Effect of BMY-25368, a potent and long-acting histamine H2-receptor antagonist, on gastric secretion and aspirin-induced gastric lesions in the dog.

BMY-25368, 1-amino-2-[3-(3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3,4-dione, a new histamine H2-receptor antagonist, has been compared to ranitidine as an inhibitor of gastric acid secretion in the Heidenhain pouch dog. Intravenous infusion of BMY-25368 antagonized histamine-stimulated gastric secretion in a competitive manner. BMY-25368 also antagonized gastric secretion stimulated by pentagastrin, bethanechol and food. When compared to ranitidine in histamine-stimulated dogs, BMY-25368 was nine times more potent after bolus intravenous administration. Oral potency relative to ranitidine and ranged from 2.8 to 4.4, depending on the secretagogue used. BMY-25368 also exhibited a significantly longer duration of action than ranitidine. Thus, its potency relative to ranitidine after oral administration, in histamine-stimulated dogs, increased from 3.2 to 28 when determined 1-3 and 10-12 h post dose, respectively. BMY-25368 administered orally also antagonized aspirin-induced gastric lesions in the dog and was nine times more potent than ranitidine in this respect.

BMY-25801, an antiemetic agent free of D2-dopamine receptor antagonist properties.

BMY-25801, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]2-(1-methyl-2-oxopropoxy ) benzamide, a new antiemetic agent free of D2-dopamine receptor antagonist properties, was effective against emesis induced by cytostatic agents (cisplatin, cyclophosphamide and doxorubicin) and total body radiation in the ferret. It also was effective against cisplatin-induced emesis in the dog; however, it was inactive against emesis caused by apomorphine and hydergine in the same species. In terms of activity profile, BMY-25801 could be differentiated both from metoclopramide and domperidone. Metoclopramide was nonselectively active against emesis induced by cytostatic agents, radiation and D2-dopamine receptor agonists, whereas domperidone was selectively effective against emesis induced by apomorphine and hydergine only. BMY-25801 failed to reveal any D2-dopamine receptor antagonist properties in several pharmacological tests (catalepsy, apomorphine stereotypy, serum prolactin, striatal dihydroxyphenylacetic acid and [3H]spiperone displacement) whereas metoclopramide was uniformly active in these tests. The activity profile of domperidone was compatible with its classification as a peripherally acting D2-dopamine receptor antagonist. BMY-25801 and metoclopramide antagonized serotonin-induced bradycardia (Bezold-Jarisch reflex) in the anesthetized rat, a response involving peripheral neuronal 5-HT3 receptors. Thus, BMY-25801 represents a novel antiemetic acting independently of D2-dopamine receptor mechanisms; however, its exact mode of action remains unknown.

Prevention of aspirin-induced gastric mucosal injury by histamine H2 receptor antagonists: a crossover endoscopic and intragastric pH study in the dog.

Histamine H2 receptor antagonists have been reported to protect the gastric mucosa of animals and humans against aspirin-induced damage. It is unclear, however, whether this protective effect can be observed at doses less than those needed to markedly inhibit gastric acid secretion. We have developed a single-dose endoscopic assay system of aspirin-induced gastric mucosal injury in normal conscious dogs. In this model, severe gastric mucosal injury and a decrease in the pH of the gastric luminal contents were consistently demonstrated 2 h after the oral administration of 100 mg/kg of aspirin. Pretreatment with three histamine H2 receptor antagonists (cimetidine, ranitidine, BMY-25271), prevented both of these effects in a dose-related manner. All three H2 receptor antagonists reduced gastric mucosal injury only at doses that were greater than those required to prevent the aspirin-induced decrease in gastric luminal pH or to inhibit histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. Plasma levels of aspirin were not altered by histamine H2 receptor antagonism. These results indicate that acid inhibition is an important component of the mechanisms whereby histamine H2 receptor antagonists protect the gastric mucosa from aspirin-induced damage in the dog.

Disease modifying activity of HWA 486 in rat adjuvant-induced arthritis.

