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Biomedical subjects

T Kuroda

Publications and source records attributed to T Kuroda.

At least 289 records · Page 16Linked to original sources
PubMed1993

Metabolism of insulin and glucagon in liver and pancreas in dogs with obstructive jaundice.

Insulin and glucagon metabolism in the pancreas with obstructive jaundice caused by complete ligation of the common bile duct and in the cholestatic liver caused by hepatic duct ligation was evaluated experimentally using dogs. The isolated perfused pancreas in obstructive jaundiced dogs, which showed a low insulin response in the peripheral blood after intravenous glucose administration, revealed depression of insulin production and no change of glucagon production in response to cholecystokinin octapeptide. The extraction of insulin in the cholestatic lobe of the liver was decreased compared with that in the noncholestatic lobe. The extraction of glucagon, on the other hand, in the cholestatic lobe and in the noncholestatic lobe showed no significant difference. So the imbalance of glucose metabolism in obstructive jaundice does not depend on the enhanced extraction of insulin in the liver, but on the depression of insulin production in the pancreas.

Animals↗
PubMed1993

Enhanced sensitivity of pancreatic cells to cholecystokinin octapeptide in obstructive jaundice.

Exocrine function of the pancreas in obstructive jaundice was examined using dogs. Jaundice induced by choledochal ligation over 3 weeks showed pancreatic hypersecretion in response to cholecystokinin octapeptide (CCK-8) stimulation. To clarify the mechanism of pancreatic hypersecretion in obstructive jaundice, three experiments were undertaken. In a perfusion experiment performed on isolated pancreas, hypersecretion in obstructive jaundice was observed in response to CCK-8 stimulation. An incubation experiment showed an increase in secretion in response to CCK-8 stimulation in a dose-dependent manner, producing a greater increase in dogs with obstructive jaundice than in controls, despite the fact that basal secretion in both groups was the same. This would suggest that at least one of the mechanisms of pancreatic hypersecretion in obstructive jaundice may be related to the degree of sensitivity of acinar cells to CCK-8. In morphological observation of acinar cells by electron microscopy, the average number of zymogen granules and total granular area per unit of cytoplasm in both groups before and after stimulation with CCK-8 were compared. There was no difference between the groups before stimulation. Following stimulation, values for the control group decreased but appeared to increase in the jaundiced pancreas. These results strongly suggest that pancreatic acinar cells in obstructive jaundice may retain their secretory potential after stimulation for 60 min, though the potential in nonjaundiced pancreatic acinar cells may decrease after stimulation.

Animals↗
PubMed1993

Effects of parathyroid hormone on pancreatic exocrine secretion.

The role of parathyroid hormone (PTH) and calcium on pancreatic exocrine secretion were observed using sham-operated and parathyroidectomized dogs. First, exocrine secretion of the pancreas stimulated with secretin and cholecystokinin octapeptide (CCK-8) was examined in vivo 3 weeks after parathyroidectomy. Secondly, perfusion experiments of isolated pancreas in the sham-operated and parathyroidectomized dogs were examined. In one experiment, volume of pancreatic juice and bicarbonate output, but not amylase output, was decreased in the parathyroidectomized dogs compared with those in the sham-operated dogs; no participation of calcium in exocrine secretion was revealed. In another experiment, high doses of PTH evoked increases of pancreatic juice and bicarbonate output without changing amylase output; as before, no participation of calcium in the exocrine secretion was observed. We conclude that (a) PTH increases volume of pancreatic juice and bicarbonate output, and (b) pancreatic exocrine secretion is modified by direct effect of PTH, and the pancreatic ductular cells, not the acinar cells, are the target for PTH.

Amylases↗
PubMed1993

1,4:3,6-Dianhydrohexitol nitrate derivatives. I. Synthesis and antianginal activity of alkylpiperazine derivatives.

A series of 5-deoxy-5-(4-substituted piperazin-1-yl)-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared and evaluated for oral anti-ischemic activities. Inhibition of lysine-vasopressin-induced T-wave elevation in the electrocardiogram (ECG) of rats (angina pectoris model) served as a primary assay. Optimum activity was observed for the compounds with the aryl-heteroatom (O,S, or N)-propyl group. Among them, the phenylthiopropyl-substituted compound 13 exhibited the most potent activity. Furthermore, intraduodenal administration (i.d.) of 13 tended to decrease left ventricular end-diastolic pressure (LVEDP) in a propranolol-induced heart failure model (dogs) and showed a potent protective effect against reperfusion arrhythmia in rats. Thus, 13 (KF 14124) is under further study as an orally active nitrate.

