Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel.

Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.

Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese.

INTRODUCTION: The aim of therapeutic regimens using proton pump inhibitors (PPIs) in patients with acid-related diseases is to potently inhibit acid secretion for the full 24 h. However, optimum treatment is still unclear because the pharmacodynamics of PPIs differ among CYP2C19 genotypes and most of the previous studies have had loss of sample power. METHODS: Using pH monitoring, we compared acid inhibition at standard dosage of omeprazole (20 mg, 50 times), lansoprazole (30 mg, 68 times), and rabeprazole (10 mg, 65 times) in Helicobacter pylori-negative healthy young Japanese volunteers. RESULTS: Median pH with rabeprazole was 5.4 (3.3-7.5), which was significantly greater than with either omeprazole [4.4 (2.1-7.3)] or lansoprazole [4.8 (3.5-6.4)] (both P < 0.05). Median 24-h pH differed among the different CYP2C19 genotypes in all three PPIs. In CYP2C19 extensive metabolizers (EMs), the genotype that is refractory to PPI treatment, median pH with omeprazole, lansoprazole, and rabeprazole was 3.8 (2.1-4.4), 4.5 (3.5-5.3) and 4.8 (3.3-7.5), respectively. DISCUSSION: Treatment with the selected PPIs at their standard dosages had difficulty maintaining acid inhibition for a full 24 h, especially in CYP2C19 EM. However, rabeprazole has the merit of less influence of CYP2C19 genotype compared with the other PPIs.

Sitafloxacin-based third-line rescue regimens for Helicobacter pylori infection in Japan.

BACKGROUNDS: Quinolone-based regimens have been used as the rescue for eradication of Helicobacter pylori. Sitafloxacin is known to have low minimum inhibitory concentration for H. pylori. Here, we compared two sitafloxacin-based eradication regimens as rescue for the eradication of H. pylori. METHODS: We attempted to eradicate H. pylori in 180 Japanese patients who had never failed in eradication of H. pylori with the triple proton pump inhibitor/amoxicillin/clarithromycin therapy (1st line) and the triple proton pump inhibitor/amoxicillin/metronidazole therapy (2nd line). They were assigned to either the triple therapy with rabeprazole 10 mg b.i.d./q.i.d., amoxicillin 500 mg q.i.d, and sitafloxacin 100 mg b.i.d. (RAS) for 1 or 2 weeks or the triple therapy with rabeprazole 10 mg b.i.d./q.i.d., metronidazole 250 mg b.i.d., and sitafloxacin 100 mg b.i.d. (RMS) for 1 or 2 weeks. Eradication was assessed via the (13) C-urea breath test and rapid urease test. RESULTS: Intention-to-treat and per-protocol analyses of eradication rates were 84.1% (37/44) and 86.4% (37/43) with RAS for 1 week, 88.9% (40/45) and 90.9% (40/44) for RAS for 2 weeks, 90.9% (40/44) and 90.9% (40/44) for 1 week-RMS and 87.2% (41/47) and 91.1% (41/45) with RMS for 2 weeks. We noted no statistical significant differences in eradication rates among four regimens. CONCLUSION: All of the above-described rescue regimens proved relatively equally useful in the eradication of H. pylori. Of them, RAS for 2 weeks and RMS for 1 or 2 weeks could attain the rescue eradication rates higher than 90% by per-protocol analysis.

Ability of rabeprazole to prevent gastric mucosal damage from clopidogrel and low doses of aspirin depends on CYP2C19 genotype.

