Current Pharmaceutical Design - Volume 25, Issue 1, 2019

Jules Cotard (1840-1889), a Parisian neurologist, described a syndrome of delirium negations which was later named after him. Some physicians in antiquity and medieval times, especially in Asia, have noticed this syndrome and categorized it as a symptom of melancholy. They have presented it as a "walking corpse syndrome", inflicting most probably veteran soldiers after suffering during ferocious battles, presenting the first cases of a post war traumatic stress disorder. Philotimus (3rd-2nd century BC) was the first to record it around 3rd century BC, and proposed a simple but pioneering treatment, by just putting a lead hat on the men's heads. Although various combined treatment strategies were proposed by modern psychiatry including pharmaceutical, electroconvulsive therapy, behavioural therapy and supportive psychotherapy, it seems that in antiquity a simple external intervention of supportive therapy was the main concept of confrontation, while drug administration was to be avoided.

Introduction: Biosimilars present a considerable potential to reduce costs related to clinical management allowing health-care providers to reinvest this money, leading to a wider access to an effective biological treatment with monoclonal antibodies (mAb). Infliximab biosimilars have already been incorporated in daily clinical practice and are currently used in all indications for which the reference product (RP) was approved. Areas covered: In the next few years, also adalimumab biosimilars will become available for the treatment of inflammatory bowel disease (IBD). In fact, several of them (ABP501, BI 695501, GP2017, and SB5) have been approved by the European Medicines Agency (EMA) with the same indications of the reference product (Humira ®). Initial preclinical data proved a strong similarity between all biosimilars and the RP. Moreover, phase 3 studies in rheumatoid arthritis and psoriasis showed no differences in terms of efficacy, safety, and immunogenicity. Data on IBD patients are urgently needed. Expert opinion: Biosimilars of adalimumab showed equivalent clinical efficacy to the RP in other immunemediated diseases. However, defining the ideal patient’s profile to receive or to be switched to a biosimilar, choosing one biosimilar vs. another, or cross-switching among biosimilars, will become the next challenge in IBD.

The introduction of biological drugs has revolutionized the management of inflammatory bowel diseases (IBD), however, the increasing financial burden of biologicals on the health care system is alarming. Biosimilars are considered to be equivalent to the reference medicinal product (RMP) in terms of pharmacokinetic properties, clinical effectiveness and safety. CT-P13 infliximab was the first biosimilar to be approved by the regulatory authorities EMA and US FDA, and others are becoming increasingly available as patents expire on the RMP. Emerging data suggests that one-way switching from the RMP to an approved biosimilar is safe and acceptable, however data on multiple-switching, reversed switching, or cross-switching between biosimilars is scarce. Accumulating data on biosimilars led to an increased acceptance amongst physicians and their use can be expected to offer increased availability for patients, and also better control of economic sustainability. This review discusses the available data on clinical efficacy and safety of approved biosimilar agents, and assesses the current impact and future perspectives of biosimilars on the health care system.

Inflammatory Bowel Disease is lifetime chronic progressive inflammatory disease. A considerable portion of patients, do not respond or lose response or experience side effect to “traditional” biological treatment such as anti-tumor necrosis factor (TNF)-α agents. The concept that the blockade of T cell traffic to the gut controls inflammation has stimulated the development of new drugs which selectively targets molecules involved in controlling cell homing to the intestine. The result is the reduction of the chronic inflammatory infiltration in the gut. In this regard, anti-adhesion molecules represent a new class of drugs for patients who don’t respond or lose response to traditional therapy. Moreover, some of these molecules such as vedolizumab, offer the advantage to target the delivery of a drug to the gut (gut selectivity) which could increase clinical efficacy and limit potential adverse events. In this article, we will give an overview of the current data on anti-adhesion molecules in Inflammatory Bowel Diseases.

Over the past decades, the advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD. However, primarily and more importantly, secondary loss of response to anti-TNF agents, is often observed. Thus, new treatment options have been actively explored and some have already been incorporated in the current clinical practice. Among the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have been first presented, in clinical practice, by the anti-p40 mAb ustekinumab in Crohn’s disease (CD). More selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream, which have failed in IBD clinical trials despite their clear efficacy in psoriasis.

