Effects of a new 1,4-dihydropyridine, lacidipine, on gastrointestinal motility and other gastrointestinal functions

Lacidipine is a new 1,4-dihydropyridine calcium entry blocker endowed with slow onset of action and potent and long-lasting antihypertensive activity. This study investigated the effect of lacidipine on some gastrointestinal functions, mainly gastrointestinal motility, in rats and dogs. In fasting conscious dogs chronically fitted with electrodes and strain gauges along the small bowel, lacidipine (12 micrograms/kg i.v. bolus or 10 micrograms/kg/h for 3 h) did not modify the migrating motor complex pattern or intestinal spike activity. In the rat, lacidipine proved less active (ED 50 greater than 100 mg/kg p.o.) than nitrendipine (ED 50 = 31 mg/kg p.o.) in inhibiting gastric emptying of a liquid meal, whereas the opposite was true after a solid meal (ED 50 = 10.9 and 35.0 mg/kg p.o., respectively). Lacidipine inhibited fecal pellet output at lower doses (ED 50 = 14.8 mg/kg p.o.) than nitrendipine (ED 50 = 40.1 mg/kg p.o.). On histamine-induced gastric acid secretion, the effect of 100 micrograms/kg i.v. lacidipine was moderate (maximum inhibition 45%). The gastrointestinal effects displayed by lacidipine appear at doses at least 5 and 50 times as high as those affecting blood pressure after intravenous and oral administration, respectively. Thus, lacidipine is unlikely to cause noteworthy unwanted effects on the gastrointestinal tract.     

Antithrombotic effect of TRK-100, a novel, stable PGI2 analogue

TRK-100, a stable PGI2 analogue structurally different from carbacyclines, was compared with other antiplatelet drugs for its effect on platelet functions using animal models. TRK-100 (10-300 nM) inhibited rat platelet aggregation induced by ADP (3 microM), collagen (12.5 micrograms/ml) and A23187 (10 microM), and its potency was about 1/3-1/7 that of PGI2. TRK-100 (0.3-3 mg/kg, p.o.) dose-dependently inhibited rabbit platelet adhesion (ED50: 2.2 mg/kg), and its effect lasted over at least 5 hr. In contrast, aspirin and ticlopidine (both at 300 mg/kg, p.o.) showed only a slight inhibition (4-7%). In the thrombocytopenia induced by collagen injection in rats, TRK-100 (3-300 micrograms/kg, i.v.; 0.1-3 mg/kg, p.o.) dose-dependently inhibited a decrease in platelet number, and its ED50 was 0.48-0.62 mg/kg orally and 13.7-16.4 micrograms/kg intravenously, while the inhibition by aspirin and ticlopidine (both at 1000 mg/kg, p.o.) was 40 and 37%, respectively. In the experimental thread thrombosis in rats. TRK-100 (0.03-3 mg/kg, p.o.) dose-dependently inhibited thrombus formation, and its ED50 was 0.46 mg/kg, being 21 and 87 times as potent as aspirin and ticlopidine, respectively. These results reveal that TRK-100 has a potent antiplatelet activity and is orally and intravenously effective for a variety of thrombosis models, suggesting that it may have a therapeutic value as an antithrombotic drug.     

Lacidipine: a calcium antagonist with potent and long-lasting antihypertensive effects in animal studies.

Lacidipine, currently being evaluated as a once-daily antihypertensive agent, acted as a calcium entry blocker on rabbit ear artery (pA2 = 9.4) with a markedly slower onset of action than that of nitrendipine; this effect was not reversed after 9 h of drug washout. Calcium entry blocker activity was also evaluated on nonvascular smooth muscles: Lacidipine showed a more pronounced vascular selectivity than nitrendipine; for both drugs, concentrations required to induce negative inotropic effects in guinea pig ventricular strip were approximately 100 times higher than concentrations needed to antagonize calcium contraction in vascular smooth muscle. In spontaneously hypertensive rats (SHR), by the tail-cuff method, lacidipine (ED25 = 0.35 mg/kg orally, p.o.) proved approximately 30 times more potent, slower in onset, and longer-acting than nitrendipine in reducing blood pressure. These features were confirmed in chronically implanted SHR after oral and intravenous (i.v.) administration (ED25 = 0.19 mg/kg p.o. and 0.006 mg/kg i.v.). A short-lasting tachycardia was detected with both drugs. No evidence of acquired tolerance emerged after repeated oral administrations over a 3-week period. Lacidipine induced a natriuretic effect in saline-loaded SHR at antihypertensive doses. In renal hypertensive dogs, lacidipine proved more potent (three to seven times), slower in onset, and longer-lasting than nitrendipine after p.o. (ED25 = 0.22 mg/kg) and i.v. (ED25 = 0.004 mg/kg) administrations.     

