Thrombocytopenia and anemia induced by niceritrol used for amelioration of hyperphosphatemia in a hemodialysis patient.
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Anemia↗
Biomedical subjects
H Wakasugi
Publications and source records attributed to H Wakasugi.
Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors.
PURPOSE: RPR 109881A is a new semisynthetic taxoid compound that has a similar mechanism of action to docetaxel. The purpose of this phase I study was to characterize the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetic profile, and antitumor effects of this agent. PATIENTS AND METHODS: Nineteen eligible patients with advanced solid tumors were enrolled. RPR 109881A was administered as a 1-hour intravenous infusion every 3 weeks at doses ranging from 15 to 75 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle. RESULTS: Neutropenia (febrile neutropenia) and fatigue were dose-limiting toxicities at doses of 60 and 75 mg/m(2) and seemed to be dose-related. Both thrombocytopenia and anemia were infrequent. Nonhematologic toxicities were generally mild. Pharmacokinetic studies indicated that RPR 109881A plasma disposition was bi- or triphasic, with a high total plasma clearance, a large volume of distribution, and a long terminal half-life. The area under the concentration-time curve (AUC) and the peak concentration of RPR 109881A seemed to increase with increasing dose proportionally, suggesting linear pharmacokinetics. Urinary excretion over 48 hours was low, with a mean of 0.8 +/- 0.36% of the administered dose. A significant relationship existed between the percentage decrease of neutrophil counts and the AUC of RPR 109881A. Among 18 assessable patients, two partial and two minor responses were documented. CONCLUSION: RPR 109881A was found to be a well-tolerated and promising taxoid agent. The MTD was 75 mg/m(2), and the recommended dose for phase II study was 60 mg/m(2) as a 1-hour infusion every 3 weeks.
Adult↗
[Effect of itraconazole on digoxin clearance in patients with congestive heart failure].
We showed a digoxin-itraconazole interaction in three patients in whom digoxin serum concentrations were increased. Their electrocardiograms revealed arrhythmias such as ventricular premature contraction, atrioventricular block, and ST depression. The elimination half-life of digoxin in case 3 patient who continued itraconazole therapy was 8.4 days, which was estimated by nonlinear least squares method from the serum concentrations of digoxin versus time curve. In order to evaluate the influence of itraconazole on pharmacokinetic parameters of digoxin, we estimated digoxin clearance by the Bayesian method using the population pharmacokinetic parameters in Japanese patients. During the concomitant use of itraconazole and digoxin, the digoxin clearance in all patients decreased to 50.5 +/- 8.8% (mean +/- S.D.) of the clearance without itraconazole. When digoxin and itraconazole are used concomitantly, careful monitoring of digoxin serum concentrations is necessary. Based on our results of digoxin clearance evaluation, the dose of digoxin should be reduced to 50% of original dose after itraconazole is started, and digoxin serum concentration might be controlled at the same level before the concomitant use.
Aged↗
[A late phase II study of raltitrexed (ZD 1694) in chemotherapy-naive patients with advanced colorectal cancer].
A multicenter co-operative late phase II study of raltitrexed (ZD1694), a specific thymidylate synthase (TS) inhibitor, was conducted in chemotherapy-naive patients with advanced colorectal cancer. Raltitrexed was infused intravenously over 15 minutes once every three weeks. Between April 1996 and September 1998, 61 patients were enrolled and 58 were eligible. Fourteen patients experienced a partial response (PR), 22 no change (NC), 20 progressive disease (PD) and 2 no evaluable (NE). The overall response rate was 24.1% (95% CI: 13.9-37.2%). Responses were seen in lung (22.7%), liver (22.9%) and deep lymph nodes (10.0%). Median survival was 11.6 months. Grade 3 or 4 toxicities were: leukopenia (13.8%), neutropenia (24.1%), hemoglobin decrease (15.5%), FBC decrease (6.9%), hematocrit decrease (6.9%), thrombocytopenia (6.9%), transient SGPT increase (6.9%), nausea/vomiting (20.7%), anorexia (15.5%), and asthenia (6.9%). These adverse reactions were considered to be manageable. Only one death was associated with drug treatment. These results suggest that raltitrexed provides an effective and convenient treatment for patients with advanced and previously untreated colorectal cancer.
