bluuebunny/crossref_metadata_2025 huggingface dataset:
Ranitidine bismuth citrate plus clarithromycin is effective for healing duodenal ulcers, eradicating H. pylori and reducing ulcer recurrence. RBC H. pylori Study Group [see comments]
Authors: Peterson WL , Ciociola AA , Sykes DL , McSorley DJ , Webb DD
Published: June 2006

AIM: To compare the efficacy of the coadministration of ranitidine bismuth citrate plus the antibiotic clarithromycin, with ranitidine bismuth citrate alone or clarithromycin alone for the healing of duodenal ulcers, eradication of H. pylori and the reduction of ulcer recurrence. METHODS: This two‐phase, randomized, double‐blind, placebo‐ controlled, multicentre study consisted of a 4‐week treatment phase followed by a 24‐week post‐treatment observation phase. Patients with an active duodenal ulcer were treated with either ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus placebo t.d.s. for first 2 weeks; placebo b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; or placebo b.d. for 4 weeks plus placebo t.d.s. for the first 2 weeks. RESULTS: Ulcer healing rates after 4 weeks of treatment were highest with ranitidine bismuth citrate plus clarithromycin (82%) followed by ranitidine bismuth citrate alone (74%; P = 0.373), clarithromycin alone (73%; P = 0.33) and placebo (52%; P = 0.007). Ranitidine bismuth citrate plus clarithromycin provided significantly better ulcer symptom relief compared with clarithromycin alone or placebo (P < 0.05). The coadministration of ranitidine bismuth citrate plus clarithromycin resulted in significantly higher H. pylori eradication rates 4 weeks post‐treatment (82%) than did treatment with either ranitidine bismuth citrate alone (0%; P < 0.001), clarithromycin alone (36%; P = 0.008) or placebo (0%; P < 0.001). Ulcer recurrence rates 24 weeks post‐treatment were lower following treatment with ranitidine bismuth citrate plus clarithromycin (21%) compared with ranitidine bismuth citrate alone (86%; P < 0.001), clarithromycin alone (40%; P = 0.062) or placebo (88%; P = 0.006). All treatments were well tolerated. CONCLUSIONS: The coadministration of ranitidine bismuth citrate plus clarithromycin is a simple, well‐tolerated and effective treatment for active H. pylori‐ associated duodenal ulcer disease. This treatment regimen effectively heals duodenal ulcers, provides effective symptom relief, eradicates H. pylori infection and reduces the rate of ulcer recurrence. The eradication of H. pylori infection in patients with recently healed duodenal ulcers is associated with a significant reduction in the rate of ulcer recurrence.
Prospective evaluation of the macrolide antibiotic dirithromycin for the treatment of Helicobacter pylori.
Authors: Laine L , Stein C , Garcia F , Trujillo M , Estrada R
Published: June 2006

BACKGROUND: Macrolide antibiotics are active in vitro and in vivo against Helicobacter pylori. We assessed a newer macrolide, dirithromycin, for the treatment of H. pylori in two separate studies. METHODS: Volunteers with H. pylori infection (by 13C‐urea breath test) were randomly assigned to 2‐week treatment regimens. Study 1: dirithromycin 500 mg q.d.s., dirithromycin 500 mg q.d.s. plus omeprazole 40 mg q.d.s., or dirithromycin 500 mg q.d.s. plus metronidazole 500 mg t.d.s. Study 2: dirithromycin 500 mg q.d.s. plus omeprazole 20 mg b.d., dirithromycin 1000 mg q.d.s. plus omeprazole 20 mg b.d., or amoxycillin 500 mg q.d.s. plus omepirazole 20 mg b.d. Four weeks after the completion of therapy a repeat 13C‐urea breath test was done to assess for cure. RESULTS: No patient taking dirithromycin alone (n = 6) or in combination with omeprazole (n = 26) achieved cure of their infection. Eradication of H. pylori was seen in one of seven patients taking dirithromycin plus metronidazole. Five of 10 patients taking omeprazole‐amoxycillin dual therapy had their H. pylori infection cured (P = 0.0007 vs. patients taking dirithromycin plus omeprazole). Eleven (47%) of 32 patients taking dirithromycin alone or combined with omeprazole reported side‐effects, but only two (6%) stopped therapy prematurely as a result of side‐effects. CONCLUSION: No subject taking dirithromycin alone or in combination with omeprazole had their H. pylori infection cured. Dirithromycin, in the regimen used, shows little promise in the treatment of patients with H. pylori infection.
Comparison of two low‐dose one‐week triple therapy regimens with and without metronidazole for cure of H. pylori infection.
Authors: Jaup BH , Norrby A
Published: June 2006

BACKGROUND: One‐week triple therapy consisting of omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and tinidazole 500 mg b.d. is an effective therapy for H. pylori infection with a cure rate of 93%. We therefore compared two similar 1‐week regimens consisting of a lansoprazole, clarithromycin and either metronidazole or tetracycline in a prospective study. METHODS: Two cohorts, each of 60 patients suffering from H. pylori infection associated with peptic ulcer disease or ulcer‐like dyspepsia, were treated for 1 week with either lansoprazole 30 mg b.d., clarithromycin 250 mg b.d. and either metronidazole 400 mg b.d. (cohort A, n = 60) or tetracycline 300 mg b.d. (cohort B, n = 60). Four weeks after treatment, cure of H. pylori infection was evaluated by endoscopy using rapid urease testing together with histology. RESULTS: In cohort A, 55 patients out of 60 showed cure of H. pylori infection (92%); the treatment was well tolerated, but three patients suffered from side‐effects. In cohort B, which was free of metronidazole, 50 out of 60 patients showed cure of H. pylori infection (83%); two patients reported side‐effects. The differences between the two cohorts were not statistically significant. CONCLUSION: Triple therapy for 1 week with lansoprazole as the antisecretory agent seems to be as effective as is reported for omeprazole‐based regimens.
Effect of proton pump inhibitors on the detection of Helicobacter pylori in gastric biopsies.
Authors: Dickey W , Kenny BD , McConnell JB
Published: June 2006

