Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-alpha plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn's disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-α plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn’s disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: future therapeutic targets

The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory bowel disease and irritable bowel syndrome. Since both disorders are associated with increased immune cell numbers, nerve growth and activation of both immune cells and nerves, we focus in this review on the involvement of immune cell–nerve interactions in inflammatory bowel disease and irritable bowel syndrome. Firstly, the possible effects of enteric nerves, especially of the nonadrenergic and noncholinergic nerves, on the intestinal immune system and their possible role in the pathogenesis of chronic intestinal inflammatory diseases are described. Secondly, the possible effects of immunological factors, from the innate (chemokines and Toll-like receptors) as well as the adaptive (cytokines and immunoglobulins) immune system, on gastro-intestinal nerves and its potential role in the development of inflammatory bowel disease and irritable bowel syndrome are reviewed. Investigations of receptor-mediated and intracellular signal pathways in neuro-immune interactions might help to develop more effective therapeutic approaches for chronic inflammatory intestinal diseases.     

Therapeutic targets in inflammatory disease

This commentary is an introduction to a special issue on "Latest Developments in the Treatment of Inflammation". It outlines some key events in the inflammatory response to infection or injury and describes some of the important drug targets of relevance to the succeeding articles, which survey inhibitors of these targets as prospective or current antiinflammatory drugs. It also highlights important limitations in the validation of inflammatory drug targets, and in the rate of discovery and development of new antiinflammatory drugs.     

Antibiotics in inflammatory bowel disease

The use of antibiotics as primary therapy in inflammatory bowel disease (IBD) has been an issue of great controversy among the experts in the field. Although the utility of certain antimicrobial agents in managing secondary complications, such as abscess formation, toxic megacolon and pouchitis, has been substantiated by clinical trials, clear evidence to support or undermine their use as primary therapeutic agents in IBD is lacking. This may be secondary to the fact that the etiology of IBD remains unknown, and, despite much speculation and research in the area, no infectious agent has been found to cause or contribute to the pathogenesis of these disorders. The dearth of data, in turn, has resulted in widely varying treatment strategies and a lack of a clear standard of care with regard to the use of antibiotics.     

Cancer in inflammatory bowel disease

The first case of cancer in inflammatory bowel disease (IBD) was reported at The Mount Sinai Hospital in 1925 in a patient with ulcerative colitis (UC). In 1956, carcinoma of the jejunum was described in a patient with regional enteritis (Crohn's disease [CD]). IBD cancers are preceded by dysplasia, and the relative risk increases with duration of the IBD. CD cancers are more proximally distributed than are UC cancers. Both tend to occur at the site of the overt disease and both develop at earlier ages (47 UC, 50 CD) than in the de novo colorectal cancer (70 years). The absolute cumulative colon cancer frequencies (8% UC, 7% CD) are identical after 20 years, emphasizing the importance of regular surveillance in both types of IBD. Moreover, the increased risk of colon cancer exists in patients with CD even when CD is confined to the small bowel, and patients with IBD have increased risks of developing extraintestinal and reticuloendothelial tumors in both CD and UC, as well as ano-vulval and malignant melanoma in CD. Colitic colorectal cancers are often diffuse, extensive, multiple and right-sided with insidious presentation. The prognosis is no worse after operation than that of de novo colon cancer. Most small bowel cancers in CD are adenocarcinomas, rather than sarcomas, and present at a younger age, more diffusely and more distally than de novo cancers, usually making them undiagnosable at a curable early stage; indeed, two-thirds present with intestinal obstruction. Strictures of the colon are common in patients with IBD, and they have a 10-fold risk for colon cancer, 30-fold for UC, and 6-fold for CD. The risk increases with disease duration. The indications for surgery are absolute, relative and incidental, and the procedures include segmental resection, total proctocolectomy, subtotal colectomy and palliative procedures.     

Emerging therapeutic targets in diabetic vascular disease

Diabetes affects nearly 14 m persons in the United States alone; worldwide, the incidence of diabetes is on the rise. It is a heterogeneous disorder of impaired insulin production/sensitivity and is associated with enhanced development of accelerated micro- and macrovasculature disease. Multiple epidemiologic studies have demonstrated that even after correction of typical risk factors, such as obesity, hyperlipidaemia, hypertension and cigarette smoking, patients with diabetes continue to experience enhanced risk of cardiovascular complications [1-2]. Thus, delineation of the factors specific and unique to diabetes that impart increased risk for the development of aggressive heart attacks and strokes is critical for the development of targeted therapy to prevent/delay accelerated macrovascular disease in diabetic patients.     

