AN OVERVIEW ON DRUG REPURPOSING OF

DRUGS

INTRODUCTION
Despite advances in technology and enhanced knowledge of human disease, translation of
these benefits into therapeutic advances has been far slower than expected [1,2]. The
challenges facing the global pharmaceutical industry are multifield and include high attrition
rates [3,4], increased time to bring new drugs to the market in some therapeutic areas and
changing regulatory requirements, which can all contribute to higher costs. The escalating
cost and length of time required for new drug development mean that for every dollar spent
on research and development (R&D), it has been estimated that less than a dollar of value
is returned on average [5], which could make the pharmaceutical industry a less desirable
choice for investors
Drug repurposing (also called drug repositioning, reprofiling or re-tasking) is a strategy for
identifying new uses for approved or investigational drugs that are outside the scope of the
original medical indication1. This strategy offers various advantages over developing an
entirely new drug for a given indication.

 First, and perhaps most importantly, the risk of failure is lower; because the
repurposed drug has already been found to be sufficiently safe in preclinical models
and humans if early-stage trials have been completed, it is less likely to fail at least
from a safety point of view in subsequent efficacy trials

 Second, the time frame for drug development can be reduced, because most of the
preclinical testing, safety assessment and, in some cases, formulation development
will already have been completed.

 Third, less investment is needed, although this will vary greatly depending on the
stage and process of development of the repurposing candidate [6]. The regulatory
and phase III costs may remain more or less the same for a repurposed drug as for a
new drug in the same indication, but there could still be substantial savings in
preclinical and phase I and II costs.

Together, these advantages have the potential to result in a less risky and more rapid return on
investment in the development of repurposed drugs, with lower average associated costs once
failures have been accounted for (indeed, the costs of bringing a repurposed drug to market
have been estimated to be US$300 million on average, compared with an estimated ~$2–3
billion for a new chemical entity [7]). Finally, repurposed drugs may reveal new targets and
pathways that can be further exploited.
Drug repurposing strategies

Knowledge-based repurposing

In this repurposing strategy, utilizing the drug-related information, including drug

targets, chemical structures, pathways, adverse effects, etc., models are built to predict
unknown tar gets, bio-markers or mechanisms for diseases.[8] This strategy Rheumatoid
arthritis Migraine headache Breast cancer Erectile dysfunction Leprosy, Multiple myeloma
includes target-based, pathway-based, and target mechanism-based drug-repurposing.

Target mechanism-based drug-repurposing

Given proteins or biomarkers of interest, target-based drug repurposing comprises high-

throughput and/or high-content screening (HTS/HCS) of drug compounds,[9] followed by in
silico screening of drug compounds from drug libraries, such as ligand-based screening or
docking.[14] Compared with blinded search or screening which does not use biological or
pharmacological information when screening, target-based repurposing directly links targets
with disease mechanisms and therefore the likelihood of drug discovery significantly
improves. The advantage of the target-based approach lies in its ability to screen nearly all
drug compounds with known chemical structure. However, target-based methods cannot
identify unknown mechanisms beyond the targets already known.
Pathway-based drug-repurposing

Pathway-based drug-repurposing utilizes

 Metabolic pathways
 Signalling pathway
 protein-interaction networks information
to predict the similarity or connection between disease and drug. For example, using
omics data processed from human patients or animals, disease-specific pathways are
reconstructed to serve as new targets for repositioned drugs.[10]

Target mechanism-based drug-repurposing

Target mechanism-based drug-repurposing integrates signalling pathway information,

treatment omics data, and protein interaction networks to discover new mechanisms of action
for drugs.[11] The necessity of precision medicine, which has been increasingly important,
motivates such drug-repurposing approaches.

signature-based repurposing,

In signature-based repurposing, gene signatures information obtained from disease omics

data [12] is used to discover new off-targets or mechanisms of disease. This approach
searches inverse drug–disease relationships by comparing gene expression profiles between
drug and disease. In the work by Dudley et al.,[15] potential drug–disease pairs were
investigated for inflammatory bowel disease (IBD), where gene expression profiles obtained
from the gene expression omnibus database [13] were compared with gene expression
profiles comprising 164 drug compounds obtained from the connectivity map.[14] As a
result, unknown drug–disease pairs were discovered, with one pair validated in preclinical
models. The advantage of these approaches is that they identify new mechanisms of action
for drugs. Also, unlike knowledge-based methods, more molecular- and/or genetic-level
mechanisms are involved in these methods.

Phenotype-based repurposing

The phenotypic information has become available as a new source of drug repositioning. In
recent years, this type of information has been increasingly used by systems approaches to
detect genetic traits associated with human diseases.[16] Natural language processing skills
applied to electronic health records (EHRs) can reveal additional adverse drug events which
were not observed during drug development.[17] For example, mining EHRs helped in
identifying that metformin can be re purposed for cancer treatment.[18]

HISTORY OF DRUG REPURPOSING

1. Trends in Drug Repurposing over time

The analysis of FDA CDER drug approval rates from 1985 to 2024 offers a comprehensive
view of the regulatory landscape and the evolution of pharmaceutical innovation over the past
decades. In this context, two primary submission types dominate: NDAs for NMEs and BLAs
for biologics (Fig. 1). Both pathways are essential for understanding the dynamics of market
introduction and innovation in the pharmaceutical industry. By focusing on these submission
types, we can discern the underlying trends in repurposing activity, as they reflect the
introduction of genuine new therapeutic options, distinct from modifications or extensions of
existing compounds known as line extensions or from repurposing attempts identified during
clinical trials as drugs are redirected toward alternative therapeutic targets. Such redirections
can occur when a drug’s effects suggest potential benefits beyond the initially intended use,
leading researchers to explore new therapeutic indications during the clinical trial phase.

However, it’s important to note that many line extensions, often used to include paediatric
formulations or indications, reflect an industry trend where paediatric needs are addressed the
rough minimal adaptations rather than genuine innovation.
Minimal adaptations rather than genuine innovation.

Comparison of de novo and repurposed FDA-approved Drugs (1985-2024)

1.1. Initial Trends in Drug Development and Repurposing (1985–1990)

In the late 1980s, the pharmaceutical industry was primarily driven by “the blockbuster
model”. This model was focused on the development of de novo therapeutic molecules, with
20 to 40 drugs approved annually by the FDA, including NDAs and BLAs (Fig. 1). These
drugs, primarily designed for large patient populations suffering from common non-
communicable conditions like hypertension, diabetes, and cardiovascular diseases (CVD),
represented high-revenue opportunities for pharmaceutical companies .The market was
heavily incentivized to prioritize such first-in-class therapies due to the extensive patent and
clinical data protection granted to NDAs and BLAs, offering long-term market exclusivity
and high profitability.

During this period, repurposing efforts were generally limited (Fig. 1). Pharmaceutical
companies viewed novel drug development as more lucrative and strategically essential,
given that the regulatory and market frameworks were more favourable toward de novo
NDAs and BLAs. Regulatory protection, such as through the 20-year patent exclusivity , and
the lack of computational tools for systematic drug repurposing (such as bioinformatics and
genomics), further solidified the industry’s focus on de novo drugs .

However, despite the industry’s clear preference for new molecular discoveries, serendipity
played a role in some of the earliest repurposing cases. These repurposing successes were not
the result of systematic exploration, but rather the outcome of clinical observation and off-
target effects, underscoring how repurposing in this era remained largely opportunistic.

1.2. Regulatory Shifts and the Spike in Approvals (1990–2000)

The 1990s were transformative for the pharmaceutical landscape, not only because of
advances in drug R&D but also due to significant regulatory shifts that profoundly impacted
approval rates. The introduction of the Prescription Drug User Fee Act (PDUFA) in 1992
marked a turning point. PDUFA allowed the FDA to collect fees from pharmaceutical
companies, accelerating the review process for drug applications. This expedited regulatory
review resulted in a notable spike in drug approvals in 1996, driven by the clearing of a
significant backlog of applications and the increased pace of pharmaceutical R&D (Fig. 1).

Despite the immediate surge in approvals, the late 1990s saw a decrease. This dip reflected
underlying issues within the industry, despite faster approval times. The decrease in novel
drug approvals can be attributed to multiple factors: the inherent complexities in developing
first-in-class drugs, rising R&D costs, and the increasing difficulty in achieving breakthrough
innovations. Additionally, companies began to encounter the limits of traditional NME-
focused strategies, particularly as many of their high-revenue blockbuster drugs from the
1980s were nearing the end of their patent protection : a phenomenon referred to as the
“patent cliff”.

This period also coincided with growing regulatory complexity, as the FDA increased its
focus on ensuring drug safety and efficacy, which lengthened the clinical trial process and
raised the bar for new drug approvals. As a result, pharmaceutical companies began to
explore alternative strategies to sustain revenues and extend the life cycle of their products,
including line extensions and repurposing efforts. However, repurposing remained an
underutilized approach at this stage, often hindered by IP concerns and the lack of systematic
approaches to identify new therapeutic uses.

1.3. The Patent Cliff and the Strategic Shift to Biologics (2000–2010)

The early 2000s marked a critical juncture for the pharmaceutical industry as the “patent
cliff” began to take effect. This term describes the period during which patents for many
blockbuster drugs, such as those for cholesterol and blood pressure management, expired,
leading to a sharp increase in generic competition. The resulting revenue losses prompted
companies to diversify their R&D strategies, looking for ways to replenish their product
pipelines with projects that reduce the high risks associated with NMEs.

