Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407).

BACKGROUND: Surgery for advanced esophageal carcinoma has its limits as regards aggressiveness and therapeutic effect, therefore effective multimodality treatment is required to obtain better survival. The objective of this study was to evaluate whether daily continuous infusion of CDDP could achieve a higher clinical response rate with less toxicity than its drip infusion in the previous phase II study that we had conducted. METHODS: Patients with primary extensive or relapsed esophageal carcinoma after esophagectomy, which had distant organ metastasis and histologically proven SCC, were eligible for this study. A dose of 20 mg/m(2) of cisplatin and 800 mg/m(2) of 5-fluorouracil was given by continuous infusion for 24 h on days 1-5. This treatment was repeated every 4 weeks for up to four cycles. A total of 36 men and six women with a median age of 64 (range 39-75) years were registered and 36 patients were eligible. RESULTS: The overall response rate of the registered patients was 33.3% (12/36) and the median response duration was 175 days. Median survival time was 201.5 days and the 1-year survival rate was 27.8%. Change from bolus to continuous infusion of cisplatin affected neither the type nor the degree of toxicity. CONCLUSION: Daily continuous infusion of cisplatin was not associated with higher response or lower toxicity than those seen with the high-dose bolus or multibolus treatment regimens. We conclude that this regimen in this setting is not worthy of further phase III trials. JEOG is now evaluating other drug combination regimens.

Changes in distribution of cystatin C, apolipoprotein E and ferritin in rat hypothalamus after hypophysectomy.

To clarify the mechanism underlying the process of degeneration of injured CNS neurons, we have immunohistochemically examined the distribution of cystatin C, apolipoprotein E, IgG, transferrin and ferritin in the hypophysectomized rat hypothalamus. Stainings for ferritin revealed that reactive microglial cells massed in the paraventricular and supraoptic nuclei 14 days after hypophysectomy, when the degeneration of vasopressin neuronal cell bodies was apparent. Cystatin C-positive magnocellular neurons first appeared at 4 days and the number of intensely-stained cells increased rapidly up to the 7th day of hypophysectomy, followed by a decrease thereafter. Most of such cystatin C-positive neurons were simultaneously stained with anti-vasopressin serum. Accumulation of apolipoprotein E in extracellular spaces was obvious in the both hypothalamic magnocellular nuclei at 7 days. Several apolipoprotein E-positive cells were localized in the supraoptic nucleus, although the number of apolipoprotein E-positive cells was much smaller than that of cystatin C-positive cells. The experiments performed with the transferrin and IgG antibodies showed undetectable levels of such molecules in and around the degenerating magnocellular neurons during whole experimental periods. These findings suggest the importance of cystatin C and apolipoprotein E in the process of degeneration and/or regeneration of magnocellular neurons after hypophysectomy.

Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and central cholinergic neurons in aged rats.

The effects of a novel prolyl endopeptidase inhibitor (PEP), (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)- 1-pyrrolidinecar-boxamide (JTP-4819), on performance of the Morris water maze task and on central cholinergic function were investigated in aged rats. Spatial memory (escape latency, path length, and swimming speed to the platform) was impaired in aged rats performing the Morris water maze task when compared to young rats. Administration of JTP-4819 (1 mg/kg, p.o.) for 14 days improved this memory deficit in aged rats, as shown by the decrease in escape latency and path length. In addition, when JTP-4819 (at doses of 1 and 3 mg/kg, p.o.) was administered for 3 wk, it reversed the age-related increase of ChAT activity in the cerebral cortex and the decrease of 3H-choline uptake in the hippocampus. These data suggest that JTP-4819 ameliorates age-related impairment of spatial memory and partly reverses central cholinergic dysfunction, possibly due to the enhancement of neuropeptide function by inhibition of PEP mediated degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone.

Appearance of beta-2-microglobulin in rat hypothalamic magnocellular neurons after hypophysectomy.

To clarify the relationship between neuronal cell degeneration and MHC class-I complex expression, we have immunohistochemically examined the distribution of beta(2)-microglobulin in the hypophysectomized rat hypothalamus. In the sham-operated control rats, positive stainings were distributed only in blood vessels in the hypothalamic areas where magnocellular neurons were localized. Three days after hypophysectomy, positive stainings appeared in a large number of magnocellular neurons in the paraventricular and supraoptic nuclei. Most of such beta(2)-microglobulin-positive cells were simultaneously stained with antivasopressin serum. The pattern of distribution of positive cells and the intensity of the stainings remained unchanged at least until the 14th day. These morphological findings suggest that the process of degeneration of hypothalamic magnocellular neurons after hypophysectomy is a useful model to investigate the role of MHC class I complex in the brain.