BACKGROUND & AIMS: Low doses of aspirin can injure the gastric mucosa. It is not clear whether other drugs such as the antiplatelet agent clopidogrel also cause gastric mucosal injury or exacerbate aspirin-induced injury, or whether proton pump inhibitors prevent damage. METHODS: Twenty Japanese subjects with different CYP2C19 genotypes were randomly assigned to groups that were given a low dose of aspirin (100 mg; A), clopidogrel (75 mg; C), low dose of aspirin and clopidogrel (AC), or low dose of aspirin in combination with clopidogrel and rabeprazole (10 mg; ACR) once daily for 7 days. Subjects underwent gastroduodenoscopy and platelet tests on days 3 and 7; gastric mucosal damage was assessed by using the modified Lanza score (MLS). We performed 24-hour intragastric pH monitoring on day 7 of each regimen. We also analyzed the effects of the AC regimen on 30 patients with different CYP2C19 genotypes. RESULTS: Subjects in groups A, C, and AC had significantly higher levels of gastric mucosal damage on days 3 and 7, compared with baseline. The median MLS for the AC group was similar to that of the A group. Helicobacter pylori-negative subjects in the ACR group with different CYP2C19 genotypes had significant differences in MLS, intragastric pH, and platelet function. Gastric mucosal injury was inhibited equally among H pylori-positive subjects in the ACR group. Rabeprazole did not appear to affect platelet function or intragastric pH in subjects given clopidogrel. CONCLUSIONS: Clopidogrel and low doses of aspirin cause a similar degree of gastric mucosal damage. Rabeprazole prevented this damage without reducing the antiplatelet function of clopidogrel. However, its prophylactic effect varies with CYP2C19 genotype in H pylori-negative subjects.

Impact of acid inhibition on esophageal mucosal injury induced by low-dose aspirin.

BACKGROUND AND AIM: Aspirin enjoys widespread use as an antithrombotic drug, but such ubiquity also increases the risk of gastrointestinal mucosal injury. Recent studies have shown that aspirin can also induce esophageal mucosal injury. We resolved to determine the intragastric pH value necessary to prevent aspirin-induced esophageal mucosal injury. METHODS: 15 healthy Japanese volunteers were dosed for 7 days in a four-way random crossover trial with 100 mg entero-coated type aspirin only once daily, 100 mg aspirin + 20 mg famotidine twice daily, 15 mg lansoprazole once daily, or 10 mg rabeprazole once daily. All subjects underwent endoscopy and intragastric pH monitoring on day 7. RESULTS: 7 individuals (46.7%) developed esophageal mucosal injury when ingesting aspirin alone. The incidence of esophageal mucosal injury was reduced however with concomitant dosing of aspirin and famotidine (26.6%; p = 0.193), lansoprazole (0%; p = 0.004), and rabeprazole (6.7%; p = 0.019). Among individuals for whom mean 24-h pH was >5.0 and who experienced pH <4.0 less than 40% of the time, none developed aspirin-induced esophageal mucosal injury. CONCLUSION: Acid inhibition achieved with a half-dose of a proton pump inhibitor effectively prevented development of aspirin-induced esophageal mucosal injury, whereas a standard dose of a histamine-2-receptor antagonist failed to achieve the same results.

Influence of different proton pump inhibitors on activity of cytochrome P450 assessed by [(13)C]-aminopyrine breath test.

Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.

Resistance of Helicobacter pylori to quinolones and clarithromycin assessed by genetic testing in Japan.

BACKGROUND AND AIM: As bacterial resistance to clarithromycin limits the efficacy of clarithromycin-based regimens for Helicobacter pylori infection, attention has turned to quinolone-based rescue therapies. Resistance of H. pylori to both clarithromycin and quinolone can be predicted by genetic testing. Here, we used this approach to evaluate the prevalence of clarithromycin- and quinolone-resistant strains of H. pylori in Japan. METHODS: DNA was extracted from gastric tissue samples obtained from 153 patients infected with H. pylori (103 naive for eradication therapy and 50 with previous eradication failure following triple proton pump inhibitor/amoxicillin/clarithromycin therapy). Mutations in H. pylori 23S rRNA and gyrA genes associated with resistance to clarithromycin and quinolones, respectively, were determined. RESULTS: Of 153 patients, 85 (55.6%) were infected with clarithromycin-resistant strains. The prevalence of clarithromycin-resistant strains in patients with previous eradication failure (90.0%, 45/50) was significantly higher than that (38.8%, 40/103) of those naive for eradication therapy (P < 0.001). Fifty-nine patients (38.6%) were infected with strains resistant to quinolones. The incidence of quinolone-resistant strains also appeared higher in patients with eradication failure (48.0%, 24/50) than in those who had not undergone therapy (34.0%, 35/103); however, the difference was not statistically significant (P = 0.112). The incidence of quinolone-resistance in clarithromycin-resistant strains (44/85, 51.8%) was significantly higher than that in clarithromycin-sensitive strains (15/68, 22.1%) (P < 0.001). CONCLUSIONS: A high incidence of quinolone-resistance was found in clarithromycin-resistant strains of H. pylori, particularly in patients with previous eradication failure. Our results suggest that testing for susceptibility of H. pylori to quinolones is useful for determining the optimal rescue eradication regimen.

Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy.

AIM: To investigate whether potent acid inhibition is effective in non-erosive reflux disease (NERD) refractory to standard rabeprazole (RPZ) treatment. METHODS: We treated 10 Japanese patients with NERD resistant to standard dosages of RPZ: 10 mg or 20 mg od, 20 mg bid, or 10 mg qid for 14 d. All patients completed a frequency scale for symptoms of gastroesophageal reflux disease questionnaire frequency scale for the symptoms of GERD (FSSG); and underwent 24 h pH monitoring on day 14. RESULTS: With increased dosages and frequency of administration of RPZ, median intragastric pH significantly increased, and FSSG scores significantly decreased. With RPZ 10 mg qid, potent acid inhibition was attained throughout 24 h. However, five subjects were refractory to RPZ 10 mg qid, although the median intragastric pH in these subjects (6.6, range: 6.2-7.1) was similar to that in the remaining five responsive subjects (6.5, range: 5.3-7.3). With baseline RPZ 10 mg od, FSSG scores in responsive patients improved by > 30%, whereas there was no significant decrease in the resistant group. CONCLUSION: NERD patients whose FSSG score fails to decrease by > 30% after treatment with RPZ 10 mg od for 14 d are refractory to higher dosage.

[A case of eosinophilic gastroenteritis accompanied with fasciitis of the extremities].

We encountered a very rare case of eosinophilic gastroenteritis accompanied with fasciitis of the extremities. The patient was a 28-year-old woman with epigastralgia, eosinophilia plus leukocytosis, massive pleural effusion and ascites, and thickening of the walls of the intestine. Increase of the eosinophilic fraction in her ascites led to a diagnosis of eosinophilic gastroenteritis. She soon developed resting pain in all limbs and MRI revealed fasciitis. Prednisolone was effective in treating both gastroenteritis and fasciitis.

Preventive effects of lansoprazole and famotidine on gastric mucosal injury induced by low-dose aspirin in Helicobacter pylori-negative healthy volunteers.

The preventive effects of lansoprazole and famotidine on low-dose aspirin-induced gastric mucosal injury in relation to gastric acidity were compared in healthy Japanese volunteers. Fifteen Helicobacter pylori-negative volunteers with different CYP2C19 genotypes were randomly administered aspirin 100 mg, aspirin plus famotidine 20 mg twice daily, or aspirin plus lansoprazole 15 mg once daily for 7 days each in a crossover fashion. Gastroscopy for the evaluation of mucosal injury based on modified Lanza score (MLS) and 24-hour intragastric pH monitoring were performed on day 7 of each regimen. Aspirin induced gastric mucosal injury (median MLS = 3). Lansoprazole significantly decreased MLS to 0, which was significantly lower than that by famotidine (MLS = 1) (P < .05). Medians of pH 3 holding time and mean 24-hour pH values with the lansoprazole regimen were significantly higher than those with famotidine (P < .05). No significant differences in MLS were observed among the different CYP2C19 genotype groups in any of the treatment regimens. In this 7-day study, lansoprazole appeared to be more protective than famotidine against low-dose aspirin-induced mucosal injury but a larger well-controlled study is necessary to establish a definitive clinical benefit.

The dual therapy with 4 times daily dosing of rabeprazole and amoxicillin as the 3rd rescue regimen for eradication of H. pylori.

