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Biomedical subjects

M Fujimaki

Publications and source records attributed to M Fujimaki.

At least 19 recordsLinked to original sources
PubMed2001

Nefiracetam metabolism by human liver microsomes: role of cytochrome P450 3A4 and cytochrome P450 1A2 in 5-hydroxynefiracetam formation.

An in-vitro study was conducted to investigate the metabolism of nefiracetam in human liver microsomes and to identify the enzymes responsible for the metabolism. Nefiracetam was hydroxylated by human liver microsomes to 5-hydroxynefiracetam (5-OHN). Eadie-Hofstee plots for the formation of 5-OHN suggested substrate activation. The kinetic parameters, apparent Km, Vmax, and Hill coefficient, for the formation of 5-OHN by pooled human liver microsomes were 4012 microM, 2.66 nmol min(-1) (mg protein)(-1), and 1.65, respectively. The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP)3A4-mediated testosterone 6beta-hydroxylase activity and dextromethorphan N-demethylase activity. The 5-OHN formation was inhibited (94%) by antibody to human CYP3A4/5. The 5-OHN formation was also inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin, but not significantly inhibited by several other P450 inhibitors. The microsomes containing cDNA-expressed CYP3A4 formed 5-OHN with sigmoidal kinetics. CYP3A5-containing microsomes did not form 5-OHN. These results indicated that CYP3A, most likely CYP3A4, was the major isozyme responsible for the formation of 5-OHN in human liver microsomes. CYP1A2 and CYP2C19 microsomes were also capable of forming 5-OHN. However, the contribution of CYP1A2 was considered to be relatively minor compared with that of CYP3A4, and the contribution of CYP2C19 was assumed to be negligible, based on the result of the immunoinhibition study and taking into account both the turnover rate by each isozyme and the relative abundance of each isozyme in human liver. We conclude that on average the formation of 5-OHN, the major metabolite of nefiracetam, is principally mediated by CYP3A4 with a relatively minor contribution by CYP1A2.

Antibodies↗
PubMed2000

Experimental study of an artificial esophagus using a collagen sponge, a latissimus dorsi muscle flap, and split-thickness skin.

The time and effort spent trying to devise an artificial esophagus have not yet resulted in success, and leakage and strictures at the anastomotic sites remain the most frequent complications. We developed an artificial esophagus with a bilayered structure made of porous collagen sponge (artificial dermis; AD), a latissimus dorsi muscle flap (LD), and split-thickness skin (STS). We investigated whether the use of AD prevented the contraction of grafted skin and its effects on the extensibility of the neoesophagus in rabbits. We experimented with two groups. In the AD group, AD was applied to the surface of the LD. Three weeks later, the STS was grafted. In the control group, the STS was grafted directly onto the LD. The sizes of the STS in both groups 3 weeks after the graft were, respectively, 56.6% +/- 4.1% and 39.0% +/- 10.2% of the initial surface area of the STS (P < 0.01). The roll made in the AD group had better extensibility than that in the control group. We replaced the cervical esophagus in 12 rabbits with the neoesophagus made from AD, STS, and LD. The longest survival period was 16 days. Esophagography did not reveal either anastomotic leakage or stenosis in any of the five rabbits in the experiments. These findings suggested that AD can thus be used to create a more suitable hybrid artificial esophagus.

Animals↗
PubMed1999

Splenic artery aneurysm associated with systemic lupus erythematosus: report of a case.

We herein report on a 64-year-old Japanese female patient who presented with a splenic artery aneurysm (SAA) associated with systemic lupus erythematosus (SLE). The saccular aneurysm, which measured 3 cm in diameter, was located in the proximal third of the splenic artery from the pancreas with a portosystemic shunt. A double ligation of the splenic artery (the distal and proximal sides of the aneurysm) was performed without a splenectomy. The postoperative course showed acute pancreatitis without either splenic infarction or portal thrombus. To our knowledge, the closed association of SLE with an aneurysmal dilatation of the splenic artery has not been previously reported. Both the pathogenesis and the management of SAA associated with SLE are discussed following the presentation of this case. This is the first reported case of SAA associated with SLE.

