General practitioner and hospital specialist attitudes to functional gastrointestinal disorders

BACKGROUND: Functional gastrointestinal symptoms generate a large workload in primary care. Research on functional gastrointestinal disorders is focused on hospital patients, but these patients may differ from those managed in primary care. AIM: To investigate any differences in attitudes of general practitioners and hospital specialists towards functional gastrointestinal illnesses. METHODS: A questionnaire was sent to 200 general practitioners and 200 British Society of Gastroenterology members. RESULTS: The response rate was 76%. Sixty-two general practitioners believed that functional gastrointestinal symptoms represented a 'real' currently unexplained gastrointestinal disorder, and 67 believed such symptoms probably represented somatization of a psychological illness. In contrast, most consultants (120) believed that functional gastrointestinal symptoms represented a 'real' gastrointestinal disorder, with only 36 perceiving them to have a psychological basis (chi2 = 26.7, P < 0.001). More consultants than general practitioners believed that the understanding of functional gastrointestinal disorders had improved in the last 20 years (chi2 = 4.31, P < 0.05). Most consultants and most general practitioners thought that treatment for these disorders had not improved over this period. Only 21% of general practitioners had heard of the Manning criteria for the diagnosis of irritable bowel syndrome, compared to 81% of consultants (chi2 = 107, P < 0.0001); 12% of general practitioners and 83% of consultants had heard of the Rome criteria for the diagnosis of functional gastrointestinal disorders (chi2 = 154, P < 0.0001); 37% of consultants used the Manning criteria and 40% used the Rome criteria; 11% of general practitioners used the Manning criteria and 3% used the Rome criteria. CONCLUSIONS: General practitioners and consultants have differing views on functional gastrointestinal disorders. In both primary and secondary care, most doctors do not use diagnostic criteria. Further research on the factors used to diagnose functional gastrointestinal disorders in primary care is warranted.     

Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials

Introduction: The most common gastrointestinal disorders that include evidence of dysmotility include: gastroparesis, the lower functional gastrointestinal disorders associated with altered bowel function (such as chronic [functional] diarrhea, chronic idiopathic constipation) and opioid-induced constipation. These conditions, which are grouped as gastrointestinal motility and functional disorders, are characterized by abnormal motor, sensory or secretory functions that alter bowel function and result in a significant disease burden, since currently available treatments do not completely alleviate symptoms. New drugs are being developed for these disorders, targeting mechanisms involved in the pathophysiology of these diseases, specifically, motor function, intestinal secretion and bile acid modulation.

Areas covered: The article provides a brief overview of motility disorders and the drugs approved and currently available for these indications. It also provides an evaluation of the efficacy, safety and possible mechanisms of the drugs currently under investigation for the treatment of gastroparesis, chronic diarrhea, chronic idiopathic constipation and opioid-induced constipation, based on animal to Phase II studies. Medications with complete Phase III trials are excluded from this discussion.

Expert opinion: Treatment of gastrointestinal motility disorders requires the understanding of the pathophysiological mechanisms, biomarkers to identify subgroups of these disorders and robust pharmacological studies from animal to Phase II studies. These are prerequisites for the development of efficacious medications and individualizing therapy in order to enhance the treatment of these patients.     

Review article: drugs interfering with visceral sensitivity for the treatment of functional gastrointestinal disorders--the clinical evidence

At present, the concept of visceral hypersensitivity provides the leading hypothesis regarding the generation of symptoms in functional gastrointestinal disorders. This paper discusses the current clinical evidence for drugs that have been proposed to interfere with visceral sensitivity in functional gastrointestinal disorders. Several possible pharmacological targets have been identified to reduce visceral pain and to reverse the processes underlying the persistence of visceral hypersensitivity. However, most of the available evidence comes from experimental animal models and cannot simply be extrapolated to patients with functional gastrointestinal disorders. In this review, we selected five drug classes that have been shown to exhibit visceral analgesic properties in experimental studies, and of which data were available regarding their clinical efficacy. These included opioid substances, serotonergic agents, antidepressants, somatostatin analogues and alpha(2)-adrenergic agonists. Although clinical trials show a limited benefit, in particular for serotonergic agents, the evidence illustrating that these effects result from normalization of visceral sensation is currently lacking. Therefore, we conclude that the concept of targeting visceral hypersensitivity as a treatment for functional gastrointestinal disorders is still controversial. Future evaluations require patient selection based on the presence of visceral hypersensitivity and application of compounds that exhibit 'true' viscerosensory effects.     

