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1.
J Can Assoc Gastroenterol ; 4(5): 214-221, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34617003

ABSTRACT

BACKGROUND: Corticosteroids (CS) have been used extensively to induce remission in Crohn's disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. AIM: The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN. METHODS: The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. RESULTS: A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. CONCLUSION: The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

2.
Clin. gastroenterol. hepatol ; 17(9): 1680-1713, Aug. 2019.
Article in English | BIGG - GRADE guidelines | ID: biblio-1026230

ABSTRACT

Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.


Subject(s)
Crohn Disease/diagnosis , Crohn Disease/therapy , Mucous Membrane , Lymphotoxin-alpha , Mesalamine/therapeutic use
3.
Gastroenterology ; 148(5)May 2015. ilus
Article in English | BIGG - GRADE guidelines | ID: biblio-965507

ABSTRACT

BACKGROUND & AIMS:: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.(AU)


Subject(s)
Colitis, Ulcerative/drug therapy , Adrenal Cortex Hormones/therapeutic use , Mesalamine/therapeutic use , Probiotics/therapeutic use , Ambulatory Care
4.
Aliment Pharmacol Ther ; 38(5): 447-59, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23848220

ABSTRACT

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Drug Monitoring , Gastrointestinal Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Algorithms , Antibodies, Monoclonal/immunology , Cost-Benefit Analysis , Dose-Response Relationship, Drug , Gastrointestinal Agents/immunology , Humans , Inflammatory Bowel Diseases/immunology , Infliximab , Practice Guidelines as Topic , Randomized Controlled Trials as Topic , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/therapeutic use
5.
Aliment Pharmacol Ther ; 37(11): 1057-64, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23581515

ABSTRACT

BACKGROUND: The impact of peri-operative use of TNFα antagonists on post-operative complications such as infection and wound healing is controversial. AIM: To conduct a systematic review and meta-analysis to assess the impact of peri-operative use of TNFα antagonists on post-operative complications such as infection and wound healing in patients with inflammatory bowel disease (IBD). METHODS: A literature search identified studies that investigated post-operative outcomes in patients with IBD using TNFα antagonists. The primary outcome was the rate of post-operative infectious complications. Secondary outcomes included the rates of non-infectious complications and total complications. Odds ratios (OR) with 95% confidence intervals (CI) are reported. RESULTS: Overall, 18 studies with 4659 participants were eligible for inclusion. Patients with IBD using preoperative anti-TNFα therapies had significant increases in post-operative infectious [OR 1.56 (95% CI, 1.09-2.24)], non-infectious [OR 1.57 (95% CI, 1.14-2.17)] and total complications [OR 1.73 (95% CI, 1.23-2.43)]. Studies limited to patients with Crohn's disease demonstrated a statistically significant increase in infectious (OR 1.93, 95% CI 1.28-2.89) and total (OR 2.19, 95% CI 1.69-2.84) complications, and a trend towards increase in non-infectious complications (OR 1.73, 95% CI 0.94-3.17). Studies of patients with ulcerative colitis did not demonstrate significant increases in infectious (OR 1.39, 95% CI 0.56-3.45), non-infectious (OR 1.40, 95% CI 0.68-2.85), or total complications (OR 1.10, 95% CI 0.81-1.47). CONCLUSION: Anti-TNFα therapies appear to increase the risk of post-operative complications. The increase in risk is small, and may well reflect residual confounding rather than a true biological effect. Nevertheless, physicians should exercise caution when continuing biological therapies during the peri-operative period.


Subject(s)
Anti-Inflammatory Agents/adverse effects , Inflammatory Bowel Diseases/surgery , Postoperative Complications , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Certolizumab Pegol , Humans , Immunoglobulin Fab Fragments/adverse effects , Immunoglobulin Fab Fragments/therapeutic use , Infliximab , Odds Ratio , Perioperative Period , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Risk Factors
6.
Aliment Pharmacol Ther ; 37(10): 947-52, 2013 May.
Article in English | MEDLINE | ID: mdl-23530880

