Commentary
Article
Reimagining Established Drugs Medicines Could Lead to Potential New Applications
Author(s):
The potential treatments include ivermectin, methylene blue, glucagon-like peptide-1 receptor agonists, and low-dose naltrexone.
INTRODUCTION
As the price tag and timeline for new drug discovery has exploded, the need to find cost-effective treatments in a timely manner has become increasingly imperative in order to control health care costs and get treatment to patients faster. Drug repurposing can help bridge many of the gaps by reusing existing drugs for new therapeutic purposes. This offers several advantages, including reduced costs and faster clinical implementation. Drug repurposing has the potential to reduce the drug discovery process up to 3 to 12 years, and the potential recycle of compounds towards a new indication is an attractive opportunity for patients in need. In addition, safety profiles have already been established for these previously approved compounds which alleviates potential contraindication and drug interaction concerns.1
Medications, Pharmacy, Pharmaceutical, Pharmacists, GLP-1, Oncology | Image Credit: davit85 | stock.adobe.com
Several compounds approved decades ago for other purposes have resurfaced as potential treatments for cancer, Lyme disease, Crohn disease, autoimmune diseases, and neurodegenerative diseases, just to name a few. The potential treatments include ivermectin, methylene blue, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and low-dose naltrexone (LDN) as important players in the drug repurposing field.
IVERMECTIN FOR CANCER
Ivermectin is an FDA-approved antiparasitic drug commonly used to treat infections like onchocerciasis, scabies, and certain intestinal worms. It has a well-documented safety profile for these uses, but emerging evidence in laboratory and animal studies suggests that ivermectin may have anti-cancer properties as well.
It appears to interfere with cancer cell signaling pathways, cell division, and mitochondrial function, and it may even enhance the immune system's ability to fight tumors.2 Additional studies suggest that ivermectin may help inhibit tumor metastasis, a major cause of cancer mortality, used either alone or in combination with chemotherapeutic drugs.3
Current research using ivermectin as a cancer therapy has included applications in melanoma, breast, digestive, urinary, hematologic, reproductive, brain, and respiratory cancers.4 Ivermectin's dosage in clinical trials for cancer is not standardized and varies depending on the study design. Some studies have used doses adjusted by body weight, ranging from 6 mg to 12 mg daily, higher than what is used for parasitic infections. Ivermectin may work synergistically with other cancer therapies, but exact combinations and protocols require extensive research. While it shows promise in preclinical research, robust evidence from large-scale, well-designed clinical trials are needed to confirm its efficacy and safety for cancer treatment.
METHYLENE BLUE FOR LYME DISEASE
In 1880, methylene blue was discovered by a microbiologist to be an effective treatment against malaria. More recently it has been used to treat methemoglobinemia, a condition where oxygen is not transported properly in the blood, as well as an antiseptic to treat urinary tract infections. Methylene blue's versatility stems from its dual ability to donate and accept electrons, making it a unique agent. At higher concentrations, it can induce oxidative stress by generating reactive oxygen species which then damages microbial cells of various pathogens.
Lyme disease, caused by Borrelia burgdorferi, is a tick-borne illness that can lead to multisystemic symptoms. Treatment typically involves antibiotics; however, persistent symptoms in some patients have led to research into alternative or adjunctive therapies. Methylene blue has shown to have activity against B. burgdorferi in laboratory studies, particularly in its persister forms, which are believed to contribute to chronic or treatment-resistant Lyme disease. Researchers found that methylene blue, in combination with antibiotics, lowered the colonies of Borrelia persisters by 60%.5 It has also shown promise in breaking down biofilms caused by the bacteria which can often make them resistant to antibiotics. While laboratory studies show promise, clinical studies specifically evaluating methylene blue for Lyme disease are limited.
GLP-1 RAS FOR POLYCYSTIC OVARY SYNDROME, METABOLIC SYNDROME, AND INFLAMMATION
GLP-1 RAs are FDA-approved for the treatment of type 2 diabetes, obesity, and for reducing cardiovascular disease risk in adults with obesity. These groundbreaking therapies revolutionized the management of these conditions, offering improved outcomes and quality of life for millions. It is estimated that 1 in 8 US adults have used a GLP-1 RA, providing a growing body of data and insights into the broader effects of these medications.6
Positive outcomes have been observed in polycystic ovary syndrome, metabolic-associated steatohepatitis (MASH), and other inflammatory disease states. Recently, GLP-1 RAs have been shown to have benefits in fertility as monotherapy or in conjunction with metformin. The advantages of using GLP-1 RAs have also been noticed in assisted reproductive settings such as in vitro fertilization, particularly beneficial for women with poor ovarian reserve or women of advanced age. Women who have failed lifestyle modifications or who have tried metformin in the past with no result, may find success in using a GLP-1 RA.7
Additional studies are in process for patients with MASH and have shown higher rates of MASH resolution compared to placebo.8 Beyond their metabolic benefits, increasing evidence suggests that GLP-1 RAs may have neuroprotective effects, offering potential applications in neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and others. The neuroprotective potential of GLP-1 RAs is linked to several mechanisms including anti-inflammatory effects, reduced oxidative stress, improved mitochondrial function, and reduced amyloid plaque buildup. If proven effective, they may represent a significant breakthrough in managing conditions that currently lack curative therapies. Further large-scale trials are needed to confirm the safety and sustained benefits of GLP-1 RAs in neurodegeneration.
