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J Uchida

Publications and source records attributed to J Uchida.

At least 37 records · Page 2Linked to original sources
PubMed1998

Preclinical antitumor efficacy of S-1: a new oral formulation of 5-fluorouracil on human tumor xenografts.

S-1 is a new oral formulation of 5-fluorouracil (5-FU) consisted of 1M tegafur, 0.4M 5-chloro-2,4-dihydroxypyridine that inhibits a degradation of 5-FU, and 1M potassium oxonate that regulates the phosphorylation of 5-FU in the gastrointestinal tract, and has shown excellent antitumor efficacy against various murine tumors in rodents, compared to the oral tegafur-based antitumor drug, UFT (1M tegafur plus 4M uracil), which is used clinically in Japan. To assess the possibility of clinically using S-1, we investigated the antitumor effect of S-1 on various human solid tumor xenografts in athymic rats and mice. In the nude rat system, S-1 was significantly effective against all 12 tumor xenografts tested when its minimum toxic dose (15 mg/kg) was administered for 14 days. Three tumors, stomach (H-81), colon (KM12C) and breast (H-31) markedly regressed in response to treatment with S-1 but not with UFT. The antitumor potency of S-1 was weak against human tumors xenografted into nude mice and likely similar to that of UFT. The reason of the discrepancy in the efficacy of S-1 between rats and mice was found to be that the 5-FU levels in the blood and tumor tissue of rats after oral administration of S-1 persisted much longer than in mice, and this prolonged maintenance of plasma 5-FU levels was significantly related to the potent antitumor activity of S-1. In conclusion, the results of this study suggested that based on its biological and pharmacokinetic characteristics, oral S-1 should be active against various human cancers.

Administration, Oral↗
PubMed1998

[Case report of a recurrent nephrotic syndrome patient with sudden onset of blindness during treatment with cyclosporin A].

We report a case of recurrent nephrotic syndrome with transient blindness after taking cyclosporin A (CsA). Renal biopsy showed minimal change of nephrotic syndrome and the patient was treated with predonisolone (PSL) and cyclophosphamide leading to remission of nephrosis. CsA was given to the patient. Because of recurrence of nephrotic syndrome after tapering off PSL to 5 mg a day, 12 days after taking CsA, the patient complained of sudden onset of left eye blindness lasting for 30 minutes. When the patient visited our hospital, the disturbed vision had recovered already and there were no abnormal neurological findings, such as tremors and seizures. Funduscopic examination revealed no evidence of abnormalities and brain computerized axial tomography was unremarkable. From these findings, we predicted that constriction of an artery and temporarily formed thromboembolization in an eyeground artery had caused the sudden vision disturbance. Even though there is a high incidence of thrombotic complications in cases of nephrotic syndrome, we believe that vascular constriction and formation of thrombi in the eyeground artery of the case were mediated by the pathogistic effects of CsA. Because actions in association with CsA may produce constriction of small arteries, there by decreasing blood flow, initiating coagulopathy and causing endothelial cell damage, all these effects may lead to the formation of thrombo-embolic complications. In addition, when using CsA for the treatment of nephrotic syndrome, anti-platelets and/or anti-coagulant medicines should be concomitantly prescribed to avoid the thrombo-embolic complications.

Adult↗
PubMed1997

Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats.

S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED50 value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC0-infinity: S-1 28 nmolh/ml, UFT 15 nmol.h/ml) and in tumor tissue (AUC0-infinity: S-1 95 nmolh/g tissue, UFT 52 nmolh/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC0-24: S-1 7.0 nmolh/mg RNA, UFT 4.3 nmolh/mg RNA) and 5-8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64 +/- 30 mg, UFT 133 +/- 52 mg; P < 0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity.

Animals↗
PubMed1997

[Clinical statistics on in-patients and operations during a 20-year period (1975-1994) at Department of Urology, Kansai Medical University].

The patients, diseases and operations experienced between 1975 and 1994 in our department were statistically analyzed. The numbers of in-patients and operations have been increasing since 1977. During these 20 years, endoscopic surgery has replaced many open surgical procedures. The introduction of extracorporeal shock wave lithotripsy has dramatically changed the therapeutic modality for urolithiasis, and decreased of the necessity of open surgery.

Female↗
PubMed1997

[Comparison of side effects caused by intra-arterial and intravenous infusion of M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) for urothelial cancer].