BACKGROUND: Proton pump inhibitors are known to decrease the activity of Helicobacter pylori organisms within the stomach and to shift their distribution proximally. This effect may reduce the sensitivity of histological examination and rapid urease testing for H. pylori on biopsies taken from recommended sites. It is of particular relevance if a proton pump inhibitor has been prescribed before the patient has undergone diagnostic endoscopy. METHODS: We studied patients referred to our open‐access upper gastrointestinal endoscopy service who had either been on no medication (controls) or were already taking proton pump inhibitors. Biopsies taken from the gastric antrum and corpus were used for rapid urease testing and for histological examination. Sera, taken from patients who had no evidence of H. pylori in biopsies, were tested for IgG H. pylori antibodies as an alternative indicator of infection. RESULTS: H. pylori organisms were detected by histological examination in 27 of 40 controls (68%) and in 13 of 25 patients taking proton pump inhibitors (52%). Among patients with positive histology (organisms detected in either antral or corpus biopsies, or both), only the sensitivity of the antral urease test read at 1 h was significantly lower in patients taking proton pump inhibitors than in controls, with no significant difference in sensitivities of the antral urease test at 24 h, of the corpus urease test at 1 or 24 h, or of histology from the antrum or corpus. Of patients with negative histology, none of 13 controls compared with six of 12 patients taking proton pump inhibitors (50%) had positive serology (P = 0.005). Five (83%) of the six histology‐negative, seropositive patients taking proton pump inhibitors had histological changes consistent with H. pylori gastritis even though no organisms were detected. CONCLUSIONS: Treatment with a proton pump inhibitor before endoscopy reduces the sensitivity of antral and corpus biopsies for H. pylori detection, both by urease testing and histological examination. If proton pump inhibitors already prescribed cannot be discontinued for an adequate period before endoscopy, patients should have biopsies taken from the corpus as well as from the antrum, and serum should be tested for H. pylori.
Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori‐positive healthy subjects.
Authors: Pommerien W , Braun M , Idstrom JP , Wrangstadh M , Londong W
Published: June 2006

BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection. It was speculated that omeprazole‐ induced hypoacidity enhances the antibacterial activity of amoxycillin. Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy. No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole. METHODS: The study was performed in a three‐way cross‐over double‐blind design. After a run‐in period on placebo with a baseline intragastric pH‐metry, 24 H. pylori‐positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d. + placebo, amoxycillin 750 mg b.d. + omeprazole 40 mg b.d. and omeprazole 40 mg b.d. + placebo for 5 days. On the last day of each regimen intragastric pH‐metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles. RESULTS: Amoxycillin monotherapy had no acid‐inhibiting effect. Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01). Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different. CONCLUSIONS: High‐dose omeprazole does not alter the pharmacokinetics of amoxycillin. The significantly lower intragastric pH during combination therapy might be due to the H. pylori‐suppressive effect of this treatment.
How accurate is the determination of blood in gastric juice? Comparison of peroxidase and porphyrin methods.
Authors: Woods KL , Kiefe C , Graham DY
Published: June 2006

BACKGROUND: Mucosal bleeding is frequently used as a measure of gastric mucosal integrity. We compared the orthotolidine method for quantifying haemoglobin in gastric juice with a method based on measurement of fluorescent porphyrins extracted from haem. We also investigated whether acid or pepsin had a deleterious effect on the results of either method. METHODS: We compared the effects of pH (2 or 7), time (up to 180 min), haemoglobin concentration and the addition of pepsin (2.5, 5 or 7.5 kU/mL hog pepsin) on the accuracy of the two methods. RESULTS: With the orthotolidine method there was a time‐dependent decline in detectable haemoglobin concentration (P < 0.02) at pH 2 that was not seen at pH 7. The time‐ and pH‐dependent decline in detectable haemoglobin was not seen using the porphyrin assay. CONCLUSION: The widely used orthotolidine method for determination of blood in gastric juice is less reliable than the porphyrin method as it is more likely to be influenced by acidic conditions in the stomach.
The role of acid in the pathogenesis of indomethacin‐induced gastric antral ulcers in the rat.
Authors: Clayton NM , Oakley I , Williams LV , Trevethick MA
Published: June 2006

