bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the cag pathogenicity island and IS605 of Helicobacter pylori strains isolated from patients with gastric cancer in Japan
Authors: Deguchi R. , Igarashi M. , Watanabe K. , Takagi A.
Published: December 2004

Background : CagA protein is encoded by the cagA gene, which is part of the cag pathogenicity island (PAI) in Helicobacter pylori. Insertion sequence (IS) elements are a diverse set of specialized DNA segments that can move to new sites in bacterial genomes.

Aim : To determine the role of cagPAI and IS605 in the development of gastric cancer, we analysed cagPAI from patients with gastric cancer and compared the results with the host's CagA antibody status.

Methods : H. pylori strains were isolated from 29 gastric cancer patients, and CagA status was determined by measuring serum antibody against CagA. The cagPAI region and IS605 were determined by PCR.

Results : CagA seropositivity tended to be higher in the IS605/PAI+ group (5/7, 71.4%) than in the IS605/PAI– group (9/22, 40.9%). Association with cag13 was more frequent in the IS605+ group (92.3%; 12/13) than in the IS605– group (25.0%; 4/16; P = 0.0005).

Conclusions : cag13 may be associated with the presence of IS605 in gastric cancer patients.
Correlation of MAP kinases with COX‐2 induction differs between MKN45 and HT29 cells
Authors: Tominaga K. , Higuchi K. , Sasaki E. , Suto R. , Watanabe T. , Fujiwara Y. , Oshitani N. , Matsumoto T. , Kim S. , Iwao H. , Arakawa T.
Published: December 2004

Background : Mitogen‐activated protein (MAP) kinases, including extracellular signal‐regulated kinases (ERK),c‐Jun NH2‐terminal kinases (JNK) and p38 MAP kinase (p38 MAPK) are important intermediates of the signal‐transduction pathway from the cell surface to the nucleus. Expression of cyclooxygenase (COX)‐2, associated with proliferation, apoptosis or both of gastrointestinal cancer cells, is mediated through MAP kinase families. However, the correlation between respective MAP kinase signals and COX‐2 in the proliferation of gastric and colon cancer cells has not been well elucidated.

Aim : We examined the effect of selective inhibitors of MAP kinases and COX‐2 on serum‐induced proliferation of gastric (MKN45) and colon (HT29) cancer cells.

Methods : After 24‐h serum starvation, cancer cells were stimulated with 2% serum and COX‐2 inhibitors (NS398 10 µmol/L, or etodolac 100 µmol/L) or 1 h after preincubation with inhibitors for ERK (PD98059 20 µmol/L) or p38 MAPK (SB203580 10 µmol/L). Phosphorylated MAP kinases and COX‐2 protein were evaluated by Western blotting, and the proliferation of cancer cells was estimated by 3H‐thymidine incorporation. Transcription factors nuclear factor‐κB and CREB were assayed by an electorophoretic mobility shift assay.

Results : Serum increased the proliferation of MKN45 and HT29 cells by 280% and 200%, respectively, compared with the control levels (100%). In both cancer cells, phosphorylated MAP kinases were increased within 30 min after stimulation. PD98059 and SB203580 inhibited the serum‐induced proliferation of MKN45 by 21% and 51% and of HT29 by 81% and 69%, respectively. NS398 and etodolac inhibited the proliferation of HT29 by 21% and 41%, respectively, but not that of MKN45. PD98059 and SB203580 also suppressed serum‐induced expression of COX‐2 protein in HT29 cells. In addition to the activation of MAP kinases and COX‐2, activities of nuclear factor‐κB and CREB were also increased during HT29 cell proliferation.

Conclusions : These results suggest that the correlation of MAP kinases with COX‐2 induction for cell proliferation differs between MKN45 and HT29 cells.
Indometacin up‐regulates TFF2 expression in gastric epithelial cells
Authors: Koitabashi A. , Shimada T. , Fujii Y. , Hashimoto T. , Hosaka K. , Tabei K. , Namatame T. , Yoneda M. , Hiraishi H. , Terano A.
Published: December 2004

Background : Trefoil factor family peptides are expressed in gastrointestinal epithelial cells and play a critical role in maintaining mucosal integrity. Although non‐steroidal anti‐inflammatory drugs (NSAIDs) are important causative agents of gastric mucosal lesions, few data are available about the effect of NSAIDs on trefoil family peptides in gastric mucosa.

Aim : To examine whether indometacin, a widely used NSAID, affects trefoil factor family expression in gastric epithelial cells.

Methods : MKN45, a cell line derived from human gastric cancer, was used. TFF1, TFF2, and TFF3 mRNA expression was assessed by real‐time quantitative reverse transcription‐polymerase chain reaction (RT‐PCR). TFF2 gene transcription was also examined by luciferase reporter gene assay.

Results : Relative expression level of TFF1, TFF2, TFF3 mRNA was 616: 12: 1 in unstimulated MKN45 cells. Although indometacin (1–250 µmol/L) had no significant effect on the expression of TFF1 and TFF3 mRNA, it up‐regulated TFF2 mRNA expression in a dose‐ and time‐dependent manner. Luciferase reporter gene assay confirmed the up‐regulation of TFF2 gene transcription by indometacin. Indometacin‐induced up‐regulation of TFF2 expression was not antagonized by externally applied prostaglandin E2.

