Inflammation is the epitome of a double-edged sword. It swiftly defends the body from invading microorganisms and assists in the healing of damaged tissues, yet simultaneously wallows in its putrid, familiar role as the root of most diseases. With excessive idle time, it suffers battle fatigue and turns toxic. It morphs from the shiny, beneficial, acute mode into a sluggish, detrimental, chronic state of inflammation, which has been tied to cardiovascular diseases, autoimmune disorders, and chronic pain. The system in place to keep the human body safe overreacts and mutiny renders external supports as necessary to prevent extensive damage.
Nowadays, anti-inflammatory medications are one of the most consumed types of drugs worldwide. Still, these are often plagued by efficacy and safety issues, leading to very expensive and serious adverse events. Thus, there is a clear need to develop analgesic agents and anti-inflammatory drugs with novel mechanisms of action that are able to overcome the delicate balance between providing a therapeutic effect while minimizing side effects and tolerance/resistance buildup. While the previous statement can be said to hold true for most drugs, progress in the development of novel anti-inflammatory drugs has been stalled by hurdles that led to a lack of new drugs reaching the market in recent years. In this article, we explore a few novel strategies that have recently been gaining traction as viable pathways towards the development of new anti-inflammatory drugs.
Key hurdles to anti-inflammatory drug development:
The frontline members of the gold standard for anti-inflammatory drugs are — nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and opioids — were integrated into the treatment of inflammation and pain decades ago; but unfortunately, since then, very few drugs with novel mechanisms of action have successfully made it to the clinics, despite substantial development efforts.
This lack of innovation goes beyond the inherent scientific questions with several existing key technical difficulties that have yet to be overcome:
- Lost in translation: A relatively large translational gap between the preclinical experimental data and the clinical results attributed to model characteristics
- Technical difficulties: Struggles with the investigational techniques (specifically for pain treatment)
- Creature conundrum: Differences among mechanisms between species
These challenges have resulted in a steady decline in drug discovery productivity, with an upward trend in the cost of successfully introducing a novel anti-inflammatory medicine over several decades.
To add to the technical challenges, additional burdens have been piling up:
- Healthcare payers and regulators require that new drugs will improve upon all existing medicines to justify the prescription medicine price amount. In order to validate premium prices, markedly improved health outcomes are required. As time goes on, this prerequisite becomes increasingly more challenging to overcome. Yet, there are still obvious unmet needs for novel anti‐inflammatory medicines; specifically, improved efficacy in targeted groups or a more generally improved therapeutic index (or ideally, both) while being competitive in administration convenience and cost.
- Lowering the risk tolerance of drug regulatory agencies would raise the bar for the introduction of novel drugs and could significantly increase the related costs of R&D.
- The tendency to integrate human and technical resources to R&D, which, until recently, has broadly led to an increase in R&D spending in major companies and for the industry generally. This tendency is most likely attributed to several factors, such as good returns on investment in R&D for the majority of the past 60 years. Unfortunately, the perspective exists that much of this growth in spending has been unproductive and ill advised.
Finding new strategies:
Despite the challenges, the field has not been devoid of active research. A few kinase inhibitors and phosphodiesterase-4 blockers (PDE4) recently have been offered up as potential new options. Also, there are some promising novel approaches traveling through different clinical stages of drug development, with focuses on transient receptor potential; for example, inhibition of voltage-gated sodium/calcium channels, antagonism of vanilloid 1/ ankyrin 1 channels, implementation of a variety of enzymes (semicarbazide-sensitive amine oxidases, kinases, and matrix metalloproteinases), transcription factors, cytokines/chemokines, administration of nerve growth factor, and even modulation of several G protein-coupled receptors (purinoceptors, cannabinoids, and neuropeptides).
PDE4 inhibitors – Target inflammation:
Over the past few decades, many PDE4 inhibitors have been created and synthesized, among which apremilast, roflumilast, and crisaborole were approved for the treatment of psoriatic arthritis, inflammatory airway diseases, and atopic dermatitis, respectively. Unfortunately, the accompanying dramatic adverse symptoms, such as nausea, emesis, and gastrointestinal reactions, knock these options off the top tier choice for consumers with chronic conditions.
