Antithrombotic activity of AT-1015, a potent 5-HT(2A) receptor antagonist, in rat arterial thrombosis model and its effect on bleeding time.

The antithrombotic activity of N-[2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino)ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate (AT-1015; a 5-HT(2A) receptor antagonist) was studied in a photochemically induced arterial thrombosis (PIT) model in the rat femoral artery, and in the tail transection bleeding time test. Ticlopidine (an antiplatelet agent) and sarpogrelate (a selective 5-HT(2A) receptor antagonist) were studied as reference compounds. Pretreatment with AT-1015 (1 mg/kg, p.o.) significantly prolonged the time required to occlusion of the artery with thrombus, and the effect (3 mg/kg, p.o.) persisted for 24 h with significant inhibition of 5-HT-induced vascular contraction. Ticlopidine and sarpogrelate also significantly prolonged the time to occlusion at 100 mg/kg, p.o. Sarpogrelate (300 mg/kg, p.o.) showed the similar antithrombotic efficacy to AT-1015 (3 mg/kg, p.o.), while the effect disappeared within 6 h. No significant bleeding time prolongation was observed at 10 mg/kg of AT-1015, which is 10 times higher than the antithrombotic effective dose; whereas ticlopidine significantly prolonged bleeding time at the same dose as the antithrombotic effective dose. These results suggested that AT-1015 is a potent and long-acting oral antithrombotic agent in this model, which may be elucidated by its potent and long-acting inhibition of vasoconstriction through 5-HT(2A) receptor.

[Multi-vasospastic angina refractory to medical therapy caused by hyperthyroid stage of chronic thyroiditis and hypereosinophilia: a case report].

A 49-year-old woman with bronchial asthma was followed up at our hospital. After 3 years, she experienced an attack of chest pain with ST elevation in the precordal leads of electrocardiography. After admission, the chest pain and ST elevation disappeared, but the chest pain recurred after 6 days. Coronary angiography revealed no significant stenosis in the coronary arteries. After discharge, she had the chest pain repeatedly. ST elevation in the II, III, aVF leads was recorded. The diagnosis was coronary multispasm. The chest pain was refractory to medical therapy. Hypereosinophilia developed and bronchial asthma worsened. After steroid administration, the angina and bronchial asthma ceased. She has lost about 15 kg during 1 year. Laboratory data revealed low thyroid-stimulating hormone, high thyroid hormone, positive thyroglobulin antibody, and negative thyroid-stimulating hormone receptor antibody. The diagnosis was chronic thyroiditis. The multi-vasospastic angina refractory to medical therapy was caused by the hyperthyroid stage of chronic thyroiditis and hypereosinophilia.

AT-1015, a novel serotonin (5-HT)2 receptor antagonist, blocks vascular and platelet 5-HT2A receptors and prevents the laurate-induced peripheral vascular lesion in rats.

The serotonin (5-HT2A) antagonistic activities and the protective effect on laurate-induced peripheral vascular lesions of AT-1015, a novel 5-HT2 receptor antagonist, were investigated. In platelet aggregation, AT-1015 selectively inhibited in vitro 5-HT2A receptor-mediated aggregation, and the activity was almost equivalent to that of ketanserin (5-HT2A/2C receptor antagonist) and 100 times more potent than sarpogrelate (5-HT2A receptor antagonist). AT-1015 also inhibited 5-HT2A receptor-mediated aggregation by oral administration in rat, and the dose required for inhibition was equivalent to ketanserin. In a 5-HT-induced vasoconstriction study in rat, AT-1015 slightly reduced maximal contraction and caused a rightward shift of the concentration-response curve (pKB value, 9.5), which was unlike competitive inhibitors such as ketanserin and sarpogrelate (pA2 value, 9.3 and 8.7, respectively). Moreover, the ex vivo inhibitory activity significantly remained after oral administration (1 mg/kg). In the rat peripheral vascular lesion model, AT-1015 (1 mg/kg, p.o.) effectively prevented progression of peripheral lesions, and it was more potent compared with ketanserin, sarpogrelate, and cilostazol. These results suggest that AT-1015 is a potent 5-HT2A receptor antagonist, and its insurmountable antagonism may be relevant to its therapeutic potential in peripheral vascular disease.

[Postoperative respiratory failure resulting from perioperative withdrawal of antiparkinsonian medications].

A patient with Parkinson's disease developed postoperative respiratory arrest due to perioperative withdrawal of antiparkinsonian medications and later presented a rapid recovery after parenteral administration of levodopa. In perioperative management of parkinsonian patients, it is important to continue antiparkinsonian medications until the operation is started and to administer levodopa parenteraly after the operation until oral administration of antiparkinsonian drugs becomes possible. In addition, we must pay attention to the choice of drugs so that parkinsonism may not be induced or aggravated.

Changes in DNA copy number in primary gastric carcinomas by comparative genomic hybridization.