Adult↗
Teleconferences between the Gustave-Roussy Institute (Villejuif, France) and the National Cancer Center (Tokyo, Japan) as a new bilateral cooperative activity.
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Humans↗
Regression and prevention of autochthonous tumors induced by 3-methylcholanthrene after injection of a T-cell receptor alpha /beta positive and CD4/CD8 double negative T-cells.
Both the therapeutic and preventative effects of a murine T-cell line, tMK-2, with T-cell receptor (TCR) alpha/beta positive and CD4-/8- double negative (DN) phenotype against autochthonously tumors induced by subcutaneous (s.c.) injection of 3-methylcholanthrene (MC) were examined. Complete regression of the tumor was observed when administration of tMK-2 cells was begun on tumors 5 mm in diameter. The tumor mass in five out of five mice was reduced in size after the administration of tMK-2 cells regardless of the routes of administration: s.c. injection of tMK-2 cells (5 x 10(7) cells) once a week around tumors, intraperitoneal (i.p.) injection (5 x 10(7) cells), or intravenous (i.v.) injection (1 x 10(7) cells). The tumors regressed to the status of a scar within 1 month of initial injection, and this status was maintained throughout the remainder of the 3 months period of tMK-2 cell injection. One month after discontinuation of tMK-2 cell administration, the diameter of the tumors had not increased regardless of the route of injection. The control groups consisted of either untreated mice, mice with i.v. injection of 1 microg of recombinant murine interleukin (IL)-12 once a week, or mice with s.c. injection of autologous splenocytes (5 x 10(7)) from BALB/c mice once a week. Continuous growth of tumors was observed in each group and all control mice died due to bleeding ulcerations of the tumors. Tumor development was effectively prevented when tMK-2 cells were administrated 1 week after the s.c. injection of MC. In the groups receiving s.c., i.p., and i.v. injection of tMK-2 cells, no MC-induced tumors developed, whereas four out of five of the control mice developed autochthonous tumors. The tMK-2 cells also exerted in vitro NK-like cytotoxic activity, and their killing activity was strongly increased in the presence of both IL-2 and IL-12. These results suggest that the injected T-cells with TCR alpha/beta positive and CD4- /8- DN phenotype and NK-like activity are important in the therapy as well as the prevention of tumor development.
Animals↗
Functional and phenotypical characteristics of hepatic NK-like T cells in NK1.1-positive and -negative mouse strains.
We previously reported and partially characterized a unique monoclonal antibody (mAb), U5A2-13, which recognizes a T cell subset similar to NK1.1+ T cells, not only in NK1.1-positive mouse strains but also in NK1.1-negative strains. In NK1.1-positive C57BL/6 mice, U5A2-13+ TCRalphabeta+ cells produced abundant IL-4 as well as extremely high levels of IFN-gamma upon CD3 cross-linking, but this did not occur with U5A2-13- TCRalphabeta+ cells. In NK1.1-negative C3H/He mice, U5A2-13+ TCRalphabeta+ cells produced high levels of IL-4 and IFN-gamma upon CD3 cross-linking, but this was not observed with U5A2-13- TCRalphabeta+ cells. To the best of our knowledge, this is the first direct evidence of the presence of NK-like T cells defined phenotypically by U5A2-13 mAb and functionally by IL-4/IFN-gamma production in NK1.1-negative mouse strains. We also demonstrated that U5A2-13- NK1.1+ T cells and U5A2-13+ NK1.1- T cells in C57BL/6 mice could produce both IL-4 and IFN-gamma. In addition, Vbeta8 or Vbeta7 usage by U5A2-13+ NK1.1- T cells was lower than that by U5A2-13+ NK1.1+ T cells, but remained higher than that by U5A2-13- NK1.1- T cells. Based on the present results, U5A2-13 mAb appears to be a valuable tool in the study of NK-like T cells.
Animals↗
Pancreatic carcinoma associated with chronic pancreatitis.
