Repurposing Immunomodulatory Drugs to Combat Tuberculosis

Tuberculosis (TB) is an infectious disease caused by an obligate intracellular pathogen, Mycobacterium tuberculosis (M.tb) and is responsible for the maximum number of deaths due to a single infectious agent. Current therapy for TB, Directly Observed Treatment Short-course (DOTS) comprises multiple antibiotics administered in combination for 6 months, which eliminates the bacteria and prevents the emergence of drug-resistance in patients if followed as prescribed. However, due to various limitations viz., severe toxicity, low efficacy and long duration; patients struggle to comply with the prescribed therapy, which leads to the development of drug resistance (DR). The emergence of resistance to various front-line anti-TB drugs urgently require the introduction of new TB drugs, to cure DR patients and to shorten the treatment course for both drug-susceptible and resistant populations of bacteria. However, the development of a novel drug regimen involving 2-3 new and effective drugs will require approximately 20-30 years and huge expenditure, as seen during the discovery of bedaquiline and delamanid. These limitations make the field of drug-repurposing indispensable and repurposing of pre-existing drugs licensed for other diseases has tremendous scope in anti-DR-TB therapy. These repurposed drugs target multiple pathways, thus reducing the risk of development of drug resistance. In this review, we have discussed some of the repurposed drugs that have shown very promising results against TB. The list includes sulfonamides, sulfanilamide, sulfadiazine, clofazimine, linezolid, amoxicillin/clavulanic acid, carbapenems, metformin, verapamil, fluoroquinolones, statins and NSAIDs and their mechanism of action with special emphasis on their immunomodulatory effects on the host to attain both host-directed and pathogen-targeted therapy. We have also focused on the studies involving the synergistic effect of these drugs with existing TB drugs in order to translate their potential as adjunct therapies against TB.

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Exploring targets of cell wall protein synthesis and overexpression mediated drug resistance for the discovery of potential M. tb inhibitors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210727165742 ◽

2021 ◽

Vol 21 ◽

Author(s):

Sisir Nandi ◽

Anil Kumar Saxena

Keyword(s):

Drug Resistance ◽

Cell Wall ◽

Mycobacterium Tuberculosis ◽

Drug Regimen ◽

World Health ◽

Tuberculosis Complex ◽

Short Course ◽

Directly Observed Treatment ◽

Health Organization ◽

Mycobacterial Cell Wall

: Tuberculosis is an infectious disease engulfing millions of lives worldwide; it is caused by mammalian tubercle bacilli, Mycobacterium tuberculosis complex which may consist of strains viz. M. tuberculosis hominis (human strain), M. microti, M. pinnipedii and M. canettii. The other pathogenic strain is M.africanum which belongs to the M. tuberculosis complex and it is fully virulent for humans. The non-pathogenic strains in the complex may include, M. fortuitum and M.smegmatis. Extensive research has been carried out to combat this dangerous disease. World Health Organization proposed Directly Observed Treatment Short-course regimen (DOTS) for the eradication of the TB. In addition, the compounds such as TBA-7371, TBI-166, AZD5847 and PBTZ-169 are under clinical trials whereas the recently FDA approved anti tubercular drugs are Pretomanid (PA-824), Bedaquiline (TMC207), Linezolid (PNU-100480) and Delamanid (OPC-67683). The early detection of mycobacterium tuberculosis can be permanently cured by DOTS comprising of Pyrazinamide (Z), Isoniazid (H), Rifampin (R) and Ethambutol (E). Duration of the treatment depends on viability of the disease. DOTS can target to disrupt the biosynthesis of mycobacterial cell wall proteins expressed by various genes. Overexpression of these genes may produce drug-resistant due to dose misuse or the intake of quality compromised anti tubercular drug regimen. Therefore, in the present review there has been a necessity to report the second line antitubercular chemotherapeutics to target various proteins which are the building block of M. tb cell wall, overexpression of which may produce drug resistance.

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Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

10.22541/au.162610374.45880274/v1 ◽

2021 ◽

Author(s):

Julianne Tieu ◽

Siddhee Sahasrabudhe ◽

Paul Orchard ◽

James Cloyd ◽

Reena Kartha

Keyword(s):

Drug Target ◽

Drug Targets ◽

Drug Repurposing ◽

Pharmacokinetics And Pharmacodynamics ◽

Drug Candidates ◽

Target Patient Population ◽

Site Of Action ◽

Repurposed Drugs ◽

Gait Disturbances ◽

Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

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Fibrotic expression profile analysis reveals repurposed drugs with potential anti-fibrotic mode of action

PLoS ONE ◽

10.1371/journal.pone.0249687 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249687

Author(s):