Conclusion : These results suggest that indometacin up‐regulates gastric epithelial cell TFF2 expression through a COX‐independent mechanism. Since TFF peptides play an important role in gastric mucosal protection, indometacin‐induced TFF2 may reduce the degree of gastric mucosal damage induced by indometacin.
High prevalence rate of Helicobacter pylori resistance to clarithromycin during long‐term multiple antibiotic therapy for chronic respiratory disease caused by non‐tuberculous mycobacteria
Authors: Kaneko F. , Suzuki H. , Hasegawa N. , Kurabayshi K. , Saito H. , Otani S. , Nakamizo H. , Kawata K. , Miyairi M. , Ishii K. , Ishii H.
Published: December 2004

Background : Helicobacter pylori resistance to clarithromycin, probably due to the frequent use of this antibiotic for the treatment of other diseases, is the greatest obstacle against its eradication.

Aim : To clarify the prevalence of clarithromycin‐resistant H. pylori in patients with non‐tuberculous mycobacterial lung disease receiving multiple antibiotic treatment, including clarithromycin.

Methods : We enrolled 88 patients with non‐tuberculous mycobacterial lung disease; 29 underwent upper gastrointestinal endoscopy for the diagnosis of H. pylori infection prior to treatment, and 60 underwent it during treatment. The diagnosis of H. pylori infection was confirmed by histological examination, urease test and microaerobic bacterial culture. The minimum inhibitory concentration of clarithromycin was determined and the DNA was analysed for each of the isolated H. pylori strains.

Results : Patients during the treatment had a high prevalence rate of clarithromycin‐resistant H. pylori (100%). Analysis of DNA of the clarithromycin‐resistant H. pylori isolates revealed point mutations at A2142G or A2143G. Moreover, a linear correlation was found between the total cumulative dose of clarithromycin and the minimum inhibitory concentration.

Conclusion : All patients with non‐tuberculous mycobacterial lung disease being treated long‐term with multiple antibiotics, including clarithromycin, harboured clarithromycin‐resistant H. pylori in the stomach. Therefore, eradication of H. pylori before commencement of long‐term therapy including clarithromycin should be recommended.
Second‐line treatment of Helicobacter pylori infection after dilution agar methods and PCR‐RFLP analysis
Authors: Masaoka T. , Suzuki Kurabayashi H., K. , Kamiya A. G. , Ishii H.
Published: December 2004

Background : After unsuccessful first‐line treatment of Helicobacter pylori infection, the percentage of clarithromycin‐resistant strains has been reported as between 30% and 70% in Japan and other countries. A high prevalence of clarithromycin‐resistant strains is reported to be associated with eradication failure.

Aim : We examined antibiotic susceptibility testing using a combination of dilution agar methods with PCR‐restriction fragment length polymorphism (RFLP) analysis.

Methods : We enrolled 41 patients in whom first‐line treatment with LAC (lansoprazole, amoxycillin and clarithromycin) was unsuccessful. Endoscopic biopsied specimens were used to examine antibiotic susceptibility to clarithromycin by dilution agar methods. PCR‐RFLP analysis was performed to determine the presence of point mutations, which are primarily responsible for resistance to clarithromycin.

Results : Clarithromycin‐resistance rate after failure of the LAC regimen was 73.2%. Drug susceptibilities of three strains obtained by PCR‐RFLP analysis were different from those by dilution agar methods. One strain with MIC values to clarithromycin of 0.05 µg/mL had a point mutation, A2144G. This strain was not eradicated by repeating LAC, but was eradicated by substituting metronidazole for clarithromycin.

Conclusions : Dilution agar methods should be combined with PCR‐RFLP analysis before second‐line eradication to increase the accuracy of clarithromycin‐susceptibility testing and to improve eradication efficacy.
Colorectal carcinoma and inflammatory bowel disease
Authors: Eaden J.
Published: December 2004

The risk of colorectal cancer for any patient with ulcerative colitis is estimated to be 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. The relative risk of colorectal cancer in Crohn's colitis is approximately 5.6 and should raise the same concerns as in ulcerative colitis. Risk factors for colorectal cancer include disease duration, early onset, extensive disease, primary sclerosing cholangitis and a family history of sporadic colorectal cancer. All patients should have a review colonoscopy 8–10 years after diagnosis to establish the extent of the disease. Surveillance should begin 8–10 years after disease onset for pancolitis and 15–20 years after disease onset for left‐sided disease. Regular surveillance is recommended, with a screening interval every 3 years in the second decade of disease and annually by the fourth decade. Random biopsies should be taken at regular intervals with attention paid to dysplasia‐associated lesions or masses, irregular plaques, villiform elevations, ulcers and strictures. Dysplasia is recognized as a premalignant condition, but the likelihood of progression to cancer is difficult to predict. High‐grade dysplasia, confirmed by two expert gastrointestinal pathologists, is a strong indication for colectomy, as is low‐grade dysplasia, although the diagnosis of low‐grade dysplasia is unreliable. Surveillance programmes indicate that the overall 5‐year survival rate is higher in surveyed patients, although patients still present with Dukes C cancers or disseminated malignancy. Surveillance has huge socioeconomic implications. As surveillance is not 100% effective, alternative ways of reducing the cancer risk with chemopreventive agents, such as aminosalicylates, are being considered.
Aminosalicylates in inflammatory bowel disease
Authors: Hanauer S. B.
Published: December 2004