BACKGROUND: The role of acid in the pathogenesis of indomethacin‐ induced ulcers of the rat gastric antrum was studied by comparing the effects of pretreating animals with both long‐acting (loxtidine, AH22216) and short‐acting (ranitidine and cimetidine) inhibitors of acid secretion. RESULTS: Ranitidine and cimetidine were much weaker at inhibiting antral damage when compared to their reported potencies as antisecretory agents. In marked contrast, loxtidine and AH22216 inhibited indomethacin‐induced antral ulcers at doses similar to their reported potencies as inhibitors of acid secretion. Histological analysis at doses causing near maximal inhibition of macroscopic damage revealed an almost complete absence of ulcers but a large and significant increase in mucosal damage due to superficial erosions. Hourly dosing with hydrochloric acid reversed the protective effect of ranitidine, cimetidine and loxtidine on macroscopic damage and, histologically, this was associated with the widespread appearance of antral ulcers and a reduction in the proportion of mucosal damage caused by superficial erosions. CONCLUSIONS: The results of this study suggest that the pathogenesis of nonsteroidal anti‐inflammatory drug (NSAID)‐induced antral ulcers involves at least two stages: (1) an initial acid‐independent formation of mucosal erosions followed by (2) an acid‐dependent conversion of erosions to frank ulcers. Clinically, drugs that suppress acid completely for long periods may be very effective in preventing NSAID‐induced gastric antral ulcers.
High‐dose ranitidine for the prevention of recurrent peptic ulcer disease in rheumatoid arthritis patients taking NSAIDs.
Authors: Ten Wolde S , Dijkmans BA , Janssen M , Hermans J , Lamers CB
Published: June 2006

BACKGROUND: Continuous therapy with low‐dose ranitidine (150 mg b.d.) is known to be effective for the prevention of recurrent nonsteroidal anti‐inflammatory drug (NSAID)‐associated duodenal ulcer but not for gastric ulcer. AIM: To investigate, in a double‐blind placebo‐ controlled study, the preventive effect of a high dose of ranitidine (300 mg b.d.) on the recurrence of both duodenal ulcers and gastric ulcers in rheumatoid arthritis patients with a continuous need for NSAIDs. METHODS: Rheumatoid arthritis patients with a history of peptic ulcer disease were randomized to receive either ranitidine 300 mg b.d. or placebo for 12 months. Endoscopy was performed at study entry and after 6 and 12 months. End‐point was the recurrence of gastric or duodenal ulcers. RESULTS: The study was stopped after a blinded interim analysis; at that time 10 of the 15 included patients in each treatment group were evaluable. Recurrent duodenal ulcers had occurred in four patients treated with placebo and none of the patients treated with ranitidine (Fisher's exact one‐tailed P = 0.04; 95% CI, ‐ 0.70 to ‐ 0.10). Recurrent gastric ulcers had occurred in six patients in the placebo group and three patients in the ranitidine group (Fisher's exact one‐tailed P = 0.18; 95% CI, ‐0.72 to 0.12). Two patients in the placebo group had developed both duodenal ulcers and gastric ulcers. No adverse events were observed. CONCLUSIONS: High dose ranitidine is effective for the prevention of recurrent duodenal ulcer but not for recurrent gastric ulcer in rheumatoid arthritis patients taking NSAIDs.
A trial of lansoprazole in refractory gastric ulcer.
Authors: Van Rensburg CJ , Louw JA , Girdwood AH , Simjee AE , Marks IN
Published: June 2006

BACKGROUND: The proton‐pump inhibitor, lansoprazole, a more potent gastric acid inhibitor with a longer action than H2‐receptor antagonists, should heal refractory gastric ulcers more effectively. METHODS: Lansoprazole's efficacy in healing refractory gastric ulcer(s) (i.e. after 6 weeks of treatment with H2‐receptor antagonists, antacids or sucralfate at recommended dosages, and/or a relapse within 1 year of documented gastric ulcer), was compared by a two‐dose regimen in a four‐ centre, randomized, parallel group study. One hundred and eighteen patients (59 per group) with an endoscopically confirmed gastric ulcer > or = 3 mm, received lansoprazole 30 or 60 mg daily. We assessed efficacy endoscopically at 4 and 8 weeks, and again after documented healing during a maintenance phase of lansoprazole 30 mg/day at 2 and 4 months. RESULTS: Demographic and anthropometric data were comparable. Healing rates at 4 weeks were 63% (30 mg) vs. 66% (60 mg) (95% CI, ‐14 to 21%) and cumulatively at 8 weeks, 83% (30 mg) vs. 81% (60 mg) (95% CI, ‐12 to 16%). Two and 4 months after documented healing, 86% and 78% of intention‐to‐treat patients remained in remission. CONCLUSION: Lansoprazole 30 or 60 mg/day appear equally effective in healing refractory gastric ulcers, while maintenance therapy of 30 mg/day effectively prevented an ulcer relapse.
Effect of erythromycin on human biliary motility.
Authors: Wehrmann T , Pfeltzer C , Caspary WF
Published: June 2006

BACKGROUND: To investigate the effects of intravenous erythromycin on human gall‐bladder and sphincter of Oddi motor function. METHODS: Twelve consecutive patients with suspected sphincter of Oddi dysfunction were studied. Gall‐bladder function was assessed by ultrasonography, and sphincter of Oddi motility was evaluated by means of endoscopic manometry. RESULTS: All patients were found to have normal gall‐bladder function. The percentage of maximal gall‐bladder emptying following a standardized, liquid test meal was significantly increased by erythromycin, whereas the postprandial residual gall‐ bladder volume was significantly decreased after erythromycin (P < 0.01). Endoscopic manometry revealed the presence of sphincter of Oddi dysfunction in two of the 12 patients. Erythromycin significantly decreased the basal sphincter of Oddi pressure and slowed the sphincter of Oddi phasic contraction frequency in all patients (P < 0.01). However, the mean duration of the sphincter phasic contractions (P < 0.05) and their amplitude (P = 0.05) were increased by the compound. CONCLUSIONS: Erythromycin stimulates gall‐bladder motility but induces varying effects on human sphincter of Oddi motility.
Gastric emptying of pancreatin granules and dietary lipids in pancreatic insufficiency.
Authors: Norregaard P , Lysgaard Madsen J , Larsen S , Worning H
Published: June 2006