Evangelos Karatzas ◽

Andrea C. Kakouri ◽

George Kolios ◽

Alex Delis ◽

George M. Spyrou

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Profile Analysis ◽

Oral Submucous Fibrosis ◽

Drug Repurposing ◽

Biological Pathways ◽

Igg4 Related Disease ◽

Submucous Fibrosis ◽

Repurposed Drugs ◽

Fibrotic Diseases

Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis, an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. In this study we highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among 9 fibrotic diseases. We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our Drug Repurposing results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis. We suggest digoxin to be tested against Oral Submucous Fibrosis, since we observe cardiomyopathy-related pathways implicated in Oral Submucous Fibrosis and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that Idiopathic Pulmonary Fibrosis shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease, IgG4-related Disease, Systemic Sclerosis and Cystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.

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Repurposing Drugs to Combat Drug Resistance in Leprosy: A Review of Opportunities

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207325666211007110638 ◽

2021 ◽

Vol 25 ◽

Author(s):

Mukul Sharma ◽

Pushpendra Singh

Keyword(s):

Synergistic Effects ◽

Drug Repurposing ◽

New Drugs ◽

Resistance Testing ◽

Promising Alternative ◽

Drug Molecules ◽

Conventional Drug ◽

Repurposed Drugs ◽

Multiple Drugs

: Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries [WHO, 2019], of which nearly two-thirds of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy [MDT], as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in the last one-decade ,and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli do not grow in vitro. Besides, developing a new drug against leprosy through the conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line [MDT] and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of “leprosy-free world”. This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

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Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing

Antibiotics ◽

10.3390/antibiotics9090550 ◽

2020 ◽

Vol 9 (9) ◽

pp. 550

Author(s):

Álvaro Mourenza ◽

José A. Gil ◽

Luis M. Mateos ◽

Michal Letek

Keyword(s):

Mycobacterium Tuberculosis ◽

Bacterial Pathogen ◽

Drug Repurposing ◽

Mycobacterial Infection ◽

Multidrug Resistant ◽

New Host ◽

Novel Treatments ◽

Mdr Tb ◽

Future Drug ◽

Repurposed Drugs

Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen Mycobacterium tuberculosis and produces 1.5 million deaths every year. The incidence of tuberculosis has decreased during the last decade, but the emergence of MultiDrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) strains of M. tuberculosis is generating a new health alarm. Therefore, the development of novel therapies based on repurposed drugs against MDR-TB and XDR-TB have recently gathered significant interest. Recent evidence, focused on the role of host molecular factors on M. tuberculosis intracellular survival, allowed the identification of new host-directed therapies. Interestingly, the mechanism of action of many of these therapies is linked to the activation of autophagy (e.g., nitazoxanide or imatinib) and other well-known molecular pathways such as apoptosis (e.g., cisplatin and calycopterin). Here, we review the latest developments on the identification of novel antimicrobials against tuberculosis (including avermectins, eltrombopag, or fluvastatin), new host-targeting therapies (e.g., corticoids, fosfamatinib or carfilzomib) and the host molecular factors required for a mycobacterial infection that could be promising targets for future drug development.

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Intracarotid Chemotherapy with a Combination of 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-Diaminedichloroplatinum (Cisplatin), and 4'-O-Demethyl-1-O-(4,6-O-2-thenylidene-β-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the Treatment of Primary and Metastatic Brain Tumors

Neurosurgery ◽

10.1097/00006123-198412000-00010 ◽

1984 ◽

Vol 15 (6) ◽

pp. 828-833 ◽

Cited By ~ 1

Author(s):

J.Stewart David ◽

Zvonimir Grahovac ◽

Brien Benoit ◽

David Addison ◽

Michael T. Richard ◽

...

Keyword(s):

Brain Tumors ◽

Vertebral Artery ◽

Response Rate ◽

Drug Regimen ◽

Cranial Irradiation ◽

Severe Toxicity ◽

Intraarterial Infusion ◽

Computed Tomographic ◽

Heavily Pretreated ◽

Previously Treated

Abstract Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU ≥ 100 mg/m2, plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses). Fully reversible toxicity was also seen, including transient decrease in ipsilateral visual acuity (11%), transient hemiparesis or hemianesthesia (5%), transient increased intracranial pressure (5%), mild ototoxicity (3%), mild to moderate vomiting (80%), severe periorbital pain and erythema during BCNU infusion (94%), and myelosuppression (30%). Vertebral artery infusion must be performed with great caution because infusions of BCNU and VM-26 (but not of cisplatin) were associated with marked but rapidly reversible somnolence and potentially life-threatening cardiac and respiratory depression. No cardiorespiratory depression was seen with carotid artery infusions. The intraarterial infusion of this three-drug regimen is quite effective in reducing the size of the tumor as seen on the computed tomographic scan in this poor prognosis group of patients, but is also potentially quite toxic. We are now initiating other studies adding i.v. drugs to our intracarotid combination.