[Protective effects of the stem of Berchemia racemosa Sieb. et Zucc. on experimental liver injuries].

The methanol extract and water extract from the stem of Berchemia racemosa (Rhamnaceae) showed protective effects on liver injuries induced by carbon tetrachloride (CCl4) and alpha-naphthylisothiocyanate (ANIT) in rats. The acetone extract of B. racemosa protected the liver injury induced by CCl4. One of the protective substances was identified as carpusin. Some fractions showed significant protective effects against the liver injury and cholestasis induced by ANIT.

[Studies on chemical radioprotectors against X-irradiation used by soft X-ray accelerator].

This review describes the modes of mice radiation injuries induced by soft X-irradiation under various conditions and the protective effects of several kinds of substances on these injuries. The models of radiation injuries in this study were bone marrow death after lethal irradiation, skin damage induced by irradiation with long length soft X-ray and leukocytopenia in the peripheral blood after sublethal irradiation. Two bioassay methods were established for the survival effect on the lethal irradiation and protective potency on the skin damage induced by soft X-irradiation. The protective potencies of various sulfur compounds, related compounds of ferulic acid, nucleic acid constitutional compounds, crude drugs and chinese traditional medicines were determined and then many effective drugs were recognized. Effective components in the methanol extracts of Cnidii Rhizoma and Aloe arborescens recognized as radioprotectable were fractionated. As a result of these studies, it was observed that the active principles in Cnidii Rhizoma were identified as ferulic acid and adenosine. The scavenge action of active oxygens, a protective effect on the damages of deoxyribonucleic acid and superoxide dismutase by in vitro soft X-irradiation were evaluated as radiation protective mechanisms.

[Protective effects of Taiwan crude drugs on experimental liver injuries].

Protective effects of 41 Taiwan crude drugs on rat hepatic injuries caused by carbon tetrachloride (CCl4) and alpha-naphthylisothiocyanate (ANIT) were investigated. The methanol extracts of Elephantopi Herba and Lonicerae Flos inhibited the release of intrahepatic enzymes and histological changes by CCl4. The methanol extracts of Canarii Radix, Arecae Pericarpium, Cynomorii Caulis, Polygoni Cuspidati Radix, Phyllodii Herba, Junci Caulis Medulla, Rubiae Herba and Rhinacanthi Herba protected the hepatic injury by ANIT. Among them, the water extracts of Cymorii Caulis and Junci Caulis Medulla showed higher protective potency than the methanol extracts. And them this two crude drugs also protected the cholestasis by ANIT.

Effects of a novel thyrotropin-releasing hormone analogue, JTP-2942, on extracellular acetylcholine and choline levels in the rat frontal cortex and hippocampus.

The effects of a novel thyrotropin-releasing hormone (TRH) analogue, N alpha-[(1S,2R)-2-methyl-4-oxocyclopentanecarbonyl]-L-histidyl-L-pr olinamide (JTP-2942) on acetylcholine (ACh) release and on the extracellular choline level were investigated in rat frontal cortex and hippocampus by microdialysis, and were compared with effects of TRH. JTP-2942 (0.3 mg/kg i.p.) produced a marked (> 300%) and persistent increase of ACh release in both the frontal cortex and hippocampus, while TRH (3 mg/kg i.p.) caused a significant but transient increase of ACh to about 200% in the frontal cortex. Both drugs significantly decreased the choline levels in both brain regions. Investigation of the effects of JTP-2942 (0.001-1 mM) and TRH (1 and 10 mM) on ACh release and choline levels when perfused through the dialysis probe revealed that JTP-2942 had a greater effect than TRH in both the frontal cortex and the hippocampus. The action of JTP-2942 was about 1000-fold more potent than that of TRH in both brain regions. Oral administration of JTP-2942 at a dose of 10 mg/kg markedly and persistently increased the release of ACh and at doses of 1-10 mg/kg decreased the extracellular choline level in the frontal cortex and hippocampus. These results also suggest that JTP-2942 has some selectivity for the hippocampus compared to the frontal cortex after both systemic administration and local injection. The increase of ACh release caused by JTP-2942 was completely antagonized by perfusion with tetrodotoxin (TTX, 1 microM), suggesting that the action of JTP-2942 on cholinergic neurons was mediated via neuronal activity.

[Protective effects of the bark of Myrica rubra Sieb. et Zucc. on experimental liver injuries].