AIM: To investigate the emptying of enzyme granules and dietary lipids in patients with pancreatic insufficiency secondary to chronic pancreatitis. PATIENTS AND METHODS: Seven patients with chronic pancreatitis and exocrine pancreatic insufficiency ingested a test meal including colloidal 99m‐technetium‐radiolabelled liver pate, and swallowed two pancreatin capsules, in which half of the granules had been replaced with 111‐indium‐radiolabelled plastic particles of comparable physical dimensions. The passage of the two isotopes was followed simultaneously by gamma camera imaging for direct visual judgement and calculation of mean gastric emptying time. RESULTS: Pancreatin granules and dietary lipids were observed to empty simultaneously. In the duodenum the particles and the test meal were well mixed. Mean gastric emptying time of radiolabelled liver pate and radiolabelled plastic particles could be calculated in six patients. The median of these values were 47 and 43 min, respectively (P = 0.69). CONCLUSION: Pancreatin granules sized 1.0‐1.5 mm seem to empty together with dietary lipids.
Pancreatin preparations used in the treatment of cystic fibrosis‐‐ lipase content and in vitro release.
Authors: Walters MP , Littlewood JM
Published: June 2006

BACKGROUND: Pancreatic extracts are essential in the treatment of the majority of cystic fibrosis patients. The clinical response to different preparations is often unpredictable and at present there is no sure method of determining the best preparation for a particular patient. METHODS: Creon, Nutrizym GR, Pancrease and the high‐lipase versions, Creon 25,000, Nutrizym 22 and Pancrease HL, were investigated for lipase content and resistance to simulated gastric conditions. The rates of lipase release in response to pH change, bile salts and duodenal solids were investigated. The stability of lipase and its binding to duodenal solids were also investigated. RESULTS: Declared values for lipase content were exceeded in all preparations. All preparations were acid resistant. The release of lipase in response to pH change showed notable differences in release rates. After 20 min at pH 5.5, Creon released three times the amount of lipase compared with Pancrease, the other preparations coming within the range. Above pH 5.75, the release rates were comparable amongst the preparations. Bile salts influenced release variably whilst release in a solid‐rich duodenal fluid was much slower than in buffers. The released lipase was susceptible to proteolysis and pH‐dependent binding to duodenal solids; these effects may compromise lipolysis. CONCLUSIONS: These results show some factors contributing to variable clinical responses to pancreatic supplements. Improvements may result if a patient is assessed on different preparations.
Association of the OGG1‐Ser326Cys polymorphism with lung adenocarcinoma risk
Authors: Kohno Takashi , Kunitoh Hideo , Toyama Kaoru , Yamamoto Seiichiro , Kuchiba Aya , Saito Daizo , Yanagitani Noriko , Ishihara Shin‐ichi , Saito Ryusei , Yokota Jun
Published: June 2006

Adenocarcinoma (ADC) is the most frequent histological type of lung cancer and comprises the majority of lung cancers in non‐smokers. Thus, genetic factors responsible for ADC susceptibility need to be determined to establish efficient ways of preventing the disease. The OGG1 gene, encoding a glycosylase for 8‐hydroxyguanine, an oxidatively damaged promutagenic base, has the polymorphism Ser326Cys, and OGG1‐326Cys protein was indicated to have a lower ability to prevent mutagenesis than the OGG1‐326Ser protein. Case‐control studies to date suggest that the OGG1‐326Cys allele is associated with a higher risk for several types of cancers, including overall lung cancer. However, the contribution of this polymorphism to lung ADC risk is unclear. In the present study, the OGG1‐Ser326Cys polymorphism was assessed for association with lung ADC risk using a case‐control study of a Japanese population consisting of 1097 cases and 394 controls. Odds ratios (OR) of the 326Cys allele carriers increased in a dose‐dependent manner with allele number (P for the trend test = 0.04). The OR of homozygotes for the 326Cys allele was increased significantly when homozygotes for the 326Ser allele were used as a reference (OR = 1.5, 95% confidence interval [CI] = 1.0–2.1, P = 0.04). Furthermore, the overall OR for lung ADC of the Cys/Cys homozygotes out of a total of 1925 ADC patients and 3449 controls from six case‐control studies reported up to the present were 1.43 (95% CI = 1.11–1.84, P = 0.0045). These results indicate that OGG1‐326Cys functions as a risk allele for lung ADC development. (Cancer Sci 2006; 97: 724–728)
Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans
Authors: Bae Sun‐Young , Choi Sun‐Keun , Kim Kyung‐Rae , Park Chang‐Shin , Lee Sung‐Keun , Roh Hyung‐Keun , Shin Dong‐Woon , Pie Jae‐Eun , Woo Ze‐Hong , Kang Ju‐Hee
Published: June 2006