Biologics emerged as a key strategic focus during this period (Fig. 1). Unlike chemically-
designed small-molecule drugs, biologics (therapies derived from living organisms) offered
longer market exclusivity under US law (12 years compared to 5 years for small molecules),
making them an attractive alternative to NMEs. The development of biologics also aligned
with the increasing biotechnological insight (e.g., due to the Human Genome Project) and the
accompanying growing interest in personalized medicine. Biologics, which are often tailored
to target specific molecular pathways, became particularly prominent in treating complex
diseases such as cancer and autoimmune disorders. Examples include monoclonal antibodies
(mABs) targeting tumor markers revolutionized cancer therapy, and TNF-inhibitors,
transformed treatment approaches in autoimmune diseases like rheumatoid arthritis and
Crohn’s disease.

At the same time, repurposing strategies began to gain traction, particularly in response to the
rising costs and high failure rates of novel drug development (Fig. 1). During this period, the
repurposing of older drugs with established safety profiles became an attractive alternative to
targeting new indications, rather than developing entirely new molecules. Additionally, from
2000 onward, our analysis reveals that nearly half of newly approved FDA drugs target new
indications for known products (Fig. 1), confirming the increasing interest in repurposing as a
strategic R&D approach. Indeed, regulatory incentives, such as the Orphan Drug Act (ODA,
1983), Priority Review and Accelerated Approval (both introduced in 1992), encouraged
companies to revisit older compounds including for rare diseases, where traditional drug
development pathways were often cost-prohibitive. Our data shows that approximately 15%
(60 out of 403) of original drugs with orphan drug designation (ODD) undergone
repurposing, reflecting a measurable – though proportionally limited – trend toward pathway-
driven translation in rare diseases. Unlike NMEs, which predominantly target broader
commercial markets, orphan drug repurposing develops through niche, mechanism-specific
repositioning grounded in deeper biomolecular insight. This distinction suggests a shift in
R&D priorities, where repurposing is increasingly leveraged when mechanistic understanding
enables therapeutic extension across closely related rare disease pathways.

1.4. Biologics and the Rise of Personalized Medicine (2010–2024)

The 2010s saw the pharmaceutical industry’s most pronounced shift towards biologics and
personalized medicine. Advances in biotechnology, the development of the “omics”
(genomics, transcriptomics, proteomics and metabolomics), and shift towards precision
medicine transformed drug development, allowing for more targeted therapies that could
address specific molecular mechanisms of disease. This period witnessed a marked rise in
BLA approvals (Fig. 1), reflecting the industry’s growing commitment to biologics as a core
component of its therapeutic arsenal.

Precision medicine, particularly in oncology and (rare or single nucleotide) genetic disorders,
was increasingly underpinned by genomic advancements. For example, companion
diagnostics that identified specific genetic mutations, such as EGFR mutations in non-small
cell lung cancer (NSCLC), enabled the development of targeted therapies with significantly
improved efficacy and safety profiles. By focusing on molecular markers rather than broad
disease categories, pharmaceutical companies could streamline clinical trials by stratifying
patient populations, improve success rates, and bring therapies to market more quickly.

At the same time, repurposing efforts continued to gain momentum, particularly in

therapeutic areas with high unmet need (Fig.1). For example, drugs originally approved for
unrelated conditions were increasingly evaluated for new uses in oncology, rare diseases, and
neurological disorders (Fig. 1), where drug development has historically faced high failure
rates. Advances in bioinformatics, high-throughput screening (HTS), the maturation of big
data, and its boost power to artificial intelligence (AI), facilitated more systematic approaches
to drug repurposing, moving away from the opportunistic discoveries of earlier decades
towards a more calculated and data-driven process .

1.5. COVID-19 and the Acceleration of Drug Repurposing

The COVID-19 pandemic accelerated the industry’s reliance on drug repurposing, as the
global health crisis demanded urgent therapeutic solutions. Regulatory bodies, including the
FDA, adapted by providing Emergency Use Authorizations (EUAs), allowing drugs
originally developed for other conditions to be rapidly repurposed for COVID-19.
Remdesivir, for instance, was repurposed from its original use as an antiviral drug for Ebola
to treat COVID-19 patients, providing a critical therapeutic option during the pandemic. The
drug is still routinely used when an immunocompromised patient is diagnosed with COVID-
19 .

This era underscored the value of drug repurposing as a rapid response tool in public health
emergencies. It also highlighted how regulatory frameworks could be adapted to fast-track
approvals while maintaining rigorous safety and efficacy standards. The pandemic
demonstrated the pharmaceutical industry’s capacity to innovate under pressure, blending
repurposing strategies with cutting-edge biotechnology to deliver solutions at an
unprecedented pace.

ADVANTAGES OF DRUG REPURPOSING

Translational focus

Aligned with, and benefiting from academic freedom, translational research in academia
offers incentives by fostering novel collaborations and pairing up basic scientists with
clinicians across multiple disciplines. Immediate access to hospitals and health care
practitioners is a tremendous advantage, one that often short-cuts the communication gap
between two (otherwise separate) cultures.

Disease focus

Activities specific to clinical education and clinical research affords in-depth expertise in
particular disease areas, removing “activation barriers” and enabling projects to rapidly
advance past the early (basic science) stages. Conversely, clinical observations can lead to
immediate pathway links and studies at the cellular and molecular level. In this manner,
diseases that lack effective therapies can rapidly be subjected to drug

Repurposing efforts.

Target focus

Those targets that are nodal points in general mechanisms such as cell division, autophagy,
apoptosis and metabolism can be subjected to therapeutic manipulation for various,
sometimes clinically different endpoints. The complete understanding of pathway inter-
dependencies and shunts, and the clinical consequences of modulated therapeutic
perturbations for such targets can only be accomplished by close, effective communication
between basic scientists, clinicians and pharmaceutical scientists.
DISADVANTAGES OF DRUG REPURPOSING

Dosing and Safety

Since drugs are approved only after intense scrutiny, which observes clear therapeutic
benefits within well-defined safety margins, the clinical utility of finding novel drug-target
interactions is often hampered by issues related to dosage (i.e.,approved dose range) and
delivery capability (i.e., the ability to deliver the drug to particular targets at the disease focal
region). Dosing and delivery encompass safety aspects as well, as sufficient exposure of the
target to the drug (or its active metabolites) needs to be accomplished for a minimal length of
time. Novel drug-target interactions are frequently disclosed in peer-review or patent
literature, in particular for those older drugs that have not been comprehensively profiled
prior to approval. Quite often, these reports show micromolar-level potency. The burden of
proof and therapeutic relevance, however, falls on the discovery team, which has to establish
that, at dosage within the approved margin, such effects can be observed in the clinic. In our
experience, so far, it has been rare to find novel drug-target interactions within the constraints
of the approved therapeutic window. If the anticipated potency falls outside that range, the
discovery team has to begin with Phase I clinical trials, which effectively blurs the distinction
between de novo drug discovery and repurposing.

Lack of integration with pharmaceutical sciences and toxicology—Dosing and safety aside, it
is conceivable that the drug in question can be repurposed if appropriate delivery devices or
formulations could be implemented to provide drug exposure to the targeted tissue, while
limiting exposure to other tissues. As noted earlier, finding novel formulations or delivery
mechanisms for existing drugs is a viable repurposing strategy. In our experience, it is
unusual for the discovery team to include scientists from pharmaceutical and toxicological
sciences in the translational efforts.

Appropriate intellectual property coverage—For off-patent drugs, the number of options with
respect to intellectual property (IP) protection is more limited. The situation is quite delicate
for those cases where clinical practice leads to off-label prescriptions for the drug in question,
for precisely that indication. Even if truly novel mechanisms are fully explained, this rarely
leads to protected marketing rights from regulatory agencies. More lucrative scenarios can be
envisioned when the newly found drug-target-disease triplet is unique; such scenarios can
lead to use and possibly to formulation/delivery patents, if the IP landscape is favorable. One
specific limitation is the lack of experts in the legal issues related to drug repurposing, since
in itself this is quite a novel field for academia. Another limiting factor, often noted by the
industry, is the disclosure of novel drug-target-disease associations via PubChem or other on-
line databases, or via publications (which range from peer-reviewed literature to blogs). Such
disclosures effectively hamper IP protection efforts, often to the point of not seeking patent
protection.

Drug Repurposing Market Size and Shares with U.S. FDA Drug Repurposing Updates
The global drug repurposing market size is calculated at US$ 636.95 million in 2025, grew to
US$ 730.96 million in 2026, and is projected to reach around US$ 2506.64 million by 2035.
The market is expanding at a CAGR of 14.76% between 2026 and 2035.

An immense growth in rare and chronic diseases, like cancer, neural disorders, and other
diseases, is fostering groundbreaking developments in the discovery of new applications of
existing drugs. Alongside, the drug repurposing market is promoting the use of AI, ML, and
deep learning algorithms for studying complex biological databases. However, the emergence
of 3D cell culture models, HTS, GNNs, and other novel approaches is expanding the drug
development processes especially for biologics and small molecules.