ABSTRACT

BACKGROUND: Current guidelines recommend the cessation of clopidogrel therapy 5 days and 7-10 days prior to colonoscopic polypectomy. Recent studies have advocated for continued clopidogrel as post-polypectomy bleeding (PPB) rates have been similar to those in the general population not on antithrombotic therapy. AIM: To assess colonoscopic post-polypectomy bleeding in patients on continued clopidogrel therapy. METHODS: A literature search was conducted for studies that investigated PPB in patients on continued clopidogrel therapy. The primary outcome of interest was the pooled relative risk ratio (RR) of colonoscopic PPB in patients on continued clopidogrel therapy vs. controls. Secondary outcomes were a comparison of immediate and delayed colonoscopy PPB in patients on continued clopidogrel therapy vs. controls. RESULTS: Five observational studies included 574 subjects on continued clopidogrel therapy and 6169 control subjects. The pooled RR for PPB on continued clopidogrel therapy was 2.54 (95% CI 1.68-3.84, P < 0.00001). For immediate PPB there was a nonsignificant pooled RR of 1.76 (95% CI 0.90-3.46, P = 0.10), and delayed PPB there was a significant pooled RR of 4.66 (95% CI 2.37-9.17, P < 0.00001). CONCLUSIONS: The results of this meta-analysis suggest that continued clopidogrel increases the risk of delayed but not immediate post-polypectomy bleeding. Clopidogrel interruption in individuals with coronary artery disease predisposes to serious acute ischaemic events. In high-risk patients, endoscopists should be cognisant of these risks and consider deferring elective colonoscopy and polypectomy until it is considered safe to interrupt clopidogrel therapy.


Subject(s)
Colonic Polyps/surgery , Colonoscopy/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Postoperative Hemorrhage/chemically induced , Ticlopidine/analogs & derivatives , Clopidogrel , Colonic Polyps/drug therapy , Humans , Risk Factors , Ticlopidine/adverse effects , Time Factors
7.
Neurogastroenterol Motil ; 24(6): 546-52, e252, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22356614

ABSTRACT

BACKGROUND: Current diagnostic criteria for functional gut disorder are based on symptom clusters observed after sporadic onset. It remains unclear whether symptoms group similarly in functional disorders of postinfectious etiology. We utilized observational data from the Walkerton Health Study (WHS) to: (i) determine groupings of functional gastrointestinal symptoms among patients exposed to acute gastroenteritis (GE), and (ii) assess the stability of these symptoms grouping over time. METHODS: WHS participants 16 years of age and older at the time of the outbreak were included, if they had completed a modified Talley's Bowel Disease Questionnaire (BDQ) and responded 'yes' to a screening question as to whether they had experienced abdominal pain in the last 2 weeks. Exploratory factor analysis (EFA) using tetrachoric correlations was undertaken to identify symptom constructs. Hierarchical cluster analysis using the k-means method was used to create cluster groupings of patients based on these factors. Confirmatory factors analysis using responses to BDQ questionnaire administered at 4, 6, and 8 years after the outbreak was performed to assess stability of symptom domains over time. KEY RESULTS: A total of 773 participants were eligible for inclusion [62.2% female, mean age 43.1 years (SD = 16.9)]. Eighty-four percent were exposed to acute GE during the outbreak. Two symptom groupings of abdominal pain with either diarrhea or constipation together explained 85.7% of the total variance. Cluster analysis identified four patients groupings based on these factors. These clusters could be qualitatively described as diarrhea- and constipation-predominant, mixed bowel pattern, and no predominance of bowel movements abnormalities. Results of the confirmatory factor analysis validating symptom domains identified in Year 1 showed that the baseline model was acceptable at 4 and 6 years after the outbreak and approached acceptability at 8 years. Values of root mean square error of approximation were 0.071 (90% CI: 0.053, 0.089) at 4 and 0.071 (90% CI: 0.049, 0.092) at 6 years and 0.089 (90% CI: 0.065, 0.114) at 8 years. CONCLUSIONS & INFERENCES: The majority of subjects with postinfectious functional bowel disorders belong to groups with symptoms of abdominal pain and either diarrhea or constipation. These symptom groupings were stable across time.


Subject(s)
Abdominal Pain/epidemiology , Constipation/epidemiology , Gastroenteritis/epidemiology , Gastrointestinal Diseases/epidemiology , Adolescent , Adult , Cluster Analysis , Disease Outbreaks , Female , Humans , Male , Middle Aged , Prevalence , Surveys and Questionnaires
8.
J Anim Sci ; 90 Suppl 4: 13-5, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23365269

