brain and presynaptically on cholinergic nerve terminals; activation of either inhibits vagus nerve activity. Intestinal secretions are inhibited by postsynaptic alpha-2 receptors located on intestinal epithelial cells. Agents which selectively activate alpha-2 receptors in the gut may therefore be beneficial in treating gastric ulcers and diarrheal states. Two such agents which activate alpha-2 receptors in the gut are WHR-1370A [1-n-butoxy-3-(2,6-dimethylphenylcarbamoyl) guanidine hydrochloride] and lidamidine. WHR-1370A is a potent gastric antisecretory and antiulcer agent which inhibits the release of acetylcholine from the vagus nerve. WHR-1370A's activity is blocked by yohimbine. Lidamidine is a clinically effective antidiarrheal agent. Lidamidine's response is partially inhibited by yohimbine in animal diarrheal models. Alpha-2 agonists represent a new class of drugs which have a promising future in the treatment of gastrointestinal disorders.

A semichronic diarrheal model.

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.

Spasmolytic effect of lidamidine on uterine smooth muscle.

1-(2,6-Dimethylphenyl)-3-methylamidinourea hydrochloride (lidamidine hydrochloride) has previously been reported to inhibit intestinal smooth muscle contractile activity in vivo and in vitro. This study showed lidamidine also inhibited contractile activity in the isolated gravid rat uterus preparation and antagonized, the spasmogenic effects of acetylcholine, serotonin, oxytocin, and PGF2 alpha and BaCl2. Increasing Ca2+ concentrations in the bathing medium from 0.9 mmol/l to 7.2 mmol/l effectively antagonized the lidamidine inhibition of responses to BaCl2 and acetylcholine in the gravid rat uterus preparation. These results suggest that the spasmolytic effect of lidamidine may be due to its interference with the availability of Ca2+ necessary for excitation-contraction coupling in smooth muscle.

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.

Antimotility and antisecretory activity of some aryl substituted amidinoureas.

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.

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.

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.

The antiphlogistic, antinociceptive and antipyretic properties of fenclorac.

Fenclorac (a,m-dichloro-p-cyclohexlphenylacetic acid, diethylammonium salt) is a potent nonsteroidal anti-inflammatory agent with significant analgesic and antipyretic activity. Fenclorac had an ED50 of 7.9 mg/kg in the carrageenan paw edema assay and had a duration of action of 18-22 hours. Comparative tests in the carrageenan paw edema assay in the rat indicated that the potency of fenclorac was 13 times that of aspirin, 3.4 times phenylbutazone, 3 times ibuprofen and 0.3 times indomethacin. Fenclorac was less potent than indomethacin, but more potent than phenylbutazone or aspirin in treatment of developing or established adjuvant arthritis. The anti-inflammatory effectiveness of fenclorac did not depend upon the integrity of the adrenopituitary axis and was not affected by the route of administration or sex of the test animal. Fenclorac was 77 times more potent than aspirin and more than twice as potent as indomethacin in reducing fever in rats rendered hyperthermic with brewer's yeast. Fenclorac did not affect normal body temperatures. Fenclorac did not interfere with cellular immune mechanisms as measured by its lack of effectiveness in experimental allergic encephalomyelitis. Antinociceptive testing indicated that fenclorac had peripheral but not central analgesic activity. Fenclorac had an acute oral LD50 in rats and mice of 285 and 430 mg/kg, respectively. The acute gastric lesion UD50 for fenclorac was 7 mg/kg in the fasted rat. Studies using 51Cr-tagged erythrocytes indicated that fenclorac did not produce significant fecal blood loss in the rat at twice the therapeutic ED50 dose for up to 12 days after dosing. Extensive and prolonged fecal blood loss was observed with a corresponding dose of indomethacin for up to nine days after administration. Comparison of the anti-inflammatory pharmacology, Therapeutic Ratio and the data obtained from the 51Cr-fecal blood loss studies indicated that fenclorac was well tolerated after acute or subacute administration to the rat.