A selective and extremely potent antagonist of the neurokinin-1 receptor.
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Biomedical subjects
Publications and source records attributed to T Sakurada.
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The non-peptide NK-1 receptor antagonist, CP 96,345, has been evaluated for antinociceptive activity in two chemical pain models in the mouse. CP 96,345, injected intrathecally (i.t.) 5 min prior to 2.0% formalin, produced significant antinociception in both the early and late phases of the formalin-induced paw licking procedure. Antinociception could also be observed during the late phase by treatment with CP 96,345 after formalin. In the capsaicin (CAP) test, i.t. injection of CP 96,345 produced a dose-dependent reduction of the paw-licking response at doses much less than antinociceptive doses in the formalin test. Naloxone did not affect antinociception in either test. CP 96,345 evoked a reversible deficit in motor performance as assayed by the rotarod test. The results indicate that i.t. CP 96,345 is antinociceptive in the capsaicin test at doses showing no overt behavioural effects but there is an overlap in doses producing antinociceptive and motor effects in the formalin test.
Rats were given repeated subcutaneous injections of [D-Arg2, Sar4]-dermorphin (1-4) [DAS-DER-(1-4)] and/or morphine over a period of 4 or 7 days. Antinociception was determined at 90 min for DAS-DER (1-4) and 30 min for morphine after each morning injection (9:00 a.m.), using the tail-flick and digit pinching tests in rats. Subcutaneous administration of DAS-DER (1-4) and morphine produced the development of antinociceptive tolerance, respectively. A marked tolerance to DAS-DER (1-4) and morphine was seen in rats made tolerant to morphine. However, administration of morphine produced no significant decrement in the antinociceptive activity in rats made tolerant to DAS-DER (1-4). These results suggest that the site of action of DAS-DER (1-4) may be more limited than that of morphine in the nociceptive pathways, for lack of its antinociceptive efficacy in morphine-tolerant rats.
IT administration of pilocarpine in the spinal subarachnoid space of mice produced a dose-related hindlimb scratching. When coadministered with substance P IT, the pilocarpine-induced scratches were enhanced by high doses of substance P but not by subthreshold doses. This characteristic behavioral response was inhibited dose dependently by IT coadministration of spantide [D-Arg1, D-Trp7,9,Leu11] substance P. Significant antagonistic effects of [D-Phe7,D-His9] substance P (6-11), a selective antagonist for substance P receptors, and substance P (1-7), a substance P N-terminal fragment, were observed against the pilocarpine-induced scratching. Pretreatment with substance P antiserum resulted in the reduction of the response to pilocarpine. When coadministered IT with pilocarpine, atropine potently inhibited pilocarpine-induced scratching. These results demonstrate that not only muscarinic receptors but also substance P-containing neurons in the mouse spinal cord may be involved in elicitation of the scratching behavior following IT injection of pilocarpine.
Intrathecal administration of an adenosine receptor antagonist, theophylline, elicited nociceptive behavior such as licking, biting and scratching in mice. This behavioral response was dose-dependently reduced by simultaneous injection of an adenosine receptor agonist, 5'-N6-ethylcarboxamidoadenosine, or a selective N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate. This theophylline-induced behavior was not significantly reduced by the substance P (SP) analogue, the neurokinin receptor antagonist, [D-Arg1, D-Trp7.9, Leu11]SP (spantide). These results suggest the possibility that theophylline-induced nociceptive behavior may be mediated through interactions with both spinal adenosine- and NMDA receptors separately, or only through interaction(s) with adenosine receptors localized on the axon terminals of excitatory amino acid neurons. Present data have failed to reveal involvement of SP.
Central effects of intravenously (i.v.)-administered iohexol were compared with those of iopamidol in a series of tests. Mannitol was used as a reference. As assayed by the primary screening test based on Irwin's method, i.v. administration of mannitol resulted in a score of 0 in ddY mice and a score of 0.6 in ICR mice in the startle response. These results were not different from the data of both iohexol and iopamidol. Iopamidol at a dose of 1750 mgI/kg produced an inhibitory effect on the spontaneous locomotor activity. Iohexol at a dose of 7000 mgI/kg potentiated the duration of thiopental-induced narcosis. Hypothermia was caused by high doses of both iohexol and iopamidol. Electric stimulus increased the mortality of mice pretreated with high doses of iohexol and iopamidol. Both drugs had no notable activities in the anticonvulsant, electroencephalic, muscle relaxant and antinociceptive tests. These results indicate that both iohexol and iopamidol do not necessarily possess a similar pharmacological action. Judging from the LD50 of approximately 15000 mgI/kg for both drugs, they seem unlikely to have a specific pharmacological action on the central nervous system.
