Drug Repurposing: Far Beyond New Targets for Old Drugs

Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug–target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.Key words: drug repurposing, drug–target interactions, intellectual property, side effect tolerance, target identificationThere are two major “unknown unknown” categories in drug discovery [1] that can be linked to the main reasons for failure in drug approval, namely safety and efficacy [2]. The first category is related to the toxicological and pharmacokinetic profiles of the new molecular entity (NME), and it is mainly addressed in phases I and IIa clinical trials, following multiple preclinical evaluations: these evaluate the therapeutic regimen (i.e., dose and frequency) and safety aspects concerned to the NME. The second category relates to the protein target and biological pathway that are subject to therapeutic interference, and it is indirectly linked to the clinical efficacy of the NME under investigation: in this case, the question being addressed is whether the NME-induced perturbation of the chosen (hypothesized) target or pathway leads to the desired clinical effect [3]. The uncertainty related to the unknown unknown aspect of discovery is often mitigated by eliminating some of the “unknown” elements: either the NME is well understood, i.e., an approved drug [4], or the target/pathway is well described, i.e., already successfully manipulated therapeutically [5]. Preferably, both “unknowns” have been addressed previously, with the expectation that derisking the discovery aspect may lead to a higher success rate.The unknown unknown strategy has been rewarding, as many blockbuster franchises have emerged following this recipe, e.g., histamine H2 antagonists, proton pump inhibitors, anticoagulant/antithrombotic therapy, or drugs to reduce hypercholesterolemia [6]. However, such drugs are the result of a long, high-cost, and high-risk optimization process, often subject to “fast followers,” where first-in-class does not equate with the most financially rewarding NME [7]. In order to reduce time-to-market, as well as associated costs and risks, alternative strategies have continued to emerge. In this respect, it is currently believed (though not proven) that biologics, as opposed to small molecules, carry a lower risk in terms of toxicity and pharmacokinetic profile [8], thus regulatory approval milestones seem easier to reach. Therefore, one derisking strategy is to invest in NMEs from the biologics category. Another derisking approach is to capitalize on previous investments, for example by taking an approved drug that has already been optimized for safety and efficacy in a particular indication and obtain regulatory approval for novel therapeutic applications. This is normally being referred to as drug repurposing [9] or repositioning [4] and is the focus of this contribution.There is a widespread tendency in academia to assume that drug repurposing is just about identifying new targets for old drugs. Several aspects ought to be considered when assessing drug repurposing opportunities, including relevance to disease, side effect tolerability for the new indication, and intellectual property position. All these aspects are covered in the drug repurposing flowchart proposed in Fig. 1 and contextualized in the following sections.Open in a separate windowFig. 1Flowchart for drug repurposing beyond identifying new targets for old drugs. The abbreviation “db” stands for “database”     

Drug Repurposing from an Academic Perspective

Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.     

Aspirin for the Second Hundred Years: New Uses for an Old Drug

Abstract: The history of aspirin can be traced back to ancient Egypt where extract of willow bark was used to treat inflammation. The active component of the extract was identified as the glucoside of salicylic alcohol. The severe gastric side effects associated with the use of sodium salicylate prompted the synthesis of the o-acetyl-derivative as a possible pro-drug. In fact, acetylsalicylic acid was antiinflammatory, analgesic and antipyretic but also ulcerogenic to the stomach. Acetylsalicylic acid was synthesized one hundred years ago, and was mass-produced under the commercial name of ‘Aspirin’(Dreser, 1899) by the German company Bayer for the treatment of fever and rheumatism.     