Aminosalicylate therapy for ulcerative colitis remains a foundational strategy for the induction and maintenance of remission for mild to moderate disease. Although it seems clear that topical mesalazine (mesalamine) is the most efficacious approach to distal ulcerative colitis, recent trials with orally delivered azo conjugates suggest that there may be an advantage over pH‐released mesalazine as a first‐line approach to active disease. No such comparisons are available for azo products and the prolonged‐release formulation, Pentasa. However, recent meta‐analyses have demonstrated that, although there is little difference in systemic exposure between marketed products, luminal concentrations may vary. In maintenance therapy, aminosalicylates remain the standard approach after aminosalicylate‐induced remission. A number of gaps remain in the evidence base with regard to the optimal dosing of oral mesalazine as a maintenance agent, whether oral mesalazine can maintain remissions after rectal mesalazine induction, and the dose–response and efficacy of aminosalicylates after steroid‐ or ciclosporin‐induced remissions. Although aminosalicylates have been advocated for several decades in Crohn's disease, a number of controversies have evolved since the original trials with sulfasalazine in active Crohn's disease. The original trials demonstrated benefits for sulfasalazine in colonic involvement, but controlled trial evidence for the role of sulfasalazine as maintenance therapy has not been as firmly established. In addition, although oral mesalazine has been demonstrated in controlled trials to be superior to placebo in mild to moderate disease, it is less efficacious than corticosteroids at inducing remissions. The maintenance benefits of mesalazine appear to be limited to patients ‘induced into remission’ with mesalazine and in some post‐operative settings.
Antibiotics and probiotics in inflammatory bowel disease
Authors: Kruis W.
Published: December 2004

Treatment with antibiotics in inflammatory bowel disease has a long tradition and is widely used. The indications for antibiotic therapy are wide ranging, from specific situations such as abscesses or fistulae, to patients with severe disease (as an unspecific ‘protective’ measure), and to address the hypothesis that the enteric flora as a whole, or specific microorganisms such as mycobacteria, are involved in the pathogenesis of inflammatory bowel disease. The best‐studied single antibiotic compound is metronidazole. However, overall, the scientific basis for the use of antibiotics is limited, which may reflect a lack of interest from sponsors within the pharmaceutical industry. Despite this weak evidence base, antibiotics are a globally established therapeutic tool in inflammatory bowel disease. Growing evidence from human and animal studies points towards a pivotal pathogenetic role of intestinal bacteria in inflammatory bowel disease. In view of these experimental findings, clinical trials have been undertaken to elucidate the therapeutic effects of probiotics in inflammatory bowel disease. Probiotics are viable nonpathogenic microorganisms which confer health benefits to the host by improving the microbial balance of the indigenous microflora. So far, of the many candidates, one specific strain (Escherichia coli Nissle 1917) and a mixture of eight different bacteria have demonstrated convincing therapeutic efficacy in controlled studies. Maintenance therapy in ulcerative colitis and prevention therapy, as well as the treatment of pouchitis, have emerged as areas in which probiotic therapy offers a valid therapeutic alternative to current treatments. Further investigations may detect additional clinically effective probiotics and other clinical indications.
Bone disease in inflammatory bowel disease
Authors: Schulte C. M. S.
Published: December 2004

Inflammatory bowel disease (IBD) is associated with an increased incidence of osteoporosis. Osteoporosis with osteoporotic pain syndromes, fragility fractures and osteonecrosis accounts for significant morbidity and impacts negatively on the quality of life. It is generally agreed that there is a need to increase awareness for inflammatory bowel disease‐associated osteoporosis. However, the best ways in which to identify at‐risk patients, the epidemiology of fractures and an evidence‐based rational prevention strategy remain to be established. The overall prevalence of IBD‐associated osteoporosis is 15%, with higher rates seen in older and underweight subjects. The incidence of fractures is about 1 per 100 patient years, with fracture rates dramatically increasing with age. While old age is a significant risk factor, disease type (Crohn's disease or ulcerative colitis) is not related to osteoporosis risk. Corticosteroid use is a major variable influencing IBD‐associated bone loss; however, it is difficult to separate the effects of corticosteroids from those of disease activity. The recommendations in inflammatory bowel disease are similar to those for postmenopausal osteoporosis, with emphasis on lifestyle modification, vitamin D (400–800 IE daily) and calcium (1000–1500 mg daily) supplementation and hormone replacement therapy (oestrogens/selective oestrogen receptor modulators in women, testosterone in hypogonadal men). Bisphosphonates have been approved for patients with osteoporosis (T‐score < 2.5), osteoporotic fragility fractures and patients receiving continuous steroid medication. Data on the recently Food and Drug Administration‐approved osteoanabolic substance parathyroid hormone and on osteoprotegerin are promising in terms of both steroid‐induced and inflammation‐mediated osteoporosis, the key elements of inflammatory bowel disease‐associated bone disease.
Exploration of the genetic aetiology of inflammatory bowel disease — implications for diagnosis and therapy
Authors: Schreiber S. , Hanpe J. , Nikolaus S. , Foelsch U.R.
Published: December 2004

