COX-2 controversy: where are we and where do we go from here?

Much has been written in the last few months on the association between the cyclooxygenase-2 (COX-2)-selective inhibitors and cardiovascular events. We summarize the randomized controlled studies of different COX-2 inhibitors that led to rofecoxib withdrawal, provide evidence on the differences between various selective coxibs and summarize recommendations from the FDA and the American College of Rheumatology on use of COX-2 inhibitors. We give suggestions on the use of coxibs and briefly mention a general approach to the future of coxibs.     

Cytokine therapies in Crohn's disease: where are we now and where should we go?

In the gut of patients with Crohn's disease (CD), one of the major forms of inflammatory bowel diseases in humans, distinct subsets of T helper (Th) cells produce large amounts of cytokines, which are supposed to orchestrate the immuno-inflammatory process leading to the tissue damage. Indeed, cytokine blockers, including the three licensed anti-TNF-alpha and the neutralizing IL-12/p40 antibodies, have already been tested with success in CD. More than one third of patients do not respond to these treatments and response can wane with time. Moreover, blockade of such cytokines has been reported to associate with development of severe side effects and/or new immune-mediated pathologies. These findings and our better understanding of cytokine-associated effector pathways of tissue destruction suggest the necessity of novel cytokine-based therapies in CD.     

Hardcore smokers: What do we know?

Aims

The existence of smokers who are resistant to smoking cessation treatment has long been noted in the literature. There has been ongoing debate as to whether the proportion of these smokers is increasing as smoking prevalence rates stagnate. Studies define hardcore smokers inconsistently and within the context of specific illnesses, addiction, population, and/or theoretical paradigms. This review examines the existing literature related to hardcore smokers to develop a better understanding of what is known and not known about this group to guide smoking cessation treatment.

Methods

PubMed MESH search and review of research publications from 1998 to 2012 (N = 61).

Results

Inconsistent definitions of hardcore smoking make it difficult to estimate prevalence rates and to identify specific characteristics of persistent smokers. Generally, persistent smokers have higher levels of nicotine dependence, are disproportionately from lower socioeconomic groups, start smoking at an earlier age, and are more likely to have a psychological co-morbidity.

Discussion

Defining some smokers as hardcore is limiting. Targeted and tailored interventions for smoking cessation for persistent smoking have demonstrated effectiveness in a small number of studies. Treatment access barriers need to be addressed to improve the reach and effectiveness of cessation with persistent smokers. Efforts to limit early age initiation of tobacco use are a critical element in averting persistent smoking.     

Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here?

Research conducted over the last 20 years has established that inflammation of the airways is central to the airway dysfunction that characterises asthma. Typically, the airway wall is infiltrated by a variety of cells including mast cells, eosinophils and T lymphocytes, which have deviated towards a T(H)2 phenotype. Together, these cells release a plethora of mediators including interleukin (IL)-4, IL-5, granulocyte/macrophage colony-stimulating factor and eotaxin which ultimately cause the histopathology and symptoms of asthma. Glucocorticosteroids are the only drugs currently available that effectively impact upon this inflammation and resolve, to a greater or lesser extent, compromised lung function. However, steroids are nonselective and generally unsuitable for paediatric use. New drugs are clearly required. One group of potential therapeutic agents for asthma are inhibitors of cyclic AMP-specific phosphodiesterase (PDE), of which theophylline may be considered a prototype. It is now known that PDE is a generic term which refers to at least 11 distinct enzyme families that hydrolyse cAMP and/or cGMP. Over the last decade, inhibitors of PDE4 (a cAMP-specific family that negatively regulates the function of almost all pro-inflammatory and immune cells, and exerts widespread anti-inflammatory activity in animal models of asthma) have been developed with the view to reducing the adverse effects profile associated with non-selective inhibitors such as theophylline. Such is the optimism regarding PDE4 as a viable therapeutic target that more than 100 PDE4 inhibitor patent applications have been filed since 1996 by 13 major pharmaceutical companies. This article reviews the progress of PDE4 inhibitors as anti-inflammatory agents, and identifies problems that have been encountered by the pharmaceutical industry in the clinical development of these drugs and what strategies are being considered to overcome them.     

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.     

Designing drugs that overcome antibacterial resistance: where do we stand and what should we do?

Introduction: In recent years, infections caused by multidrug-resistant bacterial pathogens have become a huge issue to public healthcare systems. Indeed, the misuse of antibiotics has led to, over the past 30 years, the emergence of a number of resistant bacterial strains including Staphylococcus aureus, Neisseria gonorrhoeae, Escherichia coli and Mycobacterium tuberculosis. Unfortunately, efforts to produce new antibiotics have not been sufficient to cope with the emergence of these new antibiotic-resistant (AR) strains.

Areas covered: There is an urgent need to invent and employ unconventional strategies for antimicrobial drug development to tackle the rising global threats imposed by the spread of antimicrobial resistance. Herein, the authors discuss these novel design strategies and provide their expert perspective on the subject.

