S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Dietary taurine potentiates polychlorinated biphenyl-induced hypercholesterolemia in rats*

The effect of dietary taurine on cholesterol metabolism and the distribution of lipoprotein-cholesterol in serum of rats fed a diet containing polychlorinated biphenyls (PCB) was examined. Young male Wistar rats (60 g) were fed diets containing 0.2 g/kg diet of PCB and/or 30 g/kg diet of taurine for 15 days. The experiment was performed as the 2 (PCB) x 2 (taurine) factorial design. The addition of PCB elevated serum levels of total- and HDL-cholesterol and apolipoprotein A-I, which is a major apolipoprotein of HDL. Simultaneous supplementation of taurine with PCB amplified the increase of the serum level of total- and HDL-cholesterol. Hepatic concentrations of cholesterol and total lipids were significantly elevated by the supplementation of PCB, and taurine significantly amplified these increases caused by PCB. PCB suppressed hepatic cholesterol 7alpha-hydroxylase (CYP7A1) gene expression, and taurine induced CYP7A1 gene expression. Taurine also enhanced PCB-induced elevation of malic enzyme mRNA in the liver. These results suggest that taurine enhanced PCB-induced hyper-alpha-cholesterolemia and that taurine has a role in increasing HDL-cholesterol.

Dietary taurine alters ascorbic acid metabolism in rats fed diets containing polychlorinated biphenyls.

The effect of dietary taurine on ascorbic acid metabolism and hepatic drug-metabolizing enzymes was investigated in rats fed diets containing polychlorinated biphenyls (PCB) to determine whether taurine has an adaptive and protective function in xenobiotic-treated animals. Young male Wistar rats (60 g) were fed diets containing 0 or 0.2 g/kg diet PCB with or without 30 g/kg diet of taurine for 14 d. The rats fed the PCB-containing diets had greater liver weight, higher ascorbic acid concentrations in the liver and spleen and greater hepatic cytochrome P-450 contents than control rats that were not treated with PCB (P < 0.01). In PCB-fed rats, urinary ascorbic acid excretion was enhanced, and serum cholesterol concentration (especially HDL-cholesterol) was significantly elevated compared with those in control rats. Dietary taurine significantly potentiated the increases in the urinary excretion of ascorbic acid and the rise in the levels of cytochrome P-450 which were caused by PCB treatment. On the other hand, the supplementation of taurine to control diet did not alter these variables. Taurine may enhance the hepatic drug-metabolizing systems, leading to the stimulation of the ascorbic acid metabolism in rats fed diets containing PCB.

The human hand motor area is transiently suppressed by an unexpected auditory stimulus.

OBJECTIVE: To study the effect of a loud auditory stimulus on the excitability of the human motor cortex. METHODS: Ten normal volunteers participated in this study. The size of responses to transcranial magnetic or electrical cortical stimulation (TMS or TES) given at different times (ISIs) after a loud sound were compared with those to TMS or TES alone (control response). Different intensities and durations of sound were used at several intertrial intervals (ITIs). In addition, we examined how the presence of a preceding click modulated the effect of a loud sound (prepulse inhibition). The incidence of startle response evoked by various stimuli was also studied. RESULTS: A loud auditory stimulus suppressed EMG responses to TMS when it preceded the magnetic stimulus by 30-60 ms, whereas it did not affect responses to TES. This suggests that the suppression occurred at a cortical level. Significant suppression was evoked only when the sound was louder than 80 dB and longer than 50 ms in duration. Such stimuli frequently elicited a startle response when given alone. The effect was not evoked if the ITI was 5 s, but was evoked when it was longer than 20 s. A preceding click reduced the suppression elicited by loud sounds. CONCLUSIONS: Auditory stimuli that produced the greatest effect on responses to TMS had the same characteristics as those which yielded the most consistent auditory startle. We suggest that modulation of cortical excitability occurs in parallel with the auditory startle and both may arise from the same region of the brain-stem.

Air-puff-induced facilitation of motor cortical excitability studied in patients with discrete brain lesions.

Air-puff stimulation applied to a fingertip is known to exert a location-specific facilitatory effect on the size of the motor evoked potentials elicited in hand muscles by transcranial magnetic stimulation. In order to clarify its nature and the pathway responsible for its generation, we studied 27 patients with discrete lesions in the brain (16, 9 and 2 patients with lesions in the cerebral cortex, thalamus and brainstem, respectively). Facilitation was absent in patients with lesions affecting the primary sensorimotor area, whereas it was preserved in patients with cortical lesions that spared this area. Facilitation was abolished with thalamic lesions that totally destroyed the nucleus ventralis posterolateralis (VPL), but was preserved with lesions that at least partly spared it. Lesions of the spinothalamic tract did not impair facilitation. The size of the N20-P25 component of the somatosensory evoked potential showed a mild correlation with the amount of facilitation. The facilitation is mainly mediated by sensory inputs that ascend the dorsal column and reach the cortex through VPL. These are fed into the primary motor area via the primary sensory area, especially its anterior portion, corresponding to Brodmann areas 3 and 1 (possibly also area 2), without involving other cortical regions. The spinothalamic tract and direct thalamic inputs into the motor cortex do not contribute much to this effect. Some patients could generate voluntary movements despite the absence of the facilitatory effect. The present method will enable us to investigate in humans the function of one of the somatotopically organized sensory feedback input pathways into the motor cortex, and will be useful in monitoring ongoing finger movements during object manipulation.