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Isoniazid Induces Apoptosis Of Activated CD4+ T Cells

Journal of Biological Chemistry ◽

10.1074/jbc.c114.598946 ◽

2014 ◽

Vol 289 (44) ◽

pp. 30190-30195 ◽

Cited By ~ 22

Author(s):

Sultan Tousif ◽

Dhiraj Kumar Singh ◽

Shaheer Ahmad ◽

Prashini Moodley ◽

Maitree Bhattacharyya ◽

...

Keyword(s):

Infectious Disease ◽

T Cells ◽

Immune Responses ◽

Therapeutic Agents ◽

Current Therapy ◽

Drug Resistant ◽

Tb Treatment ◽

Short Course ◽

Directly Observed Treatment ◽

Immune Impairment

Tuberculosis (TB) remains the second highest killer from a single infectious disease worldwide. Current therapy of TB is lengthy and consists of multiple expensive antibiotics, in a strategy referred to as Directly Observed Treatment, Short Course (DOTS). Although this therapy is effective, it has serious disadvantages. These therapeutic agents are toxic and are associated with the development of a variety of drug-resistant TB strains. Furthermore, patients treated with DOTS exhibit enhanced post-treatment susceptibility to TB reactivation and reinfection, suggesting therapy-related immune impairment. Here we show that Isoniazid (INH) treatment dramatically reduces Mycobacterium tuberculosis antigen-specific immune responses, induces apoptosis in activated CD4+ T cells, and renders treated animals vulnerable to TB reactivation and reinfection. Consequently, our findings suggest that TB treatment is associated with immune impairment.

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Real-world treatment patterns, health care resource utilization (HRU), and costs among patients with Waldenstrom macroglobulinemia (WM) initiating therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.7_suppl.17 ◽

2016 ◽

Vol 34 (7_suppl) ◽

pp. 17-17

Author(s):

Brad Schenkel ◽

Lorie Ellis ◽

Stephanie Korrer ◽

Stacey DaCosta Byfield

Keyword(s):

Index Date ◽

B Cell Lymphoma ◽

Drug Regimen ◽

Current Therapy ◽

Anti Cancer ◽

The Us ◽

Us Fda ◽

Line Of Therapy ◽

Initial Drug

17 Background: WM is a rare, indolent B-cell lymphoma with 1000 to 1500 new cases diagnosed annually in the US. The disease is incurable with current therapy. Prior to January 2015 when ibrutinib was approved by the US FDA for WM, there were no therapies approved in this indication. This study describes initial systemic anti-cancer therapy (SACT) and HRU among WM patients (pts). Methods: A retrospective study using a large, national US claims database from 1/2007-10/2013 was conducted. Adult WM pts ( ≥ 2 claims for WM) with ≥ 1 claim for SACT were identified; the first SACT claim date was the index date. Pts were required to have a WM diagnosis within 3 months (m) prior to the index date and be continuously enrolled (CE) in the health plan for 12m pre- and ≥ 6m post-index date. Pregnant pts and those with SACT in the pre-index period were excluded. The first line of therapy (LOT1) period was examined; the LOT started at index date and the regimen included all drugs received within 60 days. The LOT ended at the earliest of, start of a new drug, ≥ 60-day gap in receipt of initial drug regimen, death or CE end. All-cause HRU and costs during LOT1 were examined. Results: There were 161 WM pts identified. 66% of pts were ≥ 65 yrs (mean age 69), 55% were male, and by insurance type, 49% were Medicare Advantage pts vs. 51% commercially insured. Mean total follow-up time was 23m, and mean duration of LOT1 was 4.7m. The top 4 most common LOT1 regimens accounted for 71% of patients: Rituximab (R) only (39%); bortezomib+ R (14%); bendamustine+ R (9%) and cyclophosphamide+ R (9%). No other regimens identified accounted for more than 4% of pts. Overall, 96% and 81% of pts had ≥ 1 office or hospital outpatient visit with mean per patient per month (PPPM) visits of 3.55 (standard deviation, SD = 2.41) and 2.60 (SD = 3.06), respectively. Approximately 25% and 21% had ≥ 1 ER visit or inpatient stay with mean PPPM visits of 0.11 (SD = 0.24) and 0.06 (SD = 0.16), respectively. Total mean PPPM healthcare costs during LOT1 was $13,589 (SD = $13,404). Conclusions: HRU and costs were high among WM pts initiating SACT. Future studies should examine whether differences in LOT1 regimen choice are associated with differences in cost and outcomes.

