Safety and pharmacokinetics of Alpha-1 MP (Prolastin®-C) in Japanese patients with alpha1-antitrypsin (AAT) deficiency.

BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0-7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).

Prevalence and Characteristics of Salmonella and Campylobacter in Retail Poultry Meat in Japan.

This study was performed to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Salmonella enterica subsp. enterica and Campylobacter spp. in poultry meat, and to analyze the association of genetic types of these bacteria with their geographical distribution and antimicrobial resistance profiles. Salmonella and Campylobacter isolates have been detected, respectively, in 54 and 71 samples out of 100 samples tested. Nine Salmonella serotypes were found, including S. enterica subsp. enterica serovar Infantis (33%), Schwarzengrund (12%), Manhattan (9%), and others. Campylobacter jejuni and C. coli were detected in 64 (64%) and 14 (14%) samples, respectively. S. enterica subsp. enterica isolates were very frequently resistant to tetracycline (78.3%) and streptomycin (68.3%). Many C. jejuni and C. coli isolates were resistant to sulfamethoxazole/trimethoprim (90.5%), nalidixic acid (47.3%), ampicillin (45.9%), and ciprofloxacin (40.5%). Cluster analysis was performed for the Salmonella isolates using pulsed-field gel electrophoresis (PFGE) data. For Campylobacter isolates, the cluster analysis was based on both PFGE and comparative genomic fingerprinting. The molecular typing results were compared with the information about antimicrobial resistance and geographical locations in which the poultry meat was produced. This analysis revealed that C. jejuni strains with a particular genotype and antimicrobial resistance profile are spreading in specific areas of Japan.

Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage.

Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

[Molecular Characterization of Salmonella enterica subsp. enterica Serovar 4: b: -].

Salmonella is a major causative agent of food borne diseases. Recently, monophasic strains of Salmonella, such as S. enterica 4: i: -, have been frequently reported. Here, we investigated the genetic background of S. enterica 4: b: - using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis. A total of 10 strains of S. enterica (I) 4: b: - were examined and compared with 34 strains including serovar Paratyphi B and Paratyphi B var Java, Schleissheim, and II b: -. All I 4: b: - strains were negative for hin which encodes an invertase that converts the H phases, and six were also negative for fljB, which encodes the second phase of the H antigen. An MLST analysis identified 12 sequence types (ST) and 6 ST complexes (STC) from the 44 strains. A clustering analysis of PFGE patterns almost corresponded to the STC. The monophasic I 4: b: - strains were assigned to 3 STCs (19, 32 and 155), corresponding to those of Paratyphi B var. Java or a monophasic strain according to the data of this and previous studies. These findings suggest that the monophasic strains examined in this study might have been derived from multiple clones of Paratyphi B var Java. This study shows the usefulness of molecular typing as complementation tools of the conventional serotyping system.

Two patients with atypical interstitial deletions of 8p23.1: mapping of phenotypical traits.

Chromosomal 8p23 deletion syndrome is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. The responsible gene for the heart defects in this syndrome has been identified as GATA4 on 8p23.1. Two patients with interstitial deletions of 8p23.1 were investigated; one patient showed moderate developmental delay and Ebstein anomaly, and the other showed mild delay and typical atrioventricular septum defect. The precise deletion sizes, 17 and 2.9 Mb, were determined by FISH analyses using BAC clones as probes. The latter deletion was the smallest deletion including GATA4 in the previously reported patients, and the critical regions and genes for clinical manifestation of 8p23 deletion syndrome, including facial anomalies, microcephaly, behavioral abnormality, and developmental delay, were discussed.

[A case of liver metastasis from anorectal malignant melanoma on hemodialysis treated by chemotherapy].