We retrospectively studied the toxic effects in 14 patients with urothelial cancer who had undergone intra-arterial M-VAC chemotherapy (Group A) and 13 patients who had received intravenous M-VAC chemotherapy (Group V) between February 1991 and August 1995. No statistically significant differences were found in the white blood cell count nadir, liver function, renal function or appetite between the groups. While the platelet count nadir for intra-arterial infusion (14.0 x 10(4)/mm3) was larger than for intravenous infusion (9.0 x 10(4)), the median days to nadir for this count was shorter in the intra-arterial group (9.1 days) than in the intravenous group (13.5). In addition, the difference between the beginning hemoglobin level and the nadir level was larger in the intra-arterial infusion group (2.55 g/dl) than in the intravenous infusion group (1.95 g/dl). Additionally peculiar side effects were noted in the intra-arterial infusion group which included local erythema and nerve paralysis. Side effects should be managed for intra-arterial M-VAC as well as for intravenous infusion.

Aged↗
PubMed1996

Possible involvement of calmodulin-dependent kinases in Ca(2+)-dependent enhancement of [3H]5-hydroxytryptamine uptake in rat cortex.

Effects of Ca2+ on [3H]5-hydroxytryptamine (5-HT) uptake into rat cortical synaptosomes were studied. The uptake was enhanced in the presence of Ca2+ in Krebs-Ringer medium and the uptake at 0.3-5 mM Ca2+ was 2.4-2.7 times greater than that observed in the absence of Ca2+. The maximal increase at the concentration of 1 mM Ca2+ was achieved after 2 min preincubation. Ca(2+)-dependent enhancement of the [3H]5-HT uptake reflected an increase in Vmax of the uptake process. However, Kd and Bmax values for [3H]paroxetine were not significantly changed in the presence of 1 mM Ca2+ compared with Ca(2+)-free condition. On the other hand, uptake was still enhanced after synaptosomes were washed with Ca(2+)-free after preincubation with 1 mM Ca2+. Staurosporine (a protein kinase C inhibitor) and wortmannin (a myosin light chain kinase inhibitor) did not affect Ca(2+)-dependent enhancement of the uptake, whereas 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazin e (KN-62, an inhibitor of Ca2+ /calmodulin-dependent kinase II) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7, a calmodulin antagonist) significantly reduced it. Moreover, L-type, but not P- or N-type, voltage-dependent Ca(2+)-channel blockers suppressed enhancement of the uptake. These results indicate that Ca(2+)-dependent enhancement of [3H]5-HT uptake is mediated by activation of calmodulin-dependent protein kinases, suggesting a possibility of calmodulin-dependent regulation of in vivo 5-HT uptake.

Animals↗
PubMed1996

Prolongation of survival period and improvement of cancer cachexia by long-term administration of UFT.

We assayed the antitumoral and anticachectic activity of an oral fluoropyrimidine, UFT using the Colon-26-bearing murine cachexia model in terms of the survival period and parameters corresponding to clinical symptoms. Tumor growth was inhibited by UFT dose-dependently at the dose range of 12.5-25.0 mg/kg per day. Although UFT did not show significant growth inhibition at 15.0 and 12.5 mg/kg to which UFT gave little toxicity, the survival period was shown to be superior to the case of maximum tolerated dose (25.0 mg/kg per day). Next, we compared the maximum increase of life span (ILS) value for an administration schedule of continuous 9 days and 5 weeks which mimics the clinical schedule and found that the ILS value in the latter group was superior to the former and UFT improved cachexia, in the same manner. In the following experiments, we have clarified that UFT decreased the level of both plasma interleukin-6 (IL-6) and tumorous prostaglandin E2 (PGE2) and it highly accelerated IL-6 production from Colon-26. These findings suggest that UFT therapy, in low-toxic dose, could be useful to cachectic patients with poor performance status.

Animals↗
PubMed1996

Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats.

The purpose of this study was to establish a nude rat orthotopic (organ-specific) human colorectal cancer model as an in vivo secondary screen for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in clinical]. After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growth and invasion to both the mucosal and the serosal sides were observed in all rats. Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them. Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14 consecutive days from 7 days after tumor cell implantation. S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When both drugs were administered to nude rats bearing KM12C injected into the cecal wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05). After the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase inhibition rate (percentage) in the tumor (about 20%). Collectively, these findings suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.