Genomic technologies offer new approaches to the investigation of the aetiology and pathophysiology of inflammatory bowel disease. An important field relevant to inflammatory bowel disease therapy is the pharmacogenetic investigation of gene variations that may predict responses to certain medications in order to target these therapeutic interventions more precisely. To date, only about 12 000 of the estimated 30 000–50 000 human genes have been characterized. Therefore, the use of techniques for a global analysis of gene expression may allow the identification of new pathways or molecules in the therapeutic mechanisms of drugs. Recently, NOD2 has been identified as the first disease gene in inflammatory bowel disease. DLGS and OCTN‐1 have been named as further disease genes. Although the detection of disease‐associated variants has greatly advanced our understanding of the primary events that lead to the development of inflammatory bowel disease in a subgroup of patients with Crohn's disease, the implications of the findings for diagnostic and therapeutic algorithms are less clear. However, it appears that there is a clear association between certain subphenotypes of Crohn's disease and the disease‐associated variants in the NOD2 gene. It can be anticipated that genomic findings will profoundly influence the future therapy of inflammatory bowel disease.
Systemic and topical steroids in inflammatory bowel disease
Authors: Schölmerich J.
Published: December 2004

Steroids are still widely used in the treatment of inflammatory bowel diseases. Pharmacological studies have shown that there is no major abnormality in the pharmacokinetics of steroids in these disorders. Foam preparations with rectal application decrease the bioavailability to low levels, eliminating systemic complications. For oral use, ‘nonsystemic’ steroids have been developed. In ulcerative colitis, steroids are rarely needed as 5‐aminosalicylates are effective in the majority of patients. This is true for rectal application in distal colitis, as well as in more extensive disease. In Crohn's disease, steroids are more often used; however, in population‐based studies, less than 50% of patients have been treated with steroids, as there are alternative treatments available for the large group of patients with mild to moderate activity. For those patients needing steroid treatment, budesonide seems to be a good choice in active disease, but has not shown convincing effects in the maintenance of remission over longer periods of time. There is no place for long‐term steroid treatment in ulcerative colitis and very little in Crohn's disease — immunosuppression with azathioprine or related drugs is certainly the better alternative.
Gut flora and inflammatory bowel disease
Authors: Marteau P. , Lepage P. , Mangin I. , Suau A. , Doré J. , Pochart P. , Seksik P.
Published: December 2004

The pathogenesis of inflammatory bowel disease involves interactions between the host susceptibility, mucosal immunity and intestinal microflora. There is therefore great interest in the changes in the endogenous flora in inflammatory bowel disease patients and in the establishment of potential genetic variations in host responses to endogenous bacteria. In this review, we summarize the modifications in the various regional ecosystems in the gastrointestinal tract during inflammatory bowel disease (luminal bacteria in faeces or inside the gastrointestinal tract, bacteria in mucus and bacteria directly attached to the mucosa). Results were obtained following a ‘candidate microorganism strategy’ and, as is occurring increasingly frequently, following a ‘full description strategy’, which has progressed largely due to the development of culture‐independent techniques. The possibility of modifying the ecosystem using prebiotics or probiotics offers hope for new treatment developments, particularly in the prevention of relapse.
Daily use of non‐steroidal anti‐inflammatory drugs is less frequent in patients with Barrett's oesophagus who develop an oesophageal adenocarcinoma
Authors: Tsibouris P. , Hendrickse M. T. , Isaacs P. E. T.
Published: December 2004

Background : Non‐steroidal anti‐inflammatory drugs use may protect against development of oesophageal adenocarcinoma.

Aim : To define the consequences of non‐steroidal anti‐inflammatory drugs use in patients with Barrett's oesophagus.

Methods : Records of all Barrett's oesophagus/oesophageal adenocarcinoma patients examined in Blackpool‐Wyre‐Fylde area were reviewed. All surviving patients completed validated questionnaires.

Results : Use of non‐steroidal anti‐inflammatory drugs of any type and at any frequency was more prevalent in Barrett's oesophagus patients [147 (38%) Barrett's oesophagus vs. 30 (26%) oesophageal adenocarcinoma, P = 0.02]. Daily use of non‐steroidal anti‐inflammatory drugs was more prevalent in Barrett's oesophagus patients [88 (23%) Barrett's oesophagus vs. 14 (12%) oesophageal adenocarcinoma, P = 0.02], due to more prevalent consumption of non‐aspirin non‐steroidal anti‐inflammatory drugs [48 (13%) Barrett's oesophagus vs. four (4%) oesophageal adenocarcinoma, P =0.009]. There was no difference between the two groups in usage of either daily low‐dose aspirin or of occasional non‐steroidal anti‐inflammatory drugs. In logistic regression analysis any use of non‐steroidal anti‐inflammatory drugs [odds ratio (OR) = 0571 (95% CI: 0.359–0.909), P = 0.018] and daily use of non‐aspirin non‐steroidal anti‐inflammatory drugs [OR = 0.297 (95% CI: 0.097–0.911), P = 0.034] were significant protective factors. Non‐steroidal anti‐inflammatory drugs use did not affect the survival of oesophageal adenocarcinoma patients. Oesophageal adenocarcinoma and Barrett's oesophagus consuming non‐steroidal anti‐inflammatory drugs did not differ in upper gastrointestinal bleeding [26 (15%) non‐steroidal anti‐inflammatory drugs consumers vs. 29 (9%) non‐consumers, P = 0.08], oesophageal ulcers [31 (18%) non‐steroidal anti‐inflammatory drug consumers vs. 49 (15%) non‐consumers, P = 0.43] or stricturing [19 (11%) non‐steroidal anti‐inflammatory drug consumers vs. 41 (13%) non‐consumers, P = 0.58].

