Chiral Supramolecular U-Shaped Catalysts Induce the Multiselective Diels-Alder Reaction of Propargyl Aldehyde.

The Diels-Alder reaction, which is a traditional [4 + 2] cycloaddition with two carbon-carbon bond formations, is one of the most powerful tools to synthesize versatile and unique six-membered rings. We show that chiral supramolecular U-shaped boron Lewis acid catalysts promote the unprecedented multiselective Diels-Alder reaction of propargyl aldehyde with cyclic dienes. Independent from the substrate control, enantio-, endo/exo-, π-facial-, regio-, site-, and substrate-selectivities could be controlled by the present U-shaped catalysts. The obtained reaction products could access the concise synthesis of chiral diene ligands and a key intermediate of (+)-sarkomycin. The results presented here might partially contribute to the development of artificial enzyme-like supramolecular catalysts for multiselective reactions, which will be able to target organic compounds that have thus far eluded synthesis.

Aerobic Linear Allylic C-H Amination: Overcoming Benzoquinone Inhibition.

An efficient aerobic linear allylic C-H amination reaction is reported under palladium(II)/bis-sulfoxide/Brønsted base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv of olefin, 1 atm O2 or air) with reduced Pd(II)/bis-sulfoxide catalyst loadings while providing higher turnovers and product yields than systems employing stoichiometric benzoquinone (BQ) as the terminal oxidant. Pd(II)/BQ π-acidic interactions have been invoked in various catalytic processes and are often considered beneficial in promoting reductive functionalizations. When such electrophilic activation for functionalization is not needed, however, BQ at high concentrations may compete with crucial ligand (bis-sulfoxide) binding and inhibit catalysis. Kinetic studies reveal an inverse relationship between the reaction rate and the concentration of BQ, suggesting that BQ is acting as a ligand for Pd(II) which results in an inhibitory effect on catalysis.

Catalytic enantioselective synthesis of sterically demanding alcohols using di(2 degrees -alkyl)zinc prepared by the refined Charette's method.

A highly practical, catalytic enantioselective 2 degrees -alkyl addition to aldehydes and ketones was developed. Chiral phosphoramide ligand (1) with salt-free and solvent-free di(2 degrees -alkyl)zinc reagents prepared from (2 degrees -alkyl)MgCl was essential.

Long-term follow-up after eradication of Helicobacter pylori with omeprazole, clarithromycin, and tinidazole (OCT regimen) in a Japanese population.

BACKGROUND: The long-term benefit of Helicobacter pylori eradication treatment that includes metronidazole on peptic ulcer disease in Japan is unclear. We investigated the rate of H. pylori re-infection and ulcer relapse after H. pylori eradication. MATERIALS AND METHODS: A total of 266 patients with endoscopically confirmed peptic ulcer disease and H. pylori infection were treated with triple therapy of omeprazole 40 mg (20 mg b.i.d.), clarithromycin 800 mg (400 mg b.i.d.), and tinidazole 1000 mg (500 mg b.i.d.) for 7 days. Endoscopy with gastric biopsy was performed before and 1 month, 6 months, 1.5 years, and 3.5 years after therapy. H. pylori status was determined by H. pylori culture, rapid urease test, and histopathology. 13C-urea breath test was done at 6 months after eradication therapy. Treatment was deemed successful when all tests were negative at 6 months after therapy by endoscopic biopsy. RESULTS: Successful H. pylori eradication was achieved in 262/266 (98.5%) patients with peptic ulcer. Total relapse of peptic ulcer occurred in 8/262 (3%) patients after eradication, with 3/262 (1.1%) occurring within 1.5 years after treatment and 5/262 (1.9%) within 3.5 years. All relapsed patients were found to be H. pylori-positive at the time of relapse. Of the 262 patients who experienced eradication, 20 (7.6%) were subsequently re-infected, six (2.3%) within 1.5 years and 14 (5.3%) within 3.5 years. CONCLUSION: Triple therapy with omeprazole, clarithromycin, and tinidazole (OCT) is useful for H. pylori eradication in Japan, but there is an appreciable re-infection rate in this population.

Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization.