Ion channels – Widespread regulators:
Ion channels are an alluring drug target because they are vital to controlling several physiological processes and their dysfunction can promote pathophysiology. In nonrespiratory diagnoses, there is a precedent for identifying and commercializing successful drugs that regulate the activity of voltage-gated sodium, calcium or potassium channels, or ligand-gated ion channels.
It is not clear yet why this plan of attack has not extended to respiratory conditions, but recent publications hint that this is about to shift, with increasing recognition that regulation of ion channel function could be a successful strategy for modeling the aberrant pathophysiological changes seen in chronic lung diseases.
G protein-coupled receptors – A GI-friendly anti-inflammatory option:
G protein-coupled receptors (GPCRs) are essential signaling molecules integrated into the immune response, inflammation regulation, cell proliferation, and intestinal barrier maintenance. Recent breakthroughs in the comprehension of the functions and structures of GPCRs have ignited a driving force for further exploration into the roles of GPCRs in the pathogenesis of inflammatory conditions.
Presently, a number of GPCRs have demonstrated association with inflammatory bowel disease (IBD), a diagnosis that has no tolerance for any potential GI side effects from traditional anti-inflammatory medications. Associations between GPCRs and disease severity, activity, and phenotypes have also generated new avenues for the specific management of patients with IBD. The most thoroughly studied are proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their clinical treatment potential for IBD and other inflammatory diseases.
Coxibs (celecoxib and rofecoxib) – Controversial NSAID counterpart:
Since the turn of this century, there has been major commercial development following the introduction of coxibs (celecoxib and rofecoxib), new highly selective COX-2 inhibitors, which were reported to have low GI side effects. Shockingly, in the late 2004 period, rofecoxib was withdrawn globally due to serious cardiovascular effects, calling into question coxibs. Currently, efforts are underway to determine why cardiovascular reactions occurred with coxibs, possibly identify safer coxibs, and explain the actions of COX-2 and COX-1 in stroke and cardiovascular diseases, hoping that there may be some grounds for developing newer agents (for example, nitric oxide donating NSAIDs) to control these diagnoses.
The COX isoforms discovery established their importance in many non-pain states and non-arthritic conditions with an inflammatory part of the pathogenesis, including cancer, Alzheimer’s, and other neurodegenerative diseases. The applications of NSAIDs and the coxibs in the treatment and prevention of these diagnoses, as well as other analogues and aspirin in the preventative impact potential for thrombo-embolic diseases, are among the major therapeutic developments of this century.
Novel anti-inflammatory drugs are being identified and developed based upon their effects on signal transduction and as anti-cytokine agents, and these medications are now being deemed new therapies to control diseases where cytokines and other non-prostaglandin components of chronic inflammatory and neurodegenerative diseases thrive.
Less notably, a safer application of corticosteroids and the applications of new drug delivery systems for use along with these medications as well as with NSAIDs also contribute to newer technological developments of the 21st century. What originated as medications to control pain, fever, and inflammation in the last two centuries now has evolved to reveal a huge range and type of anti-inflammatory agents and identification of new therapeutic targets to treat a wide array of conditions.
COVID-19 treatment – Glucocorticoids, IL-6 antagonist, JAK inhibitors, and chloroquine/hydroxychloroquine:
Most recently, the coronavirus has brought the dangers of inflammation front and center on the world stage, with inflammatory cytokine storms being noted as very common in patients with severe COVID-19. A cytokine storm (CS) describes uncontrolled and excessive discharge of inflammation-causing cytokines. CS syndrome can be triggered by a variety of diagnoses, including rheumatic diseases, infectious diseases, and tumor immunotherapy. Clinically, it most often presents as multiple organ failure, systemic inflammation, and high inflammatory parameters. Specifically relating to infectious diseases, CS usually begins in the focal infected region, then begins to spread all over the body via circulation.
In coronavirus pneumonia, much like Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), in combination with rapid virus replication, a massive amount of inflammatory cell infiltration and CS produce acute respiratory distress syndrome (ARDS), acute lung injury, and eventually, death. Although a definitive consensus has not yet been reached regarding which anti-inflammatory medications may best treat COVID-19 and the resulting CS, it is critical to calculate the risk and benefit ratio before initiating anti-inflammation therapies such as glucocorticoids, IL-6 antagonist, JAK inhibitors, and chloroquine/hydroxychloroquine.
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