Current Drug Targets - Volume 13, Issue 10, 2012

Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of sonographers has enhanced the role of ultrasonography that plays in the assessment of the gastrointestinal tract. In chronic inflammatory conditions, primarily CD, this technology can be used not only for diagnostic purposes, but it has also been suggested that it could play a role in the management of the disease.

There is growing evidence of the importance of mucosal healing (MH) in ulcerative colitis, but whether or not it should be a future primary treatment goal is still under intense discussion. Within the last decade many clinical trials have focused not only on response and remission rates but also on achievement of MH, while in clinical practice we still make treatment decisions on the basis of clinical symptoms. There is so far no internationally accepted definition of MH and the tools for assessment of MH vary from biomarkers to endoscopy with histological evaluation on the basis of several different scores and indices. This review will focus on present data dealing with methods to assess MH and the importance of MH for the future course of disease, the need for colectomy or risk of developing colorectal cancer and the patient’s quality of life. Many questions remain: How and when do we best assess MH? How rapidly do we need to achieve MH? What is the optimal time point to discontinue treatment after achieving MH? Well defined prospective studies are needed to address these important questions.

Inflammatory bowel disease diagnostic and management algorithms continue to rapidly evolve. This is partly driven by advanced radiologic techniques that provide objective, non-invasive evaluations. The realms of information provided by radiology and endoscopy continue to be intertwined. This has led to the question of whether radiologic applications will continue to expand, and eventually replace endoscopy in inflammatory bowel disease assessments. The likely outcome, however, will not be replacement, but rather imaging tools that complement endoscopic evaluations to provide global disease damage and activity scores.

The clinical management of Crohn's disease (CD) has evolved in recent years from symptom control to healing of mucosal lesions. Mucosal healing, induced and maintained by immunomodulators and/or biologicals, has been shown to alter the disease course in patients with CD. As a consequence, long-term disease outcomes have been dramatically improved, in particular since the introduction of anti-tumor necrosis factor (TNF) agents. CD patients with active inflammation (ileocolonic ulcers and/or increased C-reactive protein levels) benefit most from treatment with TNF antagonists. Since healing of the inflamed mucosa is now considered an important treatment goal, endoscopic monitoring is gradually entering routine practice. Therefore, the mucosal appearance will more and more influence the therapeutic decision making process. Mucosal healing has also become an end-point in therapeutic trials. We will summarize some of the fundamental issues regarding mucosal healing and discuss data to support its clinical relevance in the management of CD.

Endoscopy is currently considered the reference standard for the evaluation of disease activity and severity in patients with inflammatory bowel disease (IBD). However, information provided by endoscopy is limited to the mucosal surface and cannot always be complete. Cross-sectional imaging techniques are gaining acceptance for the assessment of patients with Crohn's disease (CD) and ulcerative colitis (UC). Overall diagnostic accuracy of ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of colonic lesions in patients with IBD is high. The main limitation of US is its high dependence on expertise of the examiner and the anatomic location of lesions, and its main strengths are wide availability safety and low cost. CT is highly accurate for the evaluation of patients with IBD, but due to safety issues related to radiation exposure this technique should be reserved for urgent situations in which US is not diagnostic. Technological advances in the area of MRI have allowed optimization for the assessment of patients with IBD, mainly CD. Available evidence suggests that magnetic resonance colonography (MRC) has a high diagnostic accuracy for the detection of disease activity, location, severity, and complications, particularly for penetrating and stricturing lesions, characteristic of CD. MRC can provide a valuable guidance for performing medical and surgical treatment with maximized efficacy and safety. Overall, MRI findings accurately reflect disease activity and provide reliable information for decision-making and patient care optimization

Capsule endoscopy (CE) represents a significant advance in the investigation of small bowel diseases. Twothirds of Crohn's disease (CD) patients have small bowel involvement at diagnosis. Study of small intestine mucosa by CE may have a strong impact on CD management in a near future. CE may be superior to small bowel cross-sectional imaging for detection of mucosal lesions consistent with CD and a normal CE has a high negative predictive value for active small bowel CD. A GI imaging study should generally precede CE to rule out complications such as fistulas and strictures. In established CD, CE may be useful in patients with unexplained symptoms when other investigations are inconclusive, if this will alter management. The low specificity of CE is its main drawback. Furthermore, there are no validated CD diagnosis criteria for CE and no severity indexes have been independently validated. The role of CE in evaluating mucosal healing and postoperative recurrence will require additional investigation.

The risk of developing colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly if the disease is extensive and its duration long-standing. Endoscopic guidelines have been developed with the goal of detecting early neoplastic changes prior to development of advanced malignancy. The current surveillance strategy of surveillance colonoscopy, with multiple random biopsies, most likely reduces morbidity and mortality associated with IBD-related CRC. Unfortunately, standard surveillance colonoscopy also has limitations, including high cost and sampling error at time of biopsy. The main issue is that colitis associated neoplasms often occur in flat mucosa of normal appearance, and are detected on taking random biopsies rather than by direct identification of these lesions via endoscopic imaging. Advances in endoscopic imaging techniques, such as vital or optical chromoendoscopy, that can enhance mucosal characteristics, may potentially aid in increasing dysplasia detection rate, and may reduce the workload of standard random biopsies. The aim of this review was to describe and summarize outcomes of more advanced endoscopic imaging techniques, including chromoendoscopy and magnification endoscopy.