Aneurysm↗
PubMed1998

A new pseudo-peptide analogue of the Arg-Gly-Asp (RGD) sequence inhibits liver metastasis of colon 26-L5 carcinoma cells.

We have investigated the effect of the pseudo-peptide analogue (FC-336) of the Arg-Gly-Asp (RGD) sequence in a liver metastasis model by the inoculation of a highly liver-metastatic cell line of colon 26 carcinoma (colon 26-L5) into the portal vein of BALB/c mice. The intraportal injection of colon 26-L5 cells with FC-336 resulted in a marked suppression of liver metastatic colonies in a dose-dependent manner and it reduced the liver weights to a normal level. However, the co-injection of tumor cells with a high dose of RGDS tetrapeptide led to a slight inhibition of liver metastasis. The multiple i.v. administration of FC-336 after tumor inoculation as well as the injection of FC-336 with tumor cells caused significant inhibition of experimental metastasis in the liver. The multiple i.v. administration of the RGDS peptide did not show any inhibitory activity. FC-336 significantly enhanced the survival rate of mice compared with untreated controls when injected intraportally with tumor cells or when intravenously administered after tumor inoculation. Zymography analysis showed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by colon 26-L5 cells, while RGDS peptide did not affect the enzymatic degradation. These findings clearly indicate that the pseudo-peptides of the RGD sequence (FC-336) have a potent inhibitory activity on liver metastasis of colon 26-L5 carcinoma cells.

Animals↗
PubMed1998

Neuroblastoma in an adult with a high serum level of carbohydrate antigen, CA125: report of a case.

We report herein the case of a 56-year-old woman with a neuroblastoma associated with a high serum level of carbohydrate antigen, CA125. The patient presented with massive ascites and a firm mass in her upper abdomen for which a laparotomy was performed. However, a recurrent tumor was found 6 months later and she died of the disease within 1 year of surgery despite several courses of adjuvant chemotherapy. Neuroblastoma rarely occurs in adults, and the features of 58 adult cases described in the world literature is summarized following the presentation of the clinical data on this case. The distribution of primary sites in adults is dispersed compared to that seen in pediatric cases, while the natural history of the disease in adults may be longer and less sensitive to chemotherapy than in children. The survival rate of adults with this disease is poor. We conclude that aggressive surgical intervention combined with appropriate chemotherapy protocols as applied in children should be performed in an attempt to achieve complete remission and improve the survival rate of adults with neuroblastoma.

Abdominal Neoplasms↗
PubMed1998

Oral administration of a Kampo (Japanese herbal) medicine Juzen-taiho-to inhibits liver metastasis of colon 26-L5 carcinoma cells.

We have investigated the inhibitory effect of oral administration of Juzen-taiho-to, a Kampo Japanese herbal medicine, on liver metastasis by the inoculation of a liver-metastatic variant (L5) of murine colon 26 carcinoma cells into the portal vein. Oral administration of Juzen-taiho-to for 7 days before tumor inoculation resulted in dose-dependent inhibition of liver tumor colonies and significant enhancement of survival rate as compared with the untreated control, without side effects. We also found that liver metastasis of L5 cells was enhanced in BALB/c mice pretreated with anti-asialo GM1 serum or 2-chloroadenosine, and in BALB/c nu/nu mice, compared to normal mice. This indicates that NK cells, macrophages, and T-cells play important roles in the prevention of metastasis of tumor cells. Juzen-taiho-to significantly inhibited the experimental liver metastasis of colon 26-L5 cells in mice pretreated with anti-asialo GM1 serum and untreated normal mice, whereas it did not inhibit metastasis in 2-chloroadenosine-pretreated mice or T-cell-deficient nude mice. Oral administration of Juzen-taiho-to activated peritoneal exudate macrophages (PEM) to become cytostatic against the tumor cells. These results show that oral administration of Juzen-taiho-to inhibited liver metastasis of colon 26-L5 cells, possibly through a mechanism mediated by the activation of macrophages and/or T-cells in the host immune system. Thus, Juzen-taiho-to may be efficacious for the prevention of cancer metastasis.