Administration, Oral↗
PubMed1993

Quantitative evaluation of the shape and the elasticity of repaired cleft lip.

Tight lip in repaired cleft lip patients with or without cleft palate (CL[P]) has been discussed as one of the causal factors of maxillary growth retardation and malocclusion. The purpose of this study was to evaluate the shape and the elasticity of repaired cleft lip quantitatively. Forty-one Japanese CL(P) patients were examined. Fifty-four noncleft patients under orthodontic treatment were used as a control group. An apparatus to stretch the anguli oris bilaterally was devised and the extensibility of the lip was measured to evaluate lip elasticity. Standardized photos of the lips were taken to examine lip shape. CL(P) patients showed poor elasticity of the lip. This trend was more apparent in bilateral CL(P) patients than in unilateral CL(P) patients. The upper lip of CL(P) patients was significantly shorter in vertical height. These results clearly demonstrated the tightness and shortness of the repaired lip in CL(P) patients.

Adolescent↗
PubMed1992

New bronchodilators. 3. Imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones.

In order to develop new oral bronchodilators, a series of novel imidazol[4,5-c][1,8]naphthyridin-4(5H)-ones 5 were designed and synthesized. Some of these new heterocycles exhibited more potent bronchodilator activity in vitro and in vivo than theophylline. With respect to modification at the 5-position, both phenyl and n-butyl substitution produced potent activity. Though bulk tolerance at N-3 is observed with short and small lipophilic groups, any substitution at the other positions and transformations of the parent skeleton eliminated activity. Thus 5-phenyl-1H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (23) (KF17625), which satisfied these conditions, was selected for further studies (antigen inhalation-induced bronchospasm model; minimum effective dose (MED) = 1 mg/kg, po; antigen-induced contraction of trachea (the Schultz-Dale reaction), IC50 = 2.2 microM). Compound 23 inhibited carbachol-, histamine-, or leukotriene D4-induced contraction and relaxed spontaneous tone in guinea pig isolated tracheal preparations with, 4- to 16-fold greater potency than aminophylline. Thus it appeared to relax directly the airway smooth muscle. 23 did not have any influence on adenosine binding at 10 microM, but inhibited canine tracheal phosphodiesterase (PDE) IV (IC50 = 12 microM) and concanavalin-A-induced histamine release from rat mast cells (44% inhibition at 10 microM). Although the detailed mechanisms of these compounds remain to be elucidated, this series of novel tricyclic heterocycles represents a new class of bronchodilator.

Animals↗
PubMed1992

New bronchodilators. 1. 1,5-Substituted 1H-imidazo[4,5-c]quinolin-4(5H)-ones.

A series of novel xanthine-based tricyclic heterocycles in 1H-imidazo[4,5-c]quinolin-4(5H)-ones was designed, synthesized, and tested as potential active bronchodilators. Inhibition of the Schulz-Dale (SD) reaction-induced contraction in trachea and inhibition of antigen inhalation-induced bronchospasm in passively sensitized guinea pigs served as primary in vitro and in vivo assays, respectively. Simultaneous measurement of acute lethal toxicity (minimum lethal dose; MLD, po) in mice allowed determination of a safety margin. The bronchodilatory activity of these heterocycles was considerably varied with the nature of substituents at the 5-position. The most active substituents at the 2- and 5-positions and on the aromatic ring were found to be hydrogen, n-butyl, and hydrogen, respectively. There was a bulk tolerance for lipophilic substituents at the 1-position. 5-Butyl-substituted compounds appeared to be less toxic than theophylline on the basis of MLD data. Thus 5-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4(5H)-one (10) (IC50 value of the SD assay = 0.25 microM, MLD > 300 mg/kg) was selected for further studies. Compound 10 (KF15570) reduced bronchoconstriction produced by antigen (Konzett-Rössler preparation in anesthetized guinea pigs, ED50 = 0.42 mg/kg, iv) more effectively than aminophylline (ethylenediamine salt of theophylline, ED50 = 7.8 mg/kg, iv) but had fewer side effects on the heart and CNS than theophylline. Compound 10 and its derivatives showed weak adenosine antagonism and phosphodiesterase (PDE) inhibition which could not account for their potent bronchodilation. Although their precise mechanism of action remains unclear, this series of novel tricyclic heterocycles represents a new class of bronchodilator.