One of the main challenges for clinicians dealing with Crohn's disease (CD) is to distinguish between inflammation and fibrosis, two sequential steps in the evolution of the intestinal disease. While inflammation is amenable to medical treatment, stricturing disease can only benefit from surgery. Magnetic resonance imaging (MRI) is a widely used tool in the diagnosis and assessment of CD. Recent data suggest that this technique might help in discriminating between fibrosis and inflammation and as such potentially guide medical decisions. In this review we will first highlight the main diagnostic techniques for CD. We will then briefly review the main mechanisms of fibrosis in this condition and the use of MRI in CD focusing on findings predictive of fibrosis and fibrotic evolution.

Double balloon enteroscopy has been available since 2004 and is slowly emerging as a valuable procedure that has the potential to reach all parts of the small intestine, allowing biopsy and therapeutic intervention. This paper describes the background to its development, the mechanics of the procedure and the current and potential roles it has in relation to small bowel Crohn's disease.

Anorectal involvement in Crohn's disease (CD) causes perianal lesions that vary from simple asymptomatic skin tags, to complex disabling fistulas and abscesses. Perianal CD affects approximately one-third of patients; its management is challenging and may require combined medical and surgical treatment, which has proven to offer the best chance of success. An optimal preoperative disease assessment is crucial in order to achieve an optimal outcome and avoid irreversible damage due to incomplete or inaccurate intervention. Imaging modalities are useful in order to confirm diagnosis, to accurately classify the disease, as to plan the most suitable treatment and monitor its results. Endoscopic Ultrasonography (EUS) and pelvic Magnetic Resonance (MRI) represent the best options from this perspective, both in terms of sensitivity and specificity, as well as for their demonstrated role in influencing treatment approach. Transperineal Ultrasonography (TPUS) may be helpful when EUS is contraindicated or not-tolerated. Computed Tomography (CT) and fistulography are generally no longer considered due to their inferior performance and the radiation exposure they involve. All imaging should be done in conjunction with an Evaluation Under Anesthesia (EUA) performed by an expert surgeon, to ensure accurate disease assessment. In this paper we review available data on each imaging modality, comparing performance and focusing on specific pros and cons, in order to assist clinicians in choosing the most appropriate treatment option for each individual patient.

In ulcerative colitis, mucosal healing has clearly been incorporated in the assessment of treatment efficacy. In Crohn's disease, this concept has only emerged in recent clinical trials with biological therapies. Systemic steroids don't reliably induce mucosal healing in Crohn's disease, but purine analogues and anti-TNF agents have a potential to heal mucosal ulcerations. Evidence for mucosal healing has now been provided for the anti-TNF agents infliximab, adalimumab and certolizumab pegol. For infliximab in Crohn's disease, mucosal healing has been associated with a reduction in clinical relapses, disease-related hospitalizations and surgeries. On the contrary, the benefit of treating asymptomatic patients with IBD more intensively until they achieve mucosal healing has not been proven. In clinical practice, assessing mucosal healing should be considered in patients with persistent symptoms despite adequate therapy as well as in patients where treatment discontinuation is being considered.

Crohn's disease leads to complications in the majority of patients on the long term. Strictures, fistulas and abscesses usually involve the bowel wall or extra-intestinal compartments, and conventional diagnostic tools, such as colonoscopy or barium studies, are not able to assess them. Magnetic resonance imaging has been proven to be accurate in detecting activity, severity and complications of Crohn's disease. Because of its reproducibility and safety, it can be considered the first-choice technique to complete Crohn's disease staging, and to monitor disease evolution. Recently, the concept of bowel damage has risen into the field of inflammatory bowel diseases. It has been shown that bowel damage induced by the disease can impact on patients' life, beyond intestinal symptoms. Data coming from rheumatology suggest that blockade of organ damage should be achieved independently from disease-related symptoms, and that a “damage driven” approach should be preferred than a “symptom-driven” one. This review of the literature aims to investigate the role of magnetic resonance imaging in assessing disease complications, which cause organ damage, and to explore future perspective in order to develop new therapeutical strategies and new tailored therapies, based on the prevention of intestinal damage.

Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer- related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa.

A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone (PTH), which causes renal osteodystrophy. PTH secretion from the parathyroid glands is controlled by the calcium-sensing receptor (CaSR) that senses extracellular calcium. High extracellular calcium activates the CaSR causing inhibition of PTH secretion through multiple signaling pathways. Cinacalcet is the first drug targeting the CaSR and can be used to effectively control and reduce PTH secretion in PTH-related diseases. Cinacalcet is a positive allosteric modulator of the CaSR and affects PTH secretion from parathyroid glands by shifting the calcium-PTH concentration-response curve to the left. One major disadvantage of cinacalcet is its hypocalcemic side effect, which may be caused by increased CaSR-mediated calcitonin secretion from the thyroid gland. However, multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways, and therefore it might be possible to develop a CaSR activating drug that selectively activates signaling pathways that inhibit PTH secretion while having no effect on signaling pathways involved in calcitonin secretion. Such a drug would have the same therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it not affecting calcitonin secretion. The present review will focus on recent advancements in understanding signaling and biased signaling of the CaSR, and how that may be utilized to discover new and smarter drugs targeting the CaSR.

Analysis of the crystal structure of beta-2 adrenoceptors (β2ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the β2AR is the best understood in terms of function, expression and activation. Regarding the interaction of β2ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for β2ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of β2ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of β2AR agonists. The deepening the understanding of the factors involved in ligand affinity for β2ARs will assist in the development of β2AR agonists that are more selective and potent, and that have longer term action. Not only are β2AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human β2ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of β2ARs.