ABSTRACT

Salmonella enterica Typhimurium (ST) is of concern in the swine industry with relevance for animal health and consumer safety. Nutritional strategies might help to reduce ST infection and transmission. This study examined the potential of wheat (Triticum aestivum) distillers dried grains with solubles (DDGS) and sugar beet (Beta vulgaris) pulp (SBP) to alter intestinal microbial communities and ST shedding using a Trojan model. Weaned pigs (n = 105; 28.5 ± 3.5 d of age) were separated into 3 treatment groups (7 pigs/pen) and fed a wheat-based control diet or the control diet formulated with 15% wheat DDGS or 6% SBP inclusion. Following 12 d of diet adaptation, 2 pigs/pen were inoculated with 2 x 10(9) cfu ST, resistant to novobiocin and nalidixic acid. Fecal swabs were taken from infected pigs and pen-mates (contact pigs) for 9 d following challenge, enriched in nutrient broth for 24 h, and plated on selective media to determine prevalence of ST. The ranges of prevalence of ST in feces were from 90 to 100% in challenged pigs and 74 to 78% in contact pigs. No influence of treatment on rectal temperature and prevalence of ST in contact pigs were observed. Fifteen contact pigs were euthanized per treatment group on 9 and 10 d postchallenge to enumerate in intestinal contents (ileum, cecum, and proximal colon), Lactobacillus spp., Enterobacteriaceae, and Clostridium clusters I, VI, and XVIa by quantitative PCR (qPCR) and to determine ST prevalence by selective culture. No significant effects of diet were observed with respect to ST prevalence in feces, ileum, cecum, colon, and lymph nodes of contact pigs. Compared with the control diet, DGGS and SBP diets showed a trend towards increased (P < 0.1) number of Lactobacillus species in the cecum and colon. Although both wheat DGGS and SBP tended to increase the Lactobacillus spp. neither of the feed ingredients affected ST prevalence.


Subject(s)
Animal Feed/analysis , Beta vulgaris , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/isolation & purification , Swine Diseases/microbiology , Triticum , Animals , Diet/veterinary , Salmonella Infections, Animal/prevention & control , Salmonella Infections, Animal/transmission , Swine , Swine Diseases/prevention & control , Weaning
9.
Can J Gastroenterol ; 22(3): 261-72, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18354755

ABSTRACT

Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Colitis, Ulcerative/drug therapy , Gastrointestinal Agents/therapeutic use , Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal/administration & dosage , Contraindications , Gastrointestinal Agents/administration & dosage , Humans , Infliximab , Infusions, Intravenous , Randomized Controlled Trials as Topic , Remission Induction , Risk Assessment
10.
Aliment Pharmacol Ther ; 26(4): 535-44, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17661757

ABSTRACT

BACKGROUND: Individual studies suggest that post-infectious irritable bowel syndrome is common, but symptoms gradually improve. AIM: To review evidence for an association between intestinal infection and development of irritable bowel syndrome, assess the prognosis of post-infectious irritable bowel syndrome and explore factors that increase the risk. METHODS: MEDLINE (1966-2007) and EMBASE (1980-2007) databases were searched to identify the studies of post-infectious irritable bowel syndrome epidemiology. Data were extracted by two independent reviewers. Pooled odds ratios (POR) and corresponding 95% CI for incidence of irritable bowel syndrome were estimated among the exposed and unexposed groups. RESULTS: Eighteen of 26 studies identified were eligible for inclusion. Intestinal infection was associated with increased odds of developing irritable bowel syndrome at study end (POR = 5.86; 95% CI: 3.60-9.54). In subgroup analysis, the odds of developing irritable bowel syndrome was increased at 3 months (POR = 7.58; 95% CI: 4.27-13.45), 6 months (POR = 5.18; 95% CI: 3.24-8.26), 12 months (POR = 6.37; 95% CI: 2.63-15.40) and 24-36 months (POR = 3.85; 95% CI: 2.95-5.02). Among all studies (controlled and uncontrolled), the pooled incidence of irritable bowel syndrome at study conclusion was 10% (95% CI: 9.4-85.6). Subjects with post-infectious irritable bowel syndrome were younger and more anxious and depressed than those without post-infectious irritable bowel syndrome. CONCLUSION: The odds of developing irritable bowel syndrome are increased sixfold after acute gastrointestinal infection. Young age, prolonged fever, anxiety and depression are risk factors for post-infectious irritable bowel syndrome.