AIM: To determine the role of interleukin (IL)-17 in gastric ulcerogenesis. METHODS: Thirty-six gastric ulcer (GU) patients and 29 non-ulcer (NU) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used in in situ stimulation for 48 h in the presence of 10 microg/mL phytohemagglutinin-P (PHA), histological examination, and Helicobacter pylori (H pylori) culture. IL-17 and IL-8 protein levels in culture supernatants were assayed by ELISA. IL-17 mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). H pylori cagA and vacA status was assessed by reverse hybridization using a line probe assay (LiPA). IL-8 levels in culture supernatants were assayed after AGS cells were co-cultured with H pylori strain 26,695 or recombinant human (rh) IL-17. RESULTS: All 36 GU patients and 15 of 29 NU patients were found to be H pylori-positive, while 14 NU patients were H pylori-negative. All 51 H pylori strains from both GU and NU patients were cagA- and vacAs1/m1-positive. Antral mucosal tissues from H pylori-positive patients contained significantly (H pylori-positive NU patients: median 467 pg/mg/protein, range 53-2,499; H pylori-negative NU patients: median 104 pg/mg/protein, range 16-312, P< 0.0005) higher levels of IL-17 than those from uninfected patients. IL-17 levels at the ulcer site were significantly (ulcer site: median 1,356 pg/mg/protein, range 121-1,3730; antrum: median 761 pg/mg/protein, range 24-7,620, P< 0.005) higher than those at distant sites in the antrum. Biopsies from H pylori-positive GU and NU patients showed IL-17 mRNA expression in all samples whereas those from the antrum of the H pylori-negative controls showed no detectable expression. A significant correlation was seen between IL-17 and IL-8 levels at each biopsy site (ulcer: r = 0.62, P< 0.0001; antrum: r = 0.61, P< 0.0001) in GU patients. RhIL-17 and H pylori strain 26,695 each stimulated IL-8 production from AGS cells. CONCLUSION: IL-17 may play an important role in the inflammatory response to H pylori colonization, and may ultimately influence the outcome of H pylori-associated diseases that arise within the context of gastritis.

Characteristics of Helicobacter pylori-induced gastritis and the effect of H. pylori eradication in patients with chronic idiopathic thrombocytopenic purpura.

BACKGROUND: The association between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has been reported widely. We investigated the prevalence of H. pylori infection, its virulence profile and the effectiveness of its eradication in patients with ITP. MATERIALS AND METHODS: Twenty patients with ITP, 20 with peptic ulcer (10 gastric ulcer (GU), 10 duodenal ulcer (DU)) and 20 with NUD were studied. The virulence profile of the strains was assessed by genotyping for cagA, vacA, iceA, and hpyIIIR/hrgA and by assaying for IL-8 and DNA fragmentation after incubation with AGS cells. Infected patients and two uninfected ITP patients received triple therapy and platelets were counted before and 1 month, 6 months, 1 year, and 2 years after eradication therapy. RESULTS: H. pylori infection was found in 17 ITP (85%), 20 ulcer (100%) and 13 NUD (65%) patients. Biopsies and strains were collected from five ITP, 20 ulcer and 13 NUD patients. The ITP patients had a pangastritis or corpus-predominant gastritis pattern. All H. pylori isolates, from ITP, ulcer and NUD patients, were cagA(+) and vacA s1/m1, and did not differ in levels of IL-8 induction or DNA fragmentation. Fifteen ITP (88%) and 17 ulcer (85%) patients had successful eradication of H. pylori. Ten of these 15 (67%) H. pylori-eradicated ITP patients had platelet recovery. There was no significant change in platelet count in the two ITP patients in whom eradication failed or in the two originally H. pylori-uninfected ITP patients, or in the treated ulcer patients. Age at onset of ITP was the main determinant of platelet recovery: 100% of patients diagnosed after the age of 60 recovered compared with only 22% of those diagnosed before 50. CONCLUSIONS: H. pylori-infected ITP patients have a corpus-predominant pattern of gastritis but the virulence profile of their strains does not differ from that of ulcer or NUD patients. Eradication of H. pylori infection is a good therapeutic option for some patients with chronic ITP, especially for those who develop ITP in older age.

[Complete response in a case of advanced scirrhous type 3 gastric cancer of with bulky N2 para-aorta lymph node metastases treated by combined chemotherapy of TS-1 and CDDP].

A 54-year-old patient with scirrhous type 3 gastric cancer having bulky N2 and para-aorta lymph node metastases was treated by combined chemotherapy of TS-1 and CDDP. Before treatment, CEA was 28.4 mg/ml. TS-1 (120 mg/day) administered for 14 days followed by 14 days rest was one course. CDDP (80 mg/m2) was administered by 24 hour continuous intravenous infusion at day 8 after the start of TS-1. After 2 courses of treatment, the level of CEA decreased to 1.4 mg/ml and the primary legion with lymph node metastases had decreased significantly. After 5 courses, endoscopic examination revealed complete disappearance of the primary tumor with no cancer cells detected by endoscopic biopsy. A CT scan also showed complete disappearance of all lymph node metastases. No severe adverse effects (NCI-CTC grade 3 of 4) were observed with this therapy. TS-1/CDDP chemotherapy is considered very effective for scirrhous gastric cancer with far advanced lymph node metastases.