Expert opinion: To deal with the growing threat of AR, it is important to cut down the use of antibiotics to the very minimum to diminish the risk of unknown drug-resistant bacteria and increase antibacterial vaccination programs. Furthermore, it is important to develop new classes of antibiotics that can deal with multidrug-resistant bacterial pathogens.     

Therapy for osteosarcoma: where do we go from here?

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. Current optimal treatment for osteosarcoma consists of multi-agent chemotherapy and aggressive surgical resection of all sites of disease involvement. The current national and international cooperative trial for patients with newly diagnosed osteosarcoma builds upon the backbone of cisplatin, doxorubicin, and methotrexate. This protocol is designed to clarify whether (i) the addition of ifosfamide and etoposide to postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a poor histologic response to 10 weeks of preoperative chemotherapy; and (ii) the addition of pegylated interferon-alpha-2b as maintenance therapy after postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a good histologic response to 10 weeks of preoperative chemotherapy. However, the optimal treatment strategy (or strategies) for patients with relapsed or metastatic disease has yet to be defined. This remains one of the persistent challenges in the treatment of osteosarcoma.Recent therapeutic advances have focused on circumventing chemotherapy resistance mechanisms, incorporation of non-classical agents into upfront therapy, targeting of the tumor micro-environment, and investigating the role of novel delivery mechanisms.In patients with localized disease the 5-year survival rate is at least 70%; patients with metastatic or recurrent disease have <20% chance of long-term survival despite aggressive therapies. These figures have changed little in the past 2 decades. This review focuses on the current therapy for osteosarcoma, and highlights emerging strategies that will hopefully change the outlook for patients with this disease.     

Beta-blockers in chronic heart failure: what have we learned? What do we still need to know?

Current heart failure guidelines mandate the use of beta-blockers in patients with symptomatic systolic heart failure. In the past 12-18 months, there have been several reported advances in our understanding of beta-blocker therapy for heart failure. Despite these advances, there remain several unanswered questions with regard to beta-blockers. These involve, firstly, clarifying the underlying mechanisms of action of beta-blockers; secondly, further analysing patients with systolic heart failure who are not well-studied in major clinical trials (e.g. the elderly); thirdly, investigating unexplored indications for beta-blockers in heart failure; and finally, directly examining the clinical relevance of pharmacological differences among agents. The impact of genetic polymorphisms on the response to beta-blocker therapy, as well as interaction of these agents with future heart failure therapies, requires extensive investigation.     

What did we learn from our study on sober living houses and where do we go from here?

Lack of a stable, alcohol- and drug-free living environment can be a serious obstacle to sustained abstinence. Destructive living environments can derail recovery for even highly motivated individuals. Sober living houses (SLHs) are alcohol- and drug-free living environments for individuals attempting to abstain from alcohol and other drugs. They are not licensed or funded by state or local governments and the residents themselves pay for costs. The philosophy of recovery emphasizes 12-Step group attendance and peer support. We studied 300 individuals entering two different types of SLHs over an 18-month period. This article summarizes our published findings documenting resident improvement on measures of alcohol and drug use, employment, arrests, and psychiatric symptoms. Involvement in 12-Step groups and characteristics of the social network were strong predictors of outcome, reaffirming the importance of social and environmental factors in recovery. This article adds to our previous reports by providing a discussion of implications for treatment and criminal justice systems. We also describe the next steps in our research on SLHs, which will include: (1) an attempt to improve outcomes for residents referred from the criminal justice system and (2) a depiction of how attitudes of stakeholder groups create a community context that can facilitate and hinder the legitimacy of SLHs as a recovery modality.     

The future of hormesis: where do we go from here?

Although the occurrence of U-shaped dose responses in toxicology (i.e., hormetic effects) have been known for more than a century, the concept of hormesis has long been marginalized under the belief that such observations could be explained by a combination of poor study designs and normal variability. However, recent efforts have established that numerous highly reliable studies demonstrating hormetic effects exist and that such findings appear to be highly generalizable across species, endpoint measures, and class of agents assessed. In light of such a long and complicated history, and its significant biomedical/toxicological implications, this article explores the unique challenges that the concept of hormesis confronts in both the experimental and institutional domains with respect to assessing its scientific foundations and validity and the impediments to its intstitutional acceptance and use with society. This perspective is then immediately critiqued by five authors in subsequent articles.     

Alcohol consumption in the Arab region: What do we know,why does it matter,and what are the policy implications for youth harm reduction?

Alcohol is a recognized global risk factor for many diseases and injury types and a major contributor to disability and death. While cost-effective interventions do exist, many countries lack a comprehensive national alcohol harm reduction policy. The Arab world includes 22 diverse countries stretching from North Africa to Western Asia having varying dispositions with regards to alcohol sale and consumption. Epidemiological data is scattered and the picture on alcohol consumption remains blurry. This paper presents the findings of an extensive review conducted on all 22 Arab countries, specifically describing: (1) the density and methodology of alcohol-related peer-reviewed publications over the last two decades (1993–2013); (2) the epidemiology of alcohol consumption given all available data; and (3) the current status of policies in the region. Our search revealed a strikingly low number of alcohol-related peer-reviewed published studies – a total of 81 publications across 22 countries and two decades. Most studies are based on clinical or student samples. Where data is available, age of onset is low and drinking is frequent, in the absence of any available or enforced harm reduction policies. We submit that countries in the Arab region can be divided into four categories by alcohol ban and published data. One category includes countries where alcohol is not banned but data is absent, suggesting an ostrich-like response to a controversial behavior, or reflecting a weak research infrastructure and/or policy landscape. Evidence-informed recommendations and future directions for policy and research are discussed and tailored to countries’ current stance on alcohol legislation and consumption. Given the particular vulnerability of youth to uptake of alcohol as well as the resulting short and long term consequences, the paper concludes by focusing on the implications of the findings for youth alcohol harm reduction.     