The aim of the present study was to evaluate the effects on the susceptibility to colorectal cancer (CRC) of genetic polymorphisms in P‐glycoprotein (PGP) and the metabolic enzymes cytochrome P450 1A2 (CYP1A2) and flavin‐containing monooxygenase 3 (FMO3). We analyzed five single‐nucleotide polymorphisms (SNP) in 93 cancer‐free volunteers and 111 patients with CRC: one common genetic variant of the PGP‐encoding MDR1 gene and four SNP in genes for metabolic enzymes (two SNP in FMO3 and two SNP in CYP1A2). The genotypes and allele frequencies of the MDR1/C3435T, FMO3/G488A, FMO3/A923G and CYP1A2/G‐3860 A polymorphisms were not significantly different in cancer‐free subjects and CRC patients. However, a significant association was found between the CYP1A2/A‐163C polymorphism and the risk of CRC, particularly in elderly (>55 years) subjects and smokers. A phenotyping study in normal smokers showed that the CYP1A2 activity of subjects with the CYP1A2/−163 AA genotype was significantly lower than that of subjects carrying the CYP1A2/−163C allele. Combined results show that the CYP1A2/−163C allele is significantly associated with an increase in CYP1A2 activity and a consequent increased risk of CRC in Koreans, particularly in elderly people and smokers. (Cancer Sci 2006; 97: 774–779)
ERK MAP kinase in G1 cell cycle progression and cancer
Authors: Torii Satoru , Yamamoto Takuya , Tsuchiya Yoshiki , Nishida Eisuke
Published: June 2006

The extracellular‐signal‐regulated kinase (ERK) mitogen‐activated protein (MAP) kinase signaling pathway plays an important role in various cellular responses, including cell proliferation, cell differentiation and cell survival. Recent studies have identified a number of Ras/ERK signaling‐related proteins, such as scaffold proteins and inhibitors. These proteins modulate ERK signaling and thereby could give variations in ERK signaling outputs that regulate cell fate decisions. Here we focus on the role of ERK signaling in cell cycle progression from G0/G1 to S phase and cancer. (Cancer Sci 2006; 97: 697–702)
Different susceptibility to peroxisome proliferator‐induced hepatocarcinogenesis in rats with polymorphic glutathione transferase genes
Authors: Kudo Toshihiro , Asano Jumpei , Shimizu Takeshi , Nanashima Naoki , Fan Yang , Akita Miki , Ookawa Keizo , Hayakari Makoto , Yokoyama Yoshihito , Suto Kohji , Tsuchida Shigeki
Published: June 2006

Although peroxisomal bifunctional enzyme (enoyl‐CoA hydratase/l‐3‐hydroxyacyl‐CoA dehydrogenase; BE) is a positive marker for peroxisome proliferation, it is completely absent or expressed very weakly in rat hepatic preneoplastic and neoplastic lesions induced by peroxisome proliferators (PP). After administration of PP for 8–15 weeks, some rats exhibit BE‐negative preneoplastic foci but other rats do not. In the present study, to investigate the involvement of glutathione S‐transferase (GST) M1 gene polymorphism in interindividual differences in susceptibility to PP, we developed a method to determine the genotypes of rats. We then examined whether rats with one type encoding 198Asn‐199Cys (NC‐type) or another encoding 198Lys‐199Ser (KS‐type) exhibit differences in clofibrate (CF) susceptibility. After administration of 0.3% CF for 6 weeks or more, BE‐negative foci were found immunohistochemically in KS/KS‐type rats, but not in NC/NC‐type rats. The number of BE‐negative foci in KS/KS rats was 15.3 ± 9.0 foci/cm2 of liver section after 6 weeks of CF administration, and the values did not alter thereafter. The mean areas of BE‐negative foci in KS/KS rat livers increased during the period from 6 to 60 weeks. At weeks 30 and 60, almost all BE‐negative foci exhibited a clear cell phenotype, a type of preneoplastic hepatic lesion. BE‐negative foci were devoid of peroxisome proliferator‐activated receptor α, whereas surrounding tissues were positive for the receptor. These results indicate that rats that are polymorphic for the GST M1 gene exhibit different susceptibilities to CF in vivo. (Cancer Sci 2006; 97: 703–709)
Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide
Authors: Zhang Wei , He Yi‐Jing , Han Chun‐Ting , Liu Zhao‐Qian , Li Qing , Fan Lan , Tan Zhi‐Rong , Zhang Wei‐Xia , Yu Bang‐Ning , Wang Dan , Hu Dong‐Li , Zhou Hong‐Hao
Published: June 2006

Aims

Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP‐C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide.

Methods

Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC.

Results

The Cmax and AUC(0,∞) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t1/2 of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in tmax values among the three genotypic groups was not statistically significant.

Conclusions

Our results suggest that OATP1B1‐mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.
Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P‐glycoprotein
Authors: Shimizu Mikiko , Uno Tsukasa , Sugawara Kazunobu , Tateishi Tomonori
Published: June 2006

Aims

We determined whether or not the extent of drug interaction of fexofenadine by itraconazole is time‐dependent.

Methods

In a randomized two‐phase crossover study, itraconazole was administered orally for 6 days, and, on days 1, 3 and 6, fexofenadine was administered simultaneously. On another occasion, fexofenadine was administered alone.

Results

Itraconazole increased fexofenadine AUC(0, ∞), and the % change for difference was 178% (95% CI 1235, 3379), 205% (95% CI 1539, 3319) and 169% (95% CI 1128, 2987) on days 1, 3 and 6 of the 6 day treatment, respectively.