HWA 486 was investigated for its ability to modify the development of adjuvant-induced polyarthritis in Lewis rats. HWA 486 (20 mg/kg/day p.o.), dosed for 8 or 16 days beginning with the day of adjuvant administration, significantly reduced edema, fibrinogen levels, and erythrocyte sedimentation rates (ESR) 42 days later. When HWA 486 (20 mg/kg/day, p.o.) and cyclosporin A (CsA 15 mg/kg/day, p.o.) were tested in the 8-day treatment regimen, the antiarthritic effects of HWA 486 were more sustained. Both compounds reduced the delayed hypersensitivity (DTH) response on day 9 followed by a rebound to an enhanced DTH response on day 21. The PHA-induced mitogenic response of splenocytes from arthritic rats was suppressed on day 9. Treatment with HWA 486 but not CsA restored the splenocyte response to the level of the negative controls.

Swallow-evoked peristalsis in opossum esophagus: role of cholinergic mechanisms.

This study examined the role of cholinergic mechanisms in esophageal smooth muscle of anesthetized opossums. Swallow-induced motility was recorded manometrically before and after treatment with physostigmine or metoclopramide. At the 5-cm site above lower esophageal sphincter (LES) the latency, duration, and amplitude of swallow-evoked contractions were 2.1 +/- 0.12 (SE) s, 1.8 +/- 0.31 s, and 74.5 +/- 6.1 mmHg, respectively. At the 1-cm site the respective values were 4.6 +/- 0.38 s, 3.8 +/- 0.24 s, and 42.0 +/- 4.6 mmHg. The calculated speed of peristalsis was 1.72 +/- 0.21 cm/s. After intravenous treatment with the physostigmine (100 micrograms X kg-1 X h-1), each swallow produced contractions that were simultaneous, repetitive, and of long duration. The values of duration and amplitude of contraction at the 5- and 1-cm site after physostigmine treatment were significantly higher than controls (P less than 0.01). There was a significant decrease in the latency of contraction at all sites. This resulted in a significant faster speed of peristalsis. Atropine (30 micrograms/kg iv) reversed the influence of physostigmine, resulting in a significantly slower speed of peristalsis. Metoclopramide (10 mg/kg iv) resulted in several changes in swallow-evoked contractions similar to those observed after physostigmine treatment. These data suggest that alteration in cholinergic mechanisms results in disordered esophageal peristalsis in the opossum.

A comparison of some of the pharmacological properties of etintidine, a new histamine H2-receptor antagonist, with those of cimetidine, ranitidine and tiotidine.

Etintidine is a competitive antagonist of histamine H2-receptors in the isolated spontaneously beating guinea-pig right atrium with a pA2 value of 6.6 relative to values of 6.2, 6.7 and 7.3 for cimetidine, ranitidine and tiotidine, respectively. Low affinities for histamine H1 (pA2 = 4.2), cholinergic (pA2 = 4.4) and beta adrenergic (pA2 = 3.8) receptors indicated that etintidine has a high degree of specificity for the H2-receptor. The other antagonists studied also exhibited low affinities for these receptors; however, relative to these compounds, etintidine demonstrated a somewhat greater affinity for cholinergic receptors. Etintidine also antagonized basal gastric acid secretion in the conscious gastric fistula rat and histamine, pentagastrin, carbachol, 2-deoxy-D-glucose and meal-stimulated gastric acid secretion in conscious gastric fistula and Heidenhain pouch dogs. After oral administration to conscious Heidenhain pouch dogs, ED50 values for the inhibition of near maximal gastric acid secretion stimulated by histamine were 7.1, 5.4, 0.74 and 0.69 mumol/kg for cimetidine, etintidine, ranitidine and tiotidine, respectively. Onset and duration of the gastric antisecretory activities of the four compounds were similar. The order of potency as histamine H2-receptor and gastric antisecretory antagonists was cimetidine less than etintidine less than ranitidine less than tiotidine. Based on the high degree of specificity for the H2-receptor and its potent gastric antisecretory activity, etintidine may prove to be a useful agent in the treatment of peptic ulcer disease.

Effects of tiodazosin, praxosin, trimazosin and phentolamine on blood pressure, heart rate and on pre- and postsynaptic alpha-adrenergic receptors in the rat.