[A pilot study of TS-1 combined with cisplatin in patients with advanced gastric cancer].

TS-1 is a novel oral fluoropyrimidine anticancer agent and show synergism with CDDP. The objectives of this study were to determine the clinical toxicities, antitumor effect, survival duration, and a recommended dosage schedule in combination with TS-1 and CDDP. Patients with measurable, locally advanced or metastatic gastric cancer were candidates for the study. Three patients were assigned to one of four levels of treatment, as follows. At first, TS-1 was administered orally twice a day for 14 consecutive days followed by 14 days rest and a 24-h infusion of CDDP (70 mg/m2) was administered on day 8 of 28 every 4 weeks. Next, duration of S1 administration was increased in increments of 25% and in increments of 50%. At last, only the dose of CDDP was increased in increments of 10 mg/m2. The first three patients did not have over grade 3 hematologic and nonhematological toxicity during any course. Grade 4 neutropenia occurred during the second course in two patients consecutively in increments of 50% of TS-1. Neutropenia was considered as a dose limiting toxicity. Nonhematologic side effects generally were mild. The overall response rate including all levels was 90.9%. Three complete responses (27.3%) and 8 partial responses (63.6%) were observed among the 11 patients. At first schedule, CR was two of three patients, and PR by the other (overall response rate, 100%). Survival rate of all cases in eight months were 100%. In conclusion, a combination of TS-1 and CDDP chemotherapy showed favorable antitumor activity and less adverse reaction compared to results reported with other chemotherapy. Administration of TS-1 for 14 days followed by 14 days rest, plus CDDP (70 mg/m2) on day 8 every 4 weeks would be recommended in the view of high responsibility and low adverse reaction.

[Complete response in an elderly patient with advanced gastric scirrhous cancer treated with combined chemotherapy of TS-1 and CDDP].

A 79-year-old male was diagnosed as having a scirrhous cancer of the stomach. Carcinomatous peritonitis was suspected on abdominal CT examination and the CA19-9 showed a high level of 95 U/ml. The patient was treated with combined chemotherapy of TS-1 and CDDP. TS-1 (100 mg/day) was administered for 14 days followed by 14 days rest as one course. CDDP was administered in 24-h continuous intravenous infusion on day 8. This treatment was done every 4 weeks regularly. After 5 courses, X-ray and endoscopy examinations revealed disappearance of cancerous lesions in the stomach with an improvement in the extensibility. No cancer cell were confirmed by endoscopic biopsy, nor did a CT-scan detect carcinomatous peritonitis. The CA19-9 decreased within the normal limit. Ten months after chemotherapy was started, the patient was very healthy without a recurrence of cancer. This combined chemotherapy has administered in 8 courses, and during this period no high grade toxicities (WHO grade 3 or 4) occurred. This TS-1/CDDP chemotherapy was effective for scirrhous gastric cancer and might be administered safely even for aged patients.

[Complete response in a case of simultaneous esophageal and gastric cancer treated by combined radiotherapy and chemotherapy of TS-1 and CDDP].

A 75-year-old male patient was hospitalized for examination of abdominal trouble. Endoscopic examination simultaneously revealed 0-I pl + II c esophageal cancer and type 3 gastric cancer. Endoscopic treatment is impossible to resect the lesion completely. It is difficult for the patient to undergo an operation because he has suffered from a cardiac infarction and pulmonary trouble. Thus, gastric cancer was treated by chemotherapy and esophageal cancer by concurrent chemoradiotherapy with chemotherapy used for gastric cancer. Chemotherapy consisted of CDDP and TS-1 every 4 weeks. TS-1 (100 mg/day) was administered on days 1 to 21, and CDDP (70 mg/m2) was infused for 24 hours on day 8. Radiotherapy (5 days/week) at 2 Gy/day was concurrently started from the beginning of chemotherapy. At day 8 in the 2nd course of chemotherapy, leucocytopenia of grade 2 and appetite loss of grade 3 (NCI-CTC) were seen. Chemoradiotherapy was then suspended for one week. After recovery from toxicity, treatment was continued for a week. A total of 64 Gy was administered. After treatment, endoscopic examination with biopsy revealed the disappearance of gastric and esophageal cancer.