Antipyrine - New Light on an Old Drug

The time courses of analgesic activity of 4 different tablets containing different amounts of antipyrine were determined in 14 volunteers using electrical tooth pulp stimulation to elicit pain. Drug action was monitored by following somatosensory evoked potentials obtained from electroencephalographic measurements as well as pain rating and pain threshold determination. The results were compared with data obtained after administration of 1000 mg acetaminophen and two different doses of aspirin (500 and 1000 mg). At the same time drug concentration in saliva of the same volunteers was analyzed by quantitative in situ thin-layer-chromatography to investigate the pharmacokinetics. Furthermore, the in vitro drug release from the different tablets was studied with a continuous flow cell model. Antipyrine produced reliable analgesic activity. The onset of action was significantly faster than after administration of the same dose of aspirin, and the effect lasted longer than after intake of the same dose of acetaminophen. Comparison of the drug action and drug level in the body showed an excellent correlation between pharmacodynamics and pharmacokinetics. The study confirms our earlier findings on the value of somatosensory evoked potentials as a method to investigate the pharmacodynamics of weak analgesics in humans. The results also suggest to reconsider the use of antipyrine as an over-the-counter analgesic.     

Regulation of Macrophage Biology by Lithium: A New Look at an Old Drug

Lithium (Li) continues to be a standard small compound used for the treatment of neurological disorders. Besides neuronal cells, Li is also known to affect immune cell function. In spite of its clinical use, potential mechanisms by which Li modulates immune cells, especially macrophages and its clinical relevance in bipolar patients are not well understood. Here, we provide an overview of the literature with regard to Li’s effects on monocytes and macrophages. We have also included some of our results showing that Li differentially modulates chemokine gene expression in the absence and presence of Toll-like receptor-4 stimulation in a human macrophage model. Given that Li has a wide range of intracellular targets both in macrophages as well as in other cell types, more studies are needed to further understand the mechanistic basis of Li’s effect in neurological and other inflammatory diseases. These studies could undoubtedly identify new therapeutic targets for treating such diseases.     

Drug Repurposing for Ebola Virus Disease: Principles of Consideration and the Animal Rule

There are no approved drugs or biologics to treat Ebola virus disease (EVD). Literature reviews identified a list of 141 drugs with reports of preliminary in vitro potency and in vivo effectiveness in animals or with reports of clinical use/trials in EVD patients. The majority of these drugs have been individually approved by the U.S. Food and Drug Administration for treating various non-EVD diseases. The anti-Ebola potency data of these drugs were curated from literature and publicly accessible databases, along with their individual biopharmaceutical and pharmacokinetic characteristics. To facilitate the development of antiviral drugs including anti-EVD drugs, highlights include optimization of the exposure-response relationship, design of a safe and effective clinical dosing regimen to achieve an adequate high ratio of clinical C_min to a plasma protein binding-adjusted EC₉₅, and the pharmacokinetic studies needed in animal models (healthy and affected) and in healthy volunteers. The exposure/response relationship for human dose selection is summarized, as described in the U.S. Food and Drug Administration “Animal Rule’’ guidance when human efficacy studies are not ethical or feasible.     

对药物葡萄糖醛酸结合反应的认识——老酶新认识

John O．Miners博士，澳大利亚佛林得寺大学医学院临床药理室和佛林德斯医疗中心教授和主任。主要研究方向为人体药物代谢，包括药物代谢酶结构和功能的关系，人体药物代谢和动力学的体外和结算机模型，药物间相互作用以及遗传药理学。目前兼任许多专业学会包括国际药理学联合会药物代谢专业委员会主席（2002-2006年），东南亚西太平洋地区药理学家联合会副主席（2003-2007年）等职，还担任《药物遗传学和基因组学》、《药物代谢综述》等杂志编委。     

Dopaminergic and Adrenergic Pathways as Targets for Drug Repurposing in the Neuroimmune Network

Journal of Neuroimmune Pharmacology - Dopamine, noradrenaline and adrenaline are catecholamines, and are all produced along the same metabolic pathway. Their discovery dates back to the early...     

Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics

The consumption of mushrooms has become increasingly popular, partly due to their nutritional and medicinal properties. This has increased the risk of confusion during picking, and thus of intoxication. In France, about 1300 cases of intoxication are observed each year, with deaths being mostly attributed to Amanita phalloides poisoning. Among amatoxins, α- and β-amanitins are the most widely studied toxins. Hepatotoxicity is the hallmark of these compounds, leading to hepatocellular failure within three days of ingestion. The toxic mechanisms of action mainly include RNA polymerase II inhibition and oxidative stress generation, leading to hepatic cell apoptosis or necrosis depending on the doses ingested. Currently, there is no international consensus concerning Amanita phalloides poisoning management. However, antidotes with antioxidant properties remain the most effective therapeutics to date suggesting the predominant role of oxidative stress in the pathophysiology. The partially elucidated mechanisms of action may reveal a suitable target for the development of an antidote. The aim of this review is to present an overview of the knowledge on amanitins, including the latest advances that could allow the proposal of new innovative and effective therapeutics.     