Conclusions

The extent of drug interaction by itraconazole was not time‐dependent.
Brain T1 intensity changes after levodopa administration in healthy subjects: a voxel‐based morphometry study
Authors: Salgado‐Pineda Pilar , Delaveau Pauline , Falcon Carles , Blin Olivier
Published: June 2006

Aim

To test T1 intensity variations induced by levodopa administration in the regional fixation area in the human brain.

Method

Using non‐invasive magnetic resonance imaging (MRI) technique [T1‐weighted sequence MPRAGE; TE/TR/TI = 5/25/800 ms; impulsion angle = 15°; field of view = 256 × 230 × 180 mm3; acquisition matrix = 256 × 192 × 104; reconstruction matrix = 256 × 256 × 128), we tested changes in the T1 MRI signal intensity resulting in changes in the grey matter automatic classification after administration of a single dose of 100 mg of levodopa by a voxel‐based morphometry method (VBM) in 12 healthy subjects.

Results

The VBM analysis demonstrated an increased number of voxels attributed to grey matter after levodopa administration in an anatomical cluster which included substantia nigra, tegmental ventral area and subthalamic nucleus bilaterally, the principal origin and first relay nuclei of projections in brain dopaminergic systems (t = 8.61; corrected for all grey matter volume P < 0.001).

Conclusion

Our results suggest that levodopa administration could induce an MRI T1 signal intensity variation that is not evident to the naked eye, but is detectable by measuring local signal intensities. Possible clinical applications are discussed.
Homoeopathic and herbal prescribing in general practice in Scotland
Authors: Ross Sarah , Simpson Colin R. , McLay James S.
Published: June 2006

What is already known about this subject

Homoeopathy and herbalism are increasingly popular among the public and prescribed by general practitioners in the NHS.

Doctors and regulatory authorities have expressed concerns about their efficacy and safety.

Studies from the 1990s suggest that between 5.9 and 7.5% of English NHS general practitioners have prescribed homoeopathy, while less than 1% have prescribed herbal remedies. Current levels of prescribing are unknown but are thought to have increased.

What this study adds

Sixty percent of Scottish general practices now prescribe homoeopathic or herbal remedies.

The prevalence of homoeopathic prescribing in those under 16 years has doubled since 2000 and is maximal in children < 1 year old, of whom 1% are prescribed a homoeopathic remedy.

Recognized drug–herb interactions were identified in 4% of patients prescribed oral herbal remedies.

Aims

To investigate the current levels of homoeopathic and herbal prescribing in Scottish general practice.

Methods

Prescribing of homoeopathic and herbal remedies in primary care was assessed in 1891 669 patients for the year 2003–2004, using computerized prescribing data retrieved from 323 general practices in Scotland.

Results

Forty‐nine percent of practices prescribed homoeopathic and 32% herbal remedies. A total of 193 homoeopathic and 17 herbal remedies were prescribed, with 5% of practices accounting for 46% of patients and 50% of remedies. Four thousand one hundred and sixty patients (2.2/1000 registered patients) were prescribed at least one homoeopathic remedy during the study period, with the highest prevalence to children under 12 months of age (9.5/1000 children of that age). Children under the age of 16 made up 16% of the population prescribed homoeopathic remedies (2.2/1000 registered patients of that age). Three hundred and sixty‐one patients (0.2/1000 registered patients) were prescribed at least one herbal remedy during the study period, 44 of whom were children < 16 years old. Patients prescribed a homoeopathic or herbal remedy were also prescribed a median of four and five conventional medicines, respectively. Of patients prescribed an oral herbal remedy, 4% were also concomitantly prescribed a conventional medicine with which a drug–herb interaction has been documented.

Conclusions

Our study reports that a substantial number of Scottish general practitioners prescribe homoeopathic and herbal remedies, with an approximate doubling in the number of children prescribed homoeopathic remedies. The level of homoeopathic and herbal prescribing raises questions about homoeopathic/herbal provision in the National Health Service and should prompt critical review.
Population analysis of a 24‐h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study
Authors: Mould Diane R. , Fleming Gini F. , Darcy Kathleen M. , Spriggs David
Published: June 2006

Aims

To examine determinants of paclitaxel disposition and the association between paclitaxel exposure and toxicity or survival in patients with advanced stage or recurrent endometrial cancer treated with doxorubicin plus paclitaxel.

Methods

A limited sampling scheme was used to examine the population pharmacokinetics of paclitaxel in 160 patients from one arm of a randomized Phase III trial of doxorubicin plus paclitaxel or cisplatin. Four plasma samples per patient were collected at approximately 0, 3, 22 and 27 h after the first 24‐h infusion of paclitaxel and submitted to the Gynecological Oncology Group (GOG) Pharmacology Core Laboratory. Total paclitaxel concentrations were quantified by LC/MS and paclitaxel disposition was examined using NONMEM. Paclitaxel exposure was evaluated for associations with toxicity or survival.

Results

Patient weight, age and serum glutamic‐oxaloacetic transaminase level were determinants of paclitaxel clearance (clearance increased 0.437 l h−1 kg−1; decreased 0.223 l h−1 year−1and 0.105 l h−1 IU−1). Bayesian shrinkage was minimal for this parameter. In different measures of paclitaxel exposure, AUC was most predictive of toxicity, with higher AUC associated with granulocytopenia [probability of 1% at AUC = 1 to 22% at AUC = 4 µg l−1 h−1for performance status (PS) = 0]. PS was more strongly associated with survival than disease stage and higher paclitaxel AUC was associated with worse survival irrespective of PS and stage.

