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K Sugihara

Publications and source records attributed to K Sugihara.

At least 127 records · Page 7Linked to original sources
PubMed1997

Pharmacokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate. 2nd communication: tissue levels and enzyme activity in rats after repeated administration, and placental and milk transfer after single administration.

The absorption, distribution and excretion of radioactivity in rats were studied during and after repeated oral administration of 30 mg/kg of NS-21 ((+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) once a day for 21 days. The plasma concentrations of radioactivity 24 h after each administration of 14C-NS-21 reached a steady state on the 5th day. 48 h after the 21st administration, the plasma concentrations of radioactivity were under the detection limit. The plasma concentrations of the radioactivity after the 7th oral administration of 14C-NS-21 was higher than that after the single administration, but similar to those after the 14th and 21st administrations. There were no marked differences in the elimination half-lives after each administration. The urinary and fecal excretion of the radioactivity was 21.5 and 81.3%, respectively, within 168 h after the 21st administration. In most tissues, no radioactivity was observed 336 h after the 21st administration. Repeated oral administration of 30 and 100 mg/kg of NS-21 once a day for 7 days had no effect on the cytochrome P-450 content, aniline hydroxylase and aminopyrine N-demethylase activity in rat liver. The transfer of radioactivity into fetuses and milk was investigated after single oral administration of 14C-NS-21 to female rats. In the 18th day pregnant rats, the radioactivity concentrations were lower in most fetal tissues than in the maternal plasma. After oral administration of 14C-NS-21 to lactating rats, the concentrations of radioactivity were higher in the milk than in the maternal plasma during an 8-h period. No radioactivity was observed in milk 48 h after administration.

Animals↗
PubMed1997

Pharmacokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate. 3rd communication: plasma concentrations of the unchanged drug and its deethylated metabolite in rats, dogs and monkeys.

1. The plasma concentrations of NS-21 ((+/-)-4-diehtylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) and its deethylated metabolite (RCC-36) after intravenous and oral administrations of (S/R)-NS-21 were measured in rats, dogs and monkeys. After intravenous administration, the plasma concentrations of NS-21 decreased biexponentially. The half-lives of NS-21 in the elimination phase were 2.2 h in rats, 5.3 h in dogs and 15.4 h in monkeys. After oral administration, the systemic availabilities were 4% in rats, 22% in dogs and 6% in monkeys. After intravenous administration, the plasma concentrations of RCC-36 were much lower than those of the unchanged drug in all the animal species tested. In contrast, after oral administration, the plasma concentrations of RCC-36 were comparable to those of the unchanged drug in rats and dogs, and were higher in monkeys. This result suggests that RCC-36 is mainly produced by the first-pass effect. 2. The plasma concentrations of NS-21 and RCC-36 after intravenous and oral administrations of (S)- or (R)-NS-21 were measured in dogs. The AUC value of the unchanged drug after intravenous administration of (R)-NS-21 was about twice as large as that of (S)-NS-21. After oral administration, the systemic availabilities of (S)- and (R)-NS-21 were 17 and 22%, respectively. There were no differences in the serum binding between (S)- and (R)-NS-21 in any of the animal species tested including humans. (S)- and (R)-NS-21 were mainly converted to RCC-36 and a 4-cyclohydroxylated metabolite (NS-21-4-OH) in hepatic microsomes of rats, dogs and monkeys. There were no marked differences in the N-deethylation of (S)- and (R)-NS-21 in all the animals. In contrast, (S)-NS-21 was converted to NS-21-4-OH more preferentially than (R)-NS-21 only in dogs. These findings indicate that the stereo-selective disposition of NS-21 in dogs is due to the stereo-selective cyclohydroxylation of NS-21.

Administration, Oral↗
PubMed1997

Pharmacokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate. 4th communication: metabolism in rats and dogs.