How do acupuncture and moxibustion act? - Focusing on the progress in Japanese acupuncture research -

The mechanisms of action of acupuncture and moxibustion as reported by Japanese researchers are reviewed. The endogenous opioid-mediated mechanisms of electroacupuncture (EA) as used in China are well understood, but these are only one component of all mechanisms of acupuncture. These studies emphasize the similarity of the analgesic action of EA to various sensory inputs to the pain inhibition mechanisms. In Japanese acupuncture therapy, careful detection of the acupuncture points and fine needling technique with comfortable subjective sensation are considered important. The role of polymodal receptors (PMR) has been stressed based on the facts that PMRs are responsive to both acupuncture and moxibustion stimuli, thermal sensitivity is essential in moxibustion therapy, and the characteristics of acupuncture points and trigger points are similar to those of sensitized PMRs. Acupuncture and moxibustion are also known to affect neurons in the brain reward systems and blood flow in skin, muscle, and nerve. Axon reflexes mediated by PMRs might be a possible mechanism for the immediate action of acupuncture and moxibustion. Reports on the curative effects of acupuncture on various digestive and urological disorders are also reviewed briefly.     

Review article: current and emerging therapies for functional dyspepsia

Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Although its precise definition has evolved over the last several decades, this disorder remains shrouded in controversy. The symptoms of functional dyspepsia may overlap with those of other functional bowel disorders including irritable bowel syndrome and non-erosive reflux disease. There may be coexistent psychological distress or disease complicating its presentation and response to therapy. Given the prevalence and chronicity of functional dyspepsia, it remains a great burden to society. Suspected physiological mechanisms underlying functional dyspepsia include altered motility, altered visceral sensation, inflammation, nervous system dysregulation and psychological distress. Yet the exact pathophysiological mechanisms that cause symptoms in an individual patient remain difficult to delineate. Numerous treatment modalities have been employed including dietary modifications, pharmacological agents directed at various targets within the gastrointestinal tract and central nervous system, psychological therapies and more recently, complementary and alternative treatments. Unfortunately, to date, all of these therapies have yielded only marginal results. A variety of emerging therapies are being developed for functional dyspepsia. Most of these therapies are intended to normalize pain perception and gastrointestinal motor and reflex function in this group of patients.     

Pediatric gastrointestinal diseases: are drugs the answer?

Owing to the lack of large randomized controlled studies, which would produce level 1 evidence, to guide management of gastrointestinal disorders in children, data are often extrapolated from adult studies to aid in treatment strategies. However, there are unique aspects to the management of children and adolescents with these chronic diseases, including issues of growth, side effects, long-term outcomes and psychosocial factors that might not be considered in adult trials. There is a major need for increased research in this population. In the future, a better understanding of the pathophysiologic mechanisms of these diseases should guide the development of rational novel therapies with better safety profiles for children with gastrointestinal disorders.     

Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications

Historically, immunological research in psychiatry was based on empirical findings and early epidemiological studies indicating a possible relationship between psychiatric symptoms and acute infectious diseases. However, aetiopathological explanations for psychiatric disorders are no longer closely related to acute infection. Nevertheless, immune hypotheses have been discussed in schizophrenia, affective disorders and infantile autism in the last decades.Although the variability between the results of the epidemiological studies conducted to date is strikingly high, there is still some evidence that the immune system might play a role in the aetiopathogenesis of these three psychiatric diseases, at least in subgroups of patients. In anxiety disorders immunological research is still very much in its infancy, and the few and inconsistent data of immune changes in these patients are believed to reflect the influence of short- or long-term stress exposure. Nevertheless, there are also some hints raising the possibility that autoimmune mechanisms could interrupt neurotransmission, which would be of significance in certain patients with anxiety and panic disorders. Drug and alcohol (ethanol) dependence are not believed to be primarily influenced by an immunological aetiology. On the other hand, immune reactions due to different drugs of abuse and alcohol may directly or indirectly influence the course of concomitant somatic diseases. In different organic brain disorders the underlying somatic disease is defined as a primary immune or autoimmune disorder, for instance HIV infection or systemic lupus erythematosus (SLE). For other neurodegenerative disorders, such as Alzheimer's disease, immunoaetiopathological mechanisms are supported by experimental and clinical studies. Treatment strategies based on immune mechanisms have been investigated in patients with schizophrenia and affective disorders. Furthermore, some antipsychotics and most antidepressants are known to have direct or indirect effects on the immune system. Different immunotherapies have been used in autism, including transfer factor, pentoxifylline, intravenous immunoglobulins and corticosteroids. Immunosuppressive and/or immunomodulating agents are well established methods for treating the neuropsychiatric sequelae of immune or autoimmune disorders, for example AIDS and SLE. Therapeutic approaches in Alzheimer's disease also apply immunological methods such as strategies of active/passive immunisation and NSAIDs.Considering the comprehensive interactive network between mind and body, future research should focus on approaches linking targets of the different involved systems.     

