Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Kerantzas, Christopher A.; Jacobs, William R.