Suppression of the Arthus reaction by Y-24180, a potent and specific antagonist of platelet-activating factor.

A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine) was investigated for the effects on the skin reactions induced by chemical mediators and the Arthus reactions. In the rat dorsal skin, Y-24180 (0.1-10 mg/kg, p.o.) inhibited increase in vascular permeability by the intradermal PAF injection in a dose dependent manner and the inhibitory activity was 60 times more potent than that of WEB 2086. While even at doses as large as 10 mg/kg, p.o., it had no effect on vascular permeability in the rat skin induced by histamine, serotonin, bradykinin and leukotriene D4. On a reversed passive Arthus reaction in rat dorsal skin, Y-24180 (0.1-1 mg/kg, p.o.) markedly inhibited vascular permeability in a dose dependent manner and the inhibitory activity was 15 times more potent than that of WEB 2086. Y-24180 also inhibited the Arthus dermal reaction in rabbits (0.03-0.3 mg/kg, p.o.) and guinea pigs (0.1-1 mg/kg, p.o.). In addition, Y-24180 (0.1-10 mg/kg, p.o.) significantly reduced the exudate volume and the number of infiltrated inflammatory cells in the reversed passive Arthus pleural reaction in rats. Furthermore, in rat passive Arthus pancreatitis, Y-24180 (0.3-10 mg/kg, p.o.) significantly inhibited the dye extravasation from the pancreas. These results provide strong evidence that endogenous PAF plays an important role as a mediator in the type III allergic inflammation.     

H2-receptor antagonist and gastric acid antisecretory properties of Wy-45,662

Investigations were carried out to delineate the biological activity of Wy-45,662, a new H2-receptor antagonist. In the pylorus-ligated rat after intraduodenal administration, total acid output (TAO) over 4 hours was inhibited by Wy-45,662 with an ED50 of 0.3 mg/kg as compared to ranitidine (ED50 = 7 mg/kg) and cimetidine (ED50 = 12 mg/kg); i.v. or i.m. administration increased Wy-45,662's potency 10-fold. In dogs with innervated gastric pouches Wy-45,662 inhibited food-stimulated TAO with ED50's of 0.35 mg/kg (p.o.), 0.045 mg/kg (i.v.) and 0.065 mg/kg (i.m.); cimetidine (ED50 = 6 mg/kg p.o.) and ranitidine (ED50 = 1 mg/kg p.o.) were less potent. Wy-45,662 also inhibited pentagastrin- or histamine-stimulated acid secretion in the conscious fistula rat. In vitro, Wy-45,662 antagonized the histamine-stimulated a) positive chronotropism in guinea pig atria and b) [14C]aminopyrine uptake by rat gastric mucosal cells, confirming its H2-receptor antagonist properties.     

Analgesic activity of a non-steroidal anti-inflammatory agent, tolmetin sodium in experimental animals (author's transl)

Effect of tolmetin sodium on the pain-like responses caused by various nociceptive stimuli was examined in experimental animals. Tolmetin sodium showed a potent inhibitory activity on the acetic acid-induced writhing in mice and rats, and its potency, (ED50 = 23.4 and 3.01 mg/kg, p.o.) was about 2.4--10.3 times that of ibuprofen and aspirin. The hypertension induced by intraarterial injection of bradykinin toward the spleen of dogs was inhibited by tolmetin sodium (ED50 = 80 mg/kg, i.v.), but the hypertension by a simultaneous injection of bradykinin and PGE1 was not inhibited by tolmetin sodium and sulpyrine, though pentazocine inhibited both hypertensions. The pain-like response caused by pressing mechanically the inflamed paws or joints of rats induced by kaolin-carrageenin or adjuvant was inhibited by tolmetin sodium (30--100 or 20--40 mg/kg, p.o., respectively), and the potency was approximately equal that of ibuprofen and phenylbutazone. Tolmetin sodium produced a significant inhibition of the pain-like response induced by electrical stimulation of tooth pulp of dogs, but showed no effect when the methods of Haffner and D'Amour-Smith were applied to mice. Anti-writhing action of tolmetin sodium was not antagonized by naloxone. From these results, it was concluded that tolmetin sodium has a potent inhibitory activity on the pain-like responses induced by the chemical nociceptive stimuli and by the mechanical pressure stimulus of the inflamed tissue, especially on the writhing. The analgesic activity probably involves a peripheral mechanism.     