Subcutaneous administration of tiodazosin (0.1-3 mg/kg), prazosin (0.01-1 mg/kg), trimazosin (10-30 mg/kg) and phentolamine (0.1-3 mg/kg) to conscious spontaneously hypertensive rats (SHR) produced graded decreases in blood pressure with the order of potency being prazosin > tiodazosin > phentolamine > trimazosin. Heart rate was elevated predominantly only by phentolamine and this was consistent with the activity of this agent for both pre- and postsynaptic alpha-adrenergic receptors. In contrast, tiodazosin, prazosin and trimazosin showed selectivity only for postsynaptic alpha-adrenergic receptors. Acute oral administration of tiodazosin and prazosin indicated tiodazosin to be about 1/2 as potent as prazosin. However, chronic administration of equivalent doses of the two compounds for 25 and 52 days via the drinking water indicated approxiately equivalent, sustained reductions in blood pressure. Furthermore, at the end of the 52-day chronic dosing period tiodazosin caused appreciably less alpha-adrenergic receptor antagonist activity than prazosin as assessed by the norepinephrine dose-pressor response profiles. These results indicate that following chronic dosing with tiodazosin in the rat other mechanisms besides alpha-adrenergic receptor antagonist activity are probably contributing to the antihypertensive effect in the rat.

Comparative gastrointestinal and biliary tract effects of morphine and butorphanol (Stadol).

Butorphanol, levo-N-cyclobutylmethyl-3,14 beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 to 8 times more potent than morphine in experimental animals and man. Butorphanol and morphine were evaluated in mice and dogs for their gastrointestinal and biliary tract smooth muscle effects. Morphine decreased the propulsion of a charcoal meal through the gastrointestinal tract of the mouse in a dose related manner with the maximal inhibition obtainable being 90%. Butorphanol produced a maximal inhibition of motility of only 40% with very high doses producing less of an inhibitory effect than lower doses. In dogs, morphine caused a dose-dependent increase in duodenal smooth muscle activity and a dose-dependent decrease in bile duct flow. A clinically effective i.v. dose of morphine (0.1 mg/kg) produced a statistically significant spasmogenic effect on dog biliary tract and gastrointestinal smooth muscle, while a clinically effective equianalgetic i.v. dose of butorphanol (0.025 mg/kg i.v.) had little or not effect on the biliary or gastrointestinal systems. These findings indicate that at equianalgetic doses, butorphanol should produce less constipation and less biliary tract and gastrointestinal smooth muscle spasm than morphine.

Comparative first dose effects of prazosin and tiodazosin (BL-5111) in spontaneously hypertensive rats.

Prazosin produces a "first-dose" phenomenon in man clinically characterized by an exaggerated hypotensive response to the initial dose of the drug, with subsequent doses not producing this exaggerated effect. In spontaneously hypertensive rats (SHR), prazosin (1 mg kg po) produced a similar effect, appreciably reducing systolic blood pressure at 12 hours after the first dose but having little or no effect at 12 hours after the subsequent doses. In contrast, BL-5111, an antihypertensive agent similar in chemical structure and shown in previous studies to be slightly less potent than prazosin but with appreciably less alpha-adrenergic receptor antagonist activity, had no effect on blood pressure at 12 hours after dosing (1 and 2 mg/kg po). Pretreatment of rats with an ineffective blood pressure lowering dose of prazosin (0.03 mg/kg po) significantly attenuated the first dose effect of prazosin, resembling the clinical observations seen in patients. Thus, the SHR may be a useful model for predicting the prazosin-like "first-dose" phenomenon with related analogs.

Antagonism of cisplatin induced emesis in the dog.

Cisplatin (cis-diammine-dichloro-platinum) administered at a dose of 3 mg/kg iv induced a reproducible and characteristic emetic response in the dog. It was characterized by a latency period (90-120 min) and multiple emetic episodes occuring within 5 hours following drug administration with sporadic delayed emesis later within the first 24 hours. There was a qualitative similarity between the emetic response of Cisplatin seen in dogs and cancer patients. Metoclopramide (1, 3 mg/kg sc) was found to be the most effective antagonsit of Cisplatin emesis in the dog while haloperidol (1 mg/kg sc) and chlorpromazine (0.3, 1, 3 mg/kg sc) offered a less complete protection. Nabilone (0.1 mg/kg iv) and AL-1612 (1 mg/kg sc) failed to to demonstrate any significant activity. A relationship between antagonism patterns of emetic responses induced by Cisplatin and apomorphine was discussed.

Pharmacological effects of a combination of butorphanol and acetaminophen.