The incidence of invasive ductal carcinoma of the pancreas was 3.1% (6 cases) in 196 patients with definite chronic pancreatitis. Five patients (3 men and 2 women) had calcific pancreatitis and 1 patient (man) had non-calcific pancreatitis. Large pancreatic stones were recognized in 2 women. Most of the patients complained of continuous intractable abdominal pain and/or back pain together with weight loss and appetite loss. Serum CA19-9 levels and exacerbation of glucose intolerance were retrospectively noted to have been elevated in 1 patient. However, it was difficult to obtain a definitive diagnosis by imaging examinations earlier, due to the presence of chronic pancreatitis. Median survival of the 6 patients was 6.5 months from admission.
Adenocarcinoma↗
[A case of adult T cell leukemia (lymphoma type) involving the pancreas].
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Aged↗
Localization of glutathione and induction of glutathione synthesis-related proteins in mouse brain by low doses of gamma-rays.
First, we determined the cerebral localization of reduced glutathione (GSH) in normal mice by means of autoradiography using 99mTc-meso-hexamethyl propylene oxime. A highly specific localization of GSH in the cerebellum and hippocampus was observed. Secondly, we measured the elevation of GSH level in the brain after low-dose gamma-irradiation. The cerebral GSH levels increased soon after irradiation with 50 cGy of gamma-rays, reaching a maximum at 3 h post-treatment, then remaining significantly higher than that of the non-irradiated control until 12 h and returning to the control level by 24 h. Thirdly, we examined the induction of the activities and the mRNAs of proteins involved in the synthesis and regeneration of GSH in the brain of mice subjected to low-dose gamma-ray irradiation. The level of mRNA for gamma-glutamylcysteine synthetase was significantly increased at 0.5 h, and remained high until 2 h post-irradiation (50 cGy). The level was transiently lowered to the non-irradiated control level at 3 h and slightly increased again after 6 h post-irradiation. gamma-Glutamylcysteine synthetase activity was significantly increased 3 h after irradiation, and remained high up to 24 h post-irradiation. As for glutathione reductase, the mRNA level was increased at 0.5 h, and peaked strongly at 2 h, while the enzyme activity was significantly increased at 6 h after irradiation, and continued to increase up to 24 h. The level of mRNA for thioredoxin, which contributes to GSH biosynthesis by supplying cysteine to the de novo pathway, peaked between 0.5 h and 2 h post-irradiation, and rapidly declined thereafter. The content of thioredoxin showed a transient decrease immediately after irradiation, but was then remarkably elevated, reaching a maximum at 3 h, and thereafter declining sharply. These results indicate that the increase in endogenous GSH in mouse brain soon after low-dose gamma-ray irradiation is a consequence of the induction of GSH synthesis-related proteins and occurs via both the de novo synthesis and the regeneration pathways.
Animals↗
Induction of mRNAs for glutathione synthesis-related proteins in mouse liver by low doses of gamma-rays.
We examined the elevation of the reduced form of glutathione (GSH)level and the induction of MRNAs for proteins involved in the synthesis and regeneration of GSH in the liver of mice after low-dose gamma-ray irradiation. The liver GSH level increased soon after irradiation with 50 cGy of gamma-rays, reached a maximum at around 12 h post-treatment. The mRNA of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for de novo synthesis for GSH, showed a small increase that peaked at 6 h after gamma-ray irradiation at a dose of 50 cGy. Only a small increase in gamma-GCS activity was observed throughout the 24-h post-irradiation period. In the case of glutathione reductase (GR), which is involved in the regeneration of GSH from the oxidized form (GSSG), the mRNA level peaked strongly at 1 h, while the activity peaked at twice the control level 12 h after irradiation. The level of mRNA for thioredoxin (TRX), which contributes to GSH biosynthesis by supplying cysteine to the de novo pathway, peaked at 1 h and declined thereafter, while the activity peaked at 3 h and then declined sharply. These results indicate that the increase in endogenous GSH immediately following low-dose gamma-ray irradiation is predominantly due to operation of the regeneration cycle and not de novo synthesis. We also examined the dependence of mRNA induction on the gamma-ray dose.