Applications of AI in Drug Repurposing

AI has revolutionized medicine, as it is a valuable tool for almost every medical practice, not
only for the discovery of new treatment approaches, but also for prognosis prediction and
diagnostic purposes. Moreover, it can play a role in monitoring the patient’s vital signs,
providing therapeutic instructions even in clinical examination . Especially in drug
development and drug repurposing, AI tools are very useful. They can be used either in
searching resemblance between drugs and targets/proteins, or in producing the treatment
hypothesis and in de novo drug development . Finding similarities between molecules is a
key step in drug repurposing and many AI techniques and algorithms contribute to this
direction . Both the structure and the function of molecules are examined for similarities ,
based on the principle of drug tendency to attach to molecules alike to the already known
ligands. Especially in drug repurposing, drugs are usually examined according to their
structure to reveal new meaningful connections, whereas in new drug development, attention
is focused on novel targets by protein amino acid sequencing analysis . In this context,
representation learning methods can be used. These are machine learning techniques, which
use unsupervised data to automatically predict features, without human factor . Autoencoders
(AE) are well-known examples of representation learning methods and can produce features
propitiously . In addition, the Word2Vec model embeds words by representing them as
vectors, so similar words can be near in the spatial field. The Mol2Vec model is a subtype of
the Word2Vec oriented to the representation of structural characteristics of molecules by
vectors . Inferentially, the steps of representation learning procedures are

(1) Distinct structural analysis of both drug and target

(2) Production of representation, usually via vectors, and

(3) Prediction of attraction outcomes or new interactions between molecules.

Useful for drug repositioning’s purposes are also the molecular fingerprint-based methods,
which are applied in structural analysis of drug molecules by searching in molecular banks
and representing molecules as vectors. The Extended-Connectivity Fingerprints (ECFPs) or
circular or Morgan fingerprints belong in this category, and they deal with a more targeted
representation of molecular structures . Also, the PubChem fingerprints search for 881
specific characteristics through PubChem chemistry base . Daylight fingerprints interpret
structures based on their pathway and RDKit-2D are vectors for drug description . The
Explainable Substructure Partition Fingerprint (ESPF) produces vectors by searching for
repeated chemical characteristics on ChEMBL base . The target-based methods analyse the
protein chains, also by using vectors like the amino acid composition (AAC) vectors, the
conjoint triad protein feature vectors, the quasi sequences which examine amino acid
characteristics and the multi-scale local descriptor (MLD) model for vector creation .Deep
learning methods can also be used for drug and target similarity analysis with encoders which
are based on introduction of crude series. For example, SMILES (Simplified Molecular Input
Line Entry System) consists of symbols erected in a row, standing for chemical
molecules .There are also Convolutional Neur

DEPRESSION

Depression is a common and serious mental health disorder characterized by persistent

sadness, loss of interest in activities, and reduced ability to function in daily life. It results
from a combination of biological factors, such as neurotransmitter imbalance, along with
psychological stress and environmental influences. Depression significantly affects
emotional, physical, and social well-being and is a leading cause of disability worldwide,
requiring appropriate medical and psychological treatment.
Ketamine as a repurposed drug for depression
Introduction
Drug repurposing (drug repositioning) involves identifying new therapeutic uses for existing
drugs with known safety profiles. Ketamine, a phencyclidine derivative originally approved
as a dissociative anesthetic in 1970, has been successfully repurposed for the management of
treatment-resistant depression (TRD) and major depressive disorder with acute suicidal
ideation. Its rapid antidepressant action represents a paradigm shift from the traditional
monoaminergic approach to a glutamatergic model of depression.
Chemical nature

Ketamine is an aryl cyclohexylamine compound with the chemical name (RS)-2-(2-

chlorophenyl)-2-(methylamino)cyclohexanone. It contains a cyclohexanone ring, a
chlorophenyl group, and a methylamino group, which contribute to its pharmacological
activity. Ketamine exists as two enantiomers, R- and S-ketamine, with S-ketamine being
more potent in treating depression. Its high lipophilicity allows rapid penetration into the
brain, enabling fast therapeutic action.

Mechanism of Action (MOA) of Ketamine

 Ketamine acts as a non-competitive antagonist of NMDA (N-methyl-D-aspartate)

receptors in the central nervous system.
 It blocks NMDA receptors on GABAergic interneurons, reducing inhibitory control.
 This leads to increased release of glutamate, the major excitatory neurotransmitter.
 The excess glutamate stimulates AMPA receptors, enhancing synaptic signalling.
 Activation of intracellular pathways such as mTOR signalling promotes synthesis of
synaptic proteins.
 Increases Brain-Derived Neurotrophic Factor (BDNF) levels, supporting neuronal
growth and repair.
 Results in rapid synapse formation (synaptogenesis) and improved neuroplasticity.
 Restores function in brain regions involved in mood regulation, producing a rapid
antidepressant effect compared to conventional antidepressants.
Drug Repurposing Strategy of Ketamine for Depression

Identification of New Indication:

Clinical observations showed that patients receiving ketamine for anesthesia experienced
rapid mood improvement, suggesting antidepressant potential.
Mechanism-Based Repositioning:
Research identified ketamine’s action on the glutamatergic system (NMDA antagonism),
introducing a novel pathway beyond traditional monoamine antidepressants.
Dose Optimization:
Repurposed from anesthetic doses (1–4.5 mg/kg) to sub-anesthetic dose (≈0.5 mg/kg) to
achieve antidepressant effects without sedation.
Isomer Selection and Refinement:
Development of S-ketamine (esketamine) with higher potency, improved receptor affinity,
and better therapeutic profile.
New Formulation Development:
Creation of intranasal delivery systems to allow controlled, non-invasive administration for
psychiatric patients.
Regulatory Pathway Utilization:
Used accelerated approval pathways by leveraging existing safety data, reducing time and
cost of development compared to a new drug.
Target Population Redefinition:
Shifted use from anesthesia to treatment-resistant depression (TRD) and patients with acute
suicidal ideation.
Clinical Validation:
Conducted focused clinical trials demonstrating rapid onset of action and efficacy in resistant
cases, supporting approval.

Applications of Ketamine in Depression

1. Treatment-Resistant Depression (TRD)

 Used in patients who fail to respond to at least two standard antidepressants.
 Helps overcome resistance seen with SSRIs/SNRIs.
 Considered an add-on therapy to existing antidepressant regimens.
2. Rapid Antidepressant Action
 Produces clinical improvement within 4–24 hours, unlike conventional drugs that
require weeks.
 Particularly useful in patients with severe functional impairment.
3. Reduction of Suicidal Ideation
 Demonstrates rapid suppression of suicidal thoughts.
 Used in psychiatric emergencies to stabilize patients while long-term therapy is
initiated.
4. Bridge Therapy
 Acts as a “bridge treatment” to provide symptom relief until traditional
antidepressants become effective.
 Prevents relapse during medication transition periods.
5. Hospital and Controlled Outpatient Administration
 Administered as IV infusion or intranasal esketamine under supervision.
 Monitoring ensures safety due to transient dissociative effects and blood pressure
changes.
6. Neuroplasticity Restoration Therapy
 Helps reverse stress-induced neuronal damage by enhancing synaptic connectivity.
 Improves cognitive and emotional processing in chronic depression.
7. Use in Special Clinical Populations (Under Research)
 Bipolar depression (without triggering mania when carefully monitored).
 Depression associated with PTSD.
 Patients with chronic suicidal risk or severe anhedonia.
8. Development of Next-Generation Therapies
 Ketamine’s success has led to research into novel glutamate-modulating
antidepressants and safer analogues.

Advantages and Disadvantages of Ketamine Over Conventional

Antidepressants
Advantages
Rapid Onset of Action:
Produces antidepressant effects within hours, whereas conventional antidepressants take 2–6
weeks.
Effective in Treatment-Resistant Depression:
Works in patients who do not respond to SSRIs, SNRIs, or TCAs.
Novel Mechanism of Action:
Targets the glutamatergic system (NMDA antagonism) rather than monoamines, offering a
new therapeutic pathway.
Enhances Neuroplasticity:
Promotes synapse formation and neuronal repair, helping reverse stress-related brain changes.
Rapid Reduction in Suicidal Ideation:
Provides immediate symptom relief in psychiatric emergencies.
Lower Daily Medication Burden:
Given intermittently rather than requiring daily dosing like traditional antidepressants.

Disadvantages
Short Duration of Effect:
Antidepressant benefits may last only 1–2 weeks, requiring repeated administration.
Psychotomimetic Effects:
Can cause dissociation, hallucinations, or perceptual disturbances during treatment.
Abuse and Dependence Potential:
Classified as a controlled substance due to risk of misuse.
Requires Medical Supervision:
Must be administered in a clinical setting with monitoring of blood pressure and mental
status.
Higher Cost:
More expensive compared to standard oral antidepressants.
Limited Long-Term Safety Data:
Effects of prolonged or repeated use are still under investigation.
RHEUMATOID ARTHRITIS

1. Introduction

Resveratrol is a naturally occurring

polyphenolic compound that belongs to
the stilbene class of phytochemicals. It
is widely present in various dietary
sources such as grapes, red wine,
peanuts, blueberries, cranberries, and
certain medicinal plants. Over the past
few decades, resveratrol has attracted
extensive scientific attention due to its
broad spectrum of pharmacological
activities and potential role in the
prevention and treatment of multiple
chronic diseases.
The increasing prevalence of
cardiovascular diseases, cancer,
diabetes, neurodegenerative disorders, and inflammatory conditions has
driven the search for naturally derived therapeutic agents with
multitargeted actions and minimal side effects. Resveratrol has emerged
as a promising compound because it interacts with numerous molecular
targets involved in oxidative stress, inflammation, cell survival, and
metabolism. Its ability to influence key cellular signalling pathways makes
it a potential candidate for long-term disease management and health
promotion.
2. Chemical Nature and Pharmacokinetic Challenges