Isobolographic analysis was used to study in mice the combined oral analgetic action of butorphanol, a new centrally acting analgetic, and acetaminophen, an antipyretic analgetic. Combinations of butorphanol-acetaminophen exhibited analgetic effects which were greater than were expected from just an additive analgetic action of each drug. Consequently, a significant synergistic effect occurred after the simultaneous oral administration of butorphanol and acetaminophen. Furthermore, oral administration of butorphanol-acetaminophen mixture to conscious dogs at approximately 20 times the recommended human dose resulted in little or no effect on aortic blood pressure and arterial blood pH,pCO2 and pO2. Heart rate was slightly reduced and this resulted in a small increase in the PR interval and a prolongation of the QT interval of the lead II surface electrocardiogram.

Effect of butorphanol and morphine on pulmonary mechanics, arterial blood pressure and venous plasma histamine in the anesthetized dog.

Butorphanol, levo-N-cyclobutylmethyl-3, 14beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 times more potent than morphine in experimental animals. Equianalgetic doses of butorphanol and morphine were compared, following rapid intravenous injection to anesthetized dogs, for their effects on pulmonary resistance, dynamic compliance, arterial blood pressure and venous plasma histamine levels. Butorphanol, 0.75 mg/kg, had no effect on pulmonary resistance, dynamic compliance or venous plasma histamine levels. Morphine, 3 mg/kg, increased pulmonary resistance, decreased dynamic compliance and elevated venous plasma histamine levels. Both drugs decreased arterial blood pressure but the hypotensive effect of butorphanol was significantly less in magnitude than that of morphine. Pretreatment with chlorpheniramine antagonized the effects of morphine on pulmonary resistance, dynamic compliance and arterial blood pressure. These results suggest that in man butorphanol may have less potential than morphine for causing airway constriction, hypotension and histamine release.

Behavioral suppressant effects of clonidine in strains of normotensive and hypertensive rats.

The behavioral effects of orally administered clonidine were investigated in Long--Evans (LE), Sprague--Dawley (SD) or Kyoto Wistar (KW) rats assumed to be normotensive and in NIH spontaneously hypertensive (SH) rats. Although clonidine (0.05-1 mg/kg) resulted in the same qualitative effect, i.e., depression of motor activity, the dose of clonidine required to depress motor activity to 50% of control levels (ED50) tended to vary according to strain. An analysis of variance of the dose response curves for the four strains of rats indicated a significant strain effect. When the effects of clonidine on food-reinforced operant responding were investigated it was observed that SD and SH rats differed with regard to rate and temporal pattering of IRT greater than 20 sec responding. Although oral administration of clonidine (0.006-0.1 mg/kg) produced similar percentage decreases from control in SH and SD rats, and analysis of the temporal patterning of responding indicated differences in responsiveness to the behavioral effects of clonidine. These studies demonstrate strain-related differences in responsiveness to the behavioral suppressant effects of clonidine. Marked differences between genetically hypertensive rats and rats assumed to be normotensive were not evident.

The effect of a potent inhibitor of platelet aggregation, BL-3459, on adrenaline-induced myocardial necrosis in beagle dogs.

The effect of a potent inhibitor of platelet aggregation, BL-3459, on adrenaline-induced myocardial necrosis was investigated in beagle dogs. BL-3459, an alpha-adrenergic receptor blocking agent, phenoxybenzamine, and a beta-adrenergic receptor blocking agent, propranolol, were compared for their ability to modify the effects of adrenaline on platelet function, arterial blood pressure and myocardial damage. Adrenaline infusion led to a dose-related myocardial damage, elevation in arterial blood pressure, elevation in screen filtration pressure (SFP) and fall in platelet count. BL-3459 inhibited the elevation in SFP and the fall in platelet count as well as limiting the extent of myocardial damage. Phenoxybenzamine significantly modified all adrenaline-induced changes except the elevation in SFP. Propranolol had little effect alone and seemed to antagonize the beneficial effects of BL-3459 when the two drugs were combined. These results suggest that while other factors may also be involved, platelet aggregation and transient hypertension are correlated with the extent of adrenaline-induced myocardial necrosis observed in this model. A potent inhibitor of platelet aggregation, BL-3459, and the alpha-adrenergic receptor blocking agent, phenoxybenzamine, appear to afford protection against the observed pathological effects.

The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic.

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.