Effects of traxanox sodium on experimental nasal allergy

The anti-allergic actions of traxanox sodium pentahydrate (traxanox) were examined using experimental allergic rhinitis models. Traxanox (10 and 30 mg/kg, p.o.), tranilast (30 and 100 mg/kg, p.o.) and disodium cromoglycate (DSCG, 3 and 10 mg/kg, i.v.) dose-dependently inhibited the increase of dye leakage in rats actively sensitized with dinitrophenol-coupled ascaris extract. Traxanox was about 4 times more potent than tranilast. In this test, the inhibitory activity of traxanox (30 mg/kg, p.o.) was not affected by predosing with the same dose for 7 days. In addition, traxanox (1-10 mg/kg, i.v.) inhibited the allergically induced increase in nasal resistance of guinea pigs actively sensitized with egg albumin, while tranilast (10 mg/kg, i.v.), DSCG (100 mg/kg, i.v.) and mepyramine (1 mg/kg, i.v.) had little effect. These results suggest that traxanox may be clinically effective in treating patients with nasal allergies.     

Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs.

YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.     

2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--I. Anticonvulsant properties

2-Amino-6-trifluoromethoxy benzothiazole (PK 26124) prevented convulsions induced in rodents by maximal electroshock, inhibitors of the synthesis of gamma-aminobutyric acid (GABA) and ouabain, but was inactive against seizures provoked by GABA antagonists, unlike diazepam, chlordiazepoxide, phenobarbital and valproic acid. 2-Amino-6-trifluoromethoxy benzothiazole prevented seizures induced by sound stimuli in DBA/2 mice (ED50 = 0.66; 2.1 and 4.1 mg/kg, i.p. according to the seizure component), postural seizures in El mice (ED50 = 7.5 mg, i.p.) and seizures induced by photic stimulation in the baboon, Papio papio, at 4 and 8 mg/kg (i.v.). This spectrum of anticonvulsant activity closely resembles that reported previously for dicarboxylic amino acid antagonists. Indeed, PK 26124 prevented seizures induced by L-glutamate (ED50 = 8.5 mg/kg, i.p.) or by kainate (ED50 = 9.25 mg/kg, i.p.) and tremors induced by harmaline (ED50 = 2.5 mg/kg, i.p.) In these tests diazepam was inactive (L-glutamate) or as potent as PK 26124 (kainate, harmaline), whereas it was 10-20 times more potent than PK 26124 against seizures induced by inhibitors of the synthesis of GABA. Together, these data suggest that PK 26124 possesses antagonistic properties of excitatory dicarboxylic amino acids, which may contribute to its anticonvulsant action.     

Pharmacological properties of droxicam, a new non-steroidal anti-inflammatory agent