We report a case on hemodialysis with liver metastases from anorectal malignant melanoma treated by dacarbazine (DTIC). A 61-year-old man presented with anal bleeding. An elastic soft mass was palpated in the anal canal, and a biopsy specimen was diagnosed as anorectal malignant melanoma histologically. After introducing hemodialysis for the chronic renal failure, abdominoperineal resection was performed. Two and a half years after surgery, computed tomography showed multiple liver metastases. We chose chemotherapy consisting of DTIC 100 mg for five consecutive days every 4 weeks in addition to hemodialysis (3 times a week). After three cycles of chemotherapy, liver metastases were stable, but new lung metastases were found. After 12 cycles of chemotherapy, liver metastases became stable, but lung metastases were progressive. Subsequently, the patient died of respiratory failure 4 years after surgery, 1 year and 7 months after the diagnosis of multiple liver metastases. No severe toxicity was observed during this period. We conclude that administration of DTIC undergoing hemodialysis for malignant melanoma with renal failure seems to be useful without severe adverse events.

Synthesis and characterization of mononuclear ruthenium(III) pyridylamine complexes and mechanistic insights into their catalytic alkane functionalization with m-chloroperbenzoic acid.

A series of mononuclear RuIII complexes [RuCl2(L)]+, where L is tris(2-pyridylmethyl)amine (TPA) or one of four TPA derivatives as tetradentate ligand, were prepared and characterized by spectroscopic methods, X-ray crystallography, and electrochemical measurements. The geometry of a RuIII complex having a non-threefold-symmetric TPA ligand bearing one dimethylnicotinamide moiety was determined to show that the nicotine moiety resides trans to a pyridine group, but not to the chlorido ligand. The substituents of the TPA ligands were shown to regulate the redox potential of the ruthenium center, as indicated by a linear Hammett plot in the range of 200 mV for RuIII/RuIV couples with a relatively large rho value (+0.150). These complexes act as effective catalysts for alkane functionalization in acetonitrile with m-chloroperbenzoic acid (mCPBA) as terminal oxidant at room temperature. They exhibited fairly good reactivity for oxidation of cyclohexane (C--H bond energy 94 kcal mol(-1)), and the reactivity can be altered significantly by the electronic effects of substituents on TPA ligands in terms of initial rates and turnover numbers. Catalytic oxygenation of cyclohexane by a RuIII complex with 16O-mCPBA in the presence of H2 18O gave 18O-labeled cyclohexanol with 100% inclusion of the 18O atom from the water molecule. Resonance Raman spectra under catalytic conditions without the substrate indicate formation of a RuIV==O intermediate with lower bonding energy. Kinetic isotope effects (KIEs) in the oxidation of cyclohexane suggest that hydrogen abstraction is the rate-determining step and the KIE values depend on the substituents of the TPA ligands. Thus, the reaction mechanism of catalytic cyclohexane oxygenation depends on the electronic effects of the ligands.

[Clinical study of S-1 for advanced gastric cancer after reduction surgery].

We investigated the clinical efficacy and safety of S-1 retrospectively for the treatment of 32 patients with advanced gastric cancer after reduction surgery (gastrectomy). S-1 was administered orally twice daily, at a standard dose of 80 mg/m(2) per day for 28 days, followed by a 14-day rest. There were 21 patients having only a single residual metastatic site and 11 with two or more metastatic sites. Major residual metastatic sites were peritoneum in 25 patients, lymph nodes in 7, liver in 4 and lung in 2. The response rate by target organ was 28.6% for lymph node metastasis, and 0% for liver and lung metastasis. Peritoneal metastasis was not considered measurable site. The median survival time (MST) after S-1 administration was 573 days (95% confidence interval, 439 to 707 days). The 1-, 2- and 3-year survival rates were 62.3%, 40.3% and 28.2%, respectively. Of the 32 patients, 14 received S-1 for more than a year, and the MST in these patients was 897 days (95% confidence interval, 255 to 1,539 days). The incidence of adverse events was 90.6%, but the incidence of grade 3 or 4 was 12.5%. Long-term administration of S-1 may serve to prolong the survival period of patients with gastric cancer after reduction surgery, particularly in peritoneal metastasis.

Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry.

