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Biomedical subjects

K Seto

Publications and source records attributed to K Seto.

At least 37 records · Page 2Linked to original sources
PubMed1992

Potentiation of the vincristine effect on P388 mouse leukemia cells by a newly synthesized dihydropyridine analogue, PAK-200.

A newly synthesized dihydropyridine analogue, 2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2-yl)-1- (2-morpholinoethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate (PAK-200), at 1 microM completely reversed the resistance to vincristine in vincristine-resistant P388 mouse leukemia cells (P388/VCR), in vitro. PAK-200 at 2 microM inhibited the efflux of [3H]vincristine from P388/VCR and increased the accumulation of [3H]vincristine in P388/VCR to a level similar to that in P388 cells. P-Glycoprotein in membrane vesicles from P388/VCR cells was photolabeled with [3H]azidopine. The labeling was completely inhibited by 10 microM PAK-200. The calcium antagonistic activity of PAK-200 was about 1000 times lower than that of another dihydropyridine analogue, nicardipine. Experiments with P388 and P388/VCR-bearing mice showed that PAK-200 enhanced the effect of vincristine on both leukemia cells in vivo. These results suggest that PAK-200 interacts with P-glycoprotein and reverses drug resistance in P388 mouse leukemia cells in vitro, and that PAK-200 has an ability to potentiate the effect of vincristine on P388 mouse leukemia cells in vivo.

Animals↗
PubMed1992

Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium-antagonistic and antihypertensive activities: novel calcium-antagonist 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol (NZ-105) and its crystal structure.

The effect of the 3-carboxylic-ester variation in 2,2-dimethyltrimethylene 3-alkoxycarbonyl-4-aryl-1,4-dihydro-2,6-dimethyl-5-pyridinephosphonat es (1) was investigated with relation to the calcium-antagonistic and antihypertensive activities: the analogs containing the alkyl groups of not more than 12 carbons and an amino functionality in the carboxylic-ester moiety were synthesized to be examined for biological activities. Among them, 2-[benzyl(phenyl)amino]-ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridine-carboxylate hydrochloride ethanol (NZ-105) showed particularly beneficial activities and was selected for further pharmacological studies and clinical development. Some aspects of the structure-activity relationships and solid-state structure of NZ-105 by X-ray crystallographic analysis were described.

Animals↗
PubMed1992

Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101).

Six optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101, 1.2HCl.2H2O), a potent calcium antagonist, were successfully prepared by using optically active (2R,4R)-(-)- and (2S,4S)-(+)-2,4-pentanediols, and cis-2,4-pentanediol and optically active (S)-(+)-2-methoxy-2-phenylethanol. Their proton nuclear magnetic resonance investigations demonstrate that the 1,3,2-dioxaphosphorinane group is conformationally constrained around the C-P bond. Calcium-antagonistic and hypotensive activities of the optical isomers were examined and found to depend mainly on the absolute configuration at a stereogenic center in the 1,4-dihydropyridine ring rather than the configuration of the 1,3,2-dioxaphosphorinane moiety.

Animals↗
PubMed1992

Synthesis and crystal structure of optically active 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ-105).

(S)-2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate ((S)-NZ-105) and R isomer were synthesized through the fractional crystallization of (S)-2-Methoxy-2-phenylethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate. Calcium antagonism activity was found to reside in the S isomer from single crystal X-ray diffraction analysis.

Animals↗
PubMed1992

[Studies on the healing promoting action of Z-103 in chronic gastric ulcer models of rats].

We studied the healing promoting action of Z-103 on the chronic gastric ulcer induced by acetic acid (AAU) or Fe-ascorbic acid (FAU) in rats. The area of the gastric ulcers, hydroxyproline (Hyp) and DNA contents in the ulcer region were measured as an index of ulcer healing. The area of gastric ulcers was the largest on day 4 and thereafter gradually decreased, but the ulcers still remained at the 14th day. Hyp contents in the ulcer region decreased until the 7th day in both models, and then this level increased. Significant decrease in DNA contents in the ulcer region was observed on the 7th day only in FAU. In AAU and FAU, administration of Z-103 (3 mg/kg/day x 2, p.o.) resulted in a significant decrease in the area of gastric ulcers on the 14th day and a significant increase in Hyp contents in the ulcer region on the 7th day as compared with the control group. Z-103 increased the DNA contents in the ulcer region on the 4th day in AAU and on the 7th day in FAU. These results suggest that tissue destruction surrounding the ulcer region in AAU and FAU models might occur until the 4th or 7th day after operation, and that the acceleration of ulcer healing by Z-103 on these models may be facilitated by the wound healing action of this drug.