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From Off-Label to Repurposed Drug in Non-Oncological Rare Diseases: Definition and State of the Art in Selected EU Countries

Medicine Access Point of Care ◽

10.5301/maapoc.0000016 ◽

2017 ◽

Vol 1 ◽

pp. maapoc.0000016 ◽

Cited By ~ 3

Author(s):

Paola Minghetti ◽

Elena P. Lanati ◽

Josie Godfrey ◽

Oriol Solà-Morales ◽

Olivier Wong ◽

...

Keyword(s):

Rare Diseases ◽

Drug Repurposing ◽

Orphan Drugs ◽

New Drugs ◽

Success Rates ◽

Great Opportunity ◽

Off Label ◽

Research Activities ◽

Oncological Diseases ◽

Repurposed Drugs

Introduction Almost 8,000 rare diseases exist worldwide, affecting approximately 350 million people. Nevertheless, only 5% receive a specific authorized or licensed treatment. The need for effective and rapidly available therapies is still unmet for many patients. Objective The objective is to define repurposing versus off-label drugs, and to evaluate pathways of repurposed drugs for rare non-oncological diseases in Italy, France, England, and Spain (the EU4 countries). Methods This original paper is based on 3 research activities: (i) a nonsystematic literature research; (ii) a questionnaire-based survey to regulatory experts; and (iii) research on approval timelines and therapy prices of repurposed non-oncology orphan drugs. Official approval dates in England are not available if the National Institute for Health and Care Excellence does not appraise the products. Results Only France provides a specific adaptive pathway from off-label to repurposed drugs. Pricing and reimbursement assessment for the drug samples varied across the EU4 countries: time-to-market for repurposed drugs versus new drugs is longer in all analyzed countries; that is, 979 days versus 462 days in Italy, 502 days versus 350 days in France, and 624 versus 378 days in Spain. Repurposed drugs have higher success rates from development to approval than novel drugs (30% vs. 11%). Small- and medium-sized enterprises owned 9 of 12 repurposed non-oncology orphan drugs, of which only 4 were reimbursed in all EU4 countries. Prices were more homogeneous across EU4 although the reimbursement rates were different. Conclusions Drug repurposing represents a great opportunity to treat rare non-oncological diseases. However, a more homogenous assessment across EU4 could ensure reimbursement and prices high enough to reward organizations investing in this field.

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Rational Discovery of Dual-Action Multi-Target Kinase Inhibitor for Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

10.1101/465054 ◽

2018 ◽

Author(s):

Hansaim Lim ◽

Di He ◽

Yue Qiu ◽

Patrycja Krawczuk ◽

Xiaoru Sun ◽

...

Keyword(s):

Machine Learning ◽

Heart Failure ◽

Drug Resistance ◽

Drug Repurposing ◽

Target Drug ◽

Genome Wide ◽

Anti Cancer ◽

Dual Action ◽

Target Screening ◽

Genome Scale

AbstractAlthough remarkable progresses have been made in the cancer treatment, existing anti-cancer drugs are associated with increasing risk of heart failure, variable drug response, and acquired drug resistance. To address these challenges, for the first time, we develop a novel genome-scale multi-target screening platform 3D-REMAP that integrates data from structural genomics and chemical genomics as well as synthesize methods from structural bioinformatics, biophysics, and machine learning. 3D-REMAP enables us to discover marked drugs for dual-action agents that can both reduce the risk of heart failure and present anti-cancer activity. 3D-REMAP predicts that levosimendan, a drug for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to identify cancer cell-lines and patients that may respond to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe and effective multi-targeted cancer therapy, and demonstrate the potential of genome-wide multi-target screening in designing polypharmacology and drug repurposing for precision medicine.Author SummaryMulti-target drug design (a.k.a targeted polypharmacology) has emerged as a new strategy for discovering novel therapeutics that can enhance therapeutic efficacy and overcome drug resistance in tackling multi-genic diseases such as cancer. However, it is extremely challenging for conventional computational tools that are either receptor-based or ligand-based to screen compounds for selectively targeting multiple receptors. Existing multi-target drug design mainly focuses on compound screening against receptors within the same gene family but not across different gene families. Here, we develop a new computational tool 3D-REMAP that enables us to identify chemical-protein interactions across fold space on a genome scale. The genome-scale chemical-protein interaction network allows us to discover dual-action drugs that can bind to two types of targets simultaneously, one for mitigating side effect and another for enhancing the therapeutic effect. Using 3D-REMAP, we predict and subsequently experiments validate that levosimendan, a drug for heart failure, is active against multiple cancers, notably, lymphoma. This study demonstrates the potential of genome-wide multi-target screening in designing polypharmacology and drug repurposing for precision medicine.

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