Current Pharmaceutical Design - Volume 16, Issue 33, 2010

Current treatment options for the chronic gastrointestinal disorder irritable bowel syndrome (IBS) have long been limited to symptomatic treatments due to lack of pathophysiologic understanding of the syndrome. Within the past 10 years, however, a number of new pharmacological targets have been identified that may aid in the treatment of irritable bowel syndrome. Although only a limited number of new drug entities have entered the market in the past years, many new potential pharmacophores are evolving. Among them, several drugs are in the pipeline that target cholecystokinin or corticotropin-releasing factor receptors, serve as inhibitors for specific tryptophan hydroxylase iso-enzymes, modulate chloride secretion, influence immune responses via monoclonal antibodies or ATPmediated pathways, and even normalize the gastrointestinal microflora via supplementation with probiotics. While new treatments that act via chloride secretion and immune modulation present with favorable outcomes in clinical trials, other novel therapies require further evaluation. This review is intended to provide a synopsis of current and emerging pharmacotherapies for IBS.

Irritable bowel syndrome (IBS) is a highly prevalent chronic functional gastrointestinal (GI) disorder associated with abdominal pain and change in bowel habits that its etiology is not known yet. In the recent years, melatonin has been proposed as a possible candidate. In the present work, all clinical or non-clinical data about effects of melatonin in GI tract and IBS obtained from literature without time limit up to August 2010 have been studied and reviewed. Eight clinical trials were reviewed for the efficacy and disturbance of melatonin in IBS and other GI disorders. The results showed disturbances in endogenous melatonin concentration in IBS patients and significant benefits of exogenous melatonin in these patients by decreasing abdominal pain and improvement of overall IBS symptom scores. The results of seventeen non-clinical studies showed anxiolytic, anti-inflammatory, anti oxidative and motility regulatory effects of melatonin on GI tract. In conclusion, melatonin can be a target of interest in IBS because of its potentials to regulate GI motility.

Over the last 15 years, the use of various biological therapies has largely improved the way we manage patients with Inflammatory Bowel Diseases (IBDs). Blockade of cytokine synthesis and/or activity is at the forefront of this new era with the success of inhibitors of tumor necrosis factor (TNF)-α. These therapies are however not effective in all IBD patients and efficacy may wane. Moreover, patients treated with anti-TNF-α antibodies can develop severe side-effects and new immune-mediated diseases. Therefore, a new challenge is to elucidate new inflammatory networks in the IBD tissue and develop novel anti-cytokine compounds, which may act in patients who are resistant to or cannot receive anti-TNF-α therapies. In this article we review the available data supporting the pathogenic role of IL-23 and Th17-related cytokines in IBD, and discuss whether and how compounds that control the activity of these cytokines may enter into the therapeutic armamentarium of IBD.

Inflammatory bowel disease (IBD) is known as a chronic inflammation of gastrointestinal tract that its pathogenesis still is not completely understood. Several drug categories are used for management of IBD but there is no exact cure for the disease, however biological drugs targeting the inflammation of gut are on the center of attention. In investigating the anti-inflammatory drugs, phosphodiesterase inhibitors were found to be effective in different inflammatory disorders. Of them phosphodiesterase 4 (PDE4) inhibitors are considered for treatment of asthma and chronic obstructive pulmonary disease (COPD). Some of the PDE4 inhibitors showed promising efficacy in animal studies, however to date no phase III clinical study showed their effectiveness in IBD. The present study has the most relevant studies in this field. PDE4 inhibitors affect IBD in different ways including anti-inflammatory, anti-depressant, and anti-fibrotic effects. Unfortunately, the most common side effect of PDE4 inhibitors is nausea which limits its use. Tetomilast the second generation of PDE4 inhibitors showed promising effects in phase II studies with better safety profile. Other drugs in this class are ongoing phase II and III trials.

Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the gastrointestinal tract and is broadly classified into Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, our understanding of the etiology and pathogenesis of this group of disorders has been improved. More specifically, recent development of biologics and use of immunomodulator agents in IBD have made it possible to robustly control mucosal inflammation and heal mucosal ulcerations and thus provide an opportunity to potentially modify disease course and prevent complications and future surgery. However, unfortunately we have not identified reliable, sensitive and specific markers to predict disease course and to identify those patients with aggressive and progressive course that would benefit from early use of biologics to prevent future complication and surgery. Thus, optimal medical management of IBD has remained multifaceted and individualized. Our primary therapeutic goals have remained unchanged and are to: [1] improve patient quality of life by treating flare ups [induction of remission], maintaining remission, and treating symptoms like diarrhea; [2] predict and prevent/treat complication; [3] prevent/treat nutritional deficiency and maintain optimal nutrition, [4] provide appropriate psychosocial support, and of course [5] attempt to modify disease course in those with aggressive disease. We can achieve these goals by appropriate use of therapeutic agents that include 5-aminosalicylates, corticosteroids, immunosuppressive agents, antibiotics, nutritional support, and the biologic agents. Information from well designed double blind placebo controlled trials combined with knowledge of the potential impact of patient and disease characteristics on disease course which can assist us to individualized treatment plan will be the guide for us to appropriately use these therapeutic agents. For example, age of the onset of the disease, patient gender and race, mode of the disease presentation, disease location, disease-associated complications such as perianal disease/fistula, and serology and genetic markers can all help to individualize disease treatment. These factors can help to determine whether one should start with 5-ASA/antibiotic/steroid [step-up where there is no risk factors for aggressive disease course] or whether one should initiate biologic therapy at diagnosis [top-down approach], and whether it is most advisable to use monotherapy with biologic treatment [e.g. in young, Caucasian male or elderly] or use a combination therapy with a biologic and an immunomodulator. Ongoing research promises, in a near future, development of more robust set of markers to be able to model disease behavior to more accurately predict disease course and thus decide on therapeutic approach with most appropriate efficacy/risk ratio for a given patient. Furthermore, current basic laboratory research has provided a large number of potential therapeutic targets to treat IBD with new promising highly specific and targeted agents.