Animals↗
PubMed1992

Cerebellar form of progressive multifocal leukoencephalopathy in a patient with chronic renal failure.

Progressive multifocal leukoencephalopathy (PML) developed in a 64-year-old woman who had undergone hemodialysis treatment due to chronic renal failure (CRF) for 6 yr. Her initial symptom was ataxia, and computed tomographic (CT) scan and magnetic resonance imaging (MRI) suggested a demyelinating disease of the cerebellum. Her cell-mediated immunity was impaired. At autopsy, the cerebellar disease was confirmed as PML by ultrastructural and immunohistochemical studies. Moreover, the JC type of papova virus infection was verified by Southern blot analysis.

Cerebellar Diseases↗
PubMed1992

[Interaction of nicardipine and inhalational anesthetics--comparison between enflurane and isoflurane].

The effects of nicardipine 1 mg bolus injection under enflurane anesthesia were compared with those under isoflurane anesthesia. Twelve neurosurgical patients were divided into 2 groups, enflurane group (n = 6) and isoflurane group (n = 6). In all patients anesthesia was induced with midazolam, thiamylal, fentanyl and vecuronium. Anesthesia was maintained with fentanyl, nitrous oxide, pancuronium plus enflurane (enflurane group) or plus isoflurane (isoflurane group). After incision of dura mater, nicardipine 1 mg was given through forearm venous line. For about 30 minutes before and after nicardipine injection, concentration of inhalational anesthetics was kept constant and no drugs were given. Blood pressure (BP), heart rate (HR), rate pressure product (RPP), and serum concentrations of catecholamine and nicardipine were monitored for 30 minutes after nicardipine injection. In isoflurane group, BP decreased more and longer, and increases of HR and serum concentration of catecholamine continued longer compared with enflurane group. Elimination half life of nicardipine was shorter, area under the curve (AUC) was smaller and clearance of nicardipine was larger in isoflurane group than in enflurane group. It was concluded that isoflurane increased the effects of nicardipine, which were BP depression and reflex sympathetic stimulation, than enflurane and that metabolism and elimination of nicardipine were accelerated more by isoflurane than by enflurane.

Anesthesia, Inhalation↗
PubMed1992

[Epidural midazolam with bupivacaine--optimal dose for postoperative pain relief].

Optimal dose of epidural midazolam with bupivacaine for postoperative pain relief was investigated. Forty seven patients for upper abdominal surgery were divided into 5 groups. Each group had either 0.25% bupivacaine 6 ml (control group), 0.25% bupivacaine 6 ml + midazolam 0.025 mg.kg-1 (0.025 group), 0.05 mg.kg-1 (0.05 group), 0.075 mg.kg-1 (0.075 group), or 0.1 mg.kg-1 (0.1 group) administered epidurally for complaint of first postoperative pain. Blood pressure (BP), heart rate (HR), respiratory rate (RR) and sedation score (SS) were monitored for 120 minutes, and the time interval for next analgesics (TNA) was checked. In each group, BP fell down 10 minutes after injection, HR was unchanged, and RR (except for 0.1 group) decreased, compared with the preinjection level. There was no difference between control group and others in BP, HR and RR. But 3 cases in 0.075 group and 4 cases in 0.1 group needed chin lift with a pillow under the shoulder for slight airway obstruction. The most optimal SS was obtained in 0.05 group. TNA was significantly longer in 0.025 and 0.05 groups than in the control group. It was concluded that the optimal dose of epidural midazolam with 0.25% bupivacaine 6 ml was 0.05 mg.kg-1 for postoperative pain relief after an upper abdominal surgery.

Abdomen↗
PubMed1992

[Epidural midazolam with saline--optimal dose for postoperative pain].