1. The metabolism of NS-21 ((+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) was investigated in rats and dogs. Only a trace amount of the unchanged drug was excreted into urine and bile. This result indicates that NS-21 is extensively metabolized. 2. Seven metabolites (M-1 to M-7) were isolated from rat urine after oral administration of NS-21. Their chemical structures were confirmed by mass spectrometry and co-chromatography with the authentic compounds. On the basis of these results, we postulate that NS-21 is metabolized through the following 3 pathways; 1) N-deethylation, 2) hydroxylation of the cyclohexyl ring, and 3)hydrolysis of the ester bond. 3. The concentrations of NS-21 and its metabolites in the plasma, liver, kidney and lung were determined after single and repeated oral administrations of 14C-NS-21. The concentrations of the unchanged drug and its N-deethylated metabolite (RCC-36) in the tissues were higher than those in the plasma 1 h after single administration. There were no differences in the tissue concentrations of the unchanged drug between single and repeated administration except in the liver. 4. After oral administration of 14C-NS-21 to urinary-ducts cannulated rats, the concentrations of the unchanged drug and RCC-36 in the bladder, the target organ, were higher than in the plasma.

Animals↗
PubMed1997

[Sphincter saving procedure for low rectal carcinoma].

Sphincter saving procedure (SSP) was applied when, for tumor which were a localized type and well or moderate differentiated adenocarcinoma, distal clearance margin (AW) more than 2 cm was obtained and when, for tumor which was a infiltrated type or adenocarcinoma with other pathological grades, AW more than 3 cm was obtained. Between 1984 and 1993, 209 patients with rectal carcinomas, the lower border of which was located below the peritoneal reflexion, underwent curative surgery: SSP in 114 and abdominoperineal resection (APR) in 95. The APR group included more advanced cases both in the depth of invasion and in lymph node metastases (p = 0.011, p = 0.059, respectively). During the median follow-up of 68.6 months, recurrent tumors were developed in 17.5% of the SSP and in 30.5% of the APR (p = 0.027). The patients with SSP showed better prognosis than those with APR(p = 0.0007), with the 5 year survival rate of 80.2% and 70.0%, respectively. The difference may be due to higher incidence of hematogenous metastases in the APR (26.3%) than in the SSP (13.2%). There was no difference in local recurrences between them. When function after SSP was compared with that after anterior resection for middle or upper rectal carcinomas, no difference was observed between them, although most patients of the both groups complained of increased frequency of defecation and occasional soiling. The criteria of SSP for low located rectal carcinoma may be adequate with the acceptable oncological outcome, but altered function after SSP should be improved.

Adenocarcinoma↗
PubMed1997

[A randomized comparative study of surgical adjuvant chemotherapy using 5-fluorouracil and dl-leucovorin with CDDP 5-FU and dl-leucovorin for colorectal cancer].

A randomized comparative study of surgical adjuvant chemotherapy using dl-leucovorin (dl-LV) and 5-fluorouracil (5-FU) (FL-therapy) with CDDP, 5-FU, and dl-LV (PFL-therapy) was conducted. The following were the administration schedules: Arm A was 13 mg/m2 of CDDP, 300 mg/m2 of 5-FU, and 30 mg/body of dl-LV for 5 consecutive days and arm B was 300 mg/m2 of 5-FU and 30 mg/body of dl-LV for 5 consecutive days. Both regimens were followed by biweekly administration of the same dose of dl-LV and 5-FU in outpatients. Arm A was started at the 26th postoperative day and arm B at the 21st day on average. Some 26 cases composed of 11 cases of arm A and 15 cases of arm B completed the administration schedules. Only one case in arm A was complicated by local recurrence around 35 months after operation. Major toxicities were anorexia and neutropenia. Both toxicities were seen more in arm A than in arm B, showing complete recovery in all cases. These data suggest that PFL-therapy and FL-therapy seem to be possible and promising surgical adjuvant therapies for advanced colorectal carcinoma.

Adenocarcinoma↗
PubMed1996

Pelvic autonomic nerve preservation for patients with rectal carcinoma. Oncologic and functional outcome.

