Drug
Drug Repositioning – Disulfuram
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Drug Repositioning – Disulfuram
Drug Repositioning ( also-known-as therapeutic switching and drug repurposing). It is an area of translational biology that identifies new or different therapeutically-useful indications for marketed drugs by targeting alternative diseases.
Molecules that have passed safety evaluation in Phase I clinical trials but proved ineffective for efficacy reasons in Phase II or Phase III trials against other diseases can also be repurposed. Successful examples of such repositioning abound: some are high profile, household names – Thalidomide, thalidomide in severe erythema nodosumleprosum; Zyban, an antidepressant, is now successful in smoking cessation; even Viagra began as a heart medicine -while others are not so well known.
Disulfuram (Antabuse)
This drug has been in clinical use since 1940 mainly to discourage alcohol abuse. It is currently in two clinical trails for glioma theraphy due to a multitude of anticancer and anti-glioma actions, including aldehyde dehydrogenase inhibition, proteasome inhibition, MGMT and P-glycoprotein inhibition, and inhibition of the two matrix metalloproteinases MMP-2 and MMP-9, which are critical for cell invasion. It must be noted however, that most of the favorable evidence in terms of glioma theraphy thus far come from invitro laboratory studies.
In vitro, disulfuram is one of the most effective agents for targeting glioma cells, In a high throughput of 2000 compounds being tested against glioblastomastem cells, disulfuram emerged as the most promising candidate for the further testing. In this study, its effects were attributed to its inhibition of the ubiquitin-proteasome pathways, as mentioned above.
Disulfuram has so many various potential modes of action that it still unclear which is the most important. A phase II trial for newly diagnosed glioblastoma has started in September 2015 in Greece, and a phase I trial currently underway at the Washington university school of Medicine (St.Louis, Missouri) will shed more light on its efficacy in brain tumors.
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Drug Repositioning – Aspirin
Drug: Aspirin, introduced as an analgesic but the number of off-label uses of medicines is growing at an impressive rate.
Original Indication: Inflammation, Pain
New Indication: Antiplatelet
In 1988, the aspirin component of the Physicians’ Health Study, a randomized, double-blind, placebo-controlled trial of 22,000 apparently healthy men, was terminated early because of the extreme reduction in the risk of a first myocardial infarction. Hence in 1988, aspirin’s role expanded beyond that of pain reliever to that of potential lifesaver when the US Food and Drug Administration (FDA) proposed using aspirin to reduce the risk of recurrent myocardial infarction and to prevent recurrent transient ischemic attacks or ministrokes in men. Recently, Bayer Health Care filed a citizen petition with the FDA to broaden the professional labeling of aspirin to include indications for the prevention of a first myocardial infarction in individuals at moderate or greater risk of coronary heart disease.
Mechanism of action: Aspirin inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 (TXA2) generation. Thromboxane A2 triggers reactions that lead to platelet activation and aggregation, aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator. These effects last for the life of the anucleate platelet, approximately 7 to 10 days.
Drug Repositioning – Nitroxoline
Drug: Nitroxoline, an old antibiotic used for the treatment of urinary tract infections (UTI).
New Indication: Anticancer Drug. Shim et al. first reported anticancer activity of nitroxoline in 2010.
Mechanism of action:
* Inhibiting human MetAP2 and sirtuins in endothelial cells
* Inducing premature senescence and inhibiting angiogenesis
* Inhibiting cathepsin B
Given that nitroxoline has a long retention time in urine, it was postulated that the drug might be particularly effective in urological cancers such as bladder cancer. Since it is inhibiting cathepsin B, it might have a role in suppressing breast cancer cell invasion. Currently the drug development is in Preclinical trials.
Drug Repositioning – Nelfinavir (From AntiViral to AntiCancer)
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Drug Repositioning – Nelfinavir (From AntiViral to AntiCancer)
Nelfinavir
Nelfinavir is a competitive inhibitor of human immunodeficiency virus (HIV) aspartyl protease and is being used in combination with other antiretroviral drugs to treat patients with HIV infection. It received the US-FDA approval in 1997 for an oral dose regimen of 750 mg three times daily. It was later modified to a regimen of 1250 mg twice daily as recommended by US-FDA. Both regimens were proven to be equally effective. Nelfinavir is a well-tolerated drug with some common side effects such as insulin resistance, hyperglycemia and lipodystrophy.
Researchers have found potential anticancer activity of nelfinavir. It was reported to inhibit the growths of Kaposi’s sarcoma, multiple myeloma, prostate cancer and breast cancer. Nelfinavir exhibited a broad-spectrum anticancer activity in vivo, being efficacious in several preclinical cancer models.
Recently conducted a Phase I clinical trial of nelfinavir and chemo radiation for locally advanced pancreatic cancer. In this trial, nelfinavir showed potent radio sensitizing and antitumor activities without adding toxicity in patients with pancreatic cancer. Although nelfinavir is known to inhibit AKT signaling pathway, it does not directly inhibit the kinase activity of AKT.