Conclusions : (i) Daily use of non‐steroidal anti‐inflammatory drugs is more prevalent in Barrett's oesophagus than oesophageal adenocarcinoma patients, because of a more prevalent use of non‐aspirin non‐steroidal anti‐inflammatory drugs. (ii) Use of non‐steroidal anti‐inflammatory drugs in Barrett's oesophagus patients is safe if acid suppression is adequate.
Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception
Authors: Siproudhis L. , Dinasquet M. , Sébille V. , Reymann J. M. , Bellissant E.
Published: December 2004

Background : Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood.

Aim : To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception.

Methods : A placebo‐controlled, randomized, double‐blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5‐level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure.

Results : Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (−18%, P = 0.0019, and −27%, P = 0.0002, respectively, for amitriptyline; −26%, P = 0.0001, and −33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (−16%, P = 0.0008).

Conclusion : Both antidepressants similarly relaxed the internal anal sphincter, probably through a non‐specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.
Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease
Authors: Franchimont N. , Putzeys V. , Collette J. , Vermeire S. , Rutgeerts P. , De Vos M. , Van Gossum A. , Franchimont D. , Fiasse R. , Pelckmans P. , Malaise M. , Belaiche J. , Louis E.
Published: December 2004

Background : Crohn's disease is associated with low bone mineral density and altered bone metabolism.

Aim : To assess the evolution of bone metabolism in Crohn's disease patients treated with infliximab.

Methods : We studied 71 Crohn's disease patients treated for the first time with infliximab for refractory Crohn's disease. Biochemical markers of bone formation (type‐I procollagen N‐terminal propeptide, bone‐specific alkaline phosphatase, osteocalcin) and of bone resorption (C‐telopeptide of type‐I collagen) were measured in the serum before and 8 weeks after infliximab therapy and compared with values in a matched healthy control group.

Results : Eight weeks after treatment with infliximab, a normalization of bone markers was observed with a median increase in formation markers of 14–51% according to marker and a lower but significant decrease in resorption marker (median 11%). A clinically relevant increase in bone formation markers was present in 30–61% of patients according to the marker. A clinically relevant decrease in C‐telopeptide of type‐I collagen was present in 38% of patients. No association was found with any tested demographic or clinical parameter.

Conclusion : Infliximab therapy in Crohn's disease may rapidly influence bone metabolism by acting either on bone formation or bone resorption. This improvement seems to be independent of clinical response to infliximab.
Esomeprazole 20 mg on‐demand is more acceptable to patients than continuous lansoprazole 15 mg in the long‐term maintenance of endoscopy‐negative gastro‐oesophageal reflux patients: the COMMAND Study
Authors: Tsai H. H. , Chapman R. , Shepherd A. , McKeith D. , Anderson M. , Vearer D. , Duggan S. , Rosen J. P.
Published: December 2004

Background : Symptom relief, through adherence to appropriate maintenance therapy, is the sole objective of treatment for patients with endoscopy‐negative gastro‐oesophageal reflux disease.

Aim : To compare the efficacy of ‘on‐demand’ treatment with esomeprazole 20 mg vs. continuous treatment with lansoprazole 15 mg daily in patients with endoscopy‐negative gastro‐oesophageal reflux disease.

Methods : Endoscopy‐negative gastro‐oesophageal reflux disease patients who achieved complete resolution of heartburn after short‐term (2–4 weeks) treatment with esomeprazole 20 mg (n = 774) were randomized to receive either esomeprazole 20 mg on‐demand (n =311) or lansoprazole 15 mg continuous daily treatment (n = 311) for 6 months.

Results : Significantly more patients were willing to continue taking esomeprazole on‐demand than lansoprazole continuous therapy after 6 months (93% vs. 88%; P = 0.02). This superior outcome was achieved despite patients on esomeprazole requiring medication only 38% as often as those on lansoprazole, leading to direct cost savings of more than one‐third (36%). Furthermore, patients receiving esomeprazole 20 mg on‐demand were more satisfied with their treatment after 1 month compared with patients taking lansoprazole 15 mg continuously.