The Japanese Gastric Cancer Association Registration Committee reported the treatment results and causes of death of patients with primary gastric cancer treated in 1991 at the leading hospitals in Japan. Data of 8851 patients with primary gastric cancer were collected from 113 hospitals, and data of 7935 patients with gastric resection were finally analyzed. The lost-to-follow-up rate was 6.9%; the direct death rate was 1.0%. The cumulative 5-year survival rate (5YSR) of all the patients was 68.2%; 89.9% for Stage I, 69.1% for Stage II, 43.5% for Stage III, and 9.9% for Stage IV. Characteristic findings of the analyzed data were (1) high proportion of early-stage cancer, (2) high resection rate, (3) low mortality rate, (4) low incidence of upper-third cancer, (5) poor treatment results in cases with scirrhous cancer, infiltrating growth, and marked lymphatic or venous invasion, and (6) predominance of systematic (D2) and extended lymphadenectomies possibly resulting in reducing local recurrence and improving survivals.

Intramolecular rearrangement for regioselective complexation by intramolecular CH/pi interaction in a hydrophobic cavity of a ruthenium coordination sphere.

A Ru(II) complex with a hydrophobic cavity formed from two 1-naphthoylamide groups was prepared. Its reactions with beta-diketones gave beta-diketonato complexes in which hydrophobic pi-pi or CH/pi interactions were confirmed by NMR spectroscopy and X-ray crystallography. In the case of the asymmetric beta-diketone benzoylacetone, an isomer with a CH/pi interaction was afforded as the sole product owing to thermodynamic control. The reaction was found to involve a novel intramolecular rearrangement from the phenyl-included isomer to the methyl-included one without rupture of Ru-beta-diketonato coordination bonds (activation energy 52 kJ mol(-1)). This indicates that CH/pi interactions can be more favored thermodynamically than pi-pi interactions in a suitable hydrophobic environment.

Structures and properties of ruthenium(II) complexes of pyridylamine ligands with oxygen-bound amide moieties: regulation of structures and proton-coupled electron transfer.

Tris(2-pyridylemthyl)amine (TPA) derivatives having two amide moieties at the 6-positions of the two pyridine rings of TPA and their Ru(II) complexes were synthesized and characterized by spectroscopic methods, X-ray crystallography, and electrochemical measurements. The complexes prepared were [RuCl(L)]PF(6) (L = N,N-bis(6-(1-naphthoylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (1), N,N-bis(6-(2-naphthoylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (2), N,N-bis(6-(isobutyrylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (3)); the crystal structures of the three compounds were established by X-ray crystallography. In variable-temperature (1)H NMR spectra of 1 and 2 in CD(3)CN solutions, the pi-pi stacking in 1 was too rigid to exhibit any fluxional motions in NMR measurements; however, the pi-pi stacking of 2 was weaker and showed fluxional behavior in nearly T-shaped pi-pi interaction for the 2-naphthly groups (DeltaH degrees = -2.3 kJ mol(-1); DeltaG degrees = -0.9 kJ mol(-1) and DeltaS degrees = -7.7 J mol(-1) K(-1) at 233 K in CD(3)CN). For each of these three complexes, one of the amide moieties coordinated to the Ru(II) center through an amide oxygen. The other uncoordinated amide N-H formed intramolecular hydrogen bonding which remained intact even in aqueous media, indicating the intramolecular hydrogen bonding was geometrically compelled to form. The amide coordination is also stabilized and strengthened by the hydrogen bonding, so that the structure of each compound is maintained in solution. It is suggested that this hydrogen bonding lowers the redox potentials of the Ru(II) centers due to polarization of the coordinated amide C=O bond, in which the oxygen atom becomes more electrostatically negative and its electron-donating ability is strengthened. The N-H protons in the coordinated amide moieties were found to undergo a reversible deprotonation-protonation process, and the redox potentials of the Ru(II) centers could be regulated in the range of 500 mV in CH(3)CN solutions. The Pourbaix diagram for 1 clearly showed that this proton-coupled redox behavior is a one-electron/one-proton process, and the pK(a) value was estimated to be approximately 6.

Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPAR delta(beta).

The nuclear receptor PPAR (peroxisome proliferator-activated receptor) has three subtypes named alpha, delta(beta), and gamma that may act as receptors for a range of compounds including antihyperglycaemic drugs, insulin sensitizers, and non-steroidal anti-inflammatory drugs (NSAIDs). Although profiling of the subtype selectivity of the compounds for PPAR is indispensable to elucidate their pharmacological action, the absence of an appropriate transactivation assay for PPAR delta led us to develop a sensitive and reproducible method. We found that co-expression of PPAR delta, retinoid X receptor (RXR) alpha, and coactivators such as CBP and SRC-1 enhanced basal and agonist-dependent activation of PPAR responsive element (PPRE)-driven transcription by PPAR delta, rendering a PPRE-driven reporter assay reliable and sensitive. Utilizing this assay for PPAR delta, we re-evaluated the subtype selectivity of a variety of anti-inflammatory drugs for human PPAR. The PPAR agonists tested included two leukotriene (LT) D(4) antagonist, seven NSAIDs, and two anti-rheumatoid drugs. We found that a novel LTD(4) antagonist, FK011 ([2-(((2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl)oxy)methyl)phenyl]acetic acid), showed marked agonistic activity for PPAR gamma. NSAIDs were classified into the following three groups: those showing no activity for all subtypes, those that were selective for PPAR gamma such as indomethacin and diclofenac, and those showing agonistic activity for the delta and gamma subtypes such as ibuprofen. These results will be important to studies on the molecular mechanisms of pharmacological actions of LTD(4) antagonists and NSAIDs.

Biphasic response of cutaneous blood flow induced by passive cutaneous anaphylaxis in rats.

In the immediate phase of passive cutaneous anaphylaxis, sensitized skin mast cells release various mediators when activated by antigen. The present study investigated the effects of the mediators on cutaneous blood flow at the antigen-antibody reaction site. Induction of passive cutaneous anaphylaxis produced a biphasic response consisting of an initial decrease, followed by a sustained increase, in the cutaneous blood flow. The initial phase was almost eliminated by the 5-hydroxytryptamine receptor antagonist methysergide, whereas the second phase was sensitive to the histamine H(2) receptor antagonist ranitidine. The histamine H(1) receptor antagonist chlorpheniramine, the denervation of sensory nerves with capsaicin, the cyclooxygenase inhibitor indomethacin, or the bradykinin B(2) receptor antagonist D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-L-(2alpha,3beta,7abeta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE140) did not affect the blood-flow changes caused by the anaphylaxis. These results suggest that 5-hydroxytryptamine and histamine H(2) receptors mediate the initial decrease and the subsequent increase in cutaneous blood flow, respectively, induced by passive cutaneous anaphylaxis in rats.

Rhythmical contractions in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats.

Rhythmical contractions accompanied by an increase in cytosolic Ca2+ concentrations were produced in ring preparations of endothelium-denuded pulmonary arteries from monocrotaline-treated rats, but not in those from vehicle-treated rats, 2-3 h after a resting tension of 15 mN (150-180% of the initial wall length of the artery) was applied. The rhythmical contractions were abolished by nicardipine and ryanodine. Cyclopiazonic acid reduced the relaxation phase of the rhythmical contractions, finally leading to a sustained contraction. Similarly, apamin caused a sustained contraction, whereas charybdotoxin increased the amplitude of the rhythmical contractions. Glibenclamide had no apparent effects on them. Indomethacin and the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 abolished the rhythmical contractions and reduced the tension, but the thromboxane synthase inhibitor ozagrel had no effect. These results suggest that optimal stretch induces rhythmical contractions in the pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats, to which both Ca2+ influx through voltage-operated Ca2+ channels and Ca2+ release from the endoplasmic reticulum seem to contribute. It is also suggested that small-conductance Ca(2+)-activated K+ channels participate in the relaxation phase of rhythmical contractions. Furthermore, prostaglandin H2 released from nonendothelial cells is likely to play a pivotal role in the induction of rhythmical contractions.