Optimal dose of epidural midazolam with saline for postoperative pain relief was investigated. Forty three patients for upper abdominal surgery were divided into 5 groups. Each group had either 10 ml saline only (saline group), 10 ml saline + midazolam 0.025 mg.kg-1 (0.025 group), 10 ml saline + midazolam 0.05 mg.kg-1 (0.05 group), 10 ml saline + midazolam 0.075 mg.kg-1 (0.075 group), or 10 ml saline + midazolam 0.1 mg.kg-1 (0.1 group) administered epidurally for complaint of postoperative pain. Blood pressure (BP), heart rate (HR), respiratory rate (RR) and sedation score (SS) were monitored for 120 minutes, and the time interval for next analgesics (TNA) was checked. In each group, BP was unchanged compared with preinjection level. HR changes were less in 0.05 and 0.1 group than in others. RR changes were less in 0.025 and 0.05 group than in others. Optimal SSs were obtained in 0.025 and 0.05 groups. In 0.075 and 0.1 groups, many patients fell into complete sleep (not responded to verbal command). TNA was about 2 hours in 0.025 and 0.05 groups, over 6 hours in 0.075 and 0.1 groups. Complete sleep was the cause of long TNA in 0.075 and 0.1 groups. It was concluded that optimal dose of epidural midazolam with saline 10 ml was 0.05 mg.kg-1 for postoperative pain relief after upper abdominal surgery.

Abdomen↗
PubMed1992

[Surgical stress stimulates release of polymorphonuclear leukocyte elastase from a segmented neutrophil].

The studies were performed to find out whether increased serum levels of polymorphonuclear leukocyte elastase (PMNE) depend on increase of segmented neutrophils or increase of PMNE release from a segmented neutrophil on 17 patients for various elective surgeries. Serum levels of PMNE, leukocyte count and leukogram were determined before incision (preoperation), as well as on the 1st, 3rd and 5th day after operation. Serum levels of PMNE, segmented cell count, stab cell count, stab cell-segmented cell ratio increased most on the 1st postoperative day and decreased thereafter. Leukocyte count showed no significant changes. Serum levels of PMNE correlated well with PMNE released from a segmented neutrophil, but not with leukocyte count or segmented cell count. It was concluded that increased serum levels of PMNE by surgical stress depend on the increased PMNE release from a segmented neutrophil but not on the increased segmented cell count.

Adult↗
PubMed1991

The effect of incomplete bile duct obstruction on diisopropanolnitrosamine-induced cholangiocarcinoma.

This study was carried out to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence and proliferation of cholangiocarcinoma and to evaluate the effect of release of IBDO at an early stage, using 175 Syrian golden hamsters. These hamsters received 500 mg/kg body weight of diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and then were divided into 3 groups, consisting of the simple laparotomy group (SL group), the IBDO group and 2 week IBDO group, in which IBDO was released after 2 weeks. The occurrence rates of cholangiocarcinoma at 20 weeks were 42% in the SL group, 76% in the IBDO group and 30% in the 2 week IBDO group. The mean numbers of tumors per hamster in the IBDO group were significantly greater than those in other groups (p less than 0.05). Both occurrence rates and numbers of tumors in the 2 week IBDO group were similar to those in the SL group. The proliferation of bile ductules and isolation of bacteria from bile in the IBDO group had higher rates at 15, 20 weeks than those found in the other groups. These results suggest that IBDO has an influence, as promoter, on the occurrence of cholangiocarcinoma induced by DIPN, and the disappearance of its promoting effect is caused by release of the obstruction.

Adenoma, Bile Duct↗
PubMed1991

[Epidural administration of midazolam with saline or bupivacaine for postoperative pain].

Postoperative pain relief and sedation with epidural midazolam-saline or midazolam-bupivacaine were studied in 46 patients after elective upper abdominal surgery. They were divided into 6 groups. In each group, 10 ml saline, 10 ml saline+midazolam 0.05 mg.kg-1, 10 ml saline+midazolam 0.1 mg.kg-1 (saline group), 0.25% bupivacaine 6 ml, 0.25% bupivacaine 6 ml + midazolam 0.05 mg.kg-1 or 0.25% bupivacaine 6 ml + midazolam 0.1 mg.kg-1 (bupivacaine group) was administered via epidural catheter for complaint of pain. For 120 minutes after epidural injection, blood pressure (BP), heart rate (HR), respiratory rate (RR), sedation score, and serum concentration of midazolam (conc midazolam) were evaluated. The time interval until next complaint of pain (pain relief time) was measured. In midazolam injected group, BP, HR, RR were not changed from preinjection value, but sufficient sedation was obtained and pain relief time was significantly prolonged compared with saline or bupivacaine injected group. Midazolam level was lower than that of sedation level. There were no significant differences between saline group and bupivacaine group, but the pain relief effect was slightly stronger in bupivacaine group. It is concluded that epidural saline - midazolam or 0.25% bupivacaine - midazolam is useful for postoperative pain relief after upper abdominal surgery.