Antibiotics: where did we go wrong?

In the late 1960s, the medical need for new antibiotics began to be questioned, and the pharmaceutical industry shifted its emphasis of antibacterials from that of a therapeutic leader to a low-priority research area. Although infectious diseases, in particular those caused by bacterial infections, are still among the top causes of mortality in the world, industrial support continues to wane. The shift from this important area of antimicrobial research has been attributed to a combination of science, medical, marketing and business reasons. This decline in antibacterial drug discovery, coupled with increasing risk as a result of infections caused by drug-resistant bacterial pathogens, represents a clear public health threat.     

Tryptophan depletion, serotonin, and depression: where do we stand?

Tryptophan depletion is a widely used paradigm to study serotonin system-related mechanisms in the pathophysiology and treatment of depression. There is convincing evidence that tryptophan depletion primarily and selectively affects serotonergic transmission. The behavioral data in healthy controls with and without genetic risk for depression, and in patient populations during the symptomatic phase of depression and when being remitted, suggest a trait abnormality of serotonin function in depression and that antidepressants may compensate for the underlying deficit. Tryptophan depletion may be a useful tool to create more integrative models for the pathophysiology of depression that take into account neurobiological systems beyond monoamines. More recent studies combining tryptophan depletion with genetic variables may provide an important approach for studying gene/environment interactions using candidate genes to define endophenotypes, which ultimately will improve currently used diagnostic categories and help to generate more advanced models to understand the neurobiology of depression. This may lead to the development of truly novel treatment approaches for depression.     

Drug therapy for atrial fibrillation: where do we go from here?

Atrial fibrillation, the most common cardiac arrhythmia requiring medical attention, has effects that range from mild symptoms to devastating stroke. Although treatments have evolved since the foxglove plant (later identified as containing digitalis) was first administered to slow the heart rate, satisfactory drug therapy has not been developed. In this review we describe present-day medical options and developments of future therapies to treat atrial fibrillation and maintain normal sinus rhythm.     

Metabolites and safety: What are the concerns, and how should we address them?

The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in circulation and excreta, is proposed as the primary source of information on human metabolites from which decisions can be made regarding the need for further risk assessment. Although radiolabel ADME studies yield quantitative metabolite profiles that are commonly reported as a percentage of the total drug related material (for circulating metabolites) and a percentage of total dose (for excretory metabolites), it is essential to convert these values into absolute abundances. The structure of a metabolite, its abundance, the biofluid in which it is observed (circulation or excreta), and the toxicity mechanism of concern serve as the four most important characteristics for determination as to whether further safety consideration is warranted. Metabolites in circulation require consideration for toxicity that can arise by effects on specific receptors and/or enzymes (either target or off-target). Metabolites in excreta require consideration for their potential to indicate a body-burden to chemically reactive intermediary metabolites, which can yield toxicities of nonspecific mechanisms commonly associated with covalent binding (e.g., carcinogenicity, immunoallergic response, etc.). Through an analysis of 24 drugs removed from the market because of human toxicity, it was concluded that further testing of human metabolites would not have yielded any additional information that could have predicted human safety findings because human metabolites would have been present in the animal species routinely used in toxicology testing after the administration of the parent compound.     

Future of toxicology--mechanisms of toxicity and drug safety: where do we go from here?

Recent high-profile drug withdrawals increase the pressure on regulators and the pharmaceutical industry to improve preclinical safety testing. Understanding mechanisms of drug toxicity is an essential step toward improving drug safety testing by providing the basis for mechanism-based risk assessments. Nonetheless, despite several decades of research on mechanisms of drug-induced toxicity and the application of various new technologies to preclinical safety assessment, the overall impact on preclinical safety testing has been modest. Assessing the risk of exposing humans to new drug candidates still depends on preclinical testing in animals, which in many, but not all cases, predicts outcomes in humans accurately. The following offers a perspective on the challenges and opportunities facing efforts to improve preclinical safety testing and outlines gaps and needs that must be addressed. A case is built for focusing solutions on defined problems within the current safety testing paradigm rather than imposing wholesale change. Targets for application of new technologies, including in silico screening, biomarkers, surrogate assays and 'omic technologies, are outlined. Improving drug safety testing will depend on improving the application of mechanism-based risk assessment but will also require improving public and private collaborations in order to focus research regarding the mechanism of drug-induced toxicity on the most important problems.