Syncrangon, a new crangonid genus, with redescriptions of S. angusticauda (De Haan) and S. dentata (Balss) (Crustacea, Decapoda, Caridea) from East Asian waters.

A new genus of the crangonid shrimps, Syncrangon, is proposed for Crangon angusticauda De Haan, 1849 and C. (Sclerocrangon) angusticauda var. dentata Balss, 1914, both from East Asian waters. The new genus is readily distinguished from all known genera of the Crangonidae by the flattened middorsal carina and the deep groove on each lateral side of the middorsal carina on the third to sixth abdominal somites. Syncrangon angusticauda new combination has previously been assigned to the genus Metacrangon, while S. dentata new combination has not been reported since the original description. These two species are easily distinguished from each other by many characters, especially the rostral and abdominal features. They are redescribed and illustrated in detail.

[A case of advanced gastric cancer resected after successful treatment with the novel oral anticancer drug TS-1].

We report a case of advanced gastric cancer resected after successful treatment with the novel oral anticancer drug TS-1. The patient was a 52-year-old male. Gastrointestinal fiberscopy showed advanced gastric cancer. Examinations by computed tomography revealed gastric cancer invasion of the pancreas and swollen para-aortic lymph nodes. This patient was treated by preoperative chemotherapy with oral administration of TS-1 (120 mg per day). After 3 courses of treatment of TS-1, the primary lesion and swollen lymph nodes were remarkably reduced. This chemotherapy enabled total gastrectomy in curative resection. The pathological effectiveness of chemotherapy was Grade 1b in the primary lesion and Grade 2 or 3 in the lymph nodes. The patient sustained few side effects. This preoperative chemotherapy regimen seems to be an effective and promising therapy for patients with advanced gastric cancer.

[A case of unresectable rectal cancer with liver and pulmonary metastases that responded remarkably to pharmacokinetic modulating chemotherapy].

We treated a patient with unresectable rectal cancer with multiple liver, pulmonary and lymph node metastases that responded remarkably to pharmacokinetic modulating chemotherapy (PMC). The patient was a 63-year-old male. Colonoscopy showed a type 3 advanced lower rectal cancer. Examinations by computed tomography and chest X-ray revealed unresectable rectal cancer invading the sacrum and bladder with multiple liver and pulmonary metastases and swollen para-aortic lymph nodes. The patient was treated by colostomy and postoperative PMC. UFT (400 mg/day) was orally administered daily and a continuous infusion of 5-FU (1,000 mg/24 h) was given once a week. After 10 courses of treatment with PMC, the primary lesion was remarkably reduced. This chemotherapy also produced partial responses in the pulmonary metastases and para-aortic lymph node swelling. The patient experienced few side effects and had good QOL in the terminal stage. This chemotherapy regimen appears to be an effective and promising therapy with few side effects, even for patients with unresectable advanced colorectal cancer.

Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug.

Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).

[The clinical effect of TS-1 in advanced and recurrent gastric cancer with peritoneal dissemination].

Eighteen patients with far advanced and recurrent gastric cancer with peritoneal dissemination were treated with a novel oral anticancer drug, TS-1, and assessed according to clinical effect. TS-1 was administered at a dose of 80-120 mg/day. One course consisted of consecutive administration of TS-1 for 28 days followed by 14 days rest. The 1- and 2-year survival rates and median survival time after administration of TS-1 were 63.2%, 23.7% and 437 days, respectively. Eight patients (44.4%) survived for 1 year or more. Adverse reactions consisted of reduction in hemoglobin level and hyperbilirubinemia at grades 3 and 4, which were observed in 3 patients and 1 patient, respectively. TS-1 is a promising drug for gastric cancer with peritoneal dissemination.