Objective: This meta-analysis of randomized controlled trials was conducted to evaluate the efficacy and tolerability of two drug groups (immunoregulators and antibiotics) in the treatment of fistula in Crohn's disease (CD). Methods: PubMed, Embase, Scopus, Google Scholar, and Web of Science were searched for clinical trial studies investigated the effects of immunoregulators and antibiotics in the treatment of fistulizing CD. Clinical response and adverse effects were the key outcomes of interest. Data were searched from the time period of 1966 through June 2010. Result: Eleven randomized placebo-controlled clinical trials that met our criteria (nine in different immunoregulators and two in antibiotics) were included in the analysis. Pooling of data showed that immunoregulators and antibiotics are significantly effective for at least a 50% reduction from baseline in the number of open actively draining fistulas with relative risk (RR) of 2.57 (95% CI of 1.55-4.25, P= 0.0003) in four trials and 2.05 (95% CI of 1.03-4.08, P= 0.0414) in two trials respectively. The summary of RR for complete closure of fistulas in nine trials was 2.65 with a 95% CI of 1.66-4.22 and a significant RR (P < 0.0001). In regard to the tolerability, both immunoregulators and antibiotics showed insignificant adverse effects in comparison to placebo with an RR of 1.11 (95% CI of 0.96-1.27, P= 0.1513) and 0.6 (95% CI of 0.36-1, P= 0.0515), respectively and discontinuation because of these adverse effects in drug-treated groups was the same as placebo. Data about severe adverse effects were only available for immunoregulators that showed a significantly higher incidence when compared to placebo (RR= 2.24 with a 95% CI of 1.05-4.79; significant at P= 0.0374). Conclusion: This meta-analysis demonstrates the efficacy of immunoregulators and antibiotics in fistulizing CD. Regarding the safety, mild to moderate adverse effects were the same in both antibiotic and immunoregulators groups in comparison to the placebo but incidence of severe adverse effects in immunoregulator groups was higher than that of antibiotics.

HIV-1 is an enveloped virus that derives its lipid envelope from the virus producing cell. The envelope glycoprotein complex (Env) mediates viral attachment to and entry in susceptible target cells and is therefore an attractive target for therapeutic intervention. The T20 peptide (Fuzeon, enfuvirtide), targeting the Env fusion machinery, was approved for clinical use in 2003 and served as salvage therapy for many HIV-1 infected individuals for whom no other effective inhibitors were available because of the development of viral resistance. The approval in 2007 of the small molecule inhibitor maraviroc (Selzentry, Celsentri), targeting the coreceptor CCR5, marked a new era for entry inhibitors, which now occupy a mature position in the repertoire of antiviral drugs available to clinicians. Very recently a major breakthrough finding in the HIV-1 microbicide field was reported. A tenofovir containing gel offered (partial) protection against infection [1]. This success illuminates the possibilities of HIV prevention by antiviral drugs. Entry inhibitors may be particularly valuable for microbicide action because they act outside the cell by preventing viral infection and thus block the virus at the portal of entry. Entry inhibitors have already shown promise as active microbicides in monkey models [2,3]. In addition, therapeutic antibodies can also be used in the microbicide setting. Since Env is the only viral protein on the outside of the HIV-1 virion, it is also the only viral component to which neutralizing antibodies can be raised and as such Env is of vital importance for vaccine research. Despite massive efforts, an Env vaccine that induces broadly neutralizing antibodies has remained elusive. The recent RV144 trial in Thailand appeared to show some protection (31%) by combining two vaccines that individually did not provide any protection [4]. The results of this trial suggest two things. 1. It is possible to generate (partial) protection against HIV acquisition by vaccination. 2. The current vaccines need to be improved considerably before they can have any significant impact on stemming of the HIV epidemic. In fact, the antibody component of the RV144 vaccine was an old-fashioned monomeric gp120 protein. Better alternatives are currently available, most notably trimeric Env immunogens, but there is a need for further improvement. This issue of Current Pharmaceutical Design contains 5 reviews in the field of Env therapeutics and vaccines. These manuscripts address diverse new findings that have recently been reported and collectively describe the exciting progress made in recent years in these fields. Pollakis and Paxton [5] introduce the cellular receptors that are involved in Env biology and that can all be targets for therapeutic intervention. The focus is on the coreceptors CCR5 and CXCR4 as well as the viral inhibitors that target these membrane proteins, of which maraviroc is the prototype. The review by Eggink et al. [6] discusses the past and the future of HIV-1 inhibitors that target the Env fusion machinery, including the T20 peptide and improved variants thereof. The article by Pantophlet [7] describes the different Env protein domains that can be targeted by antibodies and sets the stage for the next two articles. Pejchal and Wilson [8] review Env-based vaccine design from the angle of structural biology. Finally, the review by Abele et al. [9] combines the two topics of this issue - vaccines/antibodies and therapeutics - by describing the development of therapeutic antibodies. The HIV-1 Env field is exciting and fast moving, yielding valuable products for therapeutic use, yet the translation of the accumulating knowledge into an effective and safe HIV vaccine remains a daunting challenge.