9th Annual Meeting of the Eating Disorders Reasearch Society

The application of modern neurobiological probes to the field of eating disorders has yielded new and exciting insights into the underlying mechanisms and causes of these devastating conditions. Findings from neuroimaging studies and genetic investigations have further confirmed and expanded our understanding of the role of the serotonin system in anorexia nervosa (AN) and bulimia nervosa. In addition, reduced regional cerebral blood flow in the temporal lobes and related brain structures have been identified in patients with AN, even after recovery. These data may hold promise for the development of more effective treatment strategies for these often chronic and refractory conditions. Results of reported treatment studies demonstrate the role and effectiveness of psychotherapy for AN and ‘eating disorder not otherwise specified’; two eating disorders for which there is a paucity of empirically based treatments. Finally, more results from open studies of atypical antipsychotic medications in the treatment of AN are encouraging.     

9th annual meeting of the Eating Disorders Research Society

The application of modern neurobiological probes to the field of eating disorders has yielded new and exciting insights into the underlying mechanisms and causes of these devastating conditions. Findings from neuroimaging studies and genetic investigations have further confirmed and expanded our understanding of the role of the serotonin system in anorexia nervosa (AN) and bulimia nervosa. In addition, reduced regional cerebral blood flow in the temporal lobes and related brain structures have been identified in patients with AN, even after recovery. These data may hold promise for the development of more effective treatment strategies for these often chronic and refractory conditions. Results of reported treatment studies demonstrate the role and effectiveness of psychotherapy for AN and 'eating disorder not otherwise specified'; two eating disorders for which there is a paucity of empirically based treatments. Finally, more results from open studies of atypical antipsychotic medications in the treatment of AN are encouraging.     

Genetic Risk Factors in Eating Disorders

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.     

The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide

INTRODUCTION: Linaclotide is a novel intestinal secretagogue that is in the advanced stages of development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. These functional gastrointestinal disorders are highly prevalent in adults and children and often do not respond satisfactorily to available treatments. Linaclotide appears to be a promising new agent for patients who are not satisfied with currently available agents. AREAS COVERED: This article is formed from a literature review of all the studies published about linaclotide up to January 2011. It covers the pharmacodynamics and pharmacokinetics of this novel agent. It also provides a summary of the published clinical trials concerning efficacy and safety in patients with chronic constipation and IBS-C. The authors provide the reader with a better understanding of how the molecular pathophysiology of certain enteropathic diarrheal bacteria lead to the development of this novel prosecretory drug. The reader will also learn about the development of molecularly-based treatment options for chronic constipation and other constipation-associated disorders such as IBS-C. EXPERT OPINION: Linaclotide appears to be a well-tolerated and effective agent for many patients with chronic constipation and IBS-C. Two Phase III studies in chronic constipation and two in IBS-C have provided promising data on the efficacy and safety of this agent for these two disorders. The positioning of linaclotide among the various available agents for these two disorders remains to be established after approval from the FDA is granted.     

Dexloxiglumide Rotta Research Lab

Dexloxiglumide, the (R)-isomer of loxiglumide, is a selective and highly potent CCK1 receptor antagonist. It is twice as potent as the racemic compound. because the anti-CCK activity is specific to the (R)-form, whereas the (S)-isomer is almost ineffective. It has been developed by Rotta Research Lab SpA for the treatment of diseases in which CCK1 receptor activity is potentially involved, including gastrointestinal motility, food intake and pancreatic disorders [218696]. Its receptor-mediated actions have been described in multiple in vitro and in vivo pharmacological systems. Results from both preclinical and clinical studies indicate that it is an effective inhibitor of gallbladder contraction, improves lower esophegal sphincter (LES) function, accelerates gastric emptying, accelerates colonic transit and significantly decreases symptoms in IBS and functional dyspepsia patients, and therefore has potential as an effective treatment for constipation-predominant IBS. functional dyspesia, constipation, LES function, gastric emptying disorders and biliary colics. Forest Laboratories has entered into an agreement with Rotta for the development and marketing of dexloxiglumide for the treatment of constipation-predominant IBS and phase III studies are currently ongoing in the US. In August 2000, Merrill Lynch expected that dexloxiglumide would not be launched until 2004 [379892], and in June 2001, predicted a US filing date in 2003 [413928].     