2-Chloroadenosine↗
PubMed1997

Inhibitory effects of fluorinated pyrimidines, 5'-DFUR, UFT and T-506, in a model of hepatic metastasis of mouse colon 26 adenocarcinoma-assessment of inhibitory activity and adverse reactions at the maximum tolerated dose.

The effects of fluorinated pyrimidines, 5'-DFUR, UFT and T-506, on a mouse model of hepatic metastasis were assessed in regard to inhibitory activity and adverse reactions at the maximum tolerated dose. The model was prepared by injecting the mouse colonic cancer cell line, colon 26, into the portal vein of CDF1 mice. At the treatment regimens employed for 5'-DFUR (1.0 mmol/kg/day, p.o., daily from days 1 to 7), UFT (0.1 mmol/kg/day, p.o., daily from days 1 to 7), and T-506 (0.074 mmol/kg/day, i.v., days 1, 4, 7, and 10), complete inhibition of hepatic metastasis was obtained in six out of seven mice (85.7%) with 5'-DFUR, and in five out of six mice (83.3%) with T-506. Significant inhibition of hepatic metastasis was not achieved with UFT (3/7, 42.9%). 5'-DFUR and T-506 showed the highest rate of inhibition of hepatic metastasis, suggesting that these drugs would be effective for the prophylactic treatment of metastatic disease. 5'-DFUR and UFT exhibited mild adverse reactions such as loss of body weight.

Adenocarcinoma↗
PubMed1997

Ileocolon interposition as a substitute stomach after total or proximal gastrectomy.

OBJECTIVE: The authors evaluated ileocolon interposition as a substitute stomach after total gastrectomy (TG) or proximal gastrectomy (PG). SUMMARY BACKGROUND DATA: Although the jejunum frequently is used for reconstruction to create a substitute stomach after TG or PG, there are few reports on ileocolon interposition. METHODS: The authors performed ileocolon interposition in 47 patients who underwent TG (N = 18) or PG (N = 29) for malignant gastric lesion and evaluated the function of this structure as a substitute stomach using esophagoscopy, manometry, pH-metry, emptying time, oral glucose tolerance test (OGTT), and postoperative body weight changes. RESULTS: No patient reported any reflux symptoms or showed endoscopic findings of reflux esophagitis. These results were well supported by manometry and acid loading pH-metry. Emptying time and OGTT showed good capacity as a reservoir of food, and the postoperative body weight averaged more than 90% of preoperative weight. Clinically, no significant difference between these two groups was recognized during long-term follow-up for up to 12 years after operation. There were no cases of direct operative death, and the 5- and 10-year survival rates were 64.7% and 40.2%, respectively. CONCLUSIONS: Ileocolon interposition after TG or PG has the advantages of preventing postoperative reflux esophagitis and of providing functional replacement of the stomach as a reservoir for ingested food.

Adult↗
PubMed1997

Long-term effect of manidipine on renal function and structure in uninephrectomized spontaneously hypertensive rats.