We examined 33 primary gastric carcinomas using comparative genomic hybridization to detect changes in the DNA copy number and the chromosomal location of these changes. Ninety-four percent (31 of 33) showed 1 or more DNA copy number changes, such as increases at 2p23-p25 (observed in 21% of the total cases), 3q26.3-q27 (24%), 7p15 (24%), 9p22-pter (18%), and 13q22-q34 (21%) and decreases at 1p34.2-p36.2 (18%) and Y (52%). Histological examination indicated that increases at 3q26.1-q26.3 and 7p15 and decreases at 1p36.1-p36. 2 and Y were commonly observed in both differentiated and undifferentiated types. Increases at 3q27, 6q23-q25, and 7cen-p14 and decreases at 1p34.2-p35 and 17p12 were predominantly observed in the differentiated type, and increases at 2p23-pter, 9p22-pter, and 13q31-qter and a decrease at 6p21.3 were predominantly observed in the undifferentiated type. In addition, clinical staging of tumors showed that increases at 2p23-p25, 7p14-p21, 7q31-q32, and 9p22-pter and a decrease at Y were observed in early-stage tumors, whereas increases at 9q32-q33 and 15q26 were observed only in late-stage tumors. Many of the abnormalities detected in this study were not previously reported in gastric carcinomas. Our comparative genomic hybridization results indicate the presence of genetic alterations that may play some important role in the development and progression of gastric carcinomas.

Effects of yohimbine and desipramine on adrenal catecholamine release in response to splanchnic nerve stimulation in anesthetized dogs.

The effects of yohimbine and desipramine on adrenal catecholamine (CA) release in response to splanchnic nerve stimulation (SNS) were examined in anesthetized dogs. SNS and 3 Hz produced frequency-dependent increases in epinephrine (EPI) and norepinephrine (NE) output determined from adrenal venous blood. Yohimbine (30 and 100 micrograms/kg, i.v.), a selective alpha 2-adrenoceptor antagonist, enhanced the SNS-induced increases in both EPI and NE output. Desipramine (100 and 300 micrograms/kg, i.v.), an amine pump inhibitor, enhanced the SNS-induced increases in NE output, whereas no enhancement of EPI output was produced. After desipramine treatment, yohimbine further enhanced the SNS-induced increases in EPI and NE output. After yohimbine treatment, desipramine further enhanced the SNS-induced increase in NE output. These results suggest that the release of adrenal CA in response to SNS is inhibited by alpha 2-adrenoceptors, and that released NE, rather than EPI, is predominantly taken up into the dog adrenal medullary cells.

Effects of beta adrenoceptor agonists and antagonists on adrenal catecholamine release in response to splanchnic nerve stimulation in anesthetized dogs: role of beta-1 and beta-2 adrenoceptors.

The present study was performed to examine whether beta adrenoceptor agonists and antagonists modify the release of adrenal catecholamine (CA) in response to splanchnic nerve stimulation (SNS) in anesthetized dogs, in order to elucidate the beta adrenoceptor-mediated modulation of adrenal CA release. SNS at 3 Hz produced marked increases in both epinephrine and norepinephrine output determined from adrenal venous blood. Atenolol (10, 30 and 100 micrograms/kg, i.v.) and CGP20712A (10 and 30 micrograms/kg, i.v.), selective beta-1 adrenoceptor antagonists, significantly enhanced the SNS-induced increases in CA output. Neither ICI118551 (10, 30 and 100 micrograms/kg, i.v.), a selective beta-2 adrenoceptor antagonist, nor nadolol (10, 30 and 100 micrograms/kg, i.v.), a nonselective beta adrenoceptor antagonist, affected the SNS-induced increases in CA output. After the treatment with ICI118551 (100 micrograms/kg, i.v.), atenolol (10, 30 and 100 micrograms/kg, i.v.) failed to enhance the SNS-induced increases in CA output. On the other hand, neither isoproterenol (0.03 and 0.1 micrograms/kg/min, i.v.) nor the selective beta-2 adrenoceptor agonist procaterol (0.03 and 0.1 micrograms/kg/min, i.v.) affected the SNS-induced increases in CA output. After the treatment with atenolol (100 micrograms/kg, i.v.), both isoproterenol (0.03 micrograms/kg/min, i.v.) and procaterol (0.03 micrograms/kg/min, i.v.) enhanced the SNS-induced increases in CA output. The enhancing effects of isoproterenol and procaterol were abolished by ICI118551 (100 micrograms/kg, i.v.). These results indicate that activation of beta-2 adrenoceptors facilitates the SNS-evoked release of CA from the dog adrenal medulla under the condition in which beta-1 adrenoceptors are blocked, and they suggest that activation of beta-1 adrenoceptors inhibits the beta-2 adrenoceptor-mediated facilitation process of adrenal CA release.

[Pediatric anesthesia and stress response].

The hyperglycemic and adrenocortical responses to upper and lower abdominal surgery were studied in four groups of children. In F group, lower abdominal surgery was performed under light general anesthesia (halothane 0.3-0.5% plus nitrous oxide and oxygen) combined with intravenous injections of fentanyl 10-13 micrograms.kg-1. In L-E group, lower abdominal surgery was performed under light general anesthesia combined with lumbar epidural anesthesia (intermittent injections of 1.0% lidocaine). In T-E group, upper abdominal surgery was performed under light general anesthesia combined with thoracic epidural anesthesia (intermittent injections of 1.0% lidocaine). In H group, lower abdominal surgery was performed under general anesthesia (halothane 1.0-1.5% plus nitrous oxide and oxygen). The hyperglycemic and adrenocortical responses were inhibited in F group, suggesting that intravenous injections of fentanyl 10-13 micrograms.kg-1 prevented the endocrine-metabolic response. On the other hand, in other three groups, those responses were not inhibited. Therefore we must consider the concentration and the volume of lidocaine in epidural groups. But general anesthesia combined with epidural anesthesia had a excellent effect on the postoperative pain management.