BACKGROUNDS/AIMS: Most of patients who are refractory to usual standard eradication therapies for H. pylori infection have rapid metabolizer genotype of CYP2C19 and are infected with resistant strains to several antimicrobial agents. However, most of H. pylori strains are sensitive to amoxicillin. We tested whether dual therapy with the 4 times daily dosing of rabeprazole and amoxicillin was effective as the 3rd rescue regimen for eradication of H. pylori. METHODOLOGY: 49 patients who failed in eradication of H. pylori after two (1st: proton pump inhibitor (PPI)/amoxicillin/clarithromycin and 2nd: PPI/amoxicillin/metronidazole) were enrolled to the study. They were treated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. At 4 weeks after the treatment, they underwent the [13C]-urea breath test. When the result of [13C]-urea breath test was negative, they underwent the endoscopy and the successful eradication was confirmed by rapid urease test. RESULTS: All patients completed the treatment. The eradication rate was 87.8% (43/49) (95% CI = 75.2%-95.4%). No undesirable severe adverse events were observed during the study period. CONCLUSIONS: The dual therapy with 4 times daily dosing of rabeprazole and amoxicillin is well tolerated and effective as the 3rd rescue regimen for eradication of H. pylori.

Esophageal mucosal injury with low-dose aspirin and its prevention by rabeprazole.

Aspirin is used widely as an antithrombotic drug for the prevention of cardiovascular and cerebrovascular events. Although aspirin increases the risk for gastrointestinal mucosal injury, the effect on esophageal mucosa is unclear. This study investigates whether aspirin induces esophageal mucosal injury and whether a proton-pump inhibitor can prevent such injury in relation to CYP2C19 genotypes. Fifteen healthy Japanese volunteers are dosed for 7 days in a 5-way randomly crossover trial: placebo, aspirin 100 mg, rabeprazole 10 mg, and aspirin 100 mg plus rabeprazole 10 mg either once daily or 4 times per day. All subjects undergo endoscopy and 24-hour intragastric pH monitoring on day 7. With the aspirin regimen, esophageal mucosal disorders occur in 7 patients (46.7%) (5, grade M; 2, grade A). The median 24-hour pH differs significantly among subjects who develop grade M or A gastroesophageal reflux disease and those who do not develop gastroesophageal reflux disease; the median pH in grade A gastroesophageal reflux disease is significantly lower (1.5 [range, 1.1-1.9]) than that in patients without gastroesophageal reflux disease (5.6 [range, 0.8-8.4], P = .04). Rabeprazole significantly inhibits acid secretion irrespective of CYP2C19 genotypes and decreases the incidence of aspirin-related esophageal injury and symptoms according to increasing pH value. Aspirin induces esophageal mucosal injury in an acid-dependent manner. Concomitant proton-pump inhibitor therapy may prevent advanced effects of low-dose aspirin.

Relationship between low-dose aspirin-induced gastric mucosal injury and intragastric pH in healthy volunteers.

BACKGROUND AND AIMS: Gastric acid plays an important role in the pathogenesis of gastric mucosal lesions. We investigated whether aspirin-induced gastric mucosal injury might have any association with the intragastric pH. MATERIALS AND METHODS: Fifteen healthy, Helicobacter pylori-negative volunteers randomly underwent the four different 7-day regimens: (1) aspirin 100 mg, (2) rabeprazole 10 mg, (3) aspirin 100 mg + rabeprazole 10 mg, and (4) aspirin 100 mg + rabeprazole 40 mg. Gastric mucosal injury based on the modified Lanza score (MLS), 24-h intragastric pH, and histopathology of gastric mucosa were evaluated prior to the start and on day 7 of each regimen. RESULTS: The median MLSs were 0 in the baseline and the rabeprazole 10 mg regimen. The median MLS in the aspirin regimen was 3, while those in both aspirin + rabeprazole 10 mg and aspirin + rabeprazole 40 mg regimens were 0. Rabeprazole significantly prevented the gastric mucosal injury by aspirin (P = 0.001 for rabeprazole 10 mg and P = 0.005 for rabeprazole 40 mg). The MLSs were negatively correlated with the 24-h intragastric pH (P = -0.711, < 0.001), whereas aspirin had no effect on the intragastric pH. Aspirin expanded the mean diameter of the microvessels of the gastric mucosa, which, in turn, was negatively correlated with the intragastric pH. CONCLUSIONS: Aspirin might induce gastric mucosal injury by affecting the mucosal microvessels in an acid-dependent manner. Sustained maintenance of the intragastric pH at an elevated value is necessary to prevent gastric mucosal damage induced by aspirin.