Subject(s)
Bacterial Infections/complications , Gastroenteritis/complications , Irritable Bowel Syndrome/etiology , Female , Humans , Male , Odds Ratio , Risk Factors
11.
Exp Biol Med (Maywood) ; 231(8): 1333-45, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16946402

ABSTRACT

A germ-free neonatal pig model was established to determine the effects of bacterial colonization by different species on small intestinal morphology and proinflammatory cytokine gene expression. Two experimental groups of 16 pigs were aseptically delivered by cesarian section and allocated into 4 gnotobiotic isolators. Pigs were either maintained germ-free (GF), or were orally inoculated with either a single strain of nonpathogenic Escherichia coli (EC) or Lactobacillus fermentum (LF) or conventionalized with adult porcine feces (CV). After 13 days tissue samples were collected at 5 regions corresponding to 5%, 25%, 50%, 75%, and 95% of the small intestine (SI) length. In Experiment 2, the GF isolator became contaminated with Staphylococcus epidermidis (SE). In general, intestinal responses to bacterial colonization were similar among GF, LF, and SE pigs, and intestinal responses in EC pigs were more similar to CV pigs. Responses to bacterial colonization were most pronounced in the distal SI regions (50%-95%), suggesting that nonmicrobial factors may be more important in the proximal SI. Relative to CV pigs, the distal intestines of GF, LF, and SE pigs were characterized by long villi, shallow crypts, increased relative intestinal mass, and decreased lamina propria cellularity, whereas SI morphology was intermediate in EC pigs. Relative expression of proinflammatory cytokines interleukin-1beta (IL-1beta ) and IL-6 generally increased distally in the SI and was highest in EC and CV pigs. We observed regional variation in SI morphology and proinflammatory cytokine expression, which differed with bacterial species. This study demonstrates that bacterial species differentially affect intestinal morphology and expression of proinflammatory cytokines and suggests that neonatal bacterial colonization patterns may have long-term effects on intestinal health and development.


Subject(s)
Cytokines/biosynthesis , Germ-Free Life , Intestine, Small/growth & development , Intestine, Small/immunology , Intestine, Small/microbiology , Swine/growth & development , Animals , Animals, Newborn , Escherichia coli/immunology , Limosilactobacillus fermentum/immunology , Reverse Transcriptase Polymerase Chain Reaction , Staphylococcus epidermidis/immunology , Swine/immunology , Swine/microbiology , Symbiosis
13.
Aliment Pharmacol Ther ; 20(11-12): 1317-22, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15606393

ABSTRACT

BACKGROUND: Post-infectious irritable bowel syndrome is a common clinical phenomenon of uncertain aetiology. AIM: To test the association between intestinal permeability and irritable bowel syndrome symptoms 2 years after a large waterborne outbreak of bacterial gastroenteritis. METHODS: Consecutive adults with Rome I irritable bowel syndrome and controls without irritable bowel syndrome attending a community clinic were enrolled. Intestinal permeability was measured as the ratio of fractional urinary excretions of lactulose and mannitol, and compared among cases vs. controls and predictors of abnormal intestinal permeability were assessed. RESULTS: A total of 218 subjects (132 irritable bowel syndrome cases and 86 non-irritable bowel syndrome controls) completed the study protocol. About 27 (12%) had been diagnosed with the irritable bowel syndrome before the outbreak and 115 (53%) had been ill during the outbreak. Lactulose-mannitol ratios were increased among cases vs. controls (Mann-Whitney mean rank 118.8 vs. 95.3, P = 0.007), and cases were more likely to have a ratio >0.020 (P = 0.007). Among cases, those with increased intestinal permeability were more likely to report increased stool frequency. Both irritable bowel syndrome symptoms and male gender, but not diarrhoeal illness during the outbreak, were significant predictors of abnormal permeability. CONCLUSIONS: Irritable bowel syndrome symptoms are associated with a subtle increase in intestinal permeability irrespective of prior gastroenteritis. This may improve understanding of the aetiology of both sporadic and post-infectious irritable bowel syndrome.


Subject(s)
Gastroenteritis/complications , Irritable Bowel Syndrome/metabolism , Acute Disease , Adolescent , Adult , Aged , Aged, 80 and over , Bacterial Infections/epidemiology , Disease Outbreaks , Female , Gastroenteritis/epidemiology , Humans , Lactulose/metabolism , Male , Mannitol/metabolism , Middle Aged , Ontario/epidemiology , Permeability
14.
Pharmacoeconomics ; 19(10): 1039-49, 2001.
Article in English | MEDLINE | ID: mdl-11735672