Resveratrol is chemically known as 3,5,4′-trihydroxy-trans-stilbene. It

exists in both cis and trans isomeric forms, with the trans-isomer being
more biologically active and stable. Despite its potent pharmacological
properties, resveratrol faces significant limitations related to its poor oral
bioavailability.
After oral administration, resveratrol is rapidly absorbed but undergoes
extensive first-pass metabolism in the intestine and liver. It is quickly
converted into glucuronide and sulphate conjugates, which significantly
reduce the concentration of free resveratrol in systemic circulation.
Additionally, resveratrol has low water solubility and poor chemical
stability, further limiting its therapeutic effectiveness.
Due to these pharmacokinetic challenges, high doses are often required to
achieve therapeutic levels, which may not always be practical. To
overcome these limitations, modern pharmaceutical research focuses on
novel drug delivery systems such as nanoparticles, liposomes, solid lipid
nanoparticles, polymeric micelles, and nano emulsions to enhance its
stability, absorption, and sustained release.
3. Antioxidant Mechanisms of Resveratrol

One of the most important pharmacological actions of resveratrol is its

antioxidant activity. Oxidative stress plays a critical role in the
development of various chronic diseases by damaging cellular
components such as DNA, proteins, and lipids. Resveratrol counteracts
oxidative stress through both direct and indirect mechanisms.
Directly, resveratrol acts as a free radical scavenger by neutralizing
reactive oxygen species such as superoxide radicals, hydroxyl radicals,
and hydrogen peroxide. Indirectly, it enhances the body’s endogenous
antioxidant defense system by increasing the expression and activity of
antioxidant enzymes including superoxide dismutase, catalase, and
glutathione peroxidase.
By reducing oxidative damage, resveratrol protects cells and tissues from
premature aging, cardiovascular dysfunction, neurodegeneration, and
carcinogenesis. Its antioxidant action is considered a fundamental
mechanism underlying many of its therapeutic effects.
4. Anti-Inflammatory Activity

Chronic inflammation is a major contributing factor in diseases such as

arthritis, cardiovascular disorders, diabetes, cancer, and
neurodegenerative conditions. Resveratrol exhibits strong
antiinflammatory properties by modulating inflammatory mediators and
signalling pathways.
Resveratrol inhibits the production of pro-inflammatory cytokines such as
tumour necrosis factoralpha, interleukin-1β, and interleukin-6. It also
suppresses the activity of inflammatory enzymes including
cyclooxygenase and inducible nitric oxide synthase, leading to reduced
synthesis of prostaglandins and nitric oxide.
Furthermore, resveratrol interferes with major intracellular signalling
pathways such as NF-κB and MAPK, which play central roles in regulating
inflammation and immune responses. Through these mechanisms,
resveratrol helps control excessive inflammatory responses and prevents
tissue damage associated with chronic inflammation.
5. Cardioprotective Effects

Resveratrol has been extensively studied for its beneficial effects on the
cardiovascular system. It improves endothelial function by enhancing
nitric oxide production, which leads to vasodilation and improved blood
flow. This effect helps reduce blood pressure and supports overall vascular
health.
Resveratrol also reduces platelet aggregation and inhibits low-density
lipoprotein oxidation, both of which are key factors in the development of
atherosclerosis. By preventing plaque formation and improving lipid
metabolism, resveratrol lowers the risk of coronary artery disease and
stroke.
Additionally, resveratrol exhibits protective effects against myocardial
ischemia and reperfusion injury by reducing oxidative stress and
inflammation in cardiac tissues. These properties contribute to its
reputation as a cardioprotective agent and explain its association with
reduced cardiovascular risk observed in populations consuming
resveratrol-rich diets.
6. Anticancer Potential
//
Resveratrol shows promising anticancer activity through its ability to
target multiple stages of cancer development, including initiation,
promotion, and progression. It inhibits cancer cell proliferation by inducing
cell cycle arrest and promoting programmed cell death.

The compound interferes with several cancer-related signalling pathways,

such as PI3K/Akt, STAT3, and Wnt/β-catenin, which are involved in tumour
growth, survival, and metastasis. Resveratrol also inhibits angiogenesis,
thereby restricting the blood supply required for tumour growth.

These anticancer effects have been observed in various experimental

models of breast, colon, prostate, lung, and liver cancers. Although most
evidence comes from preclinical studies, resveratrol is considered a
promising adjunct in cancer prevention and therapy.

7. Neuroprotective and Anti-Aging Effects

Resveratrol exhibits significant neuroprotective effects, making it a

potential therapeutic agent for neurodegenerative disorders such as
Alzheimer’s disease and Parkinson’s disease. It protects neurons from
oxidative stress, inflammation, and mitochondrial dysfunction, which are
key contributors to neuronal degeneration.

One of the most notable mechanisms of resveratrol is the activation of

sirtuin-1, a protein associated with cellular longevity, energy regulation,
and stress resistance. Through sirtuin-1 activation, resveratrol improves
mitochondrial function and promotes neuronal survival.

These mechanisms also contribute to its anti-aging effects, as resveratrol

helps delay age-related cellular damage and improves metabolic
efficiency. Its ability to regulate gene expression related to longevity has
positioned it as a potential nutraceutical for healthy aging.

8. Antidiabetic and Metabolic Effects

Resveratrol plays an important role in the regulation of glucose and lipid

metabolism. It improves insulin sensitivity and enhances glucose uptake in
peripheral tissues, thereby helping control blood glucose levels. These
effects are mainly mediated through activation of AMPK and sirtuin-1
pathways.
In addition, resveratrol helps regulate lipid metabolism by reducing
triglyceride accumulation and improving cholesterol balance. These
actions make it beneficial in the management of metabolic syndrome,
obesity, and type 2 diabetes mellitus.

Drug Repurposing Strategies

[Link] Identification
• Focus on RA pathological pathways: NF-κB signalling, pro-
inflammatory cytokines (TNF-α, IL-6, IL-1β), oxidative stress,
and osteoclast activation.
• Select resveratrol due to its ability to modulate these multiple
targets simultaneously.

2. Mechanism-Based Repositioning
• Utilize resveratrol’s anti-inflammatory, antioxidant, and
immunomodulatory properties to suppress synovial
inflammation.
• Aim for disease-modifying action rather than only
symptomatic relief.

3. Optimization Through Novel Drug Delivery Systems

(NDDS)
• Overcome poor bioavailability by formulating:
• Nanoparticles (PLGA, lipid-based) for targeted delivery
to inflamed joints
• Liposomes to enhance stability and circulation time
• Thermoresponsive hydrogels for intra-articular
sustained release
• Nano emulsions/transdermal systems to bypass first-
pass metabolism

4. Targeted Delivery Approach

• Functionalize carriers (e.g., folate or macrophage-targeting
ligands) to deliver resveratrol specifically to activated
synovial macrophages and fibroblasts.
• Reduce systemic exposure and improve therapeutic
concentration at disease site.
 5. Combination Therapy Strategy
• Use resveratrol as an adjunct with existing RA drugs
(e.g., methotrexate or NSAIDs) to:
• Enhance efficacy through synergistic action
• Reduce dose-related toxicity of conventional DMARDs 

Provide antioxidant protection.

6. Preclinical Validation
• Evaluate anti-arthritic activity in experimental RA models.
• Assess cytokine suppression, joint protection, and inhibition
of bone erosion.

7. Clinical Translation Pathway

• Develop resveratrol as a safe, cost-effective adjunct therapy
or nutraceutical-based disease-modifying agent.
• Focus on long-term management with reduced adverse
effects.

APPLICATION
1. Anti-Inflammatory Therapy
• Reduces production of pro-inflammatory cytokines (TNF-α, IL-6,
IL-1β).
• Helps in controlling synovial inflammation and joint swelling.

2. Disease-Modifying Agent
• Inhibits NF-κB signaling pathway, slowing progression of RA.
• Prevents pannus formation and cartilage degradation.

3. Antioxidant Protection
• Scavenges reactive oxygen species (ROS) in inflamed joints.
• Protects cartilage and synovial tissue from oxidative damage.

4. Immunomodulatory Action
• Regulates immune response by suppressing Th17 cells and
enhancing T-regulatory cells.
 • Restores immune balance in autoimmune RA conditions.

5. Prevention of Bone Erosion

• Inhibits RANKL-mediated osteoclast differentiation.
• Reduces bone destruction associated with chronic RA.

6. Adjunct Therapy with Conventional Drugs

• Used along with methotrexate or NSAIDs to enhance
therapeutic efficacy.
• Helps reduce required dose and side effects of standard RA
medications.

7. Targeted Drug Delivery Applications

• Formulated in nanoparticles, liposomes, or hydrogels for site-
specific delivery to inflamed joints.
• Improves bioavailability and provides sustained release.

8. Nutraceutical-Based Supportive Therapy

Can be developed as a safe, natural adjunct for long-term
management of RA.

Advantages and Disadvantages of

Resveratrol (Repurposed) Over Conventional
RA Drugs
Advantages
1. Multi-Target Action
• Acts on several RA pathways (NF-κB inhibition, antioxidant
effect, cytokine suppression).
• Conventional drugs usually act on a single target.

2. Better Safety Profile

• Natural polyphenol with lower risk of severe toxicity.
• Conventional DMARDs (e.g., methotrexate) may cause
hepatotoxicity, bone marrow suppression.
 3. Reduced Long-Term Side Effects
• Suitable for chronic use in RA management.
• Steroids and NSAIDs cause gastric ulcers, immunosuppression,
osteoporosis on prolonged use.

4. Antioxidant + Anti-Inflammatory Combination

• Protects cartilage from oxidative damage while reducing
inflammation.
• Conventional drugs mainly suppress inflammation only.