Airway Resistance↗
PubMed1992

New antiinflammatory agents. 2. 5-Phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones: a new class of nonsteroidal antiinflammatory agents with potent activity like glucocorticoids.

We previously described new antiinflammatory agents, 4-hydroxy-2-oxo-1-phenyl-1H-1,8-naphthyridine-3-carboxamides 1. Further modification of the compounds bearing 1-phenyl-1,8-naphthyridin-2-one as a mother skeleton led to 5-phenylimidazo[4,5-c][1,8]naphthyridin-4(5H)-one derivatives 2 and 3. Regioselective synthesis of these compounds bearing a substituent at the 1- or 3-position was conducted according to the method shown in Schemes I and II. In this series of compounds, antiinflammatory activities were greatly influenced by the position and nature of substituents on imidazole. 3-Alkyl or 3-benzyl substitution result in the potent activity, but 1-substitution did not. Minor modification of the benzyl group reduced or eliminated the activity. Detailed examination of structure-activity relationships led to 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (22), which exhibited potent oral antiinflammatory activities in carrageenan-, zymosan-, and reversed passive Arthus reaction-induced rat paw edemas (ED40 = 5.3, 0.37 mg/kg, ED50 = 0.47 mg/kg, respectively). This broad activity of 22 was like that of glucocorticoids. Compound 22 did not affect activities of CO and 5-LO enzymes and receptor binding of various ligands. As one of the mechanisms of action, induction of release of glucocorticoids was postulated. These results suggest that 22 represents a novel class of antiinflammatory agents.

Animals↗
PubMed1992

A novel synthesis and potent antiinflammatory activity of 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3-carboxamides.

New antiinflammatory agents 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3- carboxamides 7 were designed and synthesized via a valuable intermediate, 1-phenyl-2H-pyrido[2,3-d][1,3]oxazine-2,4(1H)-dione (9). The nature of substituents on the amide nitrogen had a pronounced effect on antiinflamatory activity. Studies of structure-activity relationships led to compounds 33 and 34 bearing a pyridine ring on the amide nitrogen. Compounds 33 and 34 were active against carrageenin-, zymosan-, and arachidonic acid-induced rat paw edemas and also potently inhibited the reversed passive Arthus reaction in rats. Thus, they possess a broader spectrum of antiinflammatory activity than the classical nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin and piroxicam.

Animals↗
PubMed1992

MRI demonstration of Kernohan's notch: case report.

We report a left acute subdural haematoma caused by rupture of a left anterior cerebral artery aneurysm, which progressed to left hemiparesis. Coronal MRI was superior to CT for visualizing Kernohan's notch.

Acute Disease↗
PubMed1992

Priming effects of leukotriene B4 on endothelial cell injury induced by TPA-activated leukocytes.

Among arachidonic acid metabolites, leukotriene B4 (LTB4) plays an important role in inflammation, such as in the activation, adhesion, chemotaxis, and invasion of leukocytes. In this paper, we examined the effect of LTB4 on endothelial cell injury induced by polymorphonuclear leukocytes (PMNLs). 51Cr release, a marker of cellular injury, was elicited from prelabeled endothelial cells when the cells were cocultured with PMNLs activated by phorbol ester (TPA, 12-O-tetradecanoyl-phorbol-13-acetate). Under this condition, pretreatment of PMNLs with LTB4 enhanced their injury in a dose-dependent manner (0.2-2 microM). However, LTB4 alone at any dose could not induce any cellular injury. We also determined the amount of active oxygen species produced by PMNLs in response to TPA. The intensity of luminol-dependent chemiluminescence, a marker of active oxygen production, in PMNLs was also increased by pretreatment with 1 microM LTB4. These data suggest that LTB4 enhances endothelial cell injury by the priming effect on active oxygen production in activated PMNLs.

Cell Adhesion↗
PubMed1992

In vivo and in vitro antitumor activity of mitomycin C conjugates at 7-N position through a linker containing thiocarbamate bond with CD10 monoclonal antibody.