BACKGROUND: Serious problems in the surgical treatment of patients with rectal carcinoma are local failure and urinary and sexual dysfunction. To resolve these problems, pelvic autonomic nerve preservation (PANP) combined with lateral lymph note dissection has been introduced. METHODS: Of 238 consecutive patients with middle or low rectal carcinoma who underwent potentially curative surgery between 1987 and 1992, 214 underwent PANP according to pre- and intraoperative staging. PANP was evaluated from the perspectives of oncologic outcome and urinary and male sexual function with a retrospective questionnaire in a group of patients followed prospectively. RESULTS: During the median follow-up of 53 months, local recurrence developed in 5.6% of patients; no local recurrence was observed in Dukes Stage A or Dukes Stage B patients. The 5-year survival rates of Dukes Stage A (n = 55), Dukes Stage B (n = 72), and Dukes Stage C (n = 87) patients were 96.4%, 84%, and 67.3%, respectively. Of patients undergoing preservation of the unilateral pelvic plexus alone, 93.5% maintained the ability to void spontaneously. Of patients who had complete preservation of the autonomic nerve system, 70.4% maintained male sexual function, and of patients who had removal of the hypogastric nerves and preservation of the pelvic nerve plexuses, 66.7%, were capable of erection and intercourse without normal ejaculation. CONCLUSIONS: Early stage rectal carcinoma should be treated both with local cure and complete preservation of urinary and sexual function. In high risk patients with suspected perirectal lymph node metastases and tumors invading the perirectal fat, the appropriate PANP should be applied with consideration of the balance between achieving a cure and preserving autonomic function.

Adult↗
PubMed1996

Cancer cell morphology at the invasive front and expression of cell adhesion-related carbohydrate in the primary lesion of patients with colorectal carcinoma with liver metastasis.

BACKGROUND: Liver metastasis from colorectal carcinoma is an important problem in surgical treatment and profoundly affects the prognosis of patients. If it were possible to identify characteristic features in the primary lesion strongly related to liver metastasis, these could be used as prognostic markers for liver metastasis. To search for such features, the primary lesions of patients with colorectal carcinoma with liver metastasis were investigated. METHODS: Three groups of colorectal carcinoma were examined: Group A with synchronous liver metastases; Group B with only lymph node metastases without recurrence for 5 years; and Group C with recurrence of liver metastases. Groups A and B included 24 cases and Group C, 20. We focused on cancer cell morphology at the invasive front and expression of sialyl Lewis X (sialyl Lex) in the primary cancer. RESULTS: At the invasive front in Group A it was frequently found that polygonal, not columnar, cancer cells with a single or solitary trabecular form with indistinct polarity, showed an infiltrative growth pattern. This type of morphology was termed "focal dedifferentiation" and graded four levels. Eleven of 24 cases (46%) had severe focal dedifferentiation in Group A, 1 of 24 (4%) in Group B, and 6 of 20 (30%) in Group C. Sialyl Lex staining was positive in 12 of 24 cases (50%) in Group A, in 3 of 24 cases (13%) in Group B, and in 7 of 20 cases (35%) in Group C in the primary carcinoma. In respect to the staining of (sialyl Lex) at focal dedifferentiation, it was positive in 17 of 24 cases (71%) in Group A, in 4 of 24 cases (17%) in Group B and in 11 of 20 cases (55%) in Group C. Focal dedifferentiation and sialyl Lex staining in the primary cancer showed a significant difference between Groups A and B. Sialyl Lex staining at focal dedifferentiation showed a significant difference between Groups A and B and Groups B and C. Other adhesion related molecules, sialyl LeA and CEA, showed no difference among Groups A, B, and C. CONCLUSIONS: Both focal dedifferentiation and expression of sialyl Lex antigen in the primary lesion are considered good markers for assessing the metastatic proclivity of colorectal cancer.

Adult↗
PubMed1996

Clinical implications of microsatellite instability in colorectal cancers.

BACKGROUND: Microsatellite instability (MI) has been reported in some sporadic colon tumors and in cases of hereditary nonpolyposis colorectal cancer (HNPCC). The criteria for HNPCC have not been fully defined, and clinical criteria are used to identify as many HNPCC patients as possible. To clarify the conformity of these criteria with the identification of eligible HNPCC cases, we analyzed MI in HNPCC patients diagnosed using clinical criteria. METHODS: Genomic DNA was extracted from surgical specimens of 56 colorectal cancers, including 36 from patients diagnosed with HNPCC using the clinical criteria. We analyzed four microsatellite loci using 32P-labeled primers. RESULTS: Among HNPCC patients diagnosed using clinical criteria, patients who were positive for MI accounted for 62% of Group A (a confirmed group) and 35% of Group B (a high risk group); only 5% of randomly selected colorectal cancer patients (Group C), were positive for MI. Furthermore, MI-positive tumors were found in patients who had a tendency for tumors to involve the right side of the colon, an association with cancers in other organs, a lower incidence of p53 protein positivity, and a higher proportion of poorly differentiated cancers. CONCLUSIONS: The presence of MI, in concert with modified clinical criteria, may identify legitimate cases of HNPCC in patients who might otherwise be excluded by the minimum criteria.