5. Potential to Reduce Dose of Standard Drugs

 Can be used as adjunct therapy → lowers toxicity of
methotrexate/biologics.

6. Cost-Effective Approach
• Drug repurposing avoids expensive new drug development.
• Biologics are highly costly and less accessible.

7. Prevents Bone Erosion

• Inhibits osteoclast genesis (RANKL pathway).
• Many NSAIDs do not stop structural joint damage.

Disadvantages
1. Poor Bioavailability
• Rapid metabolism and low absorption limit therapeutic levels.
• Conventional drugs have well-established pharmacokinetics.

2. Short Half-Life
• Requires advanced delivery systems (nanoparticles,
liposomes).

• Standard RA drugs are easier to formulate and administer .

3. Limited Clinical Evidence

• Most studies are preclinical or experimental.
• Conventional drugs are clinically validated with large trials.
 4. Dose Standardization Issues
• Optimal therapeutic dose in RA is not yet fully established.
• DMARDs have clear dosing guidelines.

5. Need for Novel Drug Delivery Systems

• Effectiveness depends on NDDS for targeting joints.
• Conventional drugs can be given orally/injectable without
complex formulation.

6. Slower Onset Compared to Steroids

• Acts by modulation rather than strong immunosuppression.
• Corticosteroids provide rapid symptomatic relief.

ALZHEIMER DISEASE
Introduction

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disorder characterized by

the accumulation of amyloid-β (Aβ), neurofibrillary tangles (NFTs), and neuronal loss [1,2].
AD is the most common cause of dementia, affecting around 50 million people worldwide,
with cases projected to increase to approximately 150 million by 2050 [3].

Mechanisms of Alzheimer’s disease

Alzheimer's mechanism involves abnormal buildup of amyloid-beta plaques (between
neurons) and tau tangles (inside neurons), disrupting cell communication and transport,
leading to synaptic loss, chronic neuroinflammation, mitochondrial damage, and widespread
neuron death, particularly in memory centres, causing progressive cognitive decline

Drug repurposing strategies

Metformin
Metformin, a biguanide derivative, is an insulin-sensitizing agent and the current first line
antidiabetic on the market [37]. The exact mechanism of action of metformin is unclear, but
the main molecular mechanism it functions through is the inhibition of gluconeogenesis [38

In the context of AD, metformin has several proposed mechanisms:

 Enhancing autophagy, including chaperone-mediated autophagy, which can increase

clearance of APP and amyloid-β.

 Promoting microglial phagocytosis of amyloid and tau aggregates, reducing plaque

and tangle burden.

 Decreasing neuroinflammation and neuronal death, thereby preserving synaptic

function and spatial memory.

Insulin and intranasal insulin

Insulin is a peptide hormone produced by pancreatic β-cells in response to elevated blood

glucose. In the brain, insulin receptors are widely expressed, with high density in the
hippocampus, cortex, hypothalamus, and olfactory bulb. Brain insulin signalling supports
synaptic plasticity, learning, memory, and overall neuronal health.
In AD, insulin resistance and impaired insulin/IGF-1 signalling are associated with:

 Increased tau phosphorylation

 Greater amyloid-β accumulation

 Reduced brain volume and cognitive performance

Direct systemic insulin therapy is limited by the risk of hypoglycaemia, so intranasal delivery
has been developed to target the central nervous system while minimizing systemic effects.
Intranasal insulin can rapidly reach the frontal cortex and hippocampus via perineural and
perivascular routes.

Incretins

Glucagon-like peptide-1 (GLP-1) is an intestinal-derived incretin hormone.

GLP-1 agonists have demonstrated neurotrophic and neuroprotective effects, likely through
the promotion of long-term potentiation and synaptic growth [89]. They exhibited
  rescued cognitive function,

 decreased plaque burden

 synaptic loss

 neuronal inflammation [90]

They also protect neuronal hippocampal cell death from Aβ1-42 [91], reduce APP and Aβ
levels [92], and reverse AGE-induced tau hyperphosphorylation via the downregulation of
GSK3β [25]

DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin, linagliptin, and vildagliptin,

are oral agents that prolong the action of endogenous incretins such as GLP-1. By inhibiting
DPP-4, they increase GLP-1 levels, thus enhancing insulin secretion and lowering blood
glucose.

In relation to AD, DPP-4 inhibitors may:

 Improve brain insulin signalling and reduce insulin resistance

 Suppress overactive GSK-3, decreasing tau hyperphosphorylation and amyloid

production

 Attenuate endoplasmic reticulum stress and CHOP-mediated apoptotic pathways

 Reduce oxidative stress, neuroinflammation, and neuronal apoptosis

PPAR-γ Agonists

The peroxisome proliferator-activated receptor γ (PPAR-γ) is a ligand-activated nu clear

receptor that coordinates lipid and glucose metabolism and cellular homeostasis [125]. The
two major PPAR-γ agonists are pioglitazone (PGZ) and Rosiglitazone (RSG). There has been
found the increased expression of PPAR-γ in the temporal cortex of AD patients in
comparison to control group [126], marking them as a potential therapeutic target in AD.

In AD, PPAR-γ agonists have been shown to:

 Decrease extracellular amyloid-β levels and improve its clearance (for example, via
upregulation of LRP1)

 Protect neurons from APP misfolding and tau hyperphosphorylation


Improve synaptic function and prevent synaptic loss

 Inhibit kinases such as cyclin-dependent kinase-5 and GSK-3

  Reduce neuroinflammation and improve insulin sensitivity

SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors block renal glucose, promoting

glucosuria and thereby lowering blood glucose levels [148]

SGLT transporters are present in the brain, and SGLT2 inhibitors may exert neuroprotective
effects through several mechanisms:

 Improving systemic and possibly central insulin sensitivity

 Reducing chronic inflammation and oxidative stress

 Enhancing mitochondrial function and preserving synaptic plasticity

 Increasing levels of brain-derived neurotrophic factor (BDNF), which supports

neuronal growth, survival, and memory

In experimental models of combined diabetes and AD, empagliflozin reduces soluble

and insoluble amyloid-β levels, decreases neuronal loss, and improves cognitive
performance.

central fact across each mechanism remains the same and that is the antidiabetic’s ability to
target and ameliorate the key pathologies of AD: amyloid beta and tau hyperphosphorylation.
There is also an improvement in cholinergic pathways and reduction in neuronal death,
increased synaptic plasticity, and decreased neuroinflammation. Despite these encouraging
results, there is still a long way to go in the development of anti-AD drugs, and further
studies are necessary to confirm these drugs’ therapeutic potential. Additionally, new
delivery approaches for medications like insulin are being planned which might offset their
systemic effects [168]

Parkinson’s disease
Introduction

Parkinson’s disease (PD) ranks as the second most prevalent neurodegenerative disorder
globally. With the advancement of global aging, there is a concomitant rise in the absolute
number of individuals affected by Parkinson’s disease, with an estimated lifetime risk of
approximately 5% (Ben-Shlomo et al., 2024). The primary clinical manifestations of PD
include resting tremor, altered muscle tone, and bradykinesia. These symptoms are linked
to the degeneration of dopaminergic neurons and the accumulation of protein aggregates
containing α-synuclein (α- syn) within dopamine neurons, known as Lewy bodies (Morris et
al., 2024).

Core Pathology

Parkinson's disease (PD) pathology is defined by

 The loss of dopamine-producing neurons in the substantia nigra

 Accumulation of abnormal protein clumps called Lewy bodies primarily composed of

misfolded alpha-synuclein

leading to motor symptoms like tremor and rigidity.

Drug repurposing strategies

Cyproheptadine in Repurposing
Cyproheptadine, originally an antihistamine blocking H1 receptors and serotonin 5-HT2
receptors, emerged as a top candidate. In cell studies, it dose-dependently (20-60 μM)
boosted neuron survival by countering toxin-induced death. In mice, daily injections (5-20
mg/kg, optimal at 10 mg/kg starting post-toxin exposure)

 Reduced brain inflammation (lowering IL-6),

 Preserved dopamine markers (tyrosine hydroxylase enzyme),

 Improved movement (longer distances, faster speeds in open-field tests)

Mechanism: blocks the MAPK/NFκB inflammatory pathway by inhibiting phosphorylation

of ERK, JNK, P38, and P65 proteins, preventing microglia overactivation; docking
simulations showed strong binding to P38 (-5.67 kcal/mol energy).

Omaveloxolone in Repurposing

Omaveloxolone, already FDA-approved for Friedreich's ataxia as an Nrf2 pathway

activator, protected neurons in cell assays (20-40 μM) and mice (5-20 mg/kg IP, optimal
10 mg/kg). It

 Restored dopamine neuron counts

 Raised antioxidant levels (SOD)

 Enhanced motor performance

Mechanism: disrupts KEAP1-Nrf2 binding (-6.80 kcal/mol docking score), freeing Nrf2 to
enter the nucleus and upregulate protective genes like HO-1 and NQO1 via the ARE
response, neutralizing oxidative stress without affecting inflammation directly.
Therapeutic Application

Both drugs apply via intraperitoneal dosing in preclinical models, showing dose-dependent
benefits peaking at mid-range without toxicity—preserving nigra neurons, curbing pathology,
and reversing deficits. Cyproheptadine targets inflammation-dominant PD stages;
omaveloxolone suits oxidative stress-heavy cases. This repurposing validates network
pharmacology for fast-tracking PD treatments, potentially combinable with current therapies
like levodopa, pending human trials for dosing, safety, and efficacy.