Mechanisms of Acupuncture Therapy for Cerebral Ischemia: an Evidence-Based Review of Clinical and Animal Studies on Cerebral Ischemia

Ischemic stroke is a major cause of mortality and disability worldwide. As a part of Traditional Chinese Medicine (TCM), acupuncture has been shown to be effective in promoting recovery after stroke. In this article, we review the clinical and experimental studies that demonstrated the mechanisms of acupuncture treatment for cerebral ischemia. Clinical studies indicated that acupuncture activated relevant brain regions, modulated cerebral blood flow and related molecules in stroke patients. Evidence from laboratory indicated that acupuncture regulates cerebral blood flow and metabolism after the interrupt of blood supply. Acupuncture regulates multiple molecules and signaling pathways that lead to excitoxicity, oxidative stress, inflammation, neurons death and survival. Acupuncture also promotes neurogenesis, angiogenesis as well as neuroplasticity after ischemic damage. The evidence provided from clinical and laboratory suggests that acupuncture induces multi-level regulation via complex mechanisms and a single factor may not be enough to explain the beneficial effects against cerebral ischemia.     

Pharmacotherapy for functional gastrointestinal disorders in children

Functional gastrointestinal disorders are among the most common medical problems in pediatrics. However, only a few well-designed trials have evaluated the efficacy and safety of treatments in these conditions. Data obtained from studies conducted in adults are often utilized to tailor treatment to children with functional gastrointestinal disorders. This practice might lead to substantial medication under- or over-dosing, or use of drugs for an incorrect indication.     

Review article: molecular, pathological and therapeutic features of human enteric neuropathies

Background  Considerable information has been gathered on the functional organization of enteric neuronal circuitries regulating gastrointestinal motility. However, little is known about the neuropathophysiological mechanisms underlying gastrointestinal motor disorders.
Aim  To analyse the most important pathological findings, clinical implications and therapeutic management of idiopathic enteric neuropathies.
Methods  PubMed searches were used to retrieve the literature inherent to molecular determinants, pathophysiological bases and therapeutics of gastrointestinal dysmotility, such as achalasia, gastroparesis, chronic intestinal pseudo-obstruction, Hirschsprung's disease and slow transit constipation, to unravel advances on digestive disorders resulting from enteric neuropathies.
Results  Current data on molecular and pathological features of enteric neuropathies indicate that degenerative and inflammatory abnormalities can compromise the morpho-functional integrity of the enteric nervous system. These alterations lead to a massive impairment in gut transit and result in severe abdominal symptoms with associated high morbidity, poor quality of life for patients and established mortality. Many pathophysiological aspects of these severe conditions remain obscure, and therefore treatment options are quite limited and often unsatisfactory.
Conclusions  This review of enteric nervous system abnormalities provides a framework to better understand the pathological processes underlying gut dysmotility, to translate this knowledge into clinical management and to foster the development of targeted therapeutic strategies.     

Chairmen's summary: dichotomies and directions in acid-related disorders

Presentations by international experts from old and new worlds bordering the Atlantic Ocean revealed surprising similarities with respect to the diagnosis and management of patients with upper gastrointestinal disorders. It was agreed that Helicobacter pylori infection continues to play a key role in gastroduodenal disease and has a great impact on clinical management. However, testing and treatment strategies vary in patients affected by functional dyspepsia and those receiving nonsteroidal anti-inflammatory drug (NSAID) therapy including aspirin. Among patients with gastro-oesophageal reflux disease (GERD), it was clear that we need to re-evaluate the validity of the classical concept of GERD as a progressive spectrum and instead focus on the pathophysiologic mechanisms responsible for producing the common symptom of heartburn and complications that occur in the three principle subsets of GERD patients: those with endoscopic negative reflux disease, erosive oesophagitis and Barrett's oesophagus. In addition, we need to be increasingly aware of the concept of extra-oesophageal manifestations of gastro-oesophageal reflux and the fact that GERD in adults often originates in childhood. In all these gastrointestinal disorders, proton pump inhibitor therapy has become the common thread either as a diagnostic tool or an effective short-term or long-term management strategy.     

