Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?

Tamoxifen is a cheap and effective estrogen-receptor antagonist, used as the adjuvant hormonal treatment of choice in women with estrogen-receptor-positive breast cancer. Tamoxifen-induced non-alcoholic steatohepatitis (NASH) may increase the demand on oncologists, not only with regard to screening for diabetes, but also for the suggested link of NASH with high incidence of coronary heart disease. At present, there is no guideline for treatment of hyperlipidaemia associated with tamoxifen-induced NASH. However, exemstane (and other aromatase inhibitors) has been shown to lower triglyceride and have a neutral effect on low-denisty lipoprotein and cholesterol levels. These may be alternative agents if severe progressive liver disease or hyperlipidaemia were encountered with tamoxifen administration. Other lipid-lowering medications may have potential benefits in the treatment of tamoxifen-induced NASH and is discussed in this article.     

Predicting drug-drug interactions in drug discovery: where are we now and where are we going?

Pressure on drug discovery research teams to identify successful drug candidates earlier on in the drug discovery process has led to the development of a variety of ADME in vitro assays, intended to guide chemists and biologists in their decision-making process. The role of these early assays is to indicate liabilities in scaffolds relating to the absorption, distribution, metabolism and cytochrome P450 (CYP) inhibition potential of new chemical entities. Current efforts in drug-drug interaction (DDI) screening can be divided into four basic categories: bioanalytical method development, strategies relating to enzyme kinetics, recognition of CYP allelic variants and generation of computational models to predict CYP interactions. Collectively, DDI screening represents an important means not only for assessing and ranking potential drug candidates, but also for aiding in the development of mechanisms for predicting and retrospectively explaining in vivo drug performance.     

Rosacea: where are we now?

Advances continue to be made in the classification and treatment of rosacea, a chronic dermatologic syndrome. A new empiric classification system identifies 4 rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) that may aid in more precise diagnosis. Several new therapies have recently been approved for treatment of rosacea. Azelaic acid 15% gel is a new first-tier topical agent proven effective in reducing inflammatory lesions and erythema. New formulations of metronidazole and sulfacetamide 10%/sulfur 5% that offer cosmetic or tolerability advantages are now available. Intense pulsed light therapy has demonstrated effectiveness in reducing flushing, erythema, and telangiectases, with greater tolerability than existing laser systems. Other treatments under investigation include low-dose doxycycline hyclate (which may provide greater safety than existing oral antibiotics), benzoyl peroxide/clindamycin gel, and tacrolimus ointment (for steroid-induced rosacea). With this expanded armamentarium of medical and light-based therapies, clinicians can now implement a multifaceted approach to treatment, crafting new treatment combinations to address the unique and evolving features of rosacea in each individual patient.     

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.     

Deuterated drugs: where are we now?

Introduction: Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium– carbon bond modifying their metabolism. There is great interest in the current state of development of this approach.

Areas covered: This review covers recent US patent applications and prosecutions in this area that are based on beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 ‘obviousness’ rejections are emphasized, as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed.

Expert opinion: Deuterated drugs collectively are worth at least US$1 billion. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing that drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.     

Vitiligo therapy: where are we now?

Vitiligo is a disfiguring skin disease. Many insights into its pathogenesis have been identified in recent years; however, treatment remains a challenge. In this article, the various treatment options for the treatment of vitiligo are outlined and newer treatment options are discussed.     

Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective

Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery.     

B cell-ablative therapy: where are we now?

Based on their multifaceted functions, B cells participate in several pathological settings such as lymphoproliferative disorders, autoimmune diseases and graft rejection. B cell-ablative therapy has thus emerged as a mainstay in these diseases. A number of anti-B cell antibodies (Abs) have been generated, among which anti-CD20 Abs appear to be efficient. Rituximab (RTX) is one of these anti-CD20 monoclonal Abs. Originally approved for the treatment of non-Hodgkin lymphoma, RTX is now being administered in other malignant proliferations, applied to an increasing number of autoimmune diseases and required to prevent rejection of a graft. Although this medication is remarkably safe, a handful of laboratory tests have been proposed to monitor RTX-treated patients. The efficacy in different diseases, and the emergence of new anti-CD20 Abs raise many questions. Thus, their detailed understanding can lead to a better issue for inhibition of immune responses.     

Helicobacter pylori: where are we and where are we going?

This paper contains a personal view on what has been achieved in Helicobacter pylori research and what the expectations might be for further developments. Knowledge about the organism is already extensive. Particularly intriguing are the differences in genetic make-up in the various geographical regions. Sadly, detailed knowledge on how the organism spreads is still lacking. The clinical spectrum of the disease in man is largely known, but as H. pylori is disappearing worldwide, the relative frequency of H. pylori-negative ulcer disease is increasing. To what extent H. pylori disappearance and eradication is responsible for the decreasing incidence of gastric cancer remains uncertain. Antimicrobial therapy is dominated by proton pump inhibitor triple therapy as first line with quadruple therapy as second-line therapy. The long-term consequences of the rising resistance to the 'key' antimicrobials are so far unknown and speculative.     

Ataluren in cystic fibrosis: development,clinical studies and where are we now?

Introduction: Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC).