ABSTRACT

BACKGROUND: Clinical trials have shown rofecoxib, a selective inhibitor of cyclo-oxygenase-2, to be associated with fewer gastrointestinal complications than non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To evaluate the potential clinical and economic consequences of rofecoxib prescription in Ontario, Canada, for patients with osteoarthritis (OA) aged >65 years who did not respond to paracetamol (acetaminophen) therapy. DESIGN: Decision analytic modelling study. METHODS: A model was constructed to compare rofecoxib and nonselective NSAIDs with respect to their gastrointestinal complications in patients with OA. The model had a 1-year horizon and considered direct medical costs from the perspective of the Ontario Ministry of Health. Event rates were estimated from a pooled analysis of 8 phase IIb/Ill clinical trials. The number of perforations, ulcers and bleeds (PUBs) with each strategy was used as the primary measure of effectiveness. RESULTS: In the base-case scenario, the expected total cost per patient-day on nonselective NSAIDs was 1.60 Canadian dollars (Can dollars) versus 1.67 Can dollars on rofecoxib (1999 values). Rofecoxib was associated with 0.0109 fewer PUBs per patient per year. The incremental cost to avoid 1 additional PUB by substituting rofecoxib for nonselective NSAIDs was 2247 Can dollars. The rofecoxib strategy became dominant if a gastroprotective agent was prescribed to more than 27.5% of the patients receiving nonselective NSAIDs. CONCLUSION: For patients with OA aged >65 years in whom paracetamol therapy has failed, rofecoxib may represent a cost-effective alternative to nonselective NSAIDs. Increased costs for drug acquisition are offset, in part. by avoidance of gastrointestinal complications and reduced use of gastroprotective agents. Rofecoxib may offer increased benefit among patients at a higher risk of serious gastrointestinal events.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/economics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cyclooxygenase Inhibitors/economics , Cyclooxygenase Inhibitors/therapeutic use , Isoenzymes/metabolism , Lactones/economics , Lactones/therapeutic use , Osteoarthritis/drug therapy , Osteoarthritis/economics , Prostaglandin-Endoperoxide Synthases/metabolism , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cost-Benefit Analysis , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/adverse effects , Decision Support Techniques , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/economics , Humans , Lactones/adverse effects , Membrane Proteins , Ontario , Stomach Ulcer/chemically induced , Stomach Ulcer/economics , Sulfones
15.
Curr Opin Investig Drugs ; 2(4): 502-4, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11566006

ABSTRACT

Millennium (formerly LeukoSite) and Genentech are developing LDP-02, a humanized monoclonal antibody to the alpha4beta7 integrin receptor on leukocytes, for potential use in the treatment of inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis [274580]. LeukoSite intended to develop iv and sc formulations of LDP-02 for acute IBD [315156]. In December 1997, Genentech entered into a collaboration with LeukoSite to develop and commercialize LDP-02 for the treatment of IBD [275395], [279420]. A phase II SBIR grant was awarded to LeukoSite in September 1996. The US $750,000 grant was used to develop LDP-02 and to conduct preclinical tests on the antibody for the treatment of IBD [218689]. In February 1999, Lehman Brothers predicted the drug had a 10% probability of reaching market. Assuming a successful launch, Lehman Brothers analysts estimated peak sales would occur in 2011 with sales at that time of US $250 million [319225].


Subject(s)
Antibodies, Monoclonal/therapeutic use , Colitis, Ulcerative/therapy , Crohn Disease/therapy , Integrins/immunology , Animals , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal, Humanized , Clinical Trials as Topic , Humans
16.
Digestion ; 64(3): 200-4, 2001.
Article in English | MEDLINE | ID: mdl-11786669

ABSTRACT

The epidemiology of irritable bowel syndrome (IBS) in Europe and North America was analyzed from published material. The percentage of the population of Western civilisation with IBS symptoms is between 10 and 15% in most studies. The proportion of a Western population visiting a doctor for IBS symptoms is around 5%. The prevalence of IBS and the proportion of consulters do not seem to depend on age in an adult population. The female-to-male ratio of IBS in the population is close to 2. It is higher in IBS consulters in primary care and may be as high as 3 or 4 in tertiary referral centers. At least in patients from these centers, the number of physician visits and colonoscopies is considerable. Most of the consulters get a drug prescription.