Through a linker containing thiocarbomate bound to the 7-N position of mitomycin C (MMC), conjugates with a monoclonal antibody to CD10 (NL-1) were prepared, and their antitumor activities were examined. All five conjugates, except one, showed in vitro cytotoxicity to two CD10+ lymphoid cell lines superior to MMC. The conjugate displaying the highest cytotoxicity was selected and further tested against three CD10+ and two CD10- lymphoid cell lines in vitro. The conjugate with NL-1 antibody demonstrated higher cytotoxic activity against CD10+ tumor cells than the control conjugate with normal immunoglobulin, while there was no significant difference, when tested against CD10- tumors. The cytotoxic activity of the NL-1 conjugate to CD10+ tumors was significantly blocked by NL-1 antibody. In vivo antitumor activity of the NL-1 conjugate was then tested against a CD10+ tumor transplanted to nude mice, and side effects were recorded. The NL-1 conjugate (4 mg/kg) showed an in vivo antitumor effect similar to MMC (2 mg/kg), which is at nearly maximal tolerable dose; the latter induced decreases in numbers of leukocytes and platelets, while the former did not, suggesting less side effect by the NL-1 conjugate. Since MMC demonstrates a broad spectrum of antitumor activity, the conjugate, as such, may be applicable for the treatment of cancer patients.

Animals↗
PubMed1992

Growth changes and orthodontic treatment in a patient with condylolysis.

A patient with acquired bilateral degeneration of the mandibular condyles was treated orthodontically. The flattening of condyles and the shortening of the ramus began at adolescence. The facial profile changed to a convex type, with a marked mandibular retrognathia and severe Class II malocclusion. The cause seems to be due to a condylolysis of the mandible.

Child↗
PubMed1992

Preserved thyroidal secretion of thyroxine in acromegalic patients with suppressed hypophyseal secretion of thyrotrophin.

OBJECTIVE: We have assessed the mechanisms which maintain euthyroidism in acromegalic patients despite the suppression of thyrotrophin (TSH) secretion. MATERIALS: Fourteen untreated patients with acromegaly were analysed. Ten patients were also studied after pituitary surgery. METHODS: Thyroid hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and thyroidal uptake of radioactive iodine, thyrotrophin releasing hormone (TRH) test and basal metabolic rate (BMR) were measured before and after pituitary surgery. RESULTS: Nine patients had palpable goitres. The TSH response to TRH stimulation was suppressed in eight patients, who maintained normal serum levels of total T3, T4 and free T4. The patients with normal TSH response had lower levels of free and total T4 than controls. The response of TSH to TRH correlated inversely with the serum level of total and free T4, and also with the plasma level of IGF-I (r = -0.74, P less than 0.05, n = 9). After pituitary surgery, the serum levels of total and free T4 were elevated for at least up to 6 months, with a decrease in the T3/T4 ratio and the BMR. CONCLUSION: GH may have a direct stimulatory action on the thyroid secretion of T4 possibly via increased IGF-I, despite suppressed TSH secretion. The post-operative elevation of serum T4 suggests the persistent secretion of T4 from the thyroid gland, in spite of instantaneous normalization of the accelerated conversion of T4 to T3, even after reduction of excess GH secretion.

Acromegaly↗
PubMed1992

Effects of cisapride on gastrointestinal motor activity and gastric emptying of disopyramide.

The effects of cisapride on the gastrointestinal contractile activity and pharmacokinetics of disopyramide were determined in beagle dogs and patients with arrhythmia. In the animal experiments, the gastric motor index was significantly decreased by i.v. administration of disopyramide in a dose-dependent fashion. The peak decrease of the motor index was observed within 5 min after i.v. injection of disopyramide; the motor index then recovered gradually to the level present prior to drug administration. I.v. administration of cisapride (0.5 mg/kg) markedly increased gastrointestinal contractile activity following the decrease induced by disopyramide pretreatment (5 mg/kg, i.v.). In the clinical studies, the gastric emptying test was performed using the acetaminophen method. A significant correlation between plasma concentrations of disopyramide and gastric emptying time has been found (p < 0.001). The combination of disopyramide (100 mg t.i.d.) and cisapride (2.5 mg t.i.d.) significantly increased gastric emptying compared with that induced by disopyramide alone. The peak plasma concentration of disopyramide in association with cisapride oral administration was significantly higher, and the apparent absorption rate constant and lag time of disopyramide were about 2-fold higher and 2-fold shorter, respectively, than for disopyramide alone. Cisapride, acting as a cholinergic agonist, may counteract the anticholinergic effect of disopyramide on gastric motility. As a factor influencing drug absorption, gastric emptying is of importance, as it determines the rate of drug delivery to the small intestine. Therefore, the oral administration of disopyramide with cisapride may be useful for patients with delayed gastric emptying.

Administration, Oral↗