Conclusions

Paclitaxel AUC is an independent predictor of granulocytopenia and survival in patients with advanced stage or recurrent endometrial cancer. Future studies are needed to validate the latter finding. This study confirms the appropriateness of evaluating pharmacokinetics and pharmacodynamics in multicentre oncology trials.
Parents of children with cerebral palsy: a review of factors related to the process of adaptation
Authors: Rentinck I. C. M. , Ketelaar M. , Jongmans M. J. , Gorter J. W.
Published: June 2006

Background  Little is known about the way parents adapt to the situation when their child is diagnosed with cerebral palsy.

Methods  A literature search was performed to gain a deeper insight in the process of adaptation of parents with a child with cerebral palsy and on factors related to this process. The selected articles were examined with respect to (i) the type and purpose of the study, (ii) study sample, (iii) variables and instruments and (iv) results on adaptation and stress of the parents.

Results  Twenty‐two studies were found, which showed a large variety in research designs, instruments and populations. Despite methodological differences, it was possible to extract a number of factors related to resources of individual family members, the family unit as a whole and in the community, family appraisal and adaptive coping.

Conclusion  It is important to realize that parents’ adaptation may change as a function of their child’s development and changing stages of family life over time. Until now cross‐sectional studies have dominated this area of research, but in order to understand the process of adaptation over time, longitudinal studies are needed.
22q11.2 deletion syndrome: behaviour problems of infants and parental stress
Authors: Briegel W. , Schneider M. , Schwab K. O.
Published: June 2006

Background 22q11.2 deletion syndrome (22q11.2 DS) can be associated with a variety of somatic symptoms, developmental delays and psychiatric disorders. At present, there is little information on early behaviour problems, and nothing is known about parental stress and possible relations between these factors. Therefore, the aim of this study was to investigate behaviour problems of infants with 22q11.2 DS, and their primary caregivers’ stress.

Methods Parents of infants with 22q11.2 DS known to the German 22q11.2 deletion syndrome foundation were anonymously asked to fill out several questionnaires, e.g. the Child Behavior Checklist (CBCL) 1.5–5.

Results The primary caregivers of 22/30 children [12 boys and 10 girls aged 1 year 8 months to 3 years 11 months (mean age: 2 years 9 months)] sent back filled‐out questionnaires. Seventeen out of 21 children showed motor, and 15/21 language delay. Five out of 21 children were rated as clinical on at least one CBCL 1.5–5 scale. The patients’ age was correlated with anxiety problems, and girls had significantly more sleep problems than boys. Compared with the general population, the primary caregivers did not experience higher levels of strain, and compared with parents of mentally and/or physically handicapped children, their parental stress was significantly lower. Parental stress and strain were correlated to a variety of child behaviour problems, e.g. externalizing and anxious/depressed behaviour.

Conclusions Longitudinal studies are required to show whether behaviour problems and parental stress worsen when 22q11.2 DS patients grow older.
Mothers’ psychological distress 1 year after very preterm childbirth. Results of the epipage qualitative study
Authors: Garel M. , Dardennes M. , Blondel B.
Published: June 2006

Background  The objectives of this study were to assess qualitatively mothers’ physical and psychological health, their perception of their child’s health and development, and their difficulties with childcare from 2 months post discharge to 1 year after a very preterm delivery.

Methods  The study population included all mothers who delivered before 33 weeks of amenorrhea between November 1998 and November 1999 in a Parisian maternity unit and between February 2000 and February 2001 in a maternity unit located in Rouen (France). Twenty‐one of the 38 mothers contacted agreed to participate (55%). Semi‐structured interviews were conducted by a clinical psychologist at the woman’s home. They were taped, fully transcribed and subjected to content analysis.

Results  The main difficulties reported by mothers at 1 year were fatigue, depressive mood, anxiety and physical symptoms. Depressive mood was associated with social isolation, post‐traumatic symptoms, withdrawal and feelings of guilt. Most mothers also described their child as being difficult and tiring. Mothers’ reports about their own health and difficult behaviour of their child were more negative at 1 year than at 2 months post discharge.

Conclusions  The mothers’ psychological distress following a very preterm birth did not improve between 2 months post discharge and 1 year after delivery. Comprehensive follow‐up care programmes should take into account this consequence of a very preterm birth and provide access to adequate psychological support, care or treatment.
A qualitative investigation of school‐aged children’s answers to items from a generic quality of life measure
Authors: Cremeens J. , Eiser C. , Blades M.
Published: June 2006

Background  The development of instruments to measure child self‐reported quality of life (QOL) is dependent on whether children can understand the concepts behind items. Researchers need more information on how children are interpreting and answering items. This paper aims to investigate the strategies school‐aged children use to answer QOL items.

Methods  A generic 30‐item QOL measure (the TedQL) was administered to 266 healthy children (5–6, 7–9 years old). Children were asked to ‘think aloud’ while answering a selection of 10 TedQL items (n = 4 ability, n = 4 social, n = 2 mood items), and their responses were recorded verbatim.

Results  The strategies children reported using when answering items were coded into five categories: (1) social comparisons; (2) stable character references; (3) concrete examples; (4) other reasons; or (5) no reason given. Concrete examples were used most frequently by children. Strategy type was dependent on age, with 7–9‐year‐olds reporting social comparisons and concrete examples more frequently than 5–6‐year‐olds. Five‐to‐six‐year‐olds gave no reasons for their response choices more frequently than 7–9‐year‐olds. Strategy type also differed by item type, with social comparisons used more frequently for ability items, and stable character references for social items. However, concrete examples were used consistently highly across ability and social items.