Animals↗
A novel monoclonal antibody permitting recognition of NKT cells in various mouse strains.
By immunizing mouse lymphoma cell line tMK-2U derived from intermediate TCR cells of BALB/c nude mouse, U5A2-13 monoclonal antibody (mAb, a rat IgG2a) was established. U5A2-13 antigen (Ag) was expressed on around 65% of TCRint cells in the liver of the various mouse strains including both NK1.1- and NK1.1+ mouse strains, while NK1.1 Ag was expressed only in NK1.1+ C57BL/6 mouse strain. Among CD3+ cells, 26.3% cells co-expressed U5A2-13 Ag and NK1.1+ Ag, while small proportions of the CD3+ cells were U5A2-13+NK1.1- (9.2%) or U5A2-13-NK1.1+ (4.4%). Among NK1.1+ cells, 54.9% cells co-expressed CD3 and U5A2-13 Ag, while some proportions of the cells were U5A2-13+CD3- (19.4%) or U5A2-13-CD3+ (9.8%). It was found that approximately 85% of NK1.1+CD3+ cells coexpressed U5A2-13 Ag. U5A2-13 Ag with low fluorescence intensity was also expressed on 55% of NK1.1+CD3-NK cells. U5A2-13 Ag immunoprecipitated from tMK-2U cells consisted of three proteins, which were 65 kDa, 33 kDa and 32 kDa under both reducing and non-reducing conditions and these were apparently different from NK 1.1 Ag. These results indicated that U5A2-13 mAb was able to define a similar population to NK1.1+CD3+T cells and to 55% of NK1.1+CD3-NK cells in various strains, through recognizing a different molecule from NK1.1 Ag.
Animals↗
Clinical assessment of pancreatic diabetes caused by chronic pancreatitis.
Despite the high prevalence of diabetes mellitus in patients with chronic pancreatitis, few studies of pancreatic diabetes have been reported. We investigated 154 patients with chronic pancreatitis, of whom 50% were diabetics, with special reference to the features and clinical course of pancreatic diabetes. We arrived to clarify the features of pancreatic diabetes by comparing pancreatic exocrine function in 112 patients with primary diabetes with findings in a separate group of 80 patients with chronic pancreatitis. Pancreatic diabetes is proposed as a type of diabetes in which exocrine pancreatic function is markedly decreased. Progressive and fatal angiopathies were found in patients with pancreatic diabetes after a long duration of diabetes. The present investigation suggests that treatment of malnutrition is necessary in patients with pancreatic diabetes and that control of blood glucose is often difficult in these patients because of the high incidence of insulin-induced hypoglycemic episodes.
Adult↗
Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein.
We present a digoxin-clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 +/- 0.20; mean +/- SD). Because P-glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P-glycoprotein-mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P-glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration-dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P-glycoprotein-mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Mouse NK1.1+ cytotoxic T cells can be generated by IL-2 exposure from lymphocytes which express an intermediate level of T cell receptor.