Conclusions : In patients with endoscopy‐negative gastro‐oesophageal reflux disease, esomeprazole 20 mg on‐demand is more acceptable to patients and is an economically more effective treatment than lansoprazole 15 mg continuously.
Review article: tegaserod — the global experience
Authors: Chey W. D.
Published: December 2004

Studies from the Western hemisphere have established the efficacy and safety of tegaserod in women with irritable bowel syndrome and constipation. This review summarizes the results of recent studies from around the world that confirm the efficacy and safety of tegaserod, and expand our understanding of the role of this drug in the treatment of patients with irritable bowel syndrome.
Review article: the overlap between functional dyspepsia and irritable bowel syndrome — a tale of one or two disorders?
Authors: Cremonini F. , Talley N. J.
Published: December 2004

Functional dyspepsia and irritable bowel syndrome are currently considered to be two separate nosological entities. However, the overlap of symptoms and the evidence of a number of common pathophysiological characteristics suggest that functional dyspepsia and irritable bowel syndrome may be different presentations of the same disorder. In this review, we critically appraise points in common, as well as differences, in the epidemiology, pathophysiology and response to treatment of functional dyspepsia and irritable bowel syndrome. Population‐based studies and large case series show that one‐ to two‐thirds of subjects with irritable bowel syndrome have symptoms that overlap with functional dyspepsia. Symptom analyses have generally failed to support functional dyspepsia and irritable bowel syndrome as separate entities. An exaggerated motor response to meals, delayed gastric emptying and abnormal small bowel and colonic transit can all be found in subsets of functional dyspepsia and irritable bowel syndrome, and are not exclusive to either condition. Visceral hypersensitivity is a common feature to both entities and seems unlikely to be site or disease specific. There is good evidence for the post‐infectious development of irritable bowel syndrome, and this may also apply in functional dyspepsia. Psychiatric comorbidities are similar in functional dyspepsia and irritable bowel syndrome. Several common drug classes (prokinetics, visceral analgesics, psychoactive agents) may similarly improve both functional dyspepsia and irritable bowel syndrome symptoms. The evidence available suggests that at least subsets of functional dyspepsia and irritable bowel syndrome represent different manifestations of a single entity. The identification of common pathophysiological targets for therapy should be pursued in future research.
Review article: gastro‐oesophageal reflux disease as a functional gastrointestinal disorder
Authors: Kahrilas P. J.
Published: December 2004

Gastro‐oesophageal reflux disease encompasses a family of disorders united by a common pathogenesis: the excessive reflux of gastric contents. The best defined disorder is oesophagitis, but it is now evident that proton pump inhibitor therapy can resolve oesophagitis in virtually every case. The same cannot be said for gastro‐oesophageal reflux disease symptoms, however, thus moving the frontier to symptom control. Endoscopy‐negative reflux disease is a heterogeneous group, no longer bound by the common denominator of endoscopic findings. In fact, three distinct patient subgroups emerge: (i) individuals who in essence have oesophagitis, but are either in remission or simply fail to meet the endoscopic criteria; (ii) patients with hypersensitivity to oesophageal stimuli; and (iii) patients with ‘functional heartburn’ whose symptoms are not related to reflux. Given this heterogeneity, it is not surprising that the efficacy of antisecretory drugs is less impressive. This has led to new therapeutic approaches beyond acid control: mucosal protective agents, either central nervous system or peripherally acting compounds aimed at normalizing hyperalgesia, and reflux inhibitors and serotonergic agents, such as tegaserod.
Review article: gastric emptying in functional gastrointestinal disorders
Authors: Quigley E. M. M.
Published: December 2004

Although delayed gastric emptying has been described in several functional gastrointestinal disorders, and appears to be especially common in functional dyspepsia, the relationship of this finding to symptoms and basic pathophysiology is difficult to define. The delineation of the interactions between delayed gastric emptying, on the one hand, and symptom pathogenesis, on the other, has been hampered by several factors. These include the limitations of the methodology itself, the extent of overlap between the various functional disorders and the sensitivity of gastric emptying to factors external to the stomach, be they elsewhere within the gastrointestinal tract, in the central nervous system or in the environment. In many instances, delayed gastric emptying is an epiphenomenon, reflecting the overlap between inadequately defined functional syndromes, shared pathophysiology or the activation of physiological interactions between the various organs of the gut. In others, it may imply a truly diffuse motor disorder. The disappointments attendant on attempts to alleviate symptoms through approaches designed to accelerate gastric emptying should therefore not come as a surprise. Pending the definition of the true significance of delayed gastric emptying in all functional gastrointestinal disorders, caution should be exerted in the interpretation of this finding in a patient with functional symptoms.
Population pharmacokinetics of raltitrexed in patients with advanced solid tumours
Authors: Blair Elaine Y. L. , Rivory Laurent P. , Clarke Stephen J. , McLachlan Andrew J.
Published: December 2004

Aims

To investigate the population pharmacokinetics of raltitrexed in patients with advanced solid tumours and to identify patient covariates contributing to the interpatient variability in the pharmacokinetics of raltitrexed.

Methods

Patient covariate and concentration–time data were collected from patients receiving 0.1–4.5 mg m−2 raltitrexed during the early clinical trials of raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate population mean estimates for clearance (CL) and central volume of distribution (V). The relationship between individual estimates of the pharmacokinetic parameters and patient covariates was examined and the influence of significant covariates on the population parameter estimates and their variance was investigated using stepwise multiple linear regression. The performance of the developed model was tested using an independent validation dataset. All patient data were pooled in the total cohort to refine the population pharmacokinetic model for raltitrexed.