In a previous communication, we demonstrated that the introduction of air into the scala tympani of the cochlea causes a decrease of cochlear potentials; however, the change in endocochlear dc potential (EP) was mild and the decreased cochlear microphonics (CM) and compound action potentials (CAP) were, at least partially, reversible. In contrast, we have now found that air perfusion (3-60 microliters/min) in the scala vestibuli decreased cochlear potentials more drastically than that in the scala tympani. The change in the EP after air perfusion in the scala vestibuli was characterized by a decrease of the negative EP in response to anoxia. The CM drastically decreased upon the initiation of air perfusion and no recovery was observed after refilling of the perilymph. Histological examination showed collapse of Reissner's membrane in 12 out of 17 cochleas examined. The extent and frequency of the collapse increased with an increase in the amount of air perfused in the scala vestibuli. As the minimal amount of air needed to cause inner ear damage by air perfusion in the scala vestibuli is as small as 3 microliters, it is possible that the prognosis is worse in cases with fistula of the oval window compared to that of the round window area, if the pneumolabyrinth is involved in the pathophysiology of perilymphatic fistula. It is also indicated that air inflation of the middle ear is dangerous in cases with fistula in the oval window.
The operative morbidity and mortality of patients with Stanford type A acute aortic dissection undergoing urgent operation using retrograde cardioplegia for myocardial protection were evaluated to assess the efficacy of such surgery. A total of 18 patients (12 men and six women, 19-71 years of age) were operated on 9-137 h after onset of dissection using cardiopulmonary bypass with deep hypothermia and retrograde cardioplegia. Graft replacement was performed in ten patients, primary anastomosis in three, and Cabrol and Bentall operations in five. All patients were weaned from cardiopulmonary bypass, but four died in hospital (mortality rate 22%). Thirteen patients were in good health at follow-up ranging from 3 to 98 months, and the remaining patient died from rectal cancer 5 months after surgery. It is concluded that urgent operation of patients with Stanford type A acute aortic dissection can be performed with reasonable operative and excellent follow-up results. Retrograde cardioplegia is an easy and reliable method of myocardial protection to repair the fragile aortic wall.
Between April 1975 to March 1991, 17 patients (5 man and 12 women, mean age 49.8 years old) underwent surgical treatment for cardiac myxomas. Fifteen patients had left atrial myxomas, and the other 2 had the ventricular myxomas (left ventricular myxoma 1 and right ventricular myxoma 1). In cases with left atrial myxomas, the tumor was resected through the transatrial approach alone in 12 patients, and the left atriotomy was added in other 3. Left ventriculotomy was required to resect the left ventricular myxoma in addition to the atrial approach. Right ventricular myxoma, which attached the outflow tract, could be removed through the small right vertical ventriculotomy. All patients recovered well, and there was no recurrence in any patient during the follow-up period.
A 59-year-old man with coronary artery disease and arteriosclerosis obliterans of left lower extremity underwent anastomosis of left internal thoracic artery to left anterior descending artery with cardiopulmonary bypass of aortic perfusion and left femoro-popliteal bypass with saphenous vein graft. On the first postoperative day, urinary output decreased and then stopped. The transesophageal echocardiography and angiography revealed the Stanford A type acute aortic dissection. Immediately the resection of the ascending aorta including the intimal tear, which was found on the site of the previous aortic perfusion, and the reconstruction of the ascending aorta with the prosthetic graft was performed. After the reperfusion of left femoral artery, which was used as the route of the arterial perfusion during cardiopulmonary bypass, serum potassium level increased gradually and at last the heart was arrested. Hemodialysis with draining from inferior vena cava produced the stability of hemodynamics, but on the next day he died of low cardiac output syndrome. We presented the case with the acute aortic dissection after open heart surgery, which was one of the rare complications in aortic perfusion of cardiopulmonary bypass and emphasized the possibility of occurrence of myonephropathic-metabolic syndrome after the repair of acute aortic dissection with limb ischemia.
Thirty five-year-old man required reoperation, twelve years after radical operation of total anomalous pulmonary venous connection (Darling IIb type), because of the clinically apparent pulmonary venous obstruction. The stenosis of ASD was revealed by cineangiocardiography and echocardiography. The fibrous thickening of atrial septal wall and stenosis of ASD were found at the operation. Operating procedure consisted of the enlargement of ASD and cut-back of the atrial septal wall. Postoperative study showed no evidence of stenosis of pulmonary venous return. The patient was discharged well and returned to his job. Late postoperative pulmonary venous obstruction is of particular concern. Usually it occurs within the first few postoperative months. We reported this case because it is rare that pulmonary venous obstruction occurred twelve years after radical operation.