Droxicam showed high antiinflammatory activity in carrageenin-induced edema in rat. At doses of 0.25 and 0.5 mg/kg, droxicam was as active as piroxicam and more active than phenylbutazone given at 2.5 and 5 mg/kg. Against nystatin-induced edema, droxicam (ED50, p.o., 5, 6, 7, 8 h: 7.5, 12.9, 4.8, 8.4 mg/kg) was 4-11 times more active than phenylbutazone and more than 12 times more active than isoxicam. In cotton pellet-induced granuloma in rats, title compound was as active as suprofen. In U.V. light-induced erythema in guinea pigs, droxicam (ED50, p.o., 1, 2, 3, 4 h: 0.51, 0.94, 1.56, 4.88 mg/kg) was 5-9 times more active than phenylbutazone. At doses of 0.1, 0.33 and 1.0 mg/kg/day, droxicam, similar to piroxicam, showed good antiarthritic activity in rats injected with Mycobacterium butyricum against primary and secondary lesions. Droxicam demonstrated strong analgesic activity in protecting against writhings: induced by phenylbenzoquinone in mice: ED50: droxicam = 5.3, phenylbutazone = 61.5, acetylsalicylic acid = 90.7, dipyrone = 83.6, isoxicam = 88.3 mg/kg, p.o.; induced by acetylcholine bromide in mice: ED50: droxicam = 1.1, phenylbutazone = 32.1, acetylsalicylic acid = 32.2, isoxicam = 32.7 mg/kg, p.o.; induced by acetic acid in rat: ED50: droxicam = 0.94, acetylsalicylic acid = 8.72, isoxicam = 4.70 mg/kg, p.o. Antipyretic activity of title compound was demonstrated in rats with pyresis induced by brewer's yeast, being 4-13 times more active than dipyrone. In pyresis induced by Salmonella typhi, droxicam was more active than acetylsalicylic acid and 4-aminoantipyrine at all times and doses. In a study of protection against diarrhea induced by castor oil in rats, droxicam and piroxicam showed equal activity (ED50 = 0.081 and 0.079 mg/kg, p.o., respectively) and were 3.9 and 15.6 times more active than isoxicam and phenylbutazone, respectively. Droxicam significantly inhibited peritoneal capillary permeability in mice at a dose of 5 mg/kg, p.o., while isoxicam and phenylbutazone required 100 and 200 mg/kg, p.o., respectively. Droxicam did not exhibit uricosuric activity in rats. It did not show cardiovascular or respiratory effects in anesthetized cats, nor modify their response to administration of acetylcholine, norepinephrine and histamine. In the Irwin's test, droxicam did not alter rat behavior (80 mg/kg, i.p.) nor that of mice (160 mg/kg, p.o.). Induction of gastrointestinal injuries in rats by droxicam was 10 times less than by piroxicam (UD50: droxicam, 57 mg/kg, p.o.; piroxicam, 5.6 mg/kg, p.o.). The potentiation of gastric injuries induced by stress through cold in rats was also studied.(ABSTRACT TRUNCATED AT 400 WORDS)     

A sulphonamido-indanone derivative CGP 28237 (ZK 34228), a novel non-steroidal anti-inflammatory agent without gastro-intestinal ulcerogenicity in rats

CGP 28237 (5-methylsulphonylamino-6-phenoxy-1-indanone) belongs to a series of structurally novel indanones. The compound is a weak acid (pK = 6.98), but it does not contain a carboxylic group. CGP 28237 exhibits potent anti-inflammatory activity in developing and established adjuvant arthritis in rats (ED40 approximately 0.5 mg/kg p.o.) and good activity in carrageenin oedema (ED40 approximately 3 mg/kg p.o.). It inhibits yeast-induced fever in rats with ED50 values of 1, 2 and 10 mg/kg p.o. at 1, 3 and 5 hours after drug administration. The antinociceptive activity in mice (phenyl-p-benzoquinone writhing) and rats (acetic-acid writhing) is weak. CGP 28237 has been shown to be non-ulcerogenic in rats under acute and chronic test conditions: it does not cause mucosal lesions in the stomach at 2 X 400 mg/kg p.o., it does not enhance gastro-intestinal blood loss during 10 days' oral treatment with 400 mg/kg p.o., and it did not induce gastro-intestinal lesions in a 4-week toxicity study up to 1000 mg/kg p.o. Although CGP 28237 is not a cyclooxygenase inhibitor in bovine seminal vesicle microsomes, it inhibits prostaglandin synthesis in zymosan-stimulated murine macrophages (IC50 approximately 3 X 10(-6) mol/l) and protects rabbits against arachidonic acid-induced lung embolism with 10 mg/kg p.o. CGP 28237 may represent a novel anti-inflammatory drug with excellent gastro-intestinal tolerability.     

The pharmacological profile of CGP 28238, a novel highly potent anti-inflammatory compound

CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10x) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 greater than 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of less than or equal to 2 mg/kg, p.o. Although CGP28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 greater than 10(-3) mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of less than 10(-6) mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 x 10(-7) and 2 x 10(-8) mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.     

