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Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes. [1] [2] [3]
Repurposing generics can have groundbreaking effects for patients: 35% of 'transformative' drugs approved by the US FDA are repurposed products. [4] Repurposing is especially relevant for rare or neglected diseases. [4]
A number of successes have been achieved, the foremost including sildenafil (Viagra) for erectile dysfunction and pulmonary hypertension and thalidomide for leprosy and multiple myeloma. [3] [5] Clinical trials have been performed on posaconazole and ravuconazole for Chagas disease. [6]
Other antifungal agents clotrimazole and ketoconazole have been investigated for anti-trypanosome therapy. [7] Successful repositioning of antimicrobials has led to the discovery of broad-spectrum therapeutics, which are effective against multiple infection types. [8]
Drug repositioning is a "universal strategy" for neglected diseases due to 1) reduced number of required clinical trial steps could reduce the time and costs for the medicine to reach market, 2) existing pharmaceutical supply chains could facilitate "formulation and distribution" of the drug, 3) known possibility of combining with other drugs could allow more effective treatment, [1] 4) the repositioning could facilitate the discovery of "new mechanisms of action for old drugs and new classes of medicines", [1] [9] 5) the removal of “activation barriers” of early research stages can enable the project to advance rapidly into disease-oriented research. [10]
Often considered as a serendipitous approach, where repurposable drugs are discovered by chance, drug repurposing has heavily benefited from advances in human genomics, network biology, and chemoproteomics. It is now possible to identify serious repurposing candidates by finding genes involved in a specific disease and checking if they interact, in the cell, with other genes which are targets of known drugs. [11] It was shown that drugs against targets supported by human genetics are twice as likely to succeed than overall drugs in the pharmaceutical pipeline. [12] Drug repurposing can be a time and cost effective strategy for treating dreadful diseases such as cancer [13] [14] and is applied as a means of solution-finding to combat the COVID-19 pandemic.
Computational drug repurposing is the in silico screening of approved drugs for use against new indications. It can use molecular, clinical or biophysical data. [15] Electronic health records and real-world evidence gained popularity in drug repurposing, for instance for COVID 19. [16] Computational drug repurposing is expected to reduce drug development costs and time. [17]
| Drug repositioning evidence level | Quality of scientific evidence |
|---|---|
| 0 | No evidence; includes in silico predictions without confirmation |
| 1 | In vitro studies with limited value for predicting in vivo/human situation |
| 2 | Animal studies with hypothetical relevance in humans |
| 3 | Incomplete studies in humans at the appropriate dose e.g. proof of concept; few cases from medical records; some clinical effects observed |
| 4 | Well-documented clinical end points observed for repositioned drug at doses within safety limits |
According to a 2022 systematic review, inadequate resources (financial and subject matter expertise), barriers to accessing shelved compounds and their trial data, and the lack of traditional IP protections for repurposed compounds are the key barriers to drug repurposing. [18] There is a lack of financial incentives for pharmaceutical companies to explore the repurposing of generic drugs. Indeed, doctors can prescribe the drug off-label and pharmacists can switch the branded version for a cheaper generic alternative. [19] According to Pharmacologist Alasdair Breckenridge and patent judge Robin Jacob this issue is so significant that: "If a generic version of a drug is available, developers have little or no opportunity to recoup their investment in the development of the drug for a new indication". [20]
Drug repositioning present other challenges. First, the dosage required for the treatment of a novel disease usually differs from that of its original target disease, and if this happens, the discovery team will have to begin from Phase I clinical trials, which effectively strips drug repositioning of its advantages of over de novo drug discovery. [10] Second, the finding of new formulation and distribution mechanisms of existing drugs to the novel-disease-affected areas rarely includes the efforts of "pharmaceutical and toxicological" scientists. [10] Third, patent right issues can be very complicated for drug repurposing due to the lack of experts in the legal area of drug repositioning, the disclosure of repositioning online or via publications, and the extent of the novelty of the new drug purpose. [10]
Drug repurposing is considered a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options also for psychiatric disorders. [1] [21]
In bipolar disorder, repurposed drugs are emerging as feasible augmentation options. Several agents, all sustained by a plausible biological rationale, have been evaluated. Evidence from meta-analyses showed that adjunctive allopurinol and tamoxifen were superior to placebo for mania, and add-on modafinil/armodafinil and pramipexole seemed to be effective for bipolar depression, while the efficacy of celecoxib and N-acetylcysteine appeared to be limited to certain outcomes. [1] Further, meta-analytic evidence exists also for adjunctive melatonin and ramelteon in mania, and for add-on acetylsalicylic acid, pioglitazone, memantine, and inositol in bipolar depression, but findings were not significant. [1] The generally low quality of evidence does not allow making reliable recommendations for the use of repurposed drugs in clinical practice, but some of these drugs have shown promising results and deserve further attention in research. [1]
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder. Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.
Pharmacology is the science of medical drugs and medications, including a substance's origin, composition, pharmacokinetics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.
Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.
Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist. Some people use it as a dietary supplement.
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and their quantitative structure-activity relationships (QSAR).
Ivermectin is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, it is used to treat infestations including head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis and lymphatic filariasis. It works through many mechanisms to kill the targeted parasites, and can be taken by mouth, or applied to the skin for external infestations. It belongs to the avermectin family of medications.
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal, and generalized anxiety disorder (GAD). Pregabalin also has antiallodynic properties. Its use in epilepsy is as an add-on therapy for partial seizures. It is a gabapentinoid medication and acts by inhibiting certain calcium channels. When used before surgery, it reduces pain but results in greater sedation and visual disturbances. It is taken by mouth.
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). It is taken by mouth.
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process—from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials—to approved vaccine or drug typically takes more than a decade.
Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.
Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms, treat the underlying condition, or act as a prevention for other diseases (prophylaxis).
An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.
Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner. Phenotypic screening must be followed up with identification and validation, often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.
Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.
Melatonin is a dietary supplement and medication as well as naturally occurring hormone. As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from jet lag or shift work, and is typically taken orally. Evidence of its benefit for this use, however, is not strong. A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.
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