Rifaximin and eluxadoline — newly approved treatments for diarrhea-predominant irritable bowel syndrome: what is their role in clinical practice alongside alosetron?

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal condition in which patients experience abdominal pain, diarrhea, bloating, cramps, flatulence, fecal urgency, and incontinence. Areas Covered: We review two recently approved therapies that focus on treating underlying pathogenic mechanisms of IBS-D: (1) the non-absorbable antibiotic rifaximin, and (2) the opioid receptor agonist/antagonist eluxadoline. We compare the safety and efficacy data emerging from rifaximin and eluxadoline registration trials with safety and efficacy data from the alosetron clinical development program. Expert Opinion: The rifaximin and eluxadoline clinical development programs for IBS-D have demonstrated significant improvement in IBS-D endpoints compared to placebo. Direct comparison of primary endpoint results from the alosetron, rifaximin, and eluxadoline pivotal trials is not possible; however, general estimates of efficacy can be made, and these demonstrate similar and significantly greater responses to ‘adequate relief’ and a composite endpoint of abdominal pain/stool form for each agent compared to placebo. With the recent approval in the United States of rifaximin and eluxadoline for IBS-D, how should clinicians employ these agents? We suggest that they be utilized sequentially, taking into consideration patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles.     

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACT

Introduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.

Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.

Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.     

How can we develop better antispasmodics for irritable bowel syndrome?

Introduction: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal (GI) disease. Antispasmodics are a heterogeneous group of drugs that tackle IBS-associated altered bowel habit and abdominal pain. However, some studies have shown their failure to exhibit benefit over placebo. Considering the place of antispasmodics in managing key symptoms of IBS, there is a growing need for developing more efficacious and safe antispasmodics.

Areas covered: The authors discuss the role of rational drug design (RDD) in developing new antispasmodics with desired features. Furthermore, they review the potential pharmacological targets and herbal medicines with spasmolytic activity. In addition, the authors present the recent findings concerning novel mechanisms involved in GI motility modulation as well as the potential antispasmodic role of drugs used in other conditions.

Expert opinion: To develop better antispasmodics, it will be essential to gain a deeper insight into the underlying mechanisms involved in IBS-induced dysmotility and to uncover GI-specific receptors that regulating motility. New antispasmodics with GI-restricted and the multi-targeting features can be developed via implementation of RDD. Furthermore, the modification of current antispasmodics by formulation technologies might expedite the development of better antispasmodics. To conclude, the complex nature of IBS means that future successful drug discovery will require a multi-disciplinary approach.     

Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome

Introduction: Irritable bowel syndrome diarrhea predominant (IBS-D) is a highly prevalent GI disease, affecting nearly a third of all patients diagnosed with irritable bowel syndrome. Current treatment options are limited.

Areas covered: This review discusses the pharmacotherapeutic options for IBS-D including currently used medications, the two newly FDA approved medications, as well as emerging therapies with potential benefit in IBS-D. Particular emphasis is placed on rifaximin and eluxadoline and their possible use in IBS-D.

Expert Opinion: Current pharmacological treatment of IBS-D includes loperamide, bile acid sequestrants, antispasmodics, tricyclic antidepressants, alosetron, eluxadoline and rifaximin. The latter two treatments have significantly added to the pharmacotherapeutic options for patients suffering from IBS-D.     

Review article: new receptor targets for medical therapy in irritable bowel syndrome

Background  Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities.
Aims  To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT₄ agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics.
Methods  Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy.
Results  The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT₄ agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents 'borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study.
Conclusions  There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal.     