Effect of dietary taurine on endogenous hypercholesterolemia in rats fed on phenobarbital-containing diets.

The effect of dietary taurine on endogenous hypercholesterolemia induced by a phenobarbital-containing diet was investigated. Supplemented taurine did not affect the concentrations of serum cholesterol, but further potentiated the accumulation of hepatic cholesterol in the hypercholesterolemic state induced by phenobarbital. It is suggested that taurine might amplify the hepatic cholesterogenesis in phenobarbital-induced hypercholesterolemia.

A clinical study of the effectiveness of oral glutamine supplementation during total parenteral nutrition: influence on mesenteric mononuclear cells.

Bacterial translocation (BT) is a well-known insult during total parenteral nutrition (TPN) and a high incidence of morbidity has been reported in septic patients receiving TPN. Inflammatory cytokines were shown to play an important role in the pathogenesis of critical complications following sepsis. Previous studies have indicated that supplementation of TPN with glutamine is effective in preventing BT in animals, but its effectiveness in humans is unclear. The aim of this study was to determine the effectiveness of oral glutamine supplementation to patients receiving TPN in suppressing cytokine production of mesenteric blood mononuclear cells (M-MNC). Fifteen colorectal cancer patients were divided into 3 groups according to preoperative nutrition management. (1) TPN group: TPN with conventional glutamine-free amino acid solution. (2) Gln group: TPN with oral glutamine supplementation of 30 g/d. (3) CONTROL GROUP: oral intake of normal food. M-MNC were obtained immediately after laparotomy and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) production of M-MNC was evaluated with or without lipopolysaccharide (LPS) stimulation. TNF-alpha and IL-10 production by LPS-stimulated M-MNC was increased in the TPN group and suppressed in the Gln group. In conclusion, oral glutamine supplementation to patients with TPN was shown to be effective for the prevention of M-MNC activation to avoid excessive production of cytokines.

Dietary taurine enhances cholesterol degradation and reduces serum and liver cholesterol concentrations in rats fed a high-cholesterol diet.

The effect of taurine on hypercholesterolemia induced by feeding a high-cholesterol (HC) diet (10g/kg) to rats was examined. When various amounts of taurine (0.25, 0.5, 1, 2.5, 5, 10, 20, 30, 40 or 50 g/kg diet) were supplemented to HC for 2 wk, serum total cholesterol gradually and significantly decreased in a dose-dependent manner and normalized at the dose of 10 g taurine/kg, compared with the control (cholesterol free) diet group. By contrast, serum HDL-cholesterol was elevated by taurine supplementation. The HC diet caused a significant decrease in the concentration of taurine in serum, liver and heart compared to that in the control group, and the effective dose of supplemental taurine to improve its reduction was 2.5 g/kg diet. In the hypercholesterolemic rats fed the HC diet, the excretion of fecal bile acids and hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) activity and its mRNA level increased significantly, and the supplementation of taurine further enhanced these indexes, indicating an increase in cholesterol degradation. The abundance of mRNA for Apo A-I, one of the main components of HDL, was reduced by HC and recovered by taurine supplementation. Agarose gel electrophoresis revealed that, in hypercholesterolemic rats fed the HC diet, the serum level of the heavier VLDL increased significantly, but taurine repressed this increase and normalized this pattern. Significant correlations were observed between the time- and dose-dependent increases of CYP7A1 gene expression and the decrease of blood cholesterol concentration in rats fed the HC diet supplemented with taurine (time, r = -0.538, P < 0.01, n = 32; dose, r = -0.738, P < 0.001, n = 20). These results suggest that the hypocholesterolemic effects of taurine observed in the hypocholesterolemic rats fed the HC diet were mainly due to the enhancement of cholesterol degradation and the excretion of bile acid.

Improving effect of dietary taurine on marked hypercholesterolemia induced by a high-cholesterol diet in streptozotocin-induced diabetic rats.