1. Long-term effects of manidipine hydrochloride (MAN), a calcium channel blocker, were examined in three groups of spontaneously hypertensive rats (SHR). Group 1 was given uninephrectomy (UNX) and MAN treatment, group 2 was given UNX and was not treated with MAN and group 3 was given neither UNX nor MAN treatment. 2. At week 15 after UNX, inulin clearance in group 1 rats decreased compared with rats in groups 2 and 3, but remained at the same level at week 40, when the level in group 2 rats declined below that in rats in groups 1 and 3. 3. Glomerular and tubulointerstitial lesions did not differ at week 15 after UNX among the three groups, whereas at week 40 both were advanced in the order of groups 2, 1 and 3. 4. Proteinuria did not differ between rats in groups 1 and 2 over the experimental period. 5. At week 15, the kidney weights of group 1 rats were greater than those of group 2 rats, indicating more prominent tubular hypertrophy in the former group. This was confirmed by morphometry of the proximal tubuli. In contrast, the glomerular volumes of rats in groups 1 and 2 were enlarged compared with that of rats in group 3, with no difference between the former two groups. 6. The findings suggest that MAN exerts renoprotective effects in SHR, both with regard to function and morphology. An effect on glomerular haemodynamics was considered to more likely be the mechanism underlying the renoprotective effect of MAN rather than that of a lowering of systemic blood pressure. 7. Augmented tubular hypertrophy after MAN treatment was an unexpected finding of the present study and the biological significance of this finding remains to be explored.

Animals↗
PubMed1997

Characterization of a liver metastatic variant of murine colon 26 carcinoma cells.

Intraportal vein injection of highly metastatic L5 cells consistently resulted in liver metastases (increases in the number of tumor colonies in the liver), whereas inoculation of P cells rarely did. L5 cells invaded the basement membrane Matrigel in greater numbers than did P cells, suggesting that the metastatic potential of L5 cells is partly related to enhanced invasive properties. The enhanced adhesion of L5 cells to fibronectin-, laminin- and Matrigel-coated substrates, as well as their haptotactic migration to fribronectin, may be associated with the preferential expression of VLA-2 and VLA-4 integrins on the surface of these cells detected by flow cytometry. Gelatin zymograms showed that the degradative activity of 72-kD gelatinases was greater in L5 cells than P cells. These results indicate that, in addition to adhesiveness and motility, the invasive ability of L5 cells may also be attributed to enhanced gelatinolytic activity. L5 cells grew more rapidly than P cells in vitro. Thus, an experimental model using highly metastatic colon 26 L5 cells would be useful for analyzing the molecular mechanism of liver metastasis and for evaluating the efficacy of treatment of occult micrometastases which may already have been disseminated at the time of surgery.

Adenocarcinoma↗
PubMed1997

Clinical results of treatment of advanced esophageal carcinoma with hyperthermia in combination with chemoradiotherapy.

Chemoradiotherapy combined with hyperthermia was administered to 35 patients with advanced esophageal carcinoma who either required preoperative treatment or had nonresectable disease. As a rule, each patient received a total dose of 30 Gy in 15 daily fractions of 2 Gy, 5 d/wk. Bleomycin or cisplatin, in combination with fluorouracil, was employed as chemotherapy. Hyperthermia was applied by intraluminal heating twice a week for a total of six sessions using an apparatus (IH-500T; Japan Crescent Co Ltd; Tokyo, Japan) (radiofrequency, 13.56 MHz) with an intraesophageal applicator and two extracorporeal applicators placed on the chest and back. This treatment method obtained a response rate of 80%, consisting of a complete response rate of 22.9% and partial response of 57.1%. In 15 cases, the tumor became resectable (resectability rate, 42.9%) following treatment. The histologic study of the resected specimens revealed absence of viable tumor cells in five patients (33.3% of the resected cases) (markedly effective), and in six patients (40.0%), the combined therapy was considered to be moderately effective. No complications considered due to hyperthermia itself were recognized. The overall 5-year survival rate was 11.8%. In conclusion, chemoradiotherapy combined with hyperthermia was locally effective, yielding an overall response of 80.0%. However, the prognosis of the patients remains unfavorable. Advanced esophageal carcinoma requires treatment taking into account lymphatic and hematogenic metastasis at the beginning of treatment.

Aged↗
PubMed1997

Anticarcinogenic action of apple pectin on fecal enzyme activities and mucosal or portal prostaglandin E2 levels in experimental rat colon carcinogenesis.