Unlocking the concealed targets using system biology mapping for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) constitutes a neural loss in histology of brain with involvement of complex genomic and environmental factors. Accumulation of amyloid beta (Aβ) peptide and phosphorylated tau are indicative of progression and cognitive decline. Hence an understanding of the underlying biological pathways and targets along with associated mechanisms would be useful for the development of improved therapeutics for treating AD. In the present work, we aim to identify concealed targets for developing first line therapeutics and repositioning of validated targets as well as FDA- approved drugs using a system biology approach.MethodsWe have collated information pertaining to the biological targets as well as the approved drugs, from scientific literature and patents.ResultsIn all, the imbalance in the functioning of around 79 proteins and genes were identified to be involved in Alzheimer’s cascade. Amongst them, around 21 targets were found to be under therapeutic consideration for AD. Of the remaining, around 17 targets were reported as potential targets for AD, although they are under researcher’s attention for other physio-pathological conditions. The analysis further revealed that ˜41 therapeutic targets are pharmacologically concealed but structurally validated targets and may constitute as potential therapeutic candidate for future drug discovery for AD.ConclusionThe biological pathway vs. drug mapping provides a complete overview about underlying biological pathways, therapeutic targets (explored and concealed), associated mechanisms, existing therapeutics and the information pertaining to molecules currently under active drug development for further drug discovery and drug re-positioning/repurposing approaches for AD management.     

The safety of novel drugs used to treat irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process.

Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval.

Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the treatment with the lowest effective doses is advised. Ramosetron is under evaluation for diarrhea-predominant IBS due to its acceptable safety and tolerability, besides its efficacy. Rifaximin, asimadoline and renzapride are still in need of more long-term studies regarding their safety.     

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.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Rifaximin for the treatment of irritable bowel syndrome

Introduction: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS.

Areas covered: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed.

Expert opinion: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.     

The human gut microbiome – a new and exciting avenue in cardiovascular drug discovery

ABSTRACT

Introduction: Over the past decade, numerous research efforts have identified the gut microbiota as a novel regulator of human metabolic syndrome and cardiovascular disease (CVD). With the elucidation of underlying molecular mechanisms of the gut microbiota and its metabolites, the drug-discovery process of CVD therapeutics might be expedited.

Areas covered: The authors describe the evidence concerning the impact of gut microbiota on metabolic disorders and CVD and summarize the current knowledge of the gut microbial mechanisms that underlie CVD with a focus on microbial metabolites. In addition, they discuss the potential impact of the gut microbiota on the drug efficacy of available cardiometabolic therapeutic agents. Most importantly, the authors review the role of the gut microbiome as a promising source of potential drug targets and novel therapeutics for the development of new treatment modalities for CVD. This review also presents the various effective strategies to investigate the gut microbiome for CVD drug-discovery approaches.

Expert opinion: With the elucidation of its causative role in cardiometabolic disease and atherosclerosis, the human gut microbiome holds promises as a reservoir of novel potential therapeutic targets as well as novel therapeutic agents, paving a new and exciting avenue in cardiovascular drug discovery.     

Gene expression profiling and therapeutic interventions in neurodegenerative diseases: a comprehensive study on potentiality and limits

Introduction: Neurodegenerative diseases are incurable debilitating disorders of the nervous system that affect approximately 30 million people worldwide. Despite profuse efforts attempting to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. The novelty of their mechanisms represents a challenge to biology, to their related biomarkers identification and drug discovery. Because of their multifactorial aspects and complexity, gene expression analysis platforms have been extensively used to investigate altered pathways during degeneration and to identify potential biomarkers and drug targets.

Areas covered: This work offers an overview of the gene expression profiling studies carried out on Alzheimer's disease, Huntington's disease, Parkinson's disease and prion disease specimens. Therapeutic approaches are also discussed.

Expert opinion: Although many therapeutic approaches have been tested, some of them acting on several altered cellular pathways, no effective cures for these neurodegenerative diseases have been identified. Microarray technology must be associated with functional proteomics and physiology in an effort to identify specific and selective biomarkers and druggable targets, thus allowing the successful discovery of disease-modifying therapeutic treatments.     

Cardiac arrhythmia: in vivo screening in the zebrafish to overcome complexity in drug discovery

Importance of the field: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is usually based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities.

Areas covered in this review: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last 2 decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described.

What the reader will gain: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery including in vivo screening of zebrafish genetic disease models.

Take home message: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease biology, but emphasizes the importance of the rigor of the disease model.     

Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) affects about one-third of patients with IBS, which is observed in about 12% of people across five continents. The ultimate goal in this field is to identify the underlying cause of symptoms in order to individualize education of the patient, and to provide optimal treatment of this highly prevalent condition.