The effect of dietary taurine on hypercholesterolemia induced by a high-cholesterol diet in streptozotocin (STZ)-induced diabetic rats was investigated. The concentrations of serum and liver cholesterol were markedly elevated in STZ-diabetic rats fed on the cholesterol-containing diet, and dietary taurine significantly reduced this elevated level of cholesterol in the serum and liver. The gene expression of cholesterol 7 alpha-hydroxylase (CYP7A1), which is the rate-limiting enzyme for cholesterol degradation, was induced by the supplementation of taurine to the high-cholesterol diet. It is suggested that one of the reasons for this hypocholesterolemic action by taurine might have been the enhancement of cholesterol degradation.

Antifungal activity of D0870 against murine infections and its mechanism of action.

We evaluated the in vivo antifungal activity of D0870, a new triazole agent, in comparison with that of fluconazole in two murine infection models. The therapeutic mechanism of D0870 in these models was also investigated in vitro. In a pulmonary infection with Cryptococcus neoformans in immunosuppressed mice, D0870 at 10-100 mg/kg significantly reduced viable counts in lungs infected with C. neoformans to 1/10-1,000 of the control on day 14, whereas fluconazole, only at 100 mg/kg, showed a significant reduction in the viable counts and was less active than D0870 at 10 mg/kg. D0870 at 3-30 mg/kg also showed excellent therapeutic efficacy against murine vaginal candidiasis and completely eliminated viable yeasts from the vaginal cavity, whereas positive cultures were found in 20% of mice treated with 30 mg fluconazole/kg. At pH 7 and 37 degrees C, D0870 was active against C. neoformans in synthetic amino acid medium, fungal or sabouraud dextrose broth. By reducing the pH of the medium, the in vitro anticryptococcal activity of D0870 was enhanced and found to be fungicidal under all culture conditions at pH 4-5. D0870 also showed a stronger fungistatic activity against Candida albicans at pH 4. These results suggest that D0870 may exhibit a potent activity against these two murine infections by exerting an excellent antifungal activity at the infection sites thought to be acidic environments.

Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting bleeding time in rats: comparison with low molecular weight heparin.

We compared the antithrombotic and hemorrhagic effects of naturally existing human urinary soluble thrombomodulin (MR-33) with those of low molecular weight heparin (LMW-heparin) in rats. In in vitro experiments, MR-33 prolonged APTT in a dose-dependent fashion; its effect in this respect was as potent as that of LMW-heparin, but it was less potent than unfractionated heparin (UF-heparin). MR-33 was effective on endotoxin- or thromboplastin-induced disseminated intravascular coagulation (DIC) in rats. In both DIC models, infusion of MR-33 improved hematological abnormalities compatible with DIC in a dose-dependent, fashion without excessive prolongation effect on APTT. Although LMW-heparin and UF-heparin also improved both DIC models, excessive prolongation of APTT was observed at high doses. It is well-known that the excessive prolongation of APTT with antithrombotic drugs like heparins is an index for hemorrhage, which is a major side effect in the treatment of DIC. We therefore further compared the antithrombotic (Benefit: dose required for 50% inhibition of fibrinogen decrease: ED50) and hemorrhagic (Risk: minimum dose required for significant prolongation of bleeding time) effects of MR-33 and LMW-heparin in the thromboplastin-induced DIC model. As a result, Benefit-Risk ratio was 1:27 for MR-33 and 1:3 for LMW-heparin. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage compared with LMW-heparin.

Roxithromycin attenuates acid-induced cough and water-induced bronchoconstriction in children with asthma.

In the present study, we evaluated the effect of roxithromycin, a semisynthetic macrolide antibiotic, on the cough response to inhaled acetic acid (AA) and on the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with asthma. Ten hospitalized asthmatic children (8 boys and 2 girls, mean +/- SEM age 12.6 +/- 0.4 years) were enrolled in this study. They were treated with 150 mg of roxithromycin once a day orally for 8 weeks without any side effects. All the patients underwent AA inhalation challenge before and 2, 4, and 8 weeks after the administration of roxithromycin. Seven of the 10 patients, who had a fall in FEV1 of at least 20% after UNDW inhalation, underwent UNDW inhalation challege at the same time. The cough threshold values, the lowest concentrations of AA eliciting coughs, and UNDW provocative dose producing a 20% fall in FEV1 (UNDW PD20) values 4 or 8 weeks after the administration of roxithromycin increased significantly over the initial values (p < 0.05). No significant change was observed in baseline FEV1 or serum theophylline concentrations throughout the study. These results support the notion that administration of roxithromycin may have favorable results in the treatment of childhood asthma.

A clinical trial of therapeutic electrical stimulation for amyotrophic lateral sclerosis.