Pectin is a partially methoxylated polymer of galacturonic acid obtained from fruits. Among pectin, apple pectin exerts stronger bacteriostatical action on Staphylococcus aureus, Streptococcus faecalis, Pseudomonas aeruginosa and Escherichia coli in comparison with citrus pectin. In this study, we used water-soluble methoxylated pectin from apple. The diet, supplemented by 20% apple pectin, significantly decreased the number of tumors and the incidence of colon tumor. PGE2 level in distal colonic mucosa in 20% apple pectin fed rats were lower than those in basal diet fed rats. Fecal beta-glucuronidase activities in the apple pectin fed group, which has been considered a key enzyme for the final activation of Dimethylhydrazine metabolism to carcinogens in the colonic lumen, were signifieantly lower than those in control group at initiation stage of carcinogenesis. In the case the concentrations of beta-glueosidase and azoreductase were also decreased. The effect of apple pectin on the colon carcinogenesis may partially depend on PGE, concentration decrease in colonic mucosa and on the type of pectin, also related to fecal enzyme activities.

Animals↗
PubMed1997

Free ileocolon transfer after hypopharyngo-laryngo-cervical esophagectomy for speech rehabilitation.

Patients with carcinoma of the hypopharynx or the cervical esophagus usually undergo total laryngectomy with hypopharyngo-esophagectomy and, consequently, lose the power of speech. Therefore, a reconstruction method which would enable speech rehabilitation is desirable following this type of procedure. Free ileocolon transfer consists of colo-esophagostomy, pharyngo-colostomy, ileo-tracheotomy, vascular anastomosis under a microscope, and permanent tracheostomy. In this method, the colon functions as the alimentary tract, while the ileum and ileocecal valve can produce sounds. We evaluated the results in live patients with free ileocolon transfer following hypopharyngo-laryngo-cervical esophagectomy. Although there was no case of direct operative death, one patient died from cancer progression. Four patients are still alive at from 18 to 36 months after operation. Postoperatively, stenosis of the colo-esophaogostomy appeared in two patients, but there was no case of anastomotic breakdown or any other major complication. Speech rehabilitation was good, and there was no misswallowing into the airway. We think that free ileocolon graft is one of the more preferable procedures following hypopharyngo-laryngo-cervical esophagectomy.

Aged↗
PubMed1997

[My device for operation of esophageal and gastric cancer].

I employed esophageal reconstruction prior to esophagectomy as a standard surgical procedure. In this procedure, two separate teams perform the operation in the cervical and abdominal regions simultaneously, therefore the operation time is shortened, and we can estimate the degree of lymph node and distant metastasis in each area early in the operation. I applied free ileocolon transfer to 5 patients with cervical esophageal cancer because of voice restoration combined with reconstruction of cervical esophagus. They were able to achieve a fair to good voice, to swallow without aspiration. Since the founding of our institute, we have performed 185 esophagectomies with an operative death rate of 4.3% and 5-year survival rate of 20.4%. I employed ileocolon interposition as a reconstruction in 55 patients after total and proximal partial gastrectomy. In this procedure, reflux esophagitis is prevented by the Bauhin's valve and the colonic segment functions as a gastric reservoir.

Antineoplastic Agents↗
PubMed1997

[Effects of OK-432 intraportal administration on cell-mediated immune responses].

The effects of OK-432 and/or MMC on host immunity were studied in patients with advanced colorectal cancer. OK-432 was administered to the portal vein, and MMC was dispersed into the peritoneal cavity for prevention of liver metastasis. In the MMC group, NK activity was significantly reduced at 7 days postoperatively, while such a reduction was not seen in the OK and OK + MMC groups. The administration of OK-432 decreased the postoperative proportion of suppressor T cells in the lymphocyte subsets more than that of MMC group. Our results strongly suggest that intraoperative administration of BRM to the patients with advanced colorectal cancer can significantly prevent postoperative immunosuppression.

Antineoplastic Combined Chemotherapy Protocols↗