Prospective study of daily low-dose nedaplatin and continuous 5-fluorouracil infusion combined with radiation for the treatment of esophageal squamous cell carcinoma.

BACKGROUND: Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum) and continuous infusion of 5-fluorouracil (5-FU) with radiation in patients with esophageal squamous cell carcinoma. METHODS: Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day) was administered daily and 5-FU (500 mg/body/day) was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival. RESULTS: Twenty-two patients (72.7%) completed the regimen of chemoradiotherapy. Twenty patients (60.6%) achieved a complete response, 10 patients (30.3%) a partial response. One patient (3.0%) had a stable disease, and 2 (6.1%) a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%). For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8%) and the median number of courses was 3 (range, 1-5). The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease. CONCLUSION: The treatment used in our study may yield a high complete response rate and better survival for each stage of esophageal squamous cell carcinoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00197444.

A case of small bowel adenocarcinoma in a patient with Crohn's disease detected by PET/CT and double-balloon enteroscopy.

Small bowel adenocarcinoma (SBA) in patients with Crohn's disease (CD) is quite rare, difficult to diagnose without surgery, and has a poor prognosis. Here, we report a 48-year-old man with SBA and a 21-year history of CD who was diagnosed by a combination of positron emission tomography/computed tomography (PET/CT) and double-balloon enteroscopy (DBE). Since the age of 27 years, the patient had been treated for ileal CD and was referred to our hospital with persistent melena. Multiple hepatic tumors were found by CT. PET/CT detected an accumulation spot in the small bowel. DBE revealed an ulcerative tumor in the ileum about 100 cm from the ileocecal valve. An endoscopic forceps biopsy specimen showed poorly differentiated adenocarcinoma. There were some longitudinal ulcer scars near the tumor, and the chronic inflammation in the small bowel appeared to be associated with the cancer development. Previous reports suggest the risk of SBA in patients with CD is higher than in the overall population. Since early diagnosis is extremely difficult in these cases, novel techniques, such as PET/CT and DBE, may be expected to help in making a preoperative diagnosis of the development of SBA in CD.

CYP2C19 genotype is associated with symptomatic recurrence of GERD during maintenance therapy with low-dose lansoprazole.

BACKGROUND/AIMS: Maintenance therapy of gastroesophageal reflux disease (GERD) is usually performed with a low dose of a proton-pump inhibitor (PPI). Because PPIs are metabolized by CYP2C19 in the liver, we investigated whether a patient's CYP2C19 genotype was associated with symptomatic recurrence of GERD during maintenance therapy with a low dose of a PPI. METHODS: We enrolled 124 patients with erosive GERD whose esophageal mucosal breaks were endoscopically proven to be cured after treatment with lansoprazole 30 mg/day for 8 weeks. When reflux symptoms occurred less than once per week, the dose of lansoprazole was decreased to 15 mg/day, but if symptoms then occurred more than once per week, it was restored to 30 mg/day. CYP2C19 genotypes were classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). RESULTS: In 18 of 54 RMs, 28 of 56 IMs, and 8 of 14 PMs, the maintenance dose of lansoprazole was decreased to 15 mg/day, but in 16 (88.9%), 22 (78.6%), and 4 (50%), respectively, there was symptomatic recurrence of GERD and the dose was restored to 30 mg/day. The hazard ratios of symptomatic recurrence of GERD in IMs and PMs compared with RMs were 0.40 (95%CI: 0.19-0.87, P = 0.021) and 0.19 (95%CI: 0.05-0.69, P = 0.011). CONCLUSION: When the dose of lansoprazole is decreased, the RM genotype of CYP2C19 appears to be a risk factor for symptomatic recurrence of GERD. The CYP2C19 genotyping test would be useful for determining the optimal dose of a PPI for maintenance therapy of GERD.

[A case of elderly esophageal adenocarcinoma successfully treated with daily low-dose nedaplatin (CDGP) and continuous infusion of 5-FU combined with radiation].