Smooth or Risky Revisit of an Old Malaria Drug for COVID-19?

Hydroxychloroquine (HCQ) is an old medication for malaria. In addition to handling this parasitic disease, HCQ is also used to treat a number of autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus when other medications are not effective. Recently a new viral infection (COVID-19) is rocking the entire world so much that it has already taken more than 200,000 lives throughout the world within the last two months and the World Health Organization was forced to declare it as a pandemic on March 11, 2020. Interestingly, some reports indicate that this wonder drug may be also beneficial for COVID-19 and accordingly, many clinical trials have begun. Here, we discuss different modes of action (anti-inflammatory, antioxidant, inhibition of endosomal acidification, suppression of angiotensin-converting enzyme 2 or ACE2 glycosylation, etc.) of HCQ that might be responsible for its possible anti-COVID-19 effect. On the other hand, this review also makes an honest attempt to delineate mechanisms (increase in vasoconstriction, inhibition of autophagy, depletion of T cells, etc.) indicating how it may aggravate certain conditions and why caution should be taken before granting widespread repurposing of HCQ for COVID-19.

Graphical Abstract

     

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

Methylene blue is used primarily in the treatment of patients with methemoglobinemia. Most recently, methylene blue has been used as a treatment for refractory distributive shock from a variety of causes such as sepsis and anaphylaxis. Many studies suggest that the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway plays a significant role in the pathophysiology of distributive shock. There are some experimental and clinical experiences with the use of methylene blue as a selective inhibitor of the NO–cGMP pathway. Methylene blue may play a role in the treatment of distributive shock when standard treatment fails.     

Histochrome: a New Original Domestic Drug

Pharmaceutical Chemistry Journal -     

Diazin: a New Domestic Antiallergy Drug

Pharmaceutical Chemistry Journal -     

Topiramate Utilization After Phentermine/Topiramate Approval for Obesity Management: Risk Minimization in the Era of Drug Repurposing

Introduction

The US FDA required a Risk Evaluation and Mitigation Strategy (REMS) for phentermine/topiramate, an anti-obesity medication, to prevent congenital malformations. No REMS is required for single-ingredient topiramate, which may be used off-label for the same purpose.

Objective

The aim of this study was to evaluate the impact of phentermine/topiramate approval in 2012 on subsequent topiramate use among patients with obesity.

Methods

We used a national insurance claims database to conduct an interrupted time-series study (2009–2015). Enrollees aged 18–65 years in each examined calendar quarter had full insurance benefits during that quarter and the preceding 6 months. We required patients to have an obesity diagnosis and no other conditions warranting topiramate use. We calculated topiramate or comparator drug (atorvastatin, metformin) initiation rates and evaluated changes in trends before and after 2012 (transition period).

Results

Among topiramate users, 80% were female, and demographic characteristics remained consistent during the study period. Between 2009 and 2011, the topiramate initiation rate (95% confidence interval) among patients with obesity was 0.85 (0.73–0.98) per 1000 patients, with no significant upward or downward trend. In the first quarter of 2013, this rate had increased more than 2.5-fold (change: + 1.36 [1.19–1.52]). Metformin and atorvastatin initiation rates did not change. Topiramate initiation rates were threefold higher than phentermine/topiramate rates during the post-approval period.

Conclusion

Phentermine/topiramate approval was associated with increased topiramate use among patients with obesity. Prescribers are encouraged to enhance patient education and monitoring in such clinical use since topiramate prescribing information, compared with REMS for phentermine/topiramate, has less emphasis on preventing prenatal exposure.

     

Metropol: a New Prolonged-Release Drug for the Treatment of Anaerobic Infections

Pharmaceutical Chemistry Journal -