Areas covered: This review addresses the pharmacological treatments for IBS-D under three categories: drugs for IBS-D (i.e., the 5-HT₃ antagonist, alosetron); drugs approved for other indications that are used in IBS-D (e.g., opioid agonists; other 5-HT₃ antagonists; serotonergic psychoactive agents; bile acid binders; 5-ASA compounds; probiotics and non-absorbable antibiotics); as well as development of drugs that are likely to impact the management of IBS-D in the future (e.g., drug absorbents; TPH₁ inhibitors; mast cell stabilizers; centrally acting benzodiazepines). The final section addresses key findings: regulatory roadblocks; weaknesses in the current research in this field so far and opportunities to address unmet needs including restoration of normal intestinal barrier function or permeability, and suppression within the intestines of local immune activation that is thought to trigger abnormal motor, sensory and secretory functions in IBS-D.

Expert opinion: While symptomatic treatment of diarrhea is effective, there is a need for new treatments for the IBS-D complex. Greater understanding of the mechanisms in IBS-D has led to promising approaches to develop more efficacious therapies.     

Genetic susceptibility to rheumatoid arthritis and its implications for novel drug discovery

ABSTRACT

Introduction: Over 100 susceptibility loci have now been identified for rheumatoid arthritis (RA), several of which are already the targets of approved RA therapies providing proof of concept for the use of genetics in novel drug development for RA. Determining how these loci contribute to disease will be key to elucidating the mechanisms driving disease development, which has the potential for major impact on therapeutic development.

Areas covered: Here the authors review the use of genetics in drug discovery, including the use of ‘omics’ data to prioritise potential drug targets at susceptibility loci using RA as an exemplar. They discuss the current state of RA genetics its impact on stratified medicine, and how the findings from RA genetics studies can be used to inform drug discovery.

Expert opinion: It is anticipated that functional characterisation of disease variants will provide biological validation of a gene as a drug target, providing safer targets, with an increased likelihood of efficacy. In the future, techniques such as genome editing may represent a plausible option for RA therapy. Technologies such as genome-wide chromatin conformation capture Hi-C and CRISPR will be crucial to inform our understanding of how diseases develop and in developing new treatments.     

Modular pharmacology: the next paradigm in drug discovery

Introduction: Effective regulation of abnormal targets of disease requires the alteration of either the topological structure or dynamic characteristics of modules in a given target network. In order to disturb the complex direct and indirect target hubs, new approaches in adaptive pharmacology should be developed to regulate target loops using module-based designs.

Areas covered: This review discusses the formation in disease-associated structural networks with multiple drug targets and the optimization of a multi-objective system of modules.

Expert opinion: On the basis of these concepts, modular pharmacology (MP) has emerged as a method that can balance multiple outcomes by regulating the response of property modules on the basis of the benefits and risks of diversified modules and drugs, thereby allowing novel approaches for drug discovery. Further research of pharmacological mechanisms underlying diversity interactions between multiple modules is necessary for a better understanding of the basic therapeutic processes.     

Newer antibacterial drugs for a new century

Importance of the field: Antibacterial drug discovery and development has slowed considerably in recent years, with novel classes discovered decades ago and regulatory approvals tougher to get. Traditional approaches and the newer genomic mining approaches have not yielded novel classes of antibacterial compounds. Instead, improved analogues of existing classes of antibacterial drugs have been developed by improving potency, minimizing resistance and alleviating toxicity.

Areas covered in this review: This article is a comprehensive review of newer classes of antibacterial drugs introduced or approved after year 2000.

What the reader will gain: It describes their mechanisms of action/resistance, improved analogues, spectrum of activity and clinical trials. It also discusses new compounds in development with novel mechanisms of action, as well as novel unexploited bacterial targets and strategies that may pave the way for combating drug resistance and emerging pathogens in the twenty-first century.

Take home message: The outlook of antibacterial drug discovery, though challenging, may not be insurmountable in the years ahead, with legislation on incentives and funding introduced for developing an antimicrobial discovery program and efforts to conserve antibacterial drug use.