Under current therapeutic algorithms, half of the patients with moderate-severe ulcerative colitis or Crohn’s disease fail in achieving a sustained remission. New drugs with different mechanisms of action are needed. After two decades of new drug avenues in inflammatory bowel disease dominated by the development of monoclonal antibodies, in recent years we are witnessing promising developments of small molecules for these conditions. Their intrinsic characteristics make them attractive compared to the monoclonal antibodies based on their oral administration, short plasma half-life, lack of immunogenicity and predictable pharmacokinetics. Among them, Janus kinase (JAK) inhibitors are a promising new class that have demonstrated efficacy with a favorable safety profile in clinical trials. Tofacitinib has been the first JAK inhibitor approved for the treatment of ulcerative colitis. This review discusses the molecular aspects of the JAK-STAT pathway, its role in the pathogenesis of inflammatory bowel disease, and the rational use of JAK inhibitors in these conditions. The different compounds with JAK inhibitory activity tested are reviewed and we provide an overview of recent evidence from clinical trials. Finally, we consider the positioning of these drugs in the treatment of inflammatory bowel diseases.

Background: The management of complex perianal fistulas in Crohn’s disease (CD) represents a challenge for patients, gastroenterologists and colorectal surgeons. There are clear limitations with current medical and surgical options, and healing rates remain far from what is expected. A multidisciplinary approach with optimized medical therapy, usually anti-TNF agents, associated with setons and additional surgical techniques is currently the best strategy to aim fistula healing. Methods: A comprehensive review of the literature was conducted on the use of mesenchymal stem cells (MSCs). Results: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for complex fistulas in CD patients. This review summarizes the evidence of the use of MSCs in complex CD fistulas, by exploring in detail the types of cells that can be used and their modes of delivery. Additionally, the results of the most recent phase III randomized trial with local MSCs injection are described, and future challenges of this therapeutic option are discussed. Conclusion: The use of MSCs represents hope for better outcomes in patients with CD-related perianal fistulas. More research in the field will help to position this specific therapy in treatment algorithms.

Intestinal fibrosis, driven by chronic inflammation in Crohn’s disease, can be defined as an excessive accumulation of extracellular matrix in the affected gut segment ultimately leading to an impaired wound healing and cumulative tissue damage, possibly resulting in organ dysfunction, formation of stenotic lesions and necessity of surgical intervention. Despite continuous advances in developing novel treatment modalities targeting different pathways to control chronic gut inflammation in CD, no effective anti-fibrotic agents have been released, to date. Thus, a better understanding of the molecular and cellular mechanisms underlying intestinal fibrosis is key to move this area of investigation forward.

The emergence of biologic therapies has revolutionized the management of inflammatory bowel disease (IBD) by halting disease progression, increasing remission rates and improving long-term clinical outcomes. Despite these well-described benefits, many patients are reluctant to commence therapy due to drug safety concerns. Adverse events can be detected at each stage of drug development and during the post-marketing period. In this article, we review how to best assess the safety parameters of new IBD medications, from the earliest stage of development to population-based registries, with a focus on the special populations often excluded from the evaluation process.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by periodic episodes of flares and remission. Treatment is aimed at healing the bowel, to ultimately decrease hospitalization rates, need for surgeries and overall disability. In more recent years, treatment has transitioned from a reactive approach to a more proactive approach focusing on treating disease earlier and preventing complications. The challenge lies in identifying patients who need more intensive treatment early and trying to determine who will respond to which medications. Biomarkers and clinical activity scoring systems can be used to help guide treatment decisions. However, IBDs are very heterogeneous and the significance of these biomarkers can be difficult to discern on an individual basis. Recently, prognostic tools have been developed to aid in determining a patient’s prognosis as well as their likelihood to respond to different therapies. Despite this progress, clinical trials have not routinely adopted this approach in their study design. Tools for stratification of disease severity and to personalize treatment choices have the potential to improve our studies both by enriching the patient population and further guiding clinical decision making in practice. This review aims to discuss biomarkers, current prognosticating tools, tools that determine response to therapy and how incorporating these into clinical trials will be beneficial.

Pediatric inflammatory bowel diseases (IBD) are similar to the adult-onset type in many aspects, including the necessity of high-quality randomized controlled trials. However, recruiting children into clinical trials is conceptually more challenging than in adults. Furthermore, the long delay between adult and pediatric approval of new drugs leads not only to the unbearable extensive use of these drugs as off-label without appropriate dosing and safety data but also to more challenges when eventually the pediatric trial is performed. This review offers possible solutions to age-specific pitfalls in performing trials in pediatric IBD. Many of the challenges could be adequately addressed by accepting full extrapolation of efficacy from adult trials. This is advisable if small pharmacokinetics/ pharmacodynamics (PK/PD) studies show similarity to adult data. Then, pediatric trials can focus on dosing and safety while avoiding the controversial use of placebo. Judicious use of non-invasive activity scores and biomarkers, providing immediate and effective treatment in active disease and ensuring equipoise of treatments both within and outside the trial are the mainstay of a feasible trial in children. The recent trend of including adolescents in adult phase-3 trials addresses some obstacles but introduces others. Acknowledging and addressing these age-specific challenges would facilitate pediatric drug development in IBD.