Areas covered: We discuss the discovery of the small-molecule drug ataluren, which in vitro has been shown to allow read-through of PTCs and facilitate synthesis of full-length protein. We review clinical studies that have been performed involving ataluren in CF. Early-phase short-term cross-over studies showed improvement in nasal potential difference. A follow-up phase III randomised controlled trial did not show a significant difference for the primary outcome of lung function, however a post-hoc analysis suggested possible benefit in patients not receiving tobramycin. A further randomised controlled trial in patients not receiving tobramycin has been reported as showing no benefit but has not yet been published in full peer-reviewed form.

Expert opinion: A small-molecule approach to facilitate read-through of PTCs in nonsense mutations makes intuitive sense. However, at present there is no high-quality evidence of clinical efficacy for ataluren in people with CF.     

A decade of nutraceutical patents: where are we now in 2018?

ABSTRACT

Introduction: In the last 10 years, nutraceuticals have grown in interest to researchers, industry, and consumers and are now familiar in the collective imagination as a tool for preventing the onset of a disease. Often nutraceuticals are confused with biologically active phytochemicals/botanicals which can have health benefits. This is a misunderstanding however as the term nutraceutical refers to a product that must have a beneficial effect on health proven by clinical testing.

Areas covered: A search has been performed on both recent patents and the literature regarding nutraceuticals focusing on the beneficial and proven health effects on pathological conditions to give an overview of the state-of-the-art developments in this area. Patents and literature data addressing specific pathological conditions are discussed.

Expert opinion: Nutraceuticals represent a challenge for the future of drug-based pharmacotherapy, and, at the same time, are a powerful tool for the prevention of chronic disease. They are not proposed as an alternative to drugs, but instead, can be helpful to complement a pharmacological therapy and prevent the onset of chronic diseases in subjects who do not qualify for conventional pharmacological treatment.     

Pharmacotherapies for obstructive sleep apnoea: where are we now?

Obstructive sleep apnoea (OSA) is common, causes considerable morbidity and probably contributes to mortality particularly through associated cardiovascular disease. The physical therapy of continuous positive airway pressure (CPAP) is extremely effective in the majority of patients but most patients would prefer an alternative. Intuitively, OSA should be amenable to pharmacotherapy. The upper airway of affected individuals can be narrowed but is patent during wakefulness. Collapse of the airway during sleep occurs when negative intra-luminal pressure generated by inspiratory effort exceeds the tone of the upper airway dilators. This mismatch may be in part due to respiratory drive instability but the state-dependent fall in drive to the airway dilator muscles is the biggest factor in most patients.Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Various antidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators. The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects.There have been recent advances in the understanding of the neurotransmitters involved in the control of sleep and the upper airway motor neurones, offering the possibility of novel approaches to the drug treatment of OSA for those patients who cannot tolerate or do not benefit from CPAP. It seems likely that a better understanding of the mechanisms of OSA in individual patients and tailoring of drug therapy will be the way forward.     

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.     

Pharmacological approaches to CNS vasculitis: where are we at now?

The diagnosis and treatment of central nervous system (CNS) vasculitis is extremely challenging. Several conditions can mimic CNS vasculitis and require totally different treatment. CNS vasculitis, once confirmed, may result from infections or systemic diseases that will warrant specific treatments, or, more rarely, be primary and isolated (PCNSV). Prospective trials to help determine the optimal treatment for PCNSV are lacking, but data from several cohorts have provided seminal data on its management. The consensus is to use glucocorticoids as first-line agents, combined with additional immunosuppressants for the most severe cases, mainly cyclophosphamide for induction, followed by less-toxic maintenance therapy with azathioprine, methotrexate, or mycophenolate mofetil. The recent identification of PCNSV subgroups and predictors of outcomes might help in deciding the adequate treatment for each patient, keeping in mind that these data are based on a small number of patients. Other agents and biologics can be considered for patients with relapsing and/or refractory disease, but evidence is limited. In practice, the diagnosis must be re-questioned in patients with PCNSV refractory to standard treatment, especially with diagnoses not based on pathology.     

Acridine and acridone derivatives, anticancer properties and synthetic methods: where are we now?

Acridine derivatives are interesting chemotherapeutic agents that were first used as antibacterial and antiparasite agents. In this review we wish to concentrate our attention on the anticancer properties of acridines used in clinics since the 1970's. Based on recent results, an outlook on antitumour acridine chemotherapy will be proposed. The biological activity of acridines is mainly attributed to the planarity of these aromatic structures, which can intercalate within the double-stranded DNA structure, thus interfering with the cellular machinery. Recent understanding of the mode of action of acridines leads to continuous and exciting research in this heterocyclic family. Indeed, biological targets such as topoisomerases I and II, telomerase/telomere and protein kinases emerge and allow the design of novel acridine-based patterns. This review further pinpoints the latest progress in the development of anticancer agents based on naturally occurring and synthetic acridines (e.g. acridones, pyridoacridines); for this matter in vitro/in vivo studies and clinical trial results will be discussed. The DNA-affinic property of acridine is also useful to vectorise drugs into cell nuclei and some applications in hypoxia-selective treatment, platinum or N-mustard derived conjugates will be reported. Some other properties including inhibition of multidrug resistance or potential impact on Alzheimer disease will be treated. It is noteworthy that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity observed. So, we wish also to disclose a summary of recent synthetic methodologies developed for acridine synthesis.