Age of Onset↗
PubMed1996

Experimental anti-GBM glomerulonephritis induced in rats by immunization with synthetic peptides based on six alpha chains of human type IV collagen.

The anti-glomerular basement membrane (GBM)-nephritis-inducing activity of six synthetic peptides having an amino acid sequence consisting of the six alpha chains of human type IV collagen was examined by injecting the peptides into rats. The peptides consisted of 27 amino acid residues from the non-collagenous domain (NC1) of the alpha 1 to alpha 6 chains and were non-consensus sequences sandwiched between two consensus sequences near the carboxyl terminus. Each peptide was coupled to keyhole limpet haemocyanin and injected with adjuvant into the footpads of 20 female WKY/NCrj rats. The number of rats with proteinuria (over 10.0 mg of urinary protein/15 h) and haematuria was 2 with the alpha 3 peptide, 8 with the alpha 4 peptide, and 1 with the alpha 5 peptide. Histological changes seen in the glomeruli were characteristic of those in anti-GBM nephritis. Linear deposition of rat IgG along the GBM was observed in five rats injected with the alpha 4 peptide. A nephritogenic monoclonal antibody against the alpha 4 peptide was established using lymph node cells from a rat injected with the alpha 4 peptide. The results indicate that alpha 4(IV)NC1 is a potent nephritogenic antigen like alpha 3(IV)NC1, which has already been recognized as a primary target antigen in Goodpasture's syndrome.

Amino Acid Sequence↗
PubMed1996

S-(-)-nicotine-1'-N-oxide reductase activity of rat liver aldehyde oxidase.

In the present study, a rat liver cytosolic enzyme responsible for reduction of S-(-)-nicotine-1'-N-oxide to S-(-)-nicotine was investigated. We found that aldehyde oxidase (EC 1.2.3.1) can function as a S-(-)-nicotine-1'-N-oxide reductase in the presence of its electron donor such as 2-hydroxypyrimidine. The apparent K(m) and Vmax values of the enzyme for the N-oxide were 0.24 mM and 30.3 nmol/10 min/mg protein, respectively.

Aldehyde Oxidase↗
PubMed1996

Nucleotide sequence of the uricase gene from Bacillus sp. TB-90.

The nucleotide sequence of the uricase gene from the thermophilic bacterium Bacillus sp. TB-90 was determined. The primary structure of the uricase deduced from the nucleotide sequence comprised 332 amino acids, with a total molecular mass of 37,994 Da. The molecular mass of the subunit of the uricase produced by the transformant of Escherichia coli agreed well with this value. However, the molecular mass of a subunit of the uricase produced by Bacillus sp. TB-90 was found to be 34,000 Da by SDS-PAGE. The difference between these molecular masses was attributed to processing of the C-terminal 13 amino acid residue in Bacillus sp. TB-90. Comparison of the enzymatic properties of both uricases showed that the thermostability of the uricase produced by the transformant was enhanced by about 10 degrees C in comparison to that produced by Bacillus sp. TB-90.

Amino Acid Sequence↗
PubMed1996

Transrectal ultrasonography of a small rectal carcinoid tumor with lymph node metastasis: a case report.

A 27-year-old woman with a small rectal carcinoid tumor was examined by transrectal ultrasonography (TRUS) for preoperative staging. TRUS revealed regional lymph node involvement, in addition to a 10-mm hypoechoic tumor invading into not through, the submucosa. The lymph node involvement was confirmed preoperatively by TRUS-guided needle biopsy. Although the digital examination findings indicated local excision was appropriate, in accordance with TRUS and TRUS-guided biopsy findings, the patient underwent radical surgery. The TRUS findings of lymph node involvement and depth of invasion were confirmed histologically. The patient is alive and disease-free 35 months postoperatively. These observations suggest that TRUS reveals the regional lymph node involvement and the depth of invasion of rectal carcinoid tumors accurately and, therefore, helps in selecting appropriate treatment.