Results

A three‐compartment pharmacokinetic model was used to fit the concentration–time data of raltitrexed. Estimated creatinine clearance (CLCR) was found to influence significantly the CL of raltitrexed and explained 35% of variability in this parameter, whilst body weight (WT) and serum albumin concentrations (ALB) accounted for 56% of the variability in V. Satisfactory prediction (mean prediction error 0.17 µg l−1 and root mean square prediction error 4.99 µg l−1) of the observed raltitrexed concentrations was obtained in the model validation step. The final population mean estimates were 2.17 l h−1[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI 6.02, 6.70) for CL and V, respectively. Interpatient variability in the pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential covariates were included in the final model. The following covariate relationships with raltitrexed parameters were  described  by  the  final  population  model:  CL  (l h−1) = 0.54 + 0.02  CLCR (ml min−1) and V (l) = 6.64 + 0.08 WT (kg) − 0.16 ALB (g l−1).

Conclusions

A population pharmacokinetic model has been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic parameters of raltitrexed are markedly influenced by the patient's renal function, body weight and serum albumin levels, which may be taken into account in dose individualization. The use of influential covariates to guide anticancer dosage selection may result in less variability in drug exposure and potentially a better clinical outcome.
Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
Authors: Jiang Xuemin , Williams Kenneth M. , Liauw Winston S. , Ammit Alaina J. , Roufogalis Basil D. , Duke Colin C. , Day Richard O. , McLachlan Andrew J.
Published: December 2004

Aim

The aim of this study was to investigate the effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin.

Methods

This was an open‐label, three‐way crossover randomized study in 12 healthy male subjects, who received a single 25‐mg dose of warfarin alone or after 14 days’ pretreatment with St John's wort, or 7 days’ pretreatment with ginseng. Dosing with St John's wort or ginseng was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S‐7‐hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and 90% confidence intervals are reported.

Results

INR and platelet aggregation were not affected by treatment with St John's wort or ginseng. The apparent clearances of S‐warfarin after warfarin alone or with St John's wort or ginseng were, respectively, 198 ± 38 ml min−1, 270 ± 44 ml min−1 and 220 ± 29 ml min−1. The respective apparent clearances of R‐warfarin were 110 ± 25 ml min−1, 142 ± 29 ml min−1 and 119 ± 20 ml min−1. The mean ratio and 90% confidence interval (CI) of apparent clearance for S‐warfarin was 1.29 (1.16, 1.46) and for R‐warfarin it was 1.23 (1.11, 1.37) when St John's wort was coadministered. The mean ratio and 90% CI of AUC0−168 of INR was 0.79 (0.70, 0.95) when St John's wort was coadministered. St John's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers.

Conclusions

St John's wort significantly induced the apparent clearance of both S‐warfarin and R‐warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac‐warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S‐warfarin or R‐warfarin.
The I1‐imidazoline agonist moxonidine decreases sympathetic tone under physical and mental stress
Authors: Wenzel René R. , Mitchell Anna , Siffert Winfried , Bührmann Sandra , Philipp Thomas , Schäfers Rafael F.
Published: December 2004

Aims

Moxonidine is an I1‐imidazoline receptor agonist that reduces blood pressure by inhibition of central sympathetic activity. The effects of the drug under physical and mental stress have not been studied in detail.

Methods

We investigated the effects of 0.4 mg moxonidine orally on sympathetic activity, blood pressure and heart rate in a double‐blind, placebo‐controlled crossover study in 12 healthy volunteers. The subjects underwent physical exercise test using bicycle ergometry and a mental stress test using an adaptive reaction test device. Potential association of parameters with the GNB3 C825T polymorphism was also assessed.

Results

Under resting conditions, moxonidine decreased plasma noradrenaline (NA: −66.1 ± 12 pg ml−1; P < 0.01 vs placebo) and adrenaline (A: −18.8 ± 6 pg ml−1; P < 0.05 vs placebo). Physical exercise evoked a significant increase in plasma NA and A (NA: 760 ± 98 pg ml−1; A: 97 ± 9 pg ml−1; P < 0.001 vs baseline), which was significantly reduced after pretreatment with moxonidine (NA: 627 ± 68 pg ml−1; P < 0.05 vs placebo; A: 42.8 ± 4 pg ml−1; P < 0.01 vs placebo). Maximal physical exercise capacity was not limited by moxonidine (NS). During the mental stress test, increases in NA (placebo: 146 ± 24 pg ml−1, moxonidine: 84 ± 26 pg ml−1; P < 0.01 vs placebo) and A (placebo: 22.8 ± 9 pg ml−1, moxonidine: 8.0 ± 8 pg ml−1; P < 0.01 vs placebo) were significantly reduced after pretreatment with moxonidine. Increases in blood pressure during mental stress were significantly lower after pretreatment with moxonidine (P < 0.05 vs placebo). There was no association of the response to moxonidine with GNB3 genotypes (NS).

Conclusions

Moxonidine decreases total sympathetic tone under basal conditions as well as during physical exercise and mental stress without limiting absolute exercise capacity. Thus, moxonidine appears suitable for the treatment of patients with high SNS activity and hypertension induced by physical or mental stress. As the drug does not reduce exercise capacity, it may be considered as an alternative to β‐adrenoceptor blockers in selected patients.
Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers
Authors: Hua Teng C. , Pan Alan , Chan Clark , Poo Yeo K. , Skinner Michael H. , Knadler Mary P. , Gonzales Celedon R. , Wise Stephen D.
Published: December 2004

Aim

To investigate the effect of duloxetine on the pharmacokinetics and tolerability of tolterodine and its active 5‐hydroxymethyl metabolite (5‐HM).

