Synthesis and antiarrhythmic activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.

During further modification of the new antiulcer agent 5 (KW-5805), a 5,11-dihydro[1]benzoxepino[3,4-b]pyridine derivative, we found that some new derivatives had antiarrhythmic activity. So we continued synthesis and evaluation of a series of 5-substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice and in ouabain-induced ventricular arrhythmias in dogs. In chloroform-induced ventricular arrhythmias, the 7-methoxy group played an important role in activity and the type of terminal side chain at position 5 had not obvious effect on potency. On the other hand, in ouabain-induced ventricular arrhythmias, the structure-activity relationship was highly specific and only four compounds, 9, 30, 34, and 35, were effective. Compound 9,5-[[2-(diethylamino)ethyl]amino]-7-methoxy-5,11-dihydro[1] benzoxepino[3,4-b]pyridine 1.5-fumarate, which exhibited low affinity for muscarinic acetylcholine receptors and a high ED100(mydriasis)/ED50(antiarrhythmic activity) ratio, was selected for further development and clinical evaluation as KW-3407. The synthesis and antiarrhythmic activity of optically active 9 is described. The order of potency of antiarrhythmic activity in ouabain-induced ventricular arrhythmias in dogs was (-)-9, (+/-)-9, and (+)-9.

Case report on situs inversus totalis in two Sprague-Dawley rats.

We macro- and microscopically examined two cases of congenital visceral transposition (situs inversus totalis) in SD rats. We also investigated the possibility of situs inversus in association with immotile-cilia syndrome. The rats had grown normally with no clinical signs of disease. Although all organs including the vascular system were located opposite to the normal position and displayed a mirror image on macroscopic observation, no abnormality was found in any of the organs on microscopic examination. Electron-microscopic observation revealed in neither animal any structural abnormalities of the cilia and flagella, which are one of the diagnostic characterizations of immotile-cilia syndrome. Congenital transposition of the viscera is rare and there are few reports examining complications with situs inversus in rats. This report will be helpful in accumulating information on this condition.

[Effects of (E)-1-[bis (4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl) piperazine dihydrochloride(flunarizine) on cerebral circulation].

Effects of flunarizine (0.3-3 mg/kg, i.v.) on cerebral circulation were compared with those of cinnarizine (0.3-3 mg/kg, i.v.) and papaverine (0.1-1 mg/kg, i.v.) in anaesthetized dogs and cats. In dogs any of the three drugs caused a dose-related increase in vertebral, common carotid, and femoral arterial blood flow, while a transient decrease in renal blood flow was seen. In particular, the vasodilatation caused by flunarizine and cinnarizine was much more marked in the vertebral vascular beds as compared to the other ones. Flunarizine (10 and 30 mg/kg, intraduodenally) caused a greater and more prolonged increase in the vertebral blood flow than cinnarizine and papaverine did when they were used in the same doses. Concerning the local circulation in cats, flunarizine and cinnarizine produced a marked flow increase in the cerebellar cortex, and apparent blood flow and pO2 increases in the cerebral cortex with no observable concomitant changes in arterial blood pO2 and pCO2; but a slight decrease in hippocampal blood flow without any consistent effect in hypothalamic blood flow. In this study, flunarizine was shown to have a more prolonged pharmacological activity on the responses of the cerebral circulation than equal doses of cinnarizine or papaverine.

[Pharmacological studies on oxatomide (KW-4354). (7) Antagonistic effects on chemical mediators].

The effects of oxatomide, an anti-allergic drug, on the actions of chemical mediators were investigated in guinea pigs, rats and cats; and the following results were obtained: Studies on the guinea pig ileum revealed oxatomide to be a potent antagonist of histamine with a dual type of action, being competitive at low doses and noncompetitive at higher doses. Oxatomide at concentrations of 0.1 microM or higher inhibited the contractile responses evoked by crude SRS-A from sensitized guinea pig lung. Oxatomide (0.1 to 10 microM) did not inhibit the chronotropic effect of histamine in guinea pig atrium. In anaesthetized guinea pigs, serotonin-induced bronchoconstriction was antagonized by oxatomide (0.1 to 1 mg/kg, i.v.) as effectively as histamine-induced bronchoconstriction. However, oxatomide (up to 1 mg/kg, i.v.) did not inhibit acetylcholine-induced or arachidonic acid-induced bronchoconstriction. Oxatomide given orally in the range of 5 to 30 mg/kg markedly inhibited the increased vascular permeability by histamine, serotonin, and bradykinin in rats. Oxatomide at doses of 0.03 mg/kg (i.v.) or higher also prevented the contraction of the nictitating membrane induced by serotonin in cats. Oxatomide (0.3 microM and 1 microM) inhibited competitively the calcium-induced contracture of fully-depolarized taenia coli of guinea pigs. From these results, oxatomide appears to have potent antagonistic activities on the actions of various chemical mediators. These properties of oxatomide may contribute to its anti-allergic activity.