The ultimate aim of therapy or vaccine design against HIV is to eliminate ongoing virus replication or prevent HIV infection. The task at hand is daunting given the wide array of HIV variants circulating and the immense degree of variation found within the virus, especially in the envelope glycoprotein. HIV utilizes the CD4 receptor and a range of 7 transmembrane chemokine coreceptors for cell entry, specifically CCR5 and CXCR4. These receptors provide a number of targets for therapy design, however, the finding that multiple receptors allow for viral entry suggests that targeting one may cause the virus to swirch to using another receptor. The molecular interactions directing coreceptor usage are complex and can involve the same modifications associated with escape from the effect of neutralizing antibodies (NAbs), indicating that they are not unrelated and can in all likelihood impact on each other. Furthermore, a large array of other receptors, other than CD4, CCR5 and/or CXCR4 can interact with HIV with consequences for HIV tranmssion as well as disease progression.

The envelope glycoprotein complex (Env) is responsible for entry of the human immunodeficiency virus type 1 (HIV-1) into cells by mediating attachment to target cells and subsequent membrane fusion. Env consists of three gp120 subunits that mediate receptor and co-receptor attachment and three gp41 subunits responsible for membrane fusion. Several steps of the entry process can serve as drug targets. Receptor antagonists prevent attachment of gp120 to the receptor or co-receptor and conformational changes within gp41 required for membrane fusion can be inhibited by fusion inhibitors. Enfuvirtide (T20, Fuzeon) is a peptide based on the gp41 sequence and is the only approved fusion inhibitor. It prevents membrane fusion by competitively binding to gp41 and blocking the formation of the post-fusion structure. New generations of T20-like peptides have been developed with improved potency and stability. Besides T20 and derivatives, other fusion inhibitors have been developed that target different domains of gp41. Here we discuss the development of fusion inhibitors, their mode of action and their potential for incorporation in future drug regimens.

Formulating an effective HIV vaccine remains a formidable challenge despite nearly 3 decades of intense research since the virus was first isolated. One of the obstacles that need to be surmounted is the design of a preparation that elicits a potent and broadly neutralizing antibody (nAb) response, i.e. antibodies with the capacity to block infectivity of the genetically diverse pool of HIV strains that circulate globally. The primary target for nAbs on HIV-1 is the envelope glycoprotein spike (Env). Early work on elucidating the exposure of antibody epitopes on Env suggested highly restricted accessibility of antibodies to epitopes that are conserved among otherwise diverse virus isolates. Crystal structures of Env-derived antigens, most in complex with antibodies, along with structure-function studies and molecular modeling, have provided significant further insight into features of Env that limit broad antibody recognition. Despite these challenges, recent progress on various fronts has led to a growing sense that Env is not as impenetrable to nAbs as might have been believed in the past. Increased understanding of antibody epitope exposure on Env should provide new impulses for efforts to elicit nAbs that can protect against HIV-1 infection.

Traditional vaccine approaches have failed for HIV and novel strategies are now being sought to develop immunogens designed to elicit specific activity against known broad neutralization epitopes. Structure-based vaccine design has great potential but, so far, remains a largely unproven concept. Further structural information for the envelope (Env) glycoproteins, gp120 and gp41, would be extremely beneficial, particularly for understanding trimer-specific antibodies and their epitopes and to clarify the atomic details of the structural elements responsible for masking crucial epitopes and for mediating the conformational rearrangements undertaken during the process of receptor-binding and membrane fusion.

Therapeutic antibodies have evolved into an important drug class and have achieved considerable success in combating cancers and autoimmune diseases. Although their potential in the treatment of viral infections has not yet been fully explored, recently established approaches have the potential to aid the development of HIV specific antibody therapies. Antibody engineering has led to improvements in antibody isolation and increases in antibody efficacy and potency. Strategies have been developed to tailor Fc recruitment of effector functions, and conjugation of monoclonals to toxins endows them with the ability to mediate destruction of specific target cells. These technical advances introduce the possibility of designing a therapy to target and clear cells infected with a broad range of HIV strains and recommend some hypothetical clinical settings in which advanced antibody therapeutics could be employed in prophylaxis or therapy for HIV infection.