The mechanism of alteration of monoamine metabolism in brain regions in marble burying behavior-isolated housing mice and effect of oren-gedoku-to on this alteration

The mechanism of the alteration in marble burying behavior-isolated housing (MBB-IH) mice was investigated. The determination of hypothalamus monoamine and serum corticosterone contents indicated that MBB-IH mice readily responded to the stress stimuli in conditioned fear stress. Six drugs, such as buspirone (10 mg/kg, p.o.), zimelidine (10 mg/kg, p.o.), clomipramin (10 mg/kg, p.o.), yohimbine (5 mg/kg, p.o.), ethyl beta-carboline-3-carboxylate (beta-CCE, 5 mg/kg, p.o.) and flumazenil (15 mg/kg, p.o.) were singly and/or three times administered to MBB-IH mice. Their inhibitory activity on the MBB-IH mice was considered by the use of activity profiles consisting of spontaneous locomotor activity, marble burying behavior and hypothalamus monoamine content. Using these profiles, we calculated the activities as vector in three-dimensional space, and compared the distance from the control point (DCP). DCPDOPAC and DCP5-HIAA were shortened by single administration of beta-CCE and flumazenil. Oren-gedoku-to (30 and 300 mg/kg, p.o.) shortened the DCPDOPAC and DCP5-HIAA similarly to beta-CCE. The blended crude drugs in Oren-gedoku-to, Coptis rhizome (636.0 mg/kg, p.o.), Scutellaria root (644.4 mg/kg, p.o.) and Gardenia fruit (894.8 mg/kg, p.o.) shortened the DCPDOPAC. Coptis rhizome and Scutellaria root also shortened the DCP5-HIAA. These results suggest that GABA neuron function intensely affects the alteration of MBB-IH and Oren-gedoku-to has the intrinsic benzodiazepine-like activity.     

Pharmacological studies of loperamide, an anti-diarrheal agent. I. Effects on diarrhea induced by castor oil and prostaglandin E. (author's transl)]

Effects of loperamide on diarrhea induced by castor oil and prostaglandin E1 were investigated in rats and mice and compared with those of narcotic analgesics, atropine, mecamylamine and local anesthetics. The following results were obtained. Loperamide markedly suppressed the appearance of diarrhea induced by oral administration of castor oil in rats and the ED50 values for 1 and 2 hr protection was 0.082 and 0.42 mg/kg p.o., respectively. Loperamide markedly suppressed the appearance of diarrhea induced by i.v. administration of prostaglandin E1 and the ED50 value for 2 hr protection was 0.24 mg/kg p.o. in rats. The ID120 min value of loperamide which was calculated on the basis of the dose producing a 20% or more inhibition of the charcoal transport in the small intestine for 120 min was 0.8 mg/kg p.o. in mice and this activity was 9.2 times more potent than that of morphine. The analgesic ED50 value (Haffner's method) and LD50 value of loperamide was 149 and 249 mg/kg p.o., respectively. These results suggest that loperamide has a potent anti-diarrheal activity and specificity to the gastrointestinal tract and inhibits the effect of prostaglandin E1 and ricinoleic acid on the intestinal tract in rats.     

FR145715, a novel histamine H2 receptor antagonist, with specific anti-Helicobacter pylori activities.

The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (FR145715), a novel histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.     

Effects of a new anti-inflammatory imidazole derivative, fenflumizole, on platelet aggregation in the rabbit

The antiplatelet effect of fenflumizole, compared with aspirin or ticlopidine, was examined in in vitro, ex vivo and in vivo situations of the rabbit. Unlike ticlopidine, fenflumizole and aspirin effectively inhibited in vitro the platelet aggregation elicited by arachidonate and collagen. The activity of fenflumizole was 350 times more potent than that of aspirin. Fenflumizole (0.3-3 mg/kg) given p.o. was 4.2 and 8.1 times more potent than aspirin in inhibiting arachidonate- and collagen-induced platelet aggregations, respectively. Ticlopidine (300 mg/kg, p.o.) resulted in only weak effects on the aggregations. Fenflumizole (3 mg/kg) as well as aspirin (10 mg/kg) given p.o., unlike ticlopidine (300 mg/kg), effectively prevented the arachidonate-induced sudden death.     