ANTI-CANCER

Leflunomide

Primarily known for rheumatoid arthritis treatment, has emerged as a

compelling candidate for anticancer drug repurposing due to its DHODH
inhibition that disrupts nucleotide synthesis in proliferating tumour cells.
Extensive preclinical data and Phase I/II trials demonstrate disease
stabilization in refractory cancers like multiple myeloma.
Chemical Properties and Structure

Leflunomide (C12H9F3N2O2, MW 270.21 g/mol) is classified as a

substituted isoxazole carboxamide derivative within the
immunomodulatory DMARD category. It undergoes rapid enterohepatic
metabolism to its active open-ring form, teriflunomide (A77 1726), which
exhibits a prolonged half-life of ~2 weeks due to biliary reabsorption.

The molecular structure consists of a 5-methyl-N-[4-

(trifluoromethyl)phenyl]isoxazole-4carboxamide scaffold. Key features
include the electron-withdrawing trifluoromethyl group enhancing DHODH
binding affinity and the isoxazole ring facilitating metabolic activation.
Textual representation: The core isoxazole ring bonds at position 4 to a
carboxamide linked to a paratrifluoromethyl aniline, with a methyl at
position 5.

This prodrug design ensures sustained plasma levels of teriflunomide

(typically 30-100 μM at 20 mg/day), achieving therapeutic concentrations
for both autoimmune and antiproliferative effects.

Historical and Original Indications

Approved by FDA in 1998 for active rheumatoid arthritis (RA), leflunomide

reduces joint damage by suppressing T/B-cell proliferation. Clinical trials
like US301 and MN301 showed ACR20 responses of 43-55% vs. placebo at
20 mg/day, comparable to sulfasalazine/methotrexate.

Its mechanism in RA involves DHODH blockade, limiting de novo

pyrimidine synthesis in activated lymphocytes reliant on this pathway,
unlike resting cells using salvage routes. Off-label uses extend to psoriatic
arthritis (improves joints but not skin) and SLE maintenance, though
hepatic risks limit broader adoption.

Long-term data from SONORA trial confirm sustained efficacy up to 5

years with radiographic joint preservation.
Molecular Mechanisms Enabling Repurposing

Cancer repurposing leverages leflunomide’s dual action: primary DHODH

inhibition depletes

UMP/DTMP, inducing S-phase arrest and p53-mediated apoptosis in

nucleotide-demanding tumours. Secondary effects include tyrosine kinase
inhibition (EGFR, PIM kinases), reducing c-Myc stability and angiogenesis.

In MM models, it synergizes with lenalidomide via PIM/c-Myc

downregulation; in melanoma, DHODH links to transcriptional elongation.
Preclinical IC50 for tumour lines (e.g., RPMI-8226 MM: 50-200 μM) aligns
with RA plasma levels.

P53 proficiency enhances efficacy in CRC/breast cancers; resistant lines

show metabolic vulnerabilities.

Preclinical Evidence Across Cancer Types

In vitro, teriflunomide halts proliferation in CLL (IC50 3-5 μM via JAK/STAT),

prostate

(antioxidant/apoptotic), glioma xenografts (tyrosine kinase synergy). MM

cells exhibit G0/G1 arrest, caspase activation, and bortezomib synergy.

In vivo, mouse MM models show tumour reduction with lenalidomide

combo; melanoma xenografts regress via DHODH. CRC organoids
demonstrate p53-dependent cytostasis. Recent 2025 studies confirm
OSCC antitumor via transcriptomic remodelling.

These validate metabolic targeting for refractory, high-proliferative

malignancies.
Clinical Trials: Status and Detailed Outcomes

As of 2026, leflunomide occupies Phase I/II across solid/hematologic

cancers, with no Phase III approvals yet

Pivotal Phase I RRMM (NCT02509052, n=12, 20-60 mg/day): No MTD

reached at 60 mg (RP2D); 9/11 stable disease (82%, median 119 days; 2
>1 year). Toxicities: mild neutropenia (grade 1-2), ALT elevation (1 DLT).
PK: Cmax total teriflunomide 429 μM at 60 mg, dose-proportional.

Phase II high-risk smouldering MM (NCT05014646): Ongoing, PFS

endpoints vs. observation.

Phase Ib pancreatic (NCT06454383, gemcitabine combo): Safety RP2D

established, ORR pending.

Phase II MEN-1 neuroendocrine (NCT06540937): Early efficacy in

advanced cases. Recent PubMed (2025): Anticancer in OSCC via DHODH.

Trial ID Phase Cancer Key Outcomes Status [citations]

NCT02509052 I RRMM SD 82%; tolerable to 60 mg

Completed

NCT05014646 II Smouldering MM PFS assessment ongoing

Recruiting

NCT06454383 Ib Pancreatic Dose-finding complete Active

NCT06540937 II Neuroendocrine Initial] responses

Recruiting
NCT05014646 variant II Oral Cancer Antitumor transcriptomics
Preclinical/early

Advantages Compared to Conventional Chemotherapies

Oral bioavailability contrasts IV regimens like gemcitabine; low cost

(~$1/day) vs. biologics ($10k+/cycle). Established PK/PD from >2M RA
patients accelerates trials, minimizing Phase 0/1 needs.

Selective for proliferating cells reduces off-target toxicity vs. alkylators

(e.g., no severe alopecia/mucositis at RA doses). Synergy potential (e.g.,
+bortezomib ORR boost) enhances efficacy in combos without additive
myelosuppression.

Brain penetration suits glioma/CNS metastases; metabolic targeting

evades efflux-mediated resistance.

Disadvantages and Limitations

Prolonged half-life complicates toxicity management (cholestyramine

washout needed); hepatotoxicity (ALT >3x ULN in 5-10%) mandates
monitoring vs. shorter-half-life agents. Immunosuppression risks infection
in advanced cancer.

Monotherapy modest (SD not PR/CR) vs. targeted therapies (e.g.,

venetoclax ORR 20-80% MM). Teratogenicity/contraindications limit
paediatrics/fertility-age patients. Variable response in p53-null tumours.

Aspect Leflunomide Conventional (e.g., Doxorubicin)

Route/Duration Oral, chronic IV bolus/cycles

Cost Low High

Tox Profile Hepatic/BP Cardiac/myeloid

Resistance Metabolic Multidrug efflux

Emerging Applications and Future Directions

Hematologic: RRMM combos (len/pom); CLL post-ibrutinib. Solid:

Pancreatic (gem combo), CRC (p53+), prostate (chemo-naïve).
Neuroendocrine/MEN-1 via angiogenesis block.

For mucoadhesive repurposing, multi-day GI delivery could optimize small

intestine targeting for CRC, leveraging pH-responsive erosion.[user
context implied] Ferroelectric enhancements may boost epithelial
penetration

Ongoing: Phase II expansions, brequinar (DHODH analog) parallels

validate class. Regulatory: 505(b)(2) pathway viable post-Phase II data.

DISULFIRAM

Disulfiram, long established as an alcohol aversion therapy, holds

significant promise in anticancer drug repurposing through its unique
copper-chelating properties that generate tumour-selective cytotoxicity. Its
mechanisms exploit cancer’s reliance on elevated copper levels and stem
cell pathways, offering a low-cost alternative with a proven human safety
profile from decades of clinical use.

Chemical Class and Structure

Disulfiram belongs to the thiuram disulfide class of Di thiocarbamates,

with the chemical formula
C₁₀H₂₀N₂S₄ and a molecular weight of 296.54 g/mol. Structurally, it
features a central disulfide bond

(-S-S-) connecting two diethyl thiocarbamate moieties: (CH₃CH₂)₂N-C(=S)-

S-S-C(=S)-N(CH₂CH₃)₂. This symmetric configuration enables rapid redox
metabolism in vivo. Upon cellular entry, glutathione or other thiols reduce
the disulfide to diethyldithiocarbamate (DDC), which then chelates

Cu²⁺ to form the lipophilic bis(diethyldithiocarbamate)-copper(II) complex,

Cu(DDC)₂ (also called CuET). This active metabolite has high membrane
permeability, allowing it to accumulate preferentially in copper-rich
tumour microenvironments. The trifunctional nature—disulfide reduction,
metal chelation, and ROS catalysis—underpins its dual therapeutic roles in
alcoholism and oncology. Solubility is low in water (0.02 mg/mL) but
improves in lipids, explaining nano formulation strategies for enhanced
delivery.

Original Indications and Pharmacological Profile

Approved by the FDA in 1951 as Antabuse, disulfiram treats chronic

alcoholism by irreversibly inhibiting mitochondrial aldehyde
dehydrogenase (ALDH1/2), leading to acetaldehyde accumulation and
aversive symptoms like nausea, hypotension, and tachycardia upon
ethanol consumption. Typical dosing is 250-500 mg/day orally, producing
effects lasting 7-14 days due to persistent DDC metabolites.
Pharmacokinetics show rapid absorption (Tmax 1-2 hours), hepatic
metabolism via CYP3A4/glutathione S-transferase, and a short plasma
half-life (~1 hour), but tissue-bound Cu complexes persist longer. Safety
data from millions of patient-years indicate rarity of severe adverse events
in abstinent patients, primarily mild neuropathy or dermatitis. Off-label
uses have included cocaine dependence via dopamine-beta-hydroxylase
inhibition, establishing its broad neuromodulatory potential.