The methanol extract from the bark of Myrica rubra SIEB. et ZUCC. showed protective effects on liver injuries induced by carbon tetrachloride (CCl4) and alpha-naphthylisothiocyanate (ANIT) in rats. In this study, the fractions and some compounds from the bark of M. rubra were investigated for the protection against CCl4 inducing liver injuries in rats. The active principles for the protection were recognized in two fractions (M-3 and M-5 Fr. 1) obtained from the methanol extract, and one of the active principles in the fraction (M-3) was found to be myricanol 5-O-beta-D-(6'-O-galloyl)-glucopyranoside. In addition, these fractions protecting liver injuries induced by CCl4 showed significant protective effects against cholestasis induced by ANIT.

[Effects of various methanol extracts of crude drugs on experimental subacute and chronic hepatic injury].

The effects of 5 crude drugs (Myricae Cortex, Polygoni Avicularis Herba, Hyperici Erecti Herba, Forsythiae Fructus, Desmodii Herba) on subacute and chronic hepatic injuries induced by carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT) were investigated in rats. All of these crude drugs suppressed significantly the increase of several biochemical parameters with CCl4-injection twice per week for 4 weeks. Polygoni Avicularis Herba and Desmodii Herba among 5 crude drugs also protected the subacute hepatic injury induced by ANIT-injection for 4 weeks. In addition, the therapeutic effect of Desmodii Herba on the chronic hepatic injury induced by CCl4-injection for 9 weeks was recognized. Desmodii Herba has protective effects on the acute and subacute hepatic injuries induced by CCl4 or ANIT and an improving effect on the chronic injury induced by CCl4. Though the increase of hydroxylproline content in the liver began 4 weeks after the CCl4 or ANIT treatment, every crude drug had no significant effect against the liver fibrosis in these study.

[Protective effects of the fractions extracted from the callus of Acer nikoense Maxim. on alpha-naphthylisothiocyanate induced liver injury].

It has been reported that the methanol extract from the bark of Acer nikoense MAXIM. (AN) and the fractions separated from this extract showed the protection for liver injuries induced by carbontetrachloride (CCl4) in rat. On the other hand, the evidence manifested that the fractions of the callus of young branches from AN were recognized to have protective effects on the CCl4-induced liver injuries in rat. In this study, the protective activities of the fractions extracted from the callus of AN were investigated on the alpha-naphthylisothiocyanate (ANIT)-induced liver injuries in rat. The protectively active principles on the ANIT-induced liver injuries were found in the ether soluble fraction. The components of the protective effect were purified by repeated silica gel chromatographies. One of the protective substances in this fraction was identified to be beta-sitosterol. The protective fractions on the ANIT-induced liver injuries showed the protective effects on ANIT-induced cholestasis, but did not show cholagogic effects.

Studies on chemical protectors against radiation. XXXV. Effects of radioprotective Chinese traditional medicines on radiation-induced lipid peroxidation in vivo and in vitro.

The fluctuation of lipid peroxidation (LP) in 9 tissues was investigated in mice for 7 d after whole-body X-irradiation with a lethal dose of bone marrow death. LP increased significantly in bone marrow, thymus, spleen and liver following irradiation, and slightly in brain and testis, but not in blood plasma, submaxillary gland or kidney. The effects of 7 radioprotective Chinese traditional medicines (CTMs) and cysteamine (MEA) on the radiation-induced LP in 4 tissues were studied by i.p. injection before or after irradiation and their LP content in tissues was measured 2 d after irradiation. Most CTMs showed significant inhibition of radiation-induced LP in bone marrow and liver, especially when injected prior to irradiation. Some CTMs also showed such inhibition in spleen. MEA only inhibited the increase of LP in liver when injected before irradiation, but enhanced the increase of LP in spleen. None of these radioprotectors including MEA was recognized to inhibit radiation-induced LP in thymus. The in vitro experiments were carried out using mouse liver microsomal suspensions (MS). The MS were prepared from normal (non-irradiated) mice. Each of the 8 radioprotectors was added to MS before or after irradiation and then post-irradiation-incubated at 37 degrees C. All markedly inhibited radiation-induced LP if added before irradiation, but were slightly less effective if added after.

[Clinical and bacteriological study of sparfloxacin on bacterial prostatitis].