Background: Testosterone insufficiency may play a role in age-related decreases in bone mass density (BMD) and osteoporosis in aging men. Testosterone replacement therapy (T therapy) seems to be a simple and convenient way to increase BMD and improve the condition of osteoporosis. Objective: To evaluate the effects of T therapy in increasing BMD among older men with low serum testosterone concentrations. Methods: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for randomized controlled trials (RCTs) on the effect of T therapy on osteoporosis in aging men. Primary outcome measures were the change in BMD, bone turnover markers, prostate symptoms, body composition, metabolic and endocrine system markers. The final search was performed in October 2018. Results: Seven RCTs were included. A total of 800 patients met the inclusion criteria. T therapy did not significantly reverse the trend toward decreasing BMD in the spine, femoral neck, Ward’s triangle and the whole body, with the exception of the trochanter and total hip. In addition, T therapy increased prostate size, lean mass, sex hormone levels; reduced HDL concentration; and had no statistical effect on prostate symptoms, body composition, serum hormones and metabolism. Conclusion: T therapy is not effective in increasing BMD in older men. In addition, it has limited effects on prostate-specific antigen (PSA), the International Prostate Symptom Score (IPSS), body mass index (BMI), fat mass, parathyroid hormone (PTH), 25-VitD and lipid metabolism, although it can increase prostate size, lean mass, and sex hormone levels, and reduce glucose levels and HDL concentrations.

Coronary heart disease (CHD) remains the leading cause of disability and death in industrialized Countries. Among many conditions, which contribute to the etiology and progression of CHD, the presence of high low density lipoprotein-cholesterol (LDL-C) levels represents the major risk factor. Therefore, the reduction of LDL-C levels plays a key role in the management of patients with high or very high cardiovascular risk. Although statins represent the gold standard therapy for the reduction of cholesterol levels, these drugs do not allow to achieve target levels of LDL-C in all patients. Indeed, a significant number of patients resulted intolerants, especially when the dosage increased. The availability of new lipid-lowering drugs, such as ezetimibe and PCSK9 inhibitors, may represent an important alternative or complement to the conventional lipid-lowering therapies. However, long-term studies are still needed to define both efficacy and safety of use of these latter new drugs. Some nutraceuticals may become an adequate and effective support in the management of some patients. To date, several nutraceuticals with different mechanism of actions that provide a good tolerability are available as lipidlowering agents. In particular, the most investigated are red yeast rice, phytosterols, berberine, beta-glucans and soy. The aim of this review was to report recent data on the efficacy and safety of principle hypocholesterolemic drugs available and to evaluate the possible role of some nutraceuticals as support therapy in the management of patients with dyslipidemias.

Peptides containing the asparagine-glycine-arginine (NGR) motif can target the tumor neovascular biomarker CD13/aminopeptidase N receptor. D-K6L9 is a tumor-selective anti-cancer peptide. To improve the capacity of NGR peptides to target tumors, we joined the NGR and D-K6L9 peptides to form NKL. Next, we linked 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to NKL and labeled it with gallium 68 (68Ga, t1/2 = 67.7 min) to form 68Ga-DOTA-NKL. This novel probe was characterized in vitro. 68Ga-DOTA-NKL was stable in phosphate buffered saline at room temperature and in human serum at 37°C. We determined that the uptake rate of 68Ga-DOTA-NKL in CD13 receptor-positive 22Rv1 tumor cells was 3.15% ± 0.04 after 2 h, and tested 68Ga-DOTA-NKL using positron emission tomography (PET)/computed tomography imaging in vivo. MicroPET imaging results revealed that 22Rv1 tumor uptake of 68Ga-DOTA-NKL was 8.69 ± 0.20, 6.61 ± 0.22, 3.85 ± 0.06, and 1.41 ± 0.23 percentage injected dose per gram of tissue (%ID/g) at 0.5, 1, 2, and 3 h postinjection (pi), respectively. The tumor-to-background contrast in the subcutaneous human prostate cancer 22Rv1 mouse model was 9.97 ± 1.90. The 68Ga-DOTA-NKL probe has combined tumor-targeting and tumor-selective properties, and may be used to diagnose CD13-positive tumors.