Methods

Sixteen healthy subjects received two 5‐day treatment regimens in a randomized, double‐blinded, crossover fashion: tolterodine (2 mg, BID) + duloxetine (40 mg, BID), tolterodine (2 mg, BID) + duloxetine placebo (BID). Plasma concentrations of tolterodine and 5‐HM were measured on day 5. Adverse events, clinical safety laboratory data and vital signs were assessed during the study.

Results

Duloxetine increased the AUCτ,ss of tolterodine by 71%[geometric mean, 95% confidence interval (CI) 31, 123], and its Cmax,ss by 64% (CI 30, 106), and prolonged its t1/2 by 14% (CI 1, 28). Duloxetine did not affect the plasma concentrations or t1/2 of 5‐HM. Laboratory data and vital signs did not reveal any clinically significant changes or abnormalities.

Conclusions

Duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5‐HM. Coadministration of these drugs was well tolerated and demonstrated no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.
An investigation of components of variance and tachyphylaxis in a placebo‐controlled intravenous tyramine study
Authors: Cantarini M. V. , Watkins C. L. , Growcott J. , Hughes A. M.
Published: December 2004

Aims  To explore inter‐ and intra‐volunteer variability for the dose of intravenous tyramine eliciting a 20 mmHg increase in systolic blood pressure from baseline (TYR20) and to evaluate potential tachyphylaxis.

Methods  Twelve healthy volunteers received blinded placebo‐controlled ascending and descending sequences of intravenous tyramine injections on two separate occasions. The TYR20 was derived by linear interpolation, using three interventions to deal with missing data.

Results  Analysis of covariance (ancova) demonstrated no significant difference in TYR20 between sequences, regardless of the missing data methodology applied. Inter‐volunteer variability was 2.4–3.4 times larger than within‐volunteer variability. No evidence of tachyphylaxis was seen using either the sign test or generalized additive models.

Conclusions  Since inter‐volunteer variability was greater than intra‐volunteer variability, a crossover study design would be a more efficient study design, and the descending sequence of injections could be omitted since tachyphylaxis was not demonstrated.
Recombinant factor VIIa reverses the anticoagulant effect of the long‐acting pentasaccharide idraparinux in healthy volunteers
Authors: Bijsterveld Nick R. , Vink Roel , Van Aken Benien E. , Fennema Hein , Peters Ron J. G. , Meijers Joost C. M. , Büller Harry R. , Levi Marcel
Published: December 2004

We investigated whether the anticoagulant effect of idraparinux, a selective long‐acting factor Xa inhibitor, could be neutralized by recombinant factor VIIa (rFVIIa) in healthy male volunteers. We performed a randomized, placebo‐controlled trial, comparing idraparinux [7·5 mg subcutaneous (s.c.)] followed at 3 h by rFVIIa [90 μg/kg intravenous (i.v.)] (n = 6), or idraparinux (7·5 mg s.c) followed after 1 week by rFVIIa (90 μg/kg i.v.)(n = 6). rFVIIa, given 3 h after idraparinux, significantly reversed the increased thrombin generation time (TGT), the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the reduced prothrombin fragment 1+2 (F1+2) levels caused by idraparinux, although no clear effect of rFVIIa on the endogenous thrombin potential (ETP) was observed. One week after idraparinux, injection of rFVIIa resulted in a similar relative reduction of the remaining increased aPTT, PT and TGT, with correction to pre‐idraparinux values. A clear increase of F1+2 was observed, together with a small increase in ETP. We conclude that rFVIIa has significant effects on the idraparinux‐inhibited thrombin generation and clotting parameters. These results suggest that rFVIIa may be useful in serious bleeding complications in idraparinux treated patients.
Does anthracycline administration by infusion in children affect late cardiotoxicity?
Authors: Levitt G. A. , Dorup I. , Sorensen K. , Sullivan I.
Published: December 2004

The severity of late cardiotoxicity after anthracycline treatment for childhood cancer relates mainly to the cumulative anthracycline dose received, but all dose ranges cause some cardiac dysfunction. Anthracycline administration by infusion in order to lower peak drug concentration has been used in an attempt to reduce cardiotoxicity. Cardiac performance was assessed by echocardiography in children who were relapse‐free survivors of treatment for acute lymphoblastic leukaemia (ALL). They received the same cumulative anthracycline dose (daunorubicin 180 mg/m2) either by bolus injection (UKALL  X protocol, n = 40) or by infusion (UKALL XI protocol, n = 71) with a follow‐up duration of 5·3 ± 2·0 and 5·4 ± 1·0 years respectively. On analysis, both the bolus administration and infusion groups showed similar mild impairment of cardiac performance, characterized by increased left ventricular end systolic stress and impaired left ventricular function. In conclusion, subclinical abnormality of left ventricular performance was confirmed in both groups despite the relatively modest cumulative anthracycline dose received. We were unable to demonstrate an advantage of anthracycline administration by 6‐h infusion with respect to late cardiotoxicity at this dose.