Sparfloxacin (SPFX), a new oral quinolone antimicrobial, was studied for the bacterial response, pharmacokinetics and clinical efficacy in the treatment of bacterial prostatitis. The minimum inhibitory concentration (MIC) values for 48 strains isolated from expressed prostatic secretion were measured. The values for 8 out of 12 strains of S. epidermidis were below 0.05 microgram/ml and those for all 6 strains of E. coli were below 0.025 microgram/ml. The SPFX concentrations in prostatic fluid (PF) were 0.33 to 0.49 microgram/ml at 1 to 3 hours after oral administration of 200 mg, the PF/serum ratio being 1.15 to 1.47. SPFX was administered at a dose of 200 to 400 mg daily for an average of 14.1 days to 14 patients with prostatitis (5, acute: 9, chronic). The clinical efficacy judged by physician in charge was effective in 12 cases with an efficacy rate of 85.7%. The bacterial eradication rate was 93.3% (14/15 strains), and eradication was complete in all 7 cases infected with gram-negative rods. SPFX-related abnormal laboratory values were observed in one case with transient increase of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and alkaliphosphatase activities, and decrease of platelet. As side effects, one case with gastrointestinal symptoms and the other case with photosensitivity skin rash accompanied by sensory abnormality of palms were observed. The abnormal values or side effects in these patients recovered to normal or disappeared after completion of the treatment without any treatments. In view of the higher concentrations in PF than the MIC values with long remaining in the tissues, SPFX is considered to be effective in the treatment of bacterial prostatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical study of sparfloxacin, a new quinolone derivative, on urinary tract infection].

Sparfloxacin (SPFX) was evaluated for its clinical efficacy in 22 patients with acute uncomplicated cystitis (AUC) and 51 with chronic complicated urinary tract infection (CC-UTI). SPFX was administered in a single oral daily dose of 100 mg for 3 days to the patients with AUC. According to the UTI criteria, the efficacy rate was 100% (excellent rate was 78.9%). SPFX was also administered in a single oral dose of 200 to 300 mg mostly for 5 days to patients with CC-UTI. The efficacy rate according to the UTI criteria in the evaluable 22 cases was 45.5%. The efficacy rate according to the physicians in charge, evaluated as either excellent or good for the 23 cases treated with SPFX for 7 and 14 days was 65.2%, the overall efficacy rate in 49 cases including the administration for 5 days being 55.1%. In safety profile, subjective side effects were observed in 9 cases (12.3%), in 2 of which the medication was discontinued (2.7%). These side effects, flowever, recovered without any treatment to normal at the completion or discontinuation of the medication. The clinical laboratory values showed a slight elevation of BUN in 2 cases. SPFX was the most potent antimicrobial brug with a long blood elimination half life among the existing current new quinolones (NQs), indicating a possibility of once-a-day treatment regimen. In safety, side effects of SPFX were similar in general to those of other current NQs. Thus, SPFX is regarded as a highly useful antimicrobial drug when the drug is administered with consideration for its unique characteristics.

[Protective effects of the fractions extracted from the callus of Acer nikoense Maxim. on carbon tetrachloride induced liver injury].

The decoctions extracted from the bark and leaf of Acer nikoense Maxim. (AN) have been used as a folk medicine for eye-wash and hepatic disease. As previously reported, the methanol extract from the bark of AN and the fractions of the methanol extract have protective effects for liver injury induced by carbon tetrachloride (CCl4) in rats. In this study, protective effects of the fractions extracted from the callus of AN were investigated on CCl4-induced liver injury in rat. The active principles for the protection of CCl4-induced liver injury were recognized in a fraction (EF 3-3) obtained by using silica gel chromatography (solvent: CHCl3-MeOH-H2O). The components were further fractionated by silica gel chromatography followed by gel filtration (solvent: CHCl3-MeOH). In addition, the mechanism of the protective action against liver injury induced by CCl4 was also examined. The fractions with protective effects in vivo showed the inhibitory effects on CCl4-dependent lipid peroxidation in microsomal fraction in vitro.

[Studies on chemical protectors against radiation. XXXIV. Survival effects of aqueous extracts of various Chinese traditional medicines on radiation injury].

In order to develop a nontoxic radioprotector, 60 kinds of Chinese traditional medicines were chosen, and their aqueous extracts tested for their survival effects against the lethal effect of X-irradiation in mice. Radiation factors used were as follows: soft X-rays, 2100R (5.418 x 10(-1) Ckg-1), 70 kVp, 10 mA, 10 mm acrylic filter, 70R (1.806 x 10(-2) Ckg-1)/min. Among 60 medicines tested by intraperitoneal injection immediately before the irradiation, 15 are shown to have the significant survival effect. These 15 effective medicines were also tested by intraperitoneal injection after the irradiation, and the survival effect was recognized in Keisi-syakuyaku-chimo-to, Keigai-rengyo-to, Simotu-to, Syakuyaku-kanzo-to and Hange-syasin-to. On the other hand, the survival effects of 25 medicines including the above-mentioned 15 medicines were investigated by the oral administration at various times before or after the irradiation. As the result of these studies, only Keigai-rengyo-to and Bukuryo-in are shown to have the significant survival effect when administered 2 h before the irradiation.