Inhibition of angiotensin converting enzyme by (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetra- hydro-1,5-benzothiazepine-6-acetic acid (CV-5975), a non-sulfhydryl compound

CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo- 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was found to inhibit rabbit lung angiotensin converting enzyme (ACE) activity with an IC50 of 3.1 x 10(-9) M and a Ki of 2.6 x 10(-9) M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3 x 10(-8) M, and augment the bradykinin (BK)-induced contraction of the ileum with an AC50 of 9.2 x 10(-10) M. The activity of CV-5975 was comparable to or slightly more potent than that of enalaprilat. The overall inhibition constant (Ki*), calculated from a steady-state analysis of enzyme reactions, was 4.4 x 10(-12) M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0 x 10(-11) M). In rats, CV-5975 (0.03 and 0.3 mg/kg, i.v. and 3 and 10 mg/kg, p.o.) inhibited the A-I-induced pressor action more potently and for a longer period than did the corresponding doses of enalaprilat and enalapril. CV-5975 and enalapril (3 mg/kg, p.o.) augmented the BK-induced depressor action to a similar extent. In dogs, CV-5975 (0.3 and 1 mg/kg, p.o.) markedly inhibited the A-I-induced pressor action in a dose related manner, and the duration of this inhibitory activity was longer than with the corresponding doses of enalapril. These data provide evidence for the proposal that CV-5975 is a highly potent and long lasting ACE inhibitor.     

Pharmacological studies on triazine derivatives V Sedative and neuroleptic actions of 2-amino-4-[4-(2-hydroxyethyl)-piperazin-1-yl]-6-trifluoromethyl-s-triazine (TR-10).

Pharmacological properties of 2 amino-4-[4-(2-hydroxyethyl)-piperazin-1-yl]-6-trifluoromethyl-s-triazine (TR-10) were investigated in mice and rats. Chlorpromazine served as a reference compound. Tr-10 expressed in general the pharmacological profiles as neuroleptic ascertained by anti-methamphetamine activity, supression of conditioned avoidance response, taming effects, decrease in exploratory behavior and cataleptogenic activity. Among these effects, anti-methamphetamine action was most potent. Different from chlorpromazine, TR-10 showed a similar pharmacological activity pattern in the intraperitoneal and oral routes of administration as depicted from ED50/LD50 values. Although the effects relevant to neuroleptics were less potent than chlorpromazine, such were seen with TR-10 at lower doses than those causing muscle relaxation. TR-10 significantly depressed the spontaneous motor activity but showed no anti-convulsant action in mice. Hypothermic action, potentiating effects of hypnotics and alpha-adrenergic blocking action, characteristic to chlorpromazine, were very weak for TR-10. TR-10 also showed low toxicity in mice (LD50 = 820 mg/kg p.o., 465 mg/kg i.p.) compared with that of chlorpromazine (LD50 = 370 mg/kg p.o., 228 mg/kg i.p.).     

Pharmacological studies on nitro‐naproxen (naproxen‐2‐nitrooxyethylester)

Naproxen‐2‐nitrooxyethylester (S‐(+)‐2‐(6‐methoxy‐2‐naphthyl)propanoic acid‐2‐nitrooxyethylester, LE‐EK06) was synthesized from naproxen and 2‐nitrooxyethylbromide as a novel nitric oxide–releasing derivative of naproxen. Molar equivalents of LE‐EK06 (6.93–27.73 mg/kg, p.o.) to naproxen dose‐dependently exhibited greater antinociceptive activity in comparison to naproxen in a writhing assay. The compound (5.54–22.18 mg/kg, p.o.) showed greater anti‐inflammatory activity at 2 h after as comparable to its effect at 4 h after carrageenan challenge in rats. Further, LE‐EK06 (9.45 mg/kg, p.o.) was more potent in the carrageenan‐evoked hyperalgesia. LE‐EK06 (11.09 mg/kg, p.o.) and naproxen (8.0 mg/kg, p.o.) showed a comparable inhibitory effect on exudate formation and migration of polymorphonuclear leukocytes (PMNs) in a carrageenan‐induced pleurisy test. Further, the compound (11.09 mg/kg, p.o.) significantly reduced myeloperoxidase activity in carrageenan‐treated paw and demonstrated significantly less gastrotoxicity in acute and chronic (21 days) studies. The scanning electron microscopy revealed that LE‐EK06 showed only mild gastric damage (slight disruption of mucus layer) in comparison to naproxen. The present study suggested that naproxen‐2‐nitrooxyethylester (LE‐EK06) represents a novel gastric sparing NSAID. Drug Dev. Res. 61:66–78, 2004. © 2004 Wiley‐Liss, Inc.     

The antinociceptive effects of prostaglandin antagonists in the rat

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.