Adenocarcinoma↗
PubMed1996

Effect of 4G-beta-D-galactosylsucrose (lactosucrose) on fecal microflora in patients with chronic inflammatory bowel disease.

Metabolic interaction between the intestinal microflora and the host has been suggested to play a role in the pathogenesis of chronic inflammatory bowel disease. Elemental or low-fat, low-residual diets in patients with Crohn's disease or ulcerative colitis are reported to decrease anaerobic bacteria and to change the composition of the intestinal microflora. We examined the effect of an indigestible agent, 4G-beta-D-galactosylsucrose (lactosucrose), which is selectively utilized by intestinal Bifidobacterium, on the composition of the intestinal microflora. After the administration of lactosucrose to two patients with Crohn's disease and five patients with ulcerative colitis for 2 weeks, significant induction of the growth of Bifidobacterium was observed, and significant reduction in the population level of Bacteroidaceae was seen. Bowel movements improved in four patients. The intestinal environment, estimated by measuring fecal pH, fecal levels of short-chain fatty acids and putrid products, and the urinary secretion of indican, also improved in these patients. These results suggest that lactosucrose may be useful for patients with chronic inflammatory bowel disease.

Adolescent↗
PubMed1996

Profound reduction of mature B cell numbers, reactivities and serum Ig levels in mice which simultaneously carry the XID and CD40 deficiency genes.

It has been known for some time that single mutant nude or CD40T mice have apparently normal numbers of cells in the precursor compartments of bone marrow and the mature B cell compartments of the periphery. X-linked immunodeficiency (XID) mice are deficient only in some of the sIgM+sIgD+ B cells. We have investigated further the contributions of the xid mutation, of the T cell deficiency of nude of the inability of CD40T cells to cooperate with T cells in the generation of the precursor and the mature B cell compartments in mice. Double mutant XID/nu and XID/CD40T mice have precursor B cell compartments that are no more deficient than the single mutant XID mice. However, the peripheral B cell compartments of both XID/mu and XID/CD40T are even more deficient than those of single mutant XID mice. While 10% of the peripheral B cells of wild-type or CD40T, one-third of XID and half of XID/nu mice turn over rapidly, as many as three-quarters of those in XID/CD40T are short-lived. Total numbers of sIgM+sIgD+ B cells in the spleen are at best 10-15% of normal mice at 6-8 weeks of age in XID, XID/nu and XID/CD40T mice. They remain that low at 3 months of age in XID/CD40T mice, while in XID mice these peripheral B cells slowly build up in numbers with age. As expected, double mutant XID/CD40T mice do not respond to the T-dependent antigen keyhole limpet hemocyanin. Only the responses to the T-independent type I antigen, TNP-lipopolysaccharide (LPS), appear to be normal. In vitro, their splenic B cells respond poorly to LPS or to IgM-specific antibody in either the absence or presence of cytokines. Most notably, serum IgM, IgG2b or IgG3 levels are severely depressed, while IgG1, IgG2a and IgA levels are < 10 micrograms/ml. These results suggest a model of mature B cell development in which the peripheral, mature B cell compartments are generated in two parallel, not tandemly organized pathways. They could be selected and/or stimulated at the transition from immature to mature B cells: in btk controlled or in CD40 controlled ways.

Animals↗
PubMed1996

Laparoscopic nephropexy: a case report.

The laparoscopic approach is an ideal method for nephropexy because it produces less postoperative pain and allows an early recovery. We report a case of symptomatic renal ptosis treated laparoscopically with good success.

Adult↗
PubMed1996

Respiratory effects of CO2 pneumoperitoneum during transperitoneal laparoscopic urological surgery.

OBJECTIVE: To evaluate the effects of CO2 pneumoperitoneum on respiratory function during urological laparoscopic surgery with exposure of the retroperitoneal space in the lateral decubitus position. METHODS: Arterial blood gas analysis and measurements of the partial pressure of CO2 in exhaled gas (PetCO2) were performed during CO2 pneumoperitoneum in 12 patients who underwent transperitoneal laparoscopic surgery for the retroperitoneal organs (the retroperitoneal group): the results were compared to those of 11 patients who underwent laparoscopic varicocelectomy (the varicocele group) with the same anesthesia and intra-abdominal pressure. RESULTS: The increase in PaCO2 and PetCO2 and the decrease in arterial pH during CO2 insufflation were significantly greater in the retroperitoneal group than in the varicocele group. PaCO2, PetCO2 and arterial pH continued to change in the retroperitoneal group, whereas these values reached a plateau at 30 min after the beginning of CO2 insufflation in the varicocele group. CONCLUSIONS: The respiratory effects of CO2 pneumoperitoneum are more pronounced during laparoscopic urological surgery with opening of the retroperitoneum. It is possible that exposure of the retroperitoneal space increased CO2 absorption during insufflation.