Mechanism
Nelfinavir is known to have a strong anticancer activity through multiple pathways including induction of ER stress, apoptosis and autophagy, and inhibition of AKT pathway and hypoxia-inducible factor 1α (HIF-1α)-dependent angiogenesis. Nelfinavir was shown to inhibit the chymotrypsin- and trypsin-like activities of 20S human proteasome. However, whether anti-proteasome effect is the primary mechanism of nelfinavir for anticancer activity remains elusive since nelfinavir causes proteasome-dependent degradation of several proteins. HSP90 is another proposed molecular target of nelfinavir, of which the inhibition leads to a decrease in the levels of its client proteins including HER2, AKT and CDKs through proteasome-dependent degradation.
Nelfinavir is now under more than 20 Phase I/II clinical trials for cancer. Although the anticancer mechanism of nelfinavir remains to be completely elucidated, promising anticancer activities have been reported from the clinical studies
Drug Repositioning – What is it?
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Drug Repositioning
Drug Repositioning ( also-known-as therapeutic switching and drug repurposing). It is an area of translational biology that identifies new or different therapeutically-useful indications for marketed drugs by targeting alternative diseases.
What is Drug repositioning : It is an exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. Various techniques including data mining, bioinformatics, and usage of novel screening platforms have been used for identification and screening of potential repositioning candidates.
Objective: These initiatives not only add value to the portfolio of pharmaceutical companies but also provide an opportunity for academia and government laboratories to develop new and innovative uses of existing drugs for infectious and neglected diseases, especially in emerging countries like India.
Recent Method : With the accumulation of the large volumes of omics data, bioinformatics plays an increasingly important role in the discovery of new drug indications, With the drug-related data growth and open data initiatives, a set of new repositioning strategies and techniques has emerged with integrating data from various sources, like pharmacological, genetic, chemical or clinical data.
Recently, some researchers have proposed the idea of repositioning the approved drugs for the treatment of Ebola, and the debate has been surprisingly intense. Antiviral drugs or drugs with immune system’s modulation drugs were repositioned to treat Ebola, but World Health Organization has ignored these proposed FDA-approved drugs, owing to the deficiency of experimental tests, as well as the potential drug toxicity
Conclusion : computational drug repositioning research is of great significance to improve human health through discovering new uses for existing drugs. In fact, a number of studies have already been carried out with various degrees of success. It has great potentials to accelerate drug discovery with interesting opportunities in several particular disease areas (e.g. cancer)
Increased investments and development of new technologies in drug discovery have barely improved the outcome of medicinal entities in the drug discovery market from a long time. Therefore, Drug repositioning can provide an alternative approach to meet the demands of the new, potent and safer drugs in terms of both economic cost and time efficiency. The common molecular pathways of different diseases and secondary indications of most of the approved drugs, and advances in genomics, informatics and biology, as well as the availability of approved or safe drug libraries can certainly provide an improved and efficient way of screening safer drugs for new indications.
While the notion of drug repositioning is not new, the drive to rescue compounds from the brink of obscurity has gained momentum. There prevails two forms of repositioning: Drug-centered, whereby promiscuous drugs act on more than one biological target; and Disease-centered, in which diseases that share pathophysiological mechanisms can be affected by the same drug.
CR TidBit – Dose Studies
Single Ascending Dose
Single ascending dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose.This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)).
Example: Single Ascending Dose First-in-Human Study of a Novel Ant malarial Drug (CDRI 97/78)
The starting dose was 80 mg; calculation of starting dose was based on the basis of maximum tolerated dose of 100 mg/kg obtained in rats. This was used to obtain a dose of 96 mg for a 60 kg man. The formulation which was available for a dose below this was of 80 mg and hence taking these factors into consideration a starting dose of 80 mg was chosen. The following dose levels were evaluated: 80, 160, 320, 400, 500, 600, and 700 mg. The starting dose was calculated by allometric scaling from animals. At each dose level, volunteers were assessed before proceeding to the next dose. The decision to dose only 2 volunteers was taken, after analysis of data of 600 mg, wherein no remarkable adverse events were noted.
The decision to stop the dose escalation was based on the appearance of the dose limiting toxicity (DLT) which was defined as the dose at which any of the following appeared: severe nausea, vomiting, heartburn, headache, remarkable change in vital parameters such as blood pressure, heart rate, respiratory rate or oxygen saturation of blood, changes in QT interval, or any event that in the opinion of the investigators required stopping of the trial.
Multiple Ascending Dose:
Multiple ascending dose studies (MAD) are designed to test the pharmacokinetics and pharmacodynamics of multiple doses of the experimental drug. A group of subjects receives multiple doses of the drug, starting at the lowest dose and working up to a pre-determined level. At various times during the period of administration of the drug, and particularly whenever the dose is increased, samples of blood and other bodily fluids are taken. These samples are analysed in order to determine how the drug is processed within the body and how well it is tolerated by the body.
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