A 5-year-old girl admitted to our hospital complaining cardiomegaly due to pericardial fluid and punched-out area in the humerus. Analysis of pericardial fluid confirmed primary chylopericardium and the findings in the humerus suggested skeletal lymphoangiomatosis. Despite medical treatments, pericardial fluid didn't decrease. Therefore, she underwent ligation and resection of thoracic duct. She recovered uneventfully without reaccumulation of the pericardial effusion. In addition, skeletal survey resulted in lymangiomatosis.
Fifty four patients who had aneurysms (n = 35) or dissections (n = 19) associated with aortic regurgitation underwent the replacement of the ascending aorta and aortic valve by composite valve graft during 15-year period between September 1976 and December 1991. Of these, 49 (90.7%) patients had an annuloaortic ectasia and 26 (48.1%) had the Marfan syndrome. The methods of coronary artery reattachment to the graft were as follows: direct reattachment (original Bentall's technique) in 45 patients, aortic button technique (Carrel's patch technique) in 6, Cabrol's technique in 2 and Piehler's technique in 1 patients. Seven patients with a DeBakey type I dissection had concomitant replacement of the aortic arch with an aid of selective cerebral perfusion. The overall hospital mortality rate was 12.9%, and it has significantly decreased to 6.7% since we adopted a cold cardioplegia, preclotting the graft with albumin autoclave technique and coronary artery reattachment using conventional over-and-over and interrupted mattress sutures with pledgets during the last 10-years. The mean duration of follow-up period was 58.6 months. The actuarial survival rate at 10 years for all patients was 76.4%; for those with dissection, 78.4%; and for patients with Marfan syndrome, 70.4%. Reoperation for the prosthesis-related complications was necessary in only one patient, although operations on the remainder of aorta were required in 5 patients. Actuarial freedom from these operations at 10 years was 74.1%, but it was 69.3% for the subgroup with Marfan syndrome. The present data indicates that composite valve graft technique is an useful method for patients with aortic root aneurysms or dissections.
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Sendide [Tyr6,D-Phe7,D-His9]-substance P(6-11) has been examined by measurements of ligand binding to crude membrane fractions and by functional tests on the spinally mediated behavioral response. Sendide potently displaced [3H]-labeled substance P (SP) binding to mouse spinal cord membranes in a competitive manner. In vivo, sendide, intrathecally co-injected with SP, competitively antagonized SP-induced scratching, biting and licking. The behaviors elicited by physalaemin, septide and [Sar9, Met(O2)11]-SP were also reduced by co-administration of sendide. Large doses of sendide were needed to reduce the action of neurokinin A, D-septide, neurokinin B and eledoisin. The in vitro and in vivo pharmacological profile of sendide demonstrated that it is a selective and extremely potent antagonist of the neurokinin-1 receptor.
Since the D-Arg-containing dipeptides, H-Tyr-D-Arg-OMe (TDA) and H-Tyr(Et)-D-Arg-OMe, and D-Arg2-substituted dermorphin N-terminal tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-OEt (TDAPG) and H-Tyr(Et)-D-Arg-Phe-Gly-OEt gave different pharmacological responses in vivo, opioid interaction and structure-activity relationships have been investigated in vitro. In the isolated guinea-pig ileum assay, the tetrapeptides were potently inhibitory, their activity markedly exceeding that of the dipeptides. In particular, the first tetrapeptide had twice the activity of morphine, while the potency of the dipeptides was less than one twentieth that of morphine. Also in the opioid receptor binding assay, tetrapeptides had a higher affinity than the dipeptides. IC50 values of tetrapeptides were 8.46 and 23.7 nM, respectively, which were lower than that of morphine. Ethylation of the Tyr residue of TDA much increased the opioid activity whereas that of TDAPG greatly decreased it. All peptides used were extremely stable to aminopeptidase-M and carboxypeptidase-Y and had an inhibitory effect on enkephalin (EK)-degrading enzymes. From these results, it appears that the effects of the tetrapeptides are due mainly to specific interaction with opioid receptors, whereas the dipeptides do not act specifically on the opioid receptors, but are involved in non-opioid mechanisms. The resistance to enzymes and inhibitory effect of the peptides used on the EK-degrading enzymes may also account for their potent and long-lasting opioid-like activities.