Adult↗
PubMed1996

Prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the role of Japanese criteria for HNPCC.

In 1991, the Japan Research Society for Cancer of the Colon and Rectum proposed clinical criteria (Japanese criteria) for hereditary nonpolyposis colorectal cancer (HNPCC). According to the Japanese and Amsterdam criteria, three groups of patients are defined: 1) those diagnosed as having HNPCC using the Amsterdam criteria (Amsterdam HNPCC); 2) those classified as Japanese criteria category A (putative HNPCC-A) and 3) those classified as Japanese criteria category B (putative HNPCC-B). In order to evaluate the prognosis of HNPCC and the role of the Japanese criteria, the clinicopathological characteristics, recurrence and survival rates of Amsterdam HNPCC (n 14) and putative HNPCC-A (n 31) and B (n 100) patients were studied, and compared with those of patients with sporadic colorectal cancer (controls, n 1604). The Amsterdam clinicopathological characteristics and those of putative HNPCC were the same as those reported previously. Neither local nor distant recurrences were observed in the Amsterdam HNPCC and putative HNPCC-A during a median follow-up period of 137 months. The 5-year survival rates of the Amsterdam HNPCC, putative HNPCC-A, B, and control patients were 92.3%, 81.2%, 66.5% and 60.0%, respectively, and those of the former two groups were significantly better than those of the others (P<0.05). These results show that the prognosis of HNPCC is better than that of sporadic colorectal cancer, and that the Japanese criteria, especially for category A, can be used to select putative HNPCC patients from among those with sporadic colorectal cancers.

Adult↗
PubMed1996

Detection of K-ras point mutations in mesenteric venous blood from colorectal cancer patients by enriched polymerase chain reaction and single-strand conformation polymorphism analysis.

In order to confirm the presence of cancer cells in mesenteric venous blood and to examine their relationship with the occurrence of liver metastases, we attempted to detect K-ras codon 12 point mutations in perioperative mesenteric blood using enriched polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) analysis in 25 patients with primary colorectal tumors carrying K-ras point mutations. Among these patients, three with synchronous liver metastases were included. The same K-ras point mutation (substitution of GAT for GGT) was detected in both the blood and the primary tumor in a Dukes' C patient. We confirmed this result by colony hybridization and estimated the tumor-to-normal cell ratio to be 1:400. This patient has no liver metastases two years after surgery and her carcinoembryonic antigen (CEA) level remains normal. We demonstrated that considerable numbers of cancer cells can be found in mesenteric venous blood during colorectal cancer surgery. However, their potential role in the formation of liver metastases remains unclear.

Colorectal Neoplasms↗
PubMed1996

Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide.

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide), an anticonvulsant agent, is primarily metabolized to 2-sulfamoylacetylphenol by reductive cleavage of the 1,2-benzisoxazole ring. Rabbit liver cytosol with an electron donor of aldehyde oxidase exhibited a significant zonisamide reductase activity that was sensitive to inhibition by menadione, an inhibitor of aldehyde oxidase. The result suggested that the cytosolic activity is caused by aldehyde oxidase, a cytosolic enzyme. In fact, rabbit and rat liver aldehyde oxidase had the ability to reduce zonisamide when supplemented with its electron donor. Apparent KM and Vmax values of aldehyde oxidase for zonisamide were 217 microM and 42 nmol/10 min/mg protein in the case of the rabbit liver enzyme, and 542 microM and 382 nmol/10 min/mg protein in the case of the rat liver enzyme, respectively. In rabbits, hamsters, mice, and guinea pigs, zonisamide reductase activity of the liver cytosols with 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, was much higher than that of the liver microsomes with NADPH. In rats, zonisamide reductase activity was examined with liver microsomes and cytosols from seven strains. The 2-hydroxypyrimidine-dependent cytosolic activity exhibited marked strain differences, unlike the NADPH-dependent microsomal activity. 1,2-Benzisoxazole was also reduced to salicylaldehyde by rabbit liver cytosol and aldehyde oxidase in the presence of 2-hydroxypyrimidine. Stoichiometric studies showed that 2-sulfamoylacetylphenol was formed accompanying nearly equimolar ammonia from zonisamide.

Aldehyde Oxidase↗