Conclusions  Children aged 5–9 years most commonly report using concrete examples of specific instances when answering QOL items. However, strategy use varies as a function of age and types of items. Our results highlight the importance of keeping in mind children’s developmental age when interpreting responses from child QOL instruments.
Interaction of natural killer cells withTrypanosoma cruzi-infected fibroblasts
Authors: Lieke T , Steeg C , Graefe S E B , Fleischer B , Jacobs T
Published: June 2006

The protozoan parasite Trypanosoma cruzi circulates in the blood as trypomastigotes and invades a variety of cells to multiply intracellularly as amastigotes. The acute phase triggers an immune response that restricts the proliferation of the parasite. However, parasites are able to persist in different tissues causing the pathology of Chagas’ disease. Natural killer (NK) cells play an important role in innate resistance to a variety of pathogens. In the present study we demonstrate that NK cells trigger trypanocidal mechanisms in infected L929 cells that are critically dependent on inducible nitric oxide (NO) synthase (iNOS) induction which is, to a major degree, triggered by interferon (IFN)-γ provided by NK cells. This work provides a more detailed analysis of how NK cells as a part of the innate immune system participate in the control of parasites that reside intracellularly in fibroblast-like L929 cells.
Epitopes of the class I major histocompatibility complex (MHC-I) recognized in the syngeneic or allogeneic context predominantly linked to antigenic peptide loading to its binding groove
Authors: Nguyen van Binh P , Duc H T
Published: June 2006

Class1 major histocompatibility complex (MHC-I)–antigenic peptide exposed at the target cell surface is crucial for the adaptive immune response exerted in the self/syngeneic context by cytotoxic T lymphocyte (CTL). Such a complex also provides epitopes in the allogeneic context for antibody response directed against the MHC-I polymorphic determinant. In the present report we examined the formation of the MHC-I–peptide complex leading predominantly to the expression of T and/or B cell epitopes in a process of internal versus external antigenic peptide loading onto the binding groove of MHC-I. Analyses using antibodies specific to complex MHC-I–peptide generated in the syngeneic context to mimic T cell receptor (TCR) in comparison with antibodies specific to the MHC-I polymorphic determinant allowed the observation that the external peptide loading to MHC-I, while remaining necessary for inducing the formation of B cell epitopes, was less efficient than the internal one for generating T cell epitopes. Thus, external loading of peptide to the MHC-I appeared to match more closely the allogeneic situation and the humoral immunity in general, while internal peptide loading corresponded with the self/syngeneic context of the cellular CTL response.
(–)-Epigallocatechin-3-gallate protects mice from concanavalin A-induced hepatitis through suppressing immune-mediated liver injury
Authors: Wang Y , Mei Y , Feng D , Xu L
Published: June 2006

(–)-Epigallocatechin-3-gallate (EGCG) is the major active component of green tea. Increasing evidence has suggested that EGCG exhibits anti-inflammatory, anti-oxidant and immunosuppressive effects. In this study, we investigated the effect of EGCG on concanavalin A (ConA)-induced hepatitis (CIH) in mice, a model of immune-mediated liver injury in humans. We pretreated mice with EGCG before ConA injection, and then measured alanine aminotransferase (ALT) levels in plasma, inflammatory infiltration and hepatocyte apoptosis in liver. Potential therapeutic mechanisms were elucidated further by measuring several inflammatory mediators. Mice pretreated with EGCG exhibited much less increased ALT levels in plasma, reduced inflammatory infiltration and hepatocyte apoptosis in liver compared with control mice pretreated with vehicle solutions. We further investigated the mechanisms of the protective effects of EGCG. In EGCG-pretreated mice, we found abrogated tumour necrosis factor (TNF)-α and interferon (IFN)-γ at both protein levels in plasma and mRNA levels in liver. At the same time, the concentration of nitrite in plasma and inducible nitric oxide synthase production in liver were both down-regulated in these mice. Moreover, IFN-inducible protein-10 and macrophage inflammatory protein-1α expressions in liver were decreased significantly. Therefore, EGCG is capable of regulating immune-mediated liver injury in vivo. The protective effect depended on its suppressive effect on the production of important inflammatory mediators.
Patient-centred screening for primary immunodeficiency: a multi-stage diagnostic protocol designed for non-immunologists
Authors: De Vries E ,   Clinical Working Party of the European Society for Immunodeficiencies (ESID)
Published: June 2006

Efficient early identification of primary immunodeficiency disease (PID) is important for prognosis, but is not an easy task for non-immunologists. The Clinical Working Party of the European Society for Immunodeficiencies (ESID) has composed a multi-stage diagnostic protocol that is based on expert opinion, in order to increase the awareness of PID among doctors working in different fields. The protocol starts from the clinical presentation of the patient; immunological skills are not needed for its use. The multi-stage design allows cost-effective screening for PID within the large pool of potential cases in all hospitals in the early phases, while more expensive tests are reserved for definitive classification in collaboration with an immunologist at a later stage. Although many PIDs present in childhood, others may present at any age. The protocols presented here are therefore aimed at both adult physicians and paediatricians. While designed for use throughout Europe, there will be national differences which may make modification of this generic algorithm necessary.