Subject(s)
Colonic Diseases, Functional/epidemiology , Europe/epidemiology , Female , Humans , Male , North America/epidemiology , Prevalence , Sex Distribution , Surveys and Questionnaires
17.
Gastroenterology ; 119(6): 1740-4, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11113095

ABSTRACT

Increased intestinal permeability to several specific molecular probes has been observed in patients with Crohn's disease and their first-degree relatives. A positive family history is also a potent risk factor for inflammatory bowel disease. Although it has been argued that increased permeability in relatives may confer an increased future risk of developing Crohn's disease, long-term follow-up of such family members has been lacking. We describe a 24-year-old woman with a positive family history of Crohn's disease who had an elevated gut permeability to (51)Cr-EDTA at age 13, as part of a cross-sectional cohort study in patients and their first-degree relatives. She was asymptomatic at the time, and extensive investigation found no evidence of microscopic or macroscopic Crohn's disease. Repeat investigation because of symptom onset at age 21 revealed ileocolonic Crohn's disease, which required treatment with systemic corticosteroids to induce a clinical remission. In this case, a permeability defect was clearly identified to precede the onset of Crohn's disease in a subject at increased risk. This observation provides support for the hypothesis that increased gut permeability to macromolecules is an early step in the pathogenesis of this disorder.


Subject(s)
Crohn Disease/genetics , Genetic Predisposition to Disease , Intestinal Mucosa/metabolism , Adolescent , Adult , Cohort Studies , Crohn Disease/diagnosis , Cross-Sectional Studies , Edetic Acid/pharmacokinetics , Female , Humans , Male , Permeability
18.
Aliment Pharmacol Ther ; 14(11): 1451-7, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11069316

ABSTRACT

BACKGROUND: Aminobisphosphonates are recommended for postmenopausal osteoporosis but have been associated with injury to the upper gastrointestinal tract. AIM: To conduct a randomized controlled trial, to assess the endoscopic damage caused by alendronate and its effect on gastric mucosal prostaglandin synthesis. METHODS: Seventy-six healthy volunteers age 40-60 years, with normal baseline endoscopy were randomly assigned to treatment with: (A) ASA 650 mg q. d.s.; (B) alendronate 10 mg o.d.; or (C) placebo o.d. for 14 days. Mucosal injury scores on day 14 of treatment were reported by a blinded endoscopist. Gastric biopsies were analysed for prostaglandin E2 (PGE2) concentration by radioimmunoassay. RESULTS: Oesophageal injury did not differ among treatment groups. Gastric ulcers developed in five out of 26 subjects given ASA, two out of 25 given alendronate, and none of 25 given placebo. The mucosal damage scores for the alendronate group exceeded those for the placebo group in the gastric body but not at other sites. Injury scores for ASA exceeded those for placebo in the duodenum, antrum, body, and fundus. The mean change in log10[PGE2] (ng/mg protein) was - 0.07 for placebo, - 0.80 for ASA, and + 0.62 for alendronate (differences not significant). CONCLUSIONS: Alendronate is associated with injury and ulceration of the gastric mucosa. This effect was not associated with any significant change in gastric mucosal PGE2 levels.


Subject(s)
Alendronate/adverse effects , Dinoprostone/biosynthesis , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Stomach Ulcer/chemically induced , Adult , Alendronate/administration & dosage , Alendronate/therapeutic use , Analysis of Variance , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/administration & dosage , Aspirin/therapeutic use , Dose-Response Relationship, Drug , Female , Gastroscopy , Humans , Male , Middle Aged , Osteoporosis/drug therapy , Radioimmunoassay , Stomach Ulcer/pathology
19.
Am J Gastroenterol ; 95(7): 1628-36, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10925961

ABSTRACT

Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Colitis, Ulcerative/drug therapy , Mesalamine/administration & dosage , Administration, Oral , Administration, Rectal , Adrenal Cortex Hormones/therapeutic use , Aminosalicylic Acids/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Chemistry, Pharmaceutical , Drug Therapy, Combination , Humans , Mesalamine/adverse effects , Remission Induction , Severity of Illness Index
20.
Can J Gastroenterol ; 14(6): 505-9, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10888731

ABSTRACT

The rate of publication of clinical practice guidelines for the management of common medical illnesses continues to accelerate. The appropriate dissemination and uptake of high quality practice guidelines can synthesize evidence, improve patient outcomes and enhance the efficiency of health care delivery. However, the methodological rigour and relevance of the growing number of publications labelled 'clinical practice guidelines' vary widely. Health care payers, providers and advocates must learn to appraise and interpret guideline recommendations critically. A simple and practical nine-question approach to evaluating the quality, relevance and effectiveness of clinical practice guidelines is presented.


Subject(s)
Practice Guidelines as Topic , Practice Guidelines as Topic/standards , Quality Control
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