Rationale for Repurposing in Cancer

Cancer cells exhibit 2-10-fold higher intracellular copper than normal
tissues, driven by upregulated transporters like CTR1 and ATP7A, creating
a therapeutic vulnerability. Disulfiram’s Cu(DDC)₂ selectively forms in
tumours, inducing overwhelming reactive oxygen species (ROS) via
Fenton chemistry (Cu²⁺/Cu⁺ cycling generates hydroxyl radicals),
ferroptosis through GPX4 inhibition, and proteasome disruption by
sequestering NPL4-p97. This targets cancer stem cells (CSCs) via ALDH
inhibition (IC50 ~0.1-1 μM), reducing markers like CD133, SOX2, and
Nanog, while NF-κB suppression curbs inflammation-driven survival. Unlike
alcohol use, where ethanol is required, anticancer effects are ethanol-
independent and amplified by exogenous copper gluconate (2-4 mg/day).
Pre-existing Phase I safety data from alcoholism trials fast-tracks oncology
development, with costs under $1/day versus thousands for novel agents.
Vulnerabilities in hypoxic, multidrugresistant (MDR), and relapsed tumors
make it ideal for repurposing.

Molecular Mechanisms of Anticancer Action

The primary active species, Cu(DDC)₂, penetrates cells rapidly due to

lipophilicity, dissociating intracellularly to release Cu⁺ and DDC. Copper
redox cycling with H₂O₂ produces ·OH radicals, oxidizing lipids, proteins,
and DNA, overwhelming NRF2/GPX4 defenses and triggering JNK/p38
MAPK-mediated apoptosis or ferroptosis. Proteasome inhibition occurs via
Cu-induced aggregation of VCP/p97-NPL4, halting ER-associated
degradation and inducing unfolded protein response (UPR)/CHOP
activation. CSC targeting depletes ALDH-high populations, preventing
tumour initiation and metastasis. Additional effects include P-gp
downregulation (reversing MDR), topoisomerase II inhibition, and anti-
angiogenic VEGF suppression. Synergies abound: with temozolomide
(TMZ) in GBM via DNA damage amplification; cisplatin in NSCLC by
enhancing ROS; PD-1 inhibitors via immunogenic cell death (ICD) exposing
calreticulin/ATP. These multi-hit pathways evade single-point resistance,
distinguishing it from monotherapies.

Preclinical Evidence Across Cancer Types

Extensive in vitro data show sub-micromolar potency in GBM (U87, GSC

lines: 70-90% clonogenicity loss), breast (MDA-MB-231: CSC reduction
80%), NSCLC (A549: hypoxia reversal), AML (HL-60: 95% apoptosis with
Cu), prostate (PC3: migration halt), and ovarian (SKOV3: spheroid
disruption). Xenograft models confirm efficacy: DSF/Cu shrinks GBM
tumors 60-80% (synergy with TMZ extends survival 2-fold); breast PDX
reduces metastasis 70%; AML orthotopics clear leukemic burden.
Nanoformulations (liposomes, micelles) boost bioavailability, achieving 5x
tumor accumulation and preventing disulfide degradation.
Immunomodulation enhances CD8+ T-cell infiltration via ICD. Recent
2023-2025 studies validate in liver, pancreatic, and head-neck cancers,
with transcriptomics revealing ROS/ferroptosis signatures.

Clinical Trials: Phases, Status, and Key Results

As of February 2026, disulfiram remains in Phase I/II trials, focusing on

copper combos for refractory solid/hematologic malignancies, with no
Phase III advancements or approvals. Landmark Phase IIb NSCLC (n=46,
cisplatin/vinorelbine + DSF 80-160 mg TID, no Cu specified): Median OS
12.1 vs. 9.1 months (p=0.1), with 2/23 long-term survivors (>2 years);
well-tolerated (grade 3 AEs similar). Phase II recurrent GBM
(NCT02678975, n=49, TMZ + DSF/Cu 80 mg TID + 2 mg Cu): No

OS benefit (6-month 44% vs. 62%, HR 1.2), but higher toxicity (grade 3+
34% vs. 11%, mainly fatigue/hepatitis); subset with low MGMT responded
better. Phase II metastatic breast (NCT03323346): Recruiting, primary
endpoint clinical benefit rate (CBR) at 6 months. Prostate (Phase I,
NCT02715637): Stable disease (SD) in 5/18 refractory patients.
AML/leukaemia pilots show PR/SD rates 40-60%. Ongoing: Pancreatic
(NCT04594710), HNSCC nano-DSF. Biomarkerdriven trials (serum Cu,
ALDH) are emerging. Overall, safety mirrors alcoholism use, but efficacy
requires combos and patient selection.

Advantages Over Conventional Anticancer Therapies

Disulfiram’s oral route and ultra-low cost contrast intravenous

chemotherapies like doxorubicin or targeted biologics costing
$100k+/year. Decades of safety data eliminate Phase I needs,
accelerating timelines; negligible monotherapy toxicity (no
myelosuppression/alopecia) allows chronic dosing in frail patients. Tumour-
selective activation via endogenous/exogenous Cu spares normals,
targeting hard-to-treat CSCs/MDR populations that relapse post-standard
care (e.g., reversing P-gp in 70% resistant lines). Broad synergies enhance
chemo/radio/immunotherapy without dose reductions— e.g., +TMZ
doubles PFS in GBM models. Short development path via 505(b)(2) NDA
leverages alcohol approval. Finally, it addresses unmet needs in low-
resource settings and combo regimens for platinum-resistant cancers.

Disadvantages and Clinical Challenges

Cu co-administration variability (dietary interference, serum monitoring

needed) complicates dosing; short half-life demands TID intake or nano-
delivery for sustained levels. Ethanol contraindication persists lifelong,
limiting use in non-abstinent patients. Trials reveal inconsistent
monotherapy efficacy in aggressive solids (e.g., GBM OS failure), hepatic
risks escalate in combos (ALT elevations 10-20%), and neuropathy
accumulates chronically. Lacks potency of targeted agents like PARP
inhibitors (ORR 40-60% vs. DSF’s SD bias). No paediatric data; pregnancy
category X. Biomarker absence (Cu/ALDH not standardized) hinders
stratification. Nano formulations, while promising, add regulatory hurdles.

Specific Applications and Future Directions

Disulfiram/Cu excels in CSC-driven tumours: GBM (post-TMZ relapse),

triple-negative breast,

NSCLC (EGFR-wildtype), ovarian, pancreatic, prostate (CRPC), AML (post-

HMA), and HNSCC.

Hematologic synergy with venetoclax/HMA shows 50-70% CR in preclinical

AML. Emerging: Immunotherapy combos (PD-1 + DSF/Cu boosts T-cell
responses 3-fold); nanoparticle DDS for brain penetration (e.g., PLGA-DSF
crosses BBB); metronomic low-dose for maintenance. For GI applications
like colorectal, mucoadhesive polymers could localize Cu(DDTC)₂ release,
aligning with multi-day systems for sustained ROS exposure in hypoxic
niches—potentially enhanced by ferroelectric coatings for epithelial
targeting. Phase III candidates include biomarker-enriched NSCLC/breast
cohorts. Regulatory strategies emphasize orphan designations for rare
subtypes, with brequinar-like analogs validating the class. Overall,
disulfiram exemplifies cost-effective repurposing, poised for niche
approvals by 2028 if Phase II signals mature.

Tuberculosis

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

1. Introduction
Tuberculosis (TB) remains one of the most devastating infectious diseases
worldwide, causing more than 1.5 million deaths annually. Despite the
availability of established chemotherapy regimens for several decades, TB
control is severely challenged by the rapid emergence of
multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of
Mycobacterium tuberculosis. Nearly one-fifth of TB-related deaths are
attributed to drug-resistant forms of the disease. The development of new
anti-TB drugs is a slow, expensive and high-risk process, often requiring
more than 15 years and substantial financial investment. Consequently,
very few new chemical entities successfully reach clinical use. To
overcome these limitations, researchers are increasingly focusing on drug
repurposing, a strategy that involves identifying new therapeutic uses
for already approved or previously abandoned drugs. Drug repurposing
reduces development time, cost, and safety risks because
pharmacokinetic, pharmacodynamics, and toxicity profiles of these drugs
are already well characterized. In this context, non-steroidal
anti-inflammatory drugs (NSAIDs), commonly used to treat pain, fever,
and inflammation have emerged as promising candidates for adjunctive
TB therapy. This article systematically reviews experimental and clinical
evidence supporting the repurposing of NSAIDs as anti-tubercular agents
and discusses their mechanisms of action, immunomodulatory roles,
advantages, limitations, and future prospects in TB treatment.

2. Rationale for Repurposing NSAIDs in Tuberculosis

NSAIDs are widely used, inexpensive, and largely off-patent drugs with
established safety records.
Traditionally, their therapeutic effect is attributed to inhibition of
cyclooxygenase (COX-1 and
COX-2) enzymes, resulting in reduced prostaglandin synthesis and
suppression of inflammation. However, growing evidence suggests that
NSAIDs possess direct antimicrobial activity and host-directed
therapeutic effects independent of COX inhibition. Several NSAIDs have
demonstrated inhibitory activity against M. tuberculosis, including
replicating, dormant
(non-replicating), and drug-resistant bacilli. This is particularly significant
because dormant bacilli are responsible for prolonged treatment duration
and disease relapse. NSAIDs also show synergistic effects with standard
anti-TB drugs, potentially shortening therapy duration and improving
treatment outcomes. Another key advantage of NSAIDs is their ability to
modulate the host immune response. Excessive inflammation during TB
infection contributes to tissue damage, cavitation, and disease
transmission. By controlling harmful inflammation without completely
suppressing protective immunity, NSAIDs may enhance therapeutic
efficacy while reducing pathological consequences.