Effect of oxatomide, an antiallergic agent, on QT interval in dogs.

Oxatomide (CAS 60607-34-3, KW-4354) is an effective antiallergic agent for allergic rhinitis, urticaria, pruritus cutaneous, and eczema/dermatitis, etc. Terfenadine (CAS 50679-08-8) and astemizole (CAS 68844-77-9), antiallergic agents, have been reported to induce QT prolongation leading to serious ventricular arrhythmia (torsades de pointes) as cardiovascular adverse effects. The present study was carried out to determine whether oxatomide and terfenadine have effects on QT interval as a single drug or in combination with itraconazole (CAS 84625-61-6), an antifungal agent with a CYP3A4 inhibitory effect, in conscious dogs. Terfenadine alone induced QT prolongation at the dose of 30 mg/kg p.o. When itraconazole was administered at the dose of 100 mg/kg p.o. 1 h before terfenadine administration, terfenadine induced QT prolongation at the dose of 10 mg/kg p.o. On the other hand, oxatomide did not induce QT prolongation either as a single agent at the dose of 30 mg/kg p.o. or in combination with itraconazole at the dose of 10 mg/kg p.o. The results present no evidence that oxatomide has the potential to provoke ventricular arrhythmia.

[Effect of olopatadine hydrochloride, a novel antiallergic agent, on the QT interval in dogs].

Olopatadine hydrochloride (olopatadine), a novel antiallergic agent, is effective in the treatment of allergic rhinitis, chronic urticaria, eczema and dermatitis. It has been reported that terfenadine and astemizole cause side effects on the circulatory system such as QT prolongation followed by serious ventricular arrhythmias (torsades de pointes). To investigate the possibility of QT prolongation, we used both conscious normal dogs and hypokalemia-anesthetized dogs under two conditions: 1) olopatadine used alone and 2) olopatadine used in combination with itraconazole, the CYP3A4-inhibiting antifungal agent, in the present investigation. The group treated with terfenadine alone (30 mg/kg, p.o.) and the group treated with a combination of terfenadine (10 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) had a significantly prolonged QT interval. On the other hand, the group treated with olopatadine alone (30 mg/kg, p.o.) and the group treated with a combination of olopatadine (30 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) did not show any significant changes in QT interval. Moreover, olopatadine (1 and 5 mg/kg, i.v.) did not influence the QT interval in hypokalemia-anesthetized dogs. These results suggest that there is very little possibility of QT prolongation as a result of clinically used olopatadine.

Suppressive effects of benidipine on the development of hypertension and renal lesions in salt-loaded stroke-prone spontaneously hypertensive rats.

1. The effects of benidipine hydrochloride (benidipine), a long-acting dihydropyridine calcium antagonist, on the development of hypertension and renal lesions were examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were fed with 8% NaCl diet for 3 weeks from 13 weeks of age, and benidipine (1 or 3 mg/kg per day) was orally administered during the same period. 3. The high salt diet accelerated an increase in urinary excretions of total protein and albumin, and caused marked arteriole, glomerular and tubular lesions in the kidney. 4. Benidipine significantly inhibited these changes, and also suppressed the elevation of blood pressure in salt-loaded SHRSP. 5. These results reveal that benidipine has protective effects against the development of hypertension and the progression of renal lesions induced by the high salt diet in SHRSP.

[Effects of benidipine hydrochloride (Coniel) on blood pressure, heart rate and plasma norepinephrine concentration in spontaneously hypertensive rats].

We investigated the effects of benidipine hydrochloride (benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.