NK-like T cells which express the NK1.1 molecule and CD3 (or TCR) of intermediate level (CD3int or TCRint cells) were recently demonstrated to be present in various immune organs, and to have NK-like cytotoxic activity against NK target cells. In this study, we investigated whether NK1.1- T cells could express NK1.1. We found that NK1.1+ TCRint cells were much more abundant in the liver (20%) than in the spleen (2%). When hepatic and splenic mononuclear cells (MNCs) were cultured either in the absence of IL-2 or in the presence of CD3/TCR cross-linking, the original NK1.1+ TCRint cells disappeared. However, when they were cultured in the presence of a high dose of IL-2 for 4 days, a new type of NK1.1+ T cell was formed to the extent of approximately 15-20%, and the liver and spleen contained similar percentages of this new type of NK1.1+ T cells. The phenotypes of the original and the new type of NK1.1+ T cells were clearly distinct. The freshly obtained NK1.1+ TCRint cells consisted of double-negative (DN) CD4-CD8- cells and single-positive (SP) CD4+ cells, whereas the new type of NK1.1+ T cells predominantly consisted of DN CD4-CD8- cells and SP CD8+ cells and expressed a high level of CD3 (CD3high or TCRhigh cells). When NK1.1- cells or IL-2 receptor beta-chain (IL-2Rbeta)- cells were isolated from the liver and spleen, and cultured in the presence of IL-2 for 4 days, NK1.1+ T cells were generated from NK1.1- cells, but not from IL-2Rbeta- cells. Our results suggested that the NK1.1- cells, but not IL-2Rbeta- cells, contained the precursor of IL-2-stimulated NK1.1+ TCRhigh cells. When purified NK1.1- IL-2Rbeta+ TCRint cells were cultured in the presence of IL-2 for 4 days, approximately 10% of the cells became NK1.1+ TCRhigh cells. Approximately 60% of the purified NK1.1+ TCRint cells lost NK1.1 expression. The IL-2-stimulated NK1.1+ TCRhigh cells that had arisen from NK1.1- TCRint cells exerted an NK cell-like cytotoxic activity similar to that of the original NK1.1+ T cells. Thus, NK1.1- TCRint cells could express NK1.1 and exert NK-like cytotoxic activity regardless of their origin. It appears that NK1.1+ TCRhigh cells can only be induced through an IL-2-stimulation pathway but not via CD3/TCR cross-linking.
Animals↗
Elevated serum level of thioredoxin in patients with hepatocellular carcinoma.
Thioredoxin (TRX) is known to contain an active site with a redox-active disulfide and has various biological activities. The objective of the present study was to investigate whether circulating TRX levels are elevated in patients with chronic hepatitis (CH) or liver cirrhosis (LC) and hepatocellular carcinoma (HCC). An anti-TRX monoclonal antibody and polyclonal antibodies that specifically recognize TRX, were generated and used for the development of an ELISA system to measure TRX levels in human serum. The geometric mean and its 95% confidence interval of serum level of TRX in healthy volunteers was 81.75 ng/ml (74.60-89.59 ng/ml). The serum level of TRX in LC/CH patients without HCC was 80.87 ng/ml (69.66-93.88 ng/ml). The value was not statistically different from that in serum from normal volunteers (p=0.69). In contrast, the serum level of TRX in patients with HCC was 147.35 ng/ml (125.53-172.96 ng/ml), which was significantly higher when compared with the level in serum of normal volunteers (p<0.001) and in serum of LC/CH patients without HCC (p<0.001). In four patients with HCC, the initially high level of serum TRX (>150 ng/ml) decreased below 150 ng/ml after surgical removal of the tumor. The data reported herein revealed that patients with HCC had a significantly elevated serum level of TRX, suggesting that measurement of serum of TRX might be a useful clinical parameter when HCC is suspected.
Adult↗
Gastric diseases related to Helicobacter pylori and Epstein-Barr virus infection.
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Burkitt Lymphoma↗
Hypercalcemia caused by ectopic production of parathyroid hormone in a patient with papillary adenocarcinoma of the thyroid gland.
Hypercalcemia and elevation of a serum PTH level (9800 pg/mL (normal: 160-520) were found in a 72-yr-old woman who had a lung cancer. She underwent pulmonary lobectomy for a suspected PTH-producing lung cancer. However, hypercalcemia and elevation of the serum PTH level were persistent postoperatively. Subsequent examination, using parathyroid scintiscanning, revealed a hot spot in the right lower part of the thyroid gland, suggesting hypercalcemia caused by a parathyroid tumor. She underwent bilateral exploration of the neck; however, four apparently normal parathyroid glands were seen. Therefore, hemithyroidectomy was performed for the possibility of an intrathyroidal parathyroid adenoma. Serum calcium and PTH levels declined after this operation. A nodular lesion was found in the cut sections of the resected specimen, which was consistent with the result of the scintiscanning. Histological examinations revealed a papillary adenocarcinoma of the thyroid gland, and the PTH-immunoreactivity in the tumor cells was confirmed. These findings strongly suggest that PTH could be produced ectopically by the papillary adenocarcinoma of the thyroid gland.
Adenocarcinoma, Papillary↗