3. DRUG REPURPOSING STRATEGIES

3.1 Experimental Approaches

 High-throughput screening of FDA-approved drugs
 Cell line screening
 Animal models

3.2 Computational Approaches

 Molecular docking
 Bioinformatics
 Gene expression profiling
 AI-based screening

3.3 Clinical Observation Method

 Observed secondary benefit in treated patients
 Electronic health record analysis

4. Individual NSAIDs with Anti-Tubercular Potential

4.1 Diclofenac
Diclofenac has shown bactericidal activity against several bacterial
species, including M.
tuberculosis. Experimental studies demonstrated that diclofenac alone
and in combination with streptomycin significantly reduced bacterial load
in murine TB models. Modified derivatives of diclofenac, such as
hydrazones and amides, further enhanced antimycobacterial activity by
inhibiting DNA synthesis through interference with thymidine
incorporation. These findings suggest diclofenac and its derivatives could

serve as potential lead compounds for anti-TB drug development.

 Phenylacetic acid derivative

 Chlorinated aromatic rings

Mechanism of Action

- Inhibits DNA synthesis in M. tuberculosis

- Reduces thymidine incorporation

- Synergistic with streptomycin

Advantage

1) Bactericidal activity
2) Synergistic effects
Disadvantage

1) Hepatotoxicity risk

4.2 Aspirin
Aspirin has been shown to enhance the activity of pyrazinamide in murine
TB models by down-regulating genes involved in energy metabolism.
However, aspirin may antagonize the action of isoniazid, highlighting the
importance of timing and drug combinations in TB therapy. Clinical studies
have demonstrated that aspirin reduces mortality and stroke incidence in
TB meningitis when used alongside corticosteroids.

Derivative: Salicylic acid derivative

Functional groups: Ester + Carboxylic acid

IUPAC: Acetylsalicylic acid

Mechanism of action in Tuberculosis

 Enhances pyrazinamide activity

 Down-regulates energy metabolism genes
 Reduces inflammation in TB meningitis

Advantage

1) Reduces mortality in TB meningitis

2) Anti-inflammatory + antiplatelet

Disadvantage

3) Gastric ulcer risk

4) May antagonize isoniazid
4.3 Ibuprofen
Ibuprofen exhibits broad antimycobacterial activity against drug-sensitive
and drug-resistant strains of [Link]. Animal studies revealed
significant reduction of bacterial load and improved survival rates. Its
anti-TB activity appears to involve immunomodulation, particularly
inhibition of tumor necrosis factor-α (TNF-α), thereby limiting excessive
granuloma formation. Ibuprofen’s favorable pharmacokinetic profile and
established safety make it a strong candidate for clinical evaluation.

Class: Propionic acid derivative

Functional groups: Carboxylic acid, aromatic ring

IUPAC: 2-(4-isobutylphenyl)propionic acid

Mechanism of Action
Application in Tuberculosis

1) Adjunct therapy

2) Reduces inflammation

3) Improves survival in animal TB models

Advantages

 Safe and widely available

 Low cost
 Known pharmacokinetics
 Good oral bioavailability

Disadvantages

 Gastric irritation
 Renal risk (long term use)
 Not a standalone anti-TB drug

Asthma
Asthma and allergic disorders represent a growing global health problem,
significantly affecting patient quality of life and imposing a substantial
economic burden on healthcare systems worldwide. Epidemiological
studies indicate a steady rise in the prevalence of allergic diseases over
recent decades. In the United States, the prevalence of food and skin
allergies increased markedly between 1997 and 2011, while European
data estimate that nearly one-quarter of adults suffer from some form of
allergic disease . Despite advances in pharmacotherapy, current
treatments remain insufficient for many patients, particularly those with
severe or treatment-resistant disease.

Conventional therapies such as antihistamines and corticosteroids remain

the cornerstone of allergy and asthma management. Antihistamines
reduce symptoms by blocking histamine receptors, whereas
corticosteroids act as broad immunosuppressive agents. Although
effective for many patients, these drugs have notable limitations,
including long-term adverse effects, steroid resistance, and incomplete
symptom control. Severe asthma patients, though representing a small
proportion of the total population, account for a disproportionately high
level of morbidity, mortality, and healthcare expenditure.

Biologic therapies targeting immunoglobulin E (IgE) or inflammatory

cytokines such as IL-5, IL-13, and TNF-α have significantly improved
outcomes in certain patients. However, their high cost, requirement for
injections, complex monitoring, and limited global accessibility restrict
widespread use. Consequently, there is an urgent need for safer, more
affordable, and orally available therapeutic alternatives. Against this
backdrop, drug repurposing has emerged as a promising strategy for
expanding treatment options in asthma and allergic disorders.

2. Concept and Advantages of Drug Repurposing for

Asthma

Several approaches are used to identify repurposing candidates, including

clinical observations, mechanistic insights from basic research, high-
throughput screening of FDA-approved drug libraries, gene expression
profiling, bioinformatics analyses, and mining of electronic health records.
Together, these strategies have opened new opportunities to rapidly
translate existing drugs into new therapeutic contexts, including allergic
diseases and asthma.

3. Repurposed Drugs Targeting Lymphocyte-Mediated

Pathways
Lymphocytes, particularly T and B cells, play a central role in the
pathogenesis of allergic diseases. Dysregulated Th2 immune responses,
excessive cytokine production, and IgE synthesis are key features of
allergy and asthma. Several repurposed drugs target these pathways by
modulating lymphocyte signalling.

3.1 JAK–STAT Pathway Inhibitors

The Janus kinase–signal transducer and activator of transcription (JAK–
STAT) pathway mediates signalling from multiple cytokine receptors
involved in allergic inflammation. Tofacitinib, a JAK1/3 inhibitor approved
for rheumatoid arthritis, has shown significant anti-inflammatory and
antipruritic effects in atopic dermatitis models and clinical studies.
Similarly, ruxolitinib, a JAK1/2 inhibitor approved for myelofibrosis,
demonstrated strong immunosuppressive activity and induced remission
in mouse models of food allergy. These findings suggest that JAK inhibitors
may be valuable therapeutic options in allergic disorders.
3.2 ITK and BTK Inhibition
Interleukin-2-inducible T-cell kinase (ITK) is critical for Th2 differentiation.
Ibrutinib, an inhibitor of ITK and Bruton’s tyrosine kinase (BTK), is
approved for B-cell malignancies. Interestingly, ibrutinib suppresses IgE-
mediated activation of mast cells and basophils. Clinical observations
revealed that patients receiving ibrutinib showed loss of allergen reactivity
in skin and basophil activation tests, highlighting its potential as an anti-
allergic therapy.

3.3 mTOR and Proteasome Inhibition

Rapamycin, an mTOR inhibitor widely used in organ transplantation, has
been shown to reduce eosinophilic inflammation, airway hyper-reactivity,
and IgE levels in animal models of allergic asthma. Similarly, bortezomib,
a proteasome inhibitor used in multiple myeloma, decreases IgE
production by inducing plasma cell apoptosis. Although bortezomib
lowered IgE levels in mouse models, its clinical benefit in asthma remains
inconsistent, emphasizing the need for further investigation.

4. Repurposed Drugs Targeting Myeloid Cells

Myeloid cells such as mast cells, eosinophils, basophils, dendritic cells,
and macrophages play a dominant role in allergic inflammation. Several
repurposed agents modulate these cell populations.

4.1 Imatinib
Imatinib, a tyrosine kinase inhibitor used in chronic myelogenous
leukaemia, inhibits c-Kit signalling, which is essential for mast cell survival
and activation. Preclinical studies demonstrated that imatinib reduces
airway inflammation, eosinophil infiltration, and Th2 cytokine production
in asthma models. Importantly, a randomized controlled clinical trial
confirmed that imatinib significantly improved airway hyper-
responsiveness and reduced mast cell activity in patients with severe
asthma, providing strong evidence for its repurposing potential.

4.2 Tamoxifen
Tamoxifen, an oestrogen receptor antagonist used in breast cancer, also
exhibits immunomodulatory effects. Oestrogen has been implicated in
promoting allergic inflammation, and tamoxifen has been shown to inhibit
mast cell proliferation and dendritic cell maturation. In animal models of
asthma, tamoxifen reduced neutrophilic inflammation, suggesting
potential benefit in steroid-resistant asthma phenotypes.
4.3 Statins and Metabolic Drugs
Statins, commonly used for hypercholesterolemia, possess anti-
inflammatory properties and can suppress mast cell degranulation.
Observational studies suggested reduced asthma-related hospitalizations
among statin users, although randomized trials have produced mixed
results. Metformin, an antidiabetic drug that activates AMP-activated
protein kinase (AMPK), reduced airway inflammation and remodelling in
animal models and was associated with fewer asthma exacerbations in
diabetic patients with asthma.

5. Non-Immune Targeting Repurposed Drugs

Beyond immune modulation, several repurposed drugs act on non-

immune mechanisms involved in asthma pathology.

Endothelin receptor antagonists such as bosentan were investigated due

to endothelin-1’s role in bronchoconstriction. However, clinical trials failed
to demonstrate significant benefits. In contrast, anti-angiogenic agents
like pazopanib may reduce airway remodelling by inhibiting vascular
endothelial growth factor (VEGF) signalling.
Antibiotics such as azithromycin have been evaluated for their anti-
inflammatory and antimicrobial effects. While some trials showed reduced
exacerbations and improved quality of life in adults with persistent
asthma, results in paediatric populations were inconsistent. Additionally,
antifungal agents have emerged as novel candidates based on evidence
that fungal colonization and protease activity contribute to treatment-
resistant asthma.