Gastrointestinal-related adverse effects of COX-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors are used for the treatment of inflammation and pain while having the reported advantage of fewer upper gastrointestinal adverse effects compared to traditional nonsteroidal anti-inflammatory drugs. Although fewer adverse effects occur, there is still a risk for developing upper gastrointestinal adverse effects. Clinical practitioners have increased concern regarding this risk. The belief that COX-2 inhibitors are safe for the gastrointestinal tract has been questioned. This has encouraged the proposal of several explanations on the mechanism of gastromucosal injury and healing relative to COX isoenzymes. These mechanisms are delineated in the following review, along with the gastrointestinal safety, risk factors, clinical and case studies, and cost effectiveness of the COX-2 inhibitors.     

Treatment of electrolyte disorders in adult patients in the intensive care unit.

PURPOSE: The treatment of electrolyte disorders in adult patients in the intensive care unit (ICU), including guidelines for correcting specific electrolyte disorders, is reviewed. SUMMARY: Electrolytes are involved in many metabolic and homeostatic functions. Electrolyte disorders are common in adult patients in the ICU and have been associated with increased morbidity and mortality, as has the improper treatment of electrolyte disorders. A limited number of prospective, randomized, controlled studies have been conducted evaluating the optimal treatment of electrolyte disorders. Recommendations for treatment of electrolyte disorders in adult patients in the ICU are provided based on these studies, as well as case reports, expert opinion, and clinical experience. The etiologies of and treatments for hyponatremia hypotonic and hypernatremia (hypovolemic, isovolemic, and hypervolemic), hypokalemia and hyperkalemia, hypophosphatemia and hyperphosphatemia, hypocalcemia and hypercalcemia, and hypomagnesemia and hypermagnesemia are discussed, and equations for determining the proper dosages for adult patients in the ICU are provided. Treatment is often empirical, based on published literature, expert recommendations, and the patient's response to the initial treatment. Actual electrolyte correction requires individual adjustment based on the patient's clinical condition and response to therapy. Clinicians should be knowledgeable about electrolyte homeostasis and the underlying pathophysiology of electrolyte disorders in order to provide the optimal therapy to patients. CONCLUSION: Treatment of electrolyte disorders is often empirical, based on published literature, expert opinion and recommendations, and patient's response to the initial treatment. Clinicians should be knowledgeable about electrolyte homeostasis and the underlying pathophysiology of electrolyte disorders to provide optimal therapy for patients.     

Mental distress in patients with functional or organic dyspepsia: a comparative study with a sample of the general population

BACKGROUND: It has been argued that patients with functional gastrointestinal disorders have mental disorders more often than healthy controls and patients with organic disease. Most studies surveying psychological factors at the population level have relied on symptom questionnaires to diagnose functional dyspepsia. However, the symptom patterns alone are unable to adequately discriminate organic from functional dyspepsia. AIM: To evaluate the frequency of mental distress in primary care patients with organic or functional dyspepsia and compare the findings with a sample of the Finnish general population. METHODS: Four-hundred consecutive, unselected dyspeptic patients were referred for upper gastrointestinal endoscopy and other diagnostic examinations. All patients compiled a self-administered questionnaire including the 12-item General Health Questionnaire to detect cases of recent mental disorders. RESULTS: The prevalence of mental distress among patients with functional and organic dyspepsia was 38 and 36.4% respectively. The sex- and age-adjusted risk of having mental distress was nearly fourfold higher among patients with dyspepsia than in the general population. CONCLUSION: Mental distress is common among patients with functional or organic dyspepsia. Nevertheless, there is no difference between patients with functional or organic dyspepsia in the prevalence or risk of mental distress.     

Pharmacological treatment of eosinophilic gastrointestinal disorders

Introduction: Eosinophilic gastrointestinal disorders (EGIDs) are increasingly prevalent chronic inflammatory diseases characterized by eosinophilic infiltration of the gastrointestinal (GI) tract, in the absence of other known causes of eosinophilia.

Areas covered: Clinical management of EGIDs is challenging, as there are currently limited therapeutic options available. The most common EGID is eosinophilic esophagitis (EoE), and rarer forms are eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis. Clinical presentation depends on the affected GI site. Recently duodenal eosinophilia has been recognized to commonly be present in patients with functional dyspepsia. This review will provide an overview of the pathogenesis and therapeutic management of EGIDs, with particular focus on the pharmacological strategies for these conditions.

Expert commentary: Despite the considerable progress made in understanding the pathogenesis of EGIDs, there is still an urgent need for the development of specific and effective therapeutic approaches. Therapeutic management protocols are required that are based on rigorous clinical investigation in large prospective controlled trials to better understand the risks, benefits and limitations of each therapy. More well-defined and consistent end-points are also required to assess treatment outcomes, as there has been variability between patient reported outcomes, clinical outcomes, and histological outcomes in the studies to date.