This paper describes the effects of therapeutic electrical stimulation (TES) on the wasting muscles in a patient with amyotrophic lateral sclerosis. The patient is a 47-year-old male, and he has a history of progressive muscle weakness and atrophy, affected more in the right side. Percutaneously indwelling intramuscular electrodes were implanted to the affected muscles in the right upper and lower extremities but no electrode in the corresponding left region. Within a month of TES therapy, a rapid improvement of extremity motion appeared in the TES treated side. Long-term application of TES more than 3 months increased the strength of the muscle which had been evidently weaker than the non-treated side. CT findings of both the upper and lower extremities with TES therapy showed an increase in the density and a reduction in the moth-eaten image. An increase in the thickness of the muscles was also observed in the TES treated side while deterioration was observed in the muscles on the non-treated side.

Serial neuroradiological studies in focal cerebritis.

We report serial neuroradiological studies in a patient with focal cerebritis in the head of the left caudate nucleus. On the day after the onset of symptoms, CT showed an ill-defined low density lesion. The lack of contrast enhancement appeared to be the most important finding for differentiating focal cerebritis from an encapsulated brain abscess or a tumour. MRI two days later revealed the centre of the lesion to be of slightly low intensity on T1-weighted inversion recovery (IR) images and very low intensity on T2-weighted spin echo images, which appeared to correspond to the early cerebritis stage of experimentally induced cerebritis and brain abscess. Ten days after the onset of symptoms, CT revealed a thin ring of enhancement in the head of the caudate nucleus, and a similar small ring was seen in the hypothalamus 16 days after the onset, corresponding to the late cerebritis stage. MRI nine days later revealed ill-defined high signal lesions within the involved area on the T1-weighted IR images. To our knowledge, this is the first published MRI documentation of the early cerebritis stage developing into an encapsulated brain abscess. The mechanisms underlying of these radiographic changes are discussed.

Bactericidal activity of M14659 enhanced in low-iron environments.

The bactericidal activity of M14659 against Escherichia coli in low-iron environments was investigated and compared with that of ceftriaxone and ceftazidime. The bactericidal activity of M14659 against E. coli in Mueller-Hinton broth was enhanced 30- to 20,000-fold by addition of transferrin, which is an iron-binding protein, whereas the activity of ceftriaxone or ceftazidime was much less strongly affected. This enhancement by transferrin was completely inhibited by saturating the iron-binding capacity of transferrin with FeCl3. M14659 was taken up markedly into bacterial cells in the presence of transferrin, and its uptake was inhibited by the protonophore dinitrophenol, which inhibits active-transport systems coupled to an energized membrane such as the iron transport systems of E. coli. The bactericidal activity of M14659, which chelates Fe3+, was also enhanced in the presence of other iron-binding compounds such as lactoferrin and alpha,alpha'-dipyridyl or in iron-deficient Mueller-Hinton broth (Fe3+ concentration, less than 2 nM) supplemented with FeCl3 at 0.1 to 1.0 microM, but not in unsupplemented iron-deficient Mueller-Hinton broth. The E. coli used in this study was confirmed to derepress iron transport systems in the presence of transferrin, lactoferrin, and alpha,alpha'-dipyridyl and in the iron-deficient Mueller-Hinton broth supplemented with FeCl3 at 0 to 1.0 microM. M14659 also showed an excellent antibacterial activity in vitro against other gram-negative bacteria in the low-iron environments. These findings indicate that M14659 may be actively taken up with Fe3+ into bacterial cells, probably through the iron transport systems under conditions of low iron and, thus, kills bacteria effectively.

Effect of a diet rich in branched chain amino acids on severely burned guinea pigs.

This study was performed to investigate the effects of dietary supplementation with branched-chain amino acids (BCAA) for postburn nutritional management. Seventy-one burned guinea pigs (30% TBSA) with previously placed catheter gastrostomies were divided into six groups. The first, second, and third groups received 10%, 20%, and 30%, respectively, of total calories as whey protein. The other three groups received BCAA supplementation to increase BCAA to 50% of total amino acids, compared to 21.5% BCAA content in whey protein. Groups I and IV received isonitrogenous intake, as did groups II and V, and III and VI, respectively. After an initial 3-day adaptation period, all animals in all groups received continuous isocaloric (175 kcal/kg/day) intragastric tube feeding until postburn day (PBD) 14. At PBD 14, although BCAA-supplemented groups showed very high plasma levels of BCAA (IV: 169%; V: 306%; VI: 770% of normal), no BCAA group showed evidence of any beneficial effect in various nutritional parameters when compared with the corresponding whey protein group with isonitrogenous intake. Cumulative nitrogen balance and mortality during 14 days were significantly worse in BCAA groups IV and VI than in control groups I and III, respectively. It is concluded that BCAA supplementation to enteral diets has no beneficial effect for postburn nutritional management following severe burn injury. It is further suggested that when nitrogen intake is too low or very high, BCAA supplementation may have an adverse effect.