LOW-DOSE NALTREXONE
Naltrexone is an opioid receptor antagonist that blocks the effects of opioids. It was originally approved in 1984 by the FDA to treat opioid addiction at doses of 50 mg to 100 mg. Around the same time, Bernard Bihari, a neurologist and AIDS researcher, is credited with discovering that lower doses of naltrexone had therapeutic potential in treating patients with HIV and AIDS. He hypothesized that low-dose naltrexone (LDN) might modulate the immune system by transiently blocking opioid receptors. This temporary blockade leads to a rebound increase in endorphins and enkephalins, which are natural opioids involved in regulating the immune system and inflammation. Endorphins play a crucial role in pain regulation, immune modulation, and overall well-being. Since the discovery, LDN has been studied in dozens of different disease states, including autoimmune and inflammatory conditions.
In addition to promoting the release of endorphins, naltrexone acts as an antagonist of toll-like receptor 4 (TLR4), a protein involved in the innate immune response and inflammation. By modulating TLR4, LDN helps reduce systemic and central nervous system (CNS) inflammation, which is implicated in many chronic conditions like multiple sclerosis, rheumatoid arthritis, and lupus.
LDN can be beneficial to patients with neuroinflammatory and neurodegenerative conditions through its effects on microglia. Microglia are immune cells in CNS that can become overactivated in conditions involving chronic pain or inflammation. LDN is thought to reduce microglial activation, decreasing the release of pro-inflammatory cytokines and other neurotoxic substances. This may help alleviate symptoms in neuroinflammatory and neurodegenerative conditions like fibromyalgia, complex regional pain syndrome, Alzheimer disease, and Parkinson disease.
While evidence is still emerging, many patients and physicians use LDN for conditions where inflammation and immune dysregulation are key factors. Clinical trials and anecdotal reports continue to validate its potential applications. The discovery of LDN highlights the innovative repurposing of existing drugs to uncover novel treatments for challenging medical conditions.
SHARED PATHWAY IN REPURPOSED DRUGS FOR NEURODEGENERATIVE DISEASES
The shared pathway in neurodegenerative disorders offers a compelling framework for drug repurposing. By addressing common mechanisms like oxidative stress and neuroinflammation, the aforementioned drugs may be adapted to slow or halt disease progression, bringing hope to millions affected by these conditions.
Research suggests that ivermectin may inhibit pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, which are often elevated in neuroinflammatory states. Modulating neuroinflammation could help in diseases like Alzheimer or Parkinson diseases, though direct evidence of ivermectin's benefits in these conditions is limited. Similarly, methylene blue has direct antioxidant effects, scavenging free radicals and protecting cells from oxidative stress, a key factor in neurodegeneration.
Ongoing clinical trials are exploring GLP-1 RAs for their effects on Alzheimer disease and mild cognitive impairment. These studies aim to determine the efficacy, optimal dosing, and mechanisms of action in cognitive health. While the evidence is encouraging, GLP-1 RAs are not yet approved specifically for the treatment of cognitive decline. Further research is needed to confirm these benefits and identify the patient populations most likely to respond.
Finally, LDN and the multiple mechanisms by which it decreases inflammation and oxidative stress have shown promise in decreasing the progression of neurodegenerative disorders in small scale studies and anecdotal reports.
THE BROADER IMPLICATIONS
Drug repurposing often leverages existing medications for new therapeutic uses, potentially reducing the time and cost of new drug development. However, repurposing older, off-patent drugs may lead to new intellectual property protections, creating tension between innovation incentives and public health needs.
Many repurposed drugs are used off-label, bypassing regulatory approvals, raising concerns about oversight and patient safety. The regulatory landscape for drug repurposing is complex and often requires new clinical trials to demonstrate safety and efficacy for the novel indication, despite established use in their original context. Some regulatory agencies, like the FDA, offer accelerated approval programs for unmet medical needs, but eligibility criteria and processes can be inconsistent.
One solution that emerged is the Drug Repurposing Hub by the Broad Institute, an open-access repository of more than 6000 compounds, many of which have been FDA approved. The Broad’s Drug Repurposing Hub is open-access and any researcher can log-in, look up, and download the information. This makes it possible to easily search and view drugs according to their clinical status, drug indications, or mechanism of action, allowing for the ability to rapidly find agents for further evaluation.5
CONCLUSION
There is much therapeutic promise shown by repurposed drugs in a significant number of novel medical applications. While the potential to transform the treatment landscape and improve outcomes for complex diseases through innovative uses of old drugs is substantial, there is a critical need for additional research, funding, and collaboration between scientists, clinicians, and policymakers in order to further our understanding of the full capabilities of these agents.