Macrophages in inflammatory bowel disease

Blood monocytes which differentiate into tissue macrophages, are unique in that they can not only initiate immune responses but can also be effector cells which contribute to the resolution of these responses. There is no single activation phenotype, and macrophages can be induced to differentiate into cells that either exacerbate or inhibit acute inflammation. Similarly, these cells can promote, deviate or suppress adaptive immune responses. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in chronic inflammatory bowel diseases, i.e. ulcerative colitis and Crohn's disease. These mechanisms might provide attractive targets for novel therapies.     

Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease

Crohn's disease and ulcerative colitis (UC) are common, chronic inflammatory bowel diseases (IBDs) characterized by episodes of life-altering symptoms such as diarrhea, bleeding, fecal urgency and incontinence, abdominal pain and cramps, and fever lasting weeks to months at a time. Existing treatments are 5-aminosalicyclates or immunosuppressants, but long-term control of IBD is a major problem for a large number of patients. Phosphodiesterase 4 (PDE4) is a key enzyme in cell homeostasis and inflammation and its inhibition has been useful in diseases such as asthma and chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. This review focuses on the role of oxidative stress in IBD and the PDE4 inhibitor OPC-6535 (tetomilast), an investigational agent for the treatment of UC. The authors detail the clinical development of the compound and report and provide insight into some of the unpublished data from the recently completed multicenter Phase III trials in UC.     

Emerging therapeutic targets in nitric oxide-dependent cardiac disease

Nitric oxide (NO) is a free radical gas that plays paracrine/autocrine and intracrine roles in maintaining physiological cardiovascular performance. In the coronary circulation, NO mediates endothelium-dependent vasodilator responses to shear stress and agonist-induced responses to neurohumoral stimulation. In the heart, NO modulates myocardial relaxation, β-adrenergic responses, mitochondrial respiration and substrate metabolism and excitation-contraction coupling. Endothelial dysfunction and the resulting decrease in the production, bioavailability and/or second messenger response-coupling has been implicated in coronary artery disease and complications associated with restenosis following coronary angioplasty, stent placement and coronary artery bypass grafting (CABG). However, there are a number of pathophysiological conditions (ischaemia-reperfusion, cardiac transplant rejection, myocarditis, sepsis) in which unregulated overproduction of NO and other reactive oxygen species (ROS) results in deleterious effects on cardiac function. Given the importance of NO in cardiac physiology/pathophysiology it may serve as a potential target for interventions aimed at deterring therapeutic failures of percutaneous or surgical treatments of cardiac disease as well as serving as a primary medical intervention. This review will examine the function of NO in mediating/modulating cardiac function, stressing the concept that, depending on the milieu, NO has the potential to exert either beneficial or deleterious effects on cardiac function. Moreover, this review will summarise studies in laboratory models and human studies in which NO activity, production, availability, or second messenger activation has been enhanced or inhibited in order to provide new insight for future targeting of this system for drug development.     

Emerging therapeutic targets in nitric oxide-dependent cardiac disease

Nitric oxide (NO) is a free radical gas that plays paracrine/autocrine and intracrine roles in maintaining physiological cardiovascular performance. In the coronary circulation, NO mediates endothelium-dependent vasodilator responses to shear stress and agonist-induced responses to neurohumoral stimulation. In the heart, NO modulates myocardial relaxation, beta-adrenergic responses, mitochondrial respiration and substrate metabolism and excitation-contraction coupling. Endothelial dysfunction and the resulting decrease in the production, bioavailability and/or second messenger response-coupling has been implicated in coronary artery disease and complications associated with restenosis following coronary angioplasty, stent placement and coronary artery bypass grafting (CABG). However, there are a number of pathophysiological conditions (ischaemia-reperfusion, cardiac transplant rejection, myocarditis, sepsis) in which unregulated overproduction of NO and other reactive oxygen species (ROS) results in deleterious effects on cardiac function. Given the importance of NO in cardiac physiology/pathophysiology it may serve as a potential target for interventions aimed at deterring therapeutic failures of percutaneous or surgical treatments of cardiac disease as well as serving as a primary medical intervention. This review will examine the function of NO in mediating/modulating cardiac function, stressing the concept that, depending on the milieu, NO has the potential to exert either beneficial or deleterious effects on cardiac function. Moreover, this review will summarise studies in laboratory models and human studies in which NO activity, production, availability, or second messenger activation has been enhanced or inhibited in order to provide new insight for future targeting of this system for drug development.     

Inducing remission in inflammatory bowel disease

Around 2-4 in 1,000 people in Northern Europe have ulcerative colitis or Crohn's disease. Both are chronic relapsing inflammatory disorders of the gastrointestinal tract and share several clinical features. However, they are largely distinct in their risk factors, their genetic, immunological, anatomical and histological features, and their response to medical and surgical therapy. Their treatment is usually considered in two phases: the induction of remission in an acute attack, and the long-term maintenance of remission. In 2001, we discussed maintenance treatment in adults. We now discuss the induction of remission, concentrating on newer therapeutic approaches.