Different effects of carbon tetrachloride on carcinogen-induced hepatocellular carcinoma and normal liver of the rat: lowered lipid peroxidation and accelerated necrosis in cancer.

To investigate molecular responses to lipid peroxidative stimuli in neoplastic cells, lipid peroxidation was induced in liver of rats bearing 3'-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma by injecting a high dose of carbon tetrachloride (CCl4), a strong lipoperoxidative reagent. Normal rat livers with or without CCl4 treatment served as controls. CCl4 administration markedly provoked fatty metamorphosis, visualized by oil red O staining, in normal livers while minimal fatty changes were seen in hepatocellular carcinomas, where necrosis was often observed instead. After CCl4 treatment, the thiobarbituric acid values (representing levels of lipid peroxides in the tissue) were increased two-fold in the untreated normal liver, but were unchanged in the cancer tissue. Levels of vitamin C, an acutely reactive antioxidant, measured by high-performance liquid chromatography were not influenced by the CCl4 injection in the cancer tissue whereas a significant decrease was evident in normal livers. The total fatty acid content, measured by gas chromatography, was significantly lower in the cancer tissue than in the normal liver while the ratio of polyunsaturated fatty acids (PUFAs) in total fatty acids was little changed. Resistance of hepatocellular cancer cells to fatty metamorphosis and their susceptibility to necrosis induced by free radicals may be due to the paucity of the target PUFAs in their cell membrane fraction, resulting in low levels of lipid peroxides. Peroxidation of PUFAs might act as a "shock absorber" against free radical-induced toxic cell death in normal cells.

[Protective effects of various methanol extracts of crude drugs on experimental hepatic injury induced by alpha-naphthylisothiocyanate in rats].

Sixty seven methanol extracts of crude drugs were examined for their effects to protect hepatic injury induced by alpha-naphthylisothiocyanate (ANIT) in rats. In terms of the release of intrahepatic enzymes and bilirubin into the serum, 19 extracts were found to suppress the increase in the concentration of serum bilirubin by ANIT. Out of the 19 extracts those of Berchemia Racemosa Caulis, Aurantii Nobilis Pericarpium, Polygoni Avicularis Herba and Gentianae Scabrae Radix, also inhibited the release of several intrahepatic enzymes used as parenchymal injury parameter.

[Studies on chemical protectors against radiation. XXXIII. Protective mechanisms of various compounds against skin injury induced by radiation].

The radiation protective mechanisms on skin injury induced by soft X-irradiation were investigated by use of various radiation protective agents such as sulfur compounds (MEA, MEG, thiourea), nucleic acid constitutional compounds (adenosine, inosine), antioxidative compounds (sesamol, ferulic acid, ascorbic acid), crude drugs (Rosae Fructus, Anemarrhenae Rhizoma, Trapae Fructus, Forsythiae Fructus, Aloe arborescens). Scavenge action of activated oxygen, inhibitory effect of lipid peroxidation, induction of antioxidative protein and protective effect against damage of deoxyribonucleic acid and superoxide dismutase by X-irradiation were evaluated as the radiation protective mechanisms, and relationship between these results and protective effect of skin injury induced by radiation was studied.

[Protective effects of various methanol extracts of crude drugs on experimental hepatic injury induced by carbon tetrachloride in rats].

The protective effects of 67 methanol extracts of crude drugs on rat hepatic injury by carbon tetrachloride (CC14) were examined. In terms of the release of intrahepatic enzymes and bilirubin into the blood, 11 methanol extracts decreased these factors significantly. Among them methanol extracts of Caryophylli Flos, Angelicae Dahuricae Radix, Polygoni Avicularis Herba, Myricae Cortex and Forsythiae Fructus were newly found to have protective effects against acute hepatic injury induced by CCl4. And then these 11 extracts which protected hepatic injury by CCl4 were investigated for their membrane stabilizing and inhibitory effects of lipid peroxidation. The extract of Bupleuri Radix only decreased the hemolysis induced by hypotonic pressure. Nine kinds of extracts without those of Desmodii Herba and Bupleuri Radix suppressed the lipid peroxidation induced by CCl4 in rat hepatic microsomes. In addition, Scutellariae Radix, Caryophylli Flos and Myricae Cortex were shown to have inhibitory effects of non-enzymatic lipid peroxidation in rat hepatic mitochondria. This study reports that the methanol extracts of Caryophylli Flos, Angelicae Dahuricae Radix, Polygoni Avicularis Herba, Myricae Cortex and Forsythiae Fructus protect the hepatic injury by CC14 and these protective effects are connected with the inhibitory effects of the lipid peroxidation in hepatic microsomes.