Adult↗
PubMed1996

Synthesis and antitumor activities of 5'-O-aminoacyl-3'-O-benzyl derivatives of 2'-deoxy-5-fluorouridine and related compounds.

Various O-alkyl derivatives of 2'-deoxy-5-fluorouridine (FUdR) were synthesized and their antitumor activities in mice bearing sarcoma 180 (s.c.-p.o.) were evaluated in terms of the ED50 values (mg/kg/d). Most of these compounds were superior to FUdR in antitumor activity. In particular, the antitumor activity of 3'-O-(p-chloro-benzyl)-FUdR (3e) (ED50 = 0.87 mg/kg/d) was as much as 100 times that of FUdR (ED50 = 84 mg/kg/d). Further, various 5'-O-aminoacyl derivatives of 3e were synthesized and evaluated in terms of ED50 value and therapeutic index (T.I.). Both the ED50 value (0.41 mg/kg/d) and the T.I. (4.18) of 3'-O-(p-chlorobenzyl)-5'-O-glycyl-FUdR hydrochloride (6a) were significantly improved, compared with those of 3e and FUdR. FUdR plasma concentration after a single p.o. dosing of 6a was maintained for as long as 24 h.

Animals↗
PubMed1996

[Prolongation of survival and antitumor activity of antitumor drugs in murine cancer cachexia model].

We examined the activity of UFT, ADM and MMC, which are used for colon tumors, in terms of their prolongation of the survival period, growth inhibition of the primary tumor and improvement of cachexia in murine cancer cachexia model. The mean survival period of Colon 26, mouse adenocarcinoma bearing mice was 25.0 +/- 4.9 days. The maximal ILS value of the UFT administered group was 103.2%, against 7.2 and 26.0%, respectively, ADM and MMC maximal ILS value. For therapeutic activity of hypercalcemia, UFT was superior to other drugs, although all drugs showed equivalent tumor growth inhibitory activity. These findings indicate that UFT can prolong the survival period due to improvement of cancer cachexia. Therefore, we measured plasma interleukin-6 (IL-6) and found that UFT-administration lowered the plasma IL-6 level more than other drugs. Moreover, the prostaglandin E2 (PGE2) level in the tumor was significantly decreased only by UFT-administration. Since PGE2 has been shown to enhance IL-6 production from Colon 26 in vitro, it was speculated that UFT improve cachexia and prolongs life by decreased IL-6 resulting from decreased PGE2.

Animals↗
PubMed1996

[Inhibition of prostate cancer growth in nude mice by hormone and chemotherapy].

The combined effect of hormone and cytotoxic therapy on the growth of prostate cancer PC-3 in nude mice was investigated. PC-3 cell was derived from the bone metastasis of a hormone-refractory prostate cancer. Each group consisted of seven animals. After the inoculation of cancer cells, diethylstilbestrol (DES: 20 mg/kg) and futraful with uracil (UFT: 20 mg/kg) were administered for 25 days. DES and UFT synergically inhibited the growth. DES had no effect as a single agent on the growth of a hormone-independent cell line (KM20C) derived from human colon cancer. It also had no additive effect when given with UFT.

Animals↗
PubMed1995

Macroamylasemia associated with ulcerative colitis.

We describe a very rare case in which macroamylasemia was associated with ulcerative colitis of total colitis type. The patient's serum amylase isozyme pattern by electrophoresis showed a broad abnormal peak toward the side of the positive pole compared with regular salivary and pancreatic fractions. Sephadex G-200 column chromatography showed a sedimentation coefficient of 6.6 S. Amylase activity was bound to IgG. Double diffusion experiments demonstrated that amylase activity could be precipitated in gel by an antibody to the lambda chain. Although inflammatory bowel disease is occasionally associated with hyperamylasemia due to pancreatitis, we emphasize that, when hyperamylasemia is recognized in patients with inflammatory bowel disease, macroamylasemia also should be considered.

Adult↗