We report an elderly patient with esophageal adenocarcinoma in whom a complete response (CR) was obtained by chemoradiotherapy using daily low-dose nedaplatin (CDGP) and continuous infusion of 5-FU. A 86-year-old man who had non-tuberculous mycobacterial infection was admitted for dysphagia, and diagnosed with Stage II A (T2N0M0) esophageal adenocarcinoma of the lower esophagus according to the TNM classification (sixth edition) of the International Union against Cancer (UICC). Chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5- FU was performed, and thereafter one cycle of chemotherapy using CDGP and 5-FU was added. As the side effects of treatment, grade 3 leucopenia was observed while he was receiving chemoradiotherapy. A year later, he presented with grade 2 pericardial and pleural effusion and recovered with conservative treatment. CR was obtained and has been continued for two years. Definitive chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5-FU is an effective choice for elderly and high-risk patients with esophageal adenocarcinoma.

Effect of MDR1 C3435T polymorphism on lansoprazole in healthy Japanese subjects.

BACKGROUND AND AIMS: The effect of multidrug resistance transporter gene 1 (MDR1) on the bioavailability and kinetics of several substrates has not yet been fully elucidated. We evaluated the influence of MDR1 C3435T polymorphism on the pharmacokinetics and pharmacodynamics of lansoprazole in Japanese subjects. METHODS: Fifteen healthy volunteers with the rapid extensive metabolizer genotype of CYP2C19 were classified into three MDR1 C3435T genotype groups: C/C (n = 5), C/T (n = 5), and T/T (n = 5). Lansoprazole 30 mg was administered orally for 15 days. The intragastric pH and plasma lansoprazole levels were determined on days 1 and 15. RESULTS: On day 1, the mean C(max) of lansoprazole in the T/T group was significantly higher than that in the C/C or C/T groups (T/T 1,248, C/C 618, C/T 607 ng/ml; P = 0.038). On day 15, similar MDR1 genotype-dependent differences were observed in the C(max) of lansoprazole, although smaller than the differences observed on day 1. In contrast, the intragastric pH attained after lansoprazole administration did not differ among MDR1 genotype groups on either day 1 or day 15. CONCLUSION: Although the sample size was small, our study demonstrated that the MDR1 C3435T polymorphism influenced the pharmacokinetics, but not the pharmacodynamics (i.e., intragastric pH), of lansoprazole in rapid metabolizers of CYP2C19.

Polymorphisms of matrix metalloproteinase-7 and chymase are associated with susceptibility to and progression of gastric cancer in Japan.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most macromolecules making up the extracellular matrix. MMPs are involved in not only the gastric mucosal inflammatory response but also the pathogenesis of Helicobacter pylori-associated diseases. In the renin-angiotensin system, chymase (CMA) is related to gastric carcinogenesis and angiogenesis in H. pylori-infected patients. We aimed to clarify the association of MMP-7-181 and CMA/B polymorphisms with susceptibility to gastric cancer and cancer progression in H. pylori-infected patients. METHODS: We assessed the MMP-7-181 and CMA/B polymorphisms in H. pylori-positive patients with gastric cancer (n = 160), gastric ulcer (n = 157), duodenal ulcer (n = 121), and H. pylori-positive gastritis alone as controls (n = 156). RESULTS: For gastric cancer risk, the age-and sex-adjusted odds ratio (OR) of the MMP-7-181 G allele carrier relative to the A/A genotype was significantly increased [OR, 2.32; 95% confidence interval (CI), 1.24-4.35], especially in patients with noncardia cancer (OR, 2.31; 95% CI, 1.22-4.36) and those with clinical stage III or IV cancer (OR, 3.66; 95% CI, 1.54-8.73). Carriage of the CMA/B A allele was significantly associated with gastric cancer development (OR, 1.73; 95% CI, 1.10-2.71). Simultaneous carriage of both the MMP-7-181 G allele and the CMA/B A allele dramatically increased the gastric cancer risk (OR, 8.18; 95% CI, 2.79-23.93). CONCLUSIONS: In Japan, carriage of the MMP-7-181 G allele and of the CMA/B A allele were each associated with an increased risk for H. pylori-related noncardia gastric cancer development. MMP-7-181 and CMA/B genotyping tests might be useful tools for screening for individuals with higher gastric cancer risk.