Abdomen↗
PubMed1991

[Epidural midazolam for treatment of postoperative pain].

Postoperative pain relief and sedation with epidural midazolam were studied. Twenty-one patients for elective upper abdominal surgery were divided into 3 groups. Epidural catheter was inserted into thoracic epidural space before induction of general anesthesia. In each group, either 10 ml saline only, midazolam 0.05 mg.kg-1 + 10 ml saline, or midazolam 0.1 mg.kg-1 + 10 ml saline was injected into epidural catheter for complaint of pain in recovery room. For 120 minutes after epidural injection, blood pressure, heart rate, respiratory rate, serum concentration of midazolam, and sedation score were monitored. In midazolam injected groups, only slight changes were seen in blood pressure, heart rate, and respiratory rate. Sedation score was graded from 1 to 6:1 means complete sleep, and not responded to verbal command, 6 means agitated and many complaints. Midazolam 0.1 mg.kg-1 + 10 ml saline group had the lowest score, and saline 10 ml group had the highest score. Prolonged sedation and pain relief were obtained in midazolam injected group, especially 0.1 mg.kg-1 + 10 ml saline group. Serum midazolam concentrations were lower than 200 ng.ml-1. These values were considered as the lower limit for sedation by intravenous administration. In conclusion, epidural midazolam was useful for postoperative pain relief. The mechanism is considered to involve spinally mediated CNS action or direct spinal action.

Adult↗
PubMed1990

GABAergic mechanisms are involved in the control of tuberoinfundibular arcuate neurons by the accessory olfactory bulb.

In this study we examined electrophysiologically the involvement of the intrinsic GABAergic system of the accessory olfactory bulb (AOB) in controlling the activity of tuberoinfundibular (TI) arcuate neurons in anaesthetized female mice. Local infusions of the gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline into the AOB enhanced the spontaneous firing activity of TI arcuate neurons with excitatory inputs from the AOB. This finding reveals a neural mechanism responsible for the pregnancy blocking effect of this drug in freely behaving female mice and, taken together with the cytoarchitecture of the AOB, suggests that the reciprocal dendrodendritic interaction between mitral cells and GABAergic granule cells in the AOB is critical to control of AOB output to TI arcuate neurons as part of the final common pathway of the accessory olfactory system.

Animals↗
PubMed1990

Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts.

Four pyridine analogues and their dihydropyridine counterparts were examined for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-C2. Two pyridine analogues were more able to reverse drug resistance than their dihydropyridine counterparts. The other two pyridine analogues had an effect on drug resistance similar to their dihydropyridine counterparts. The calcium channel-blocking activity of all the pyridine analogues was considerably lower than that of the dihydropyridine analogues. Of the pyridine analogues, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4 -(3- nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) was the most effective in reversing multidrug resistance. PAK-104P (1 and 5 microM) completely reversed the drug resistance in KB-8-5 and KB-C2 cells, respectively. The reversing effect of PAK-104P was greater than that of other multidrug resistance-reversing agents, cepharanthine, verapamil, nimodipine, and nicardipine. PAK-104P at 1 microM increased about 10-fold the accumulation of vinblastine in KB-C2 cells, whereas verapamil at the same concentration increased the accumulation about 2-fold. The inhibition of [3H]azidopine photolabeling of P-glycoprotein by the pyridine and dihydropyridine analogues except 2-[methyl(phenyl-methyl)amino]ethyl 4-(2-chlorophenyl)-5-(4-methyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-d ihydro-2,6- dimethyl-3-pyridinecarboxylate P-oxide correlated with the reversing of drug resistance by the analogues. Some newly synthesized pyridine analogues seemed to have lower calcium channel-blocking activity and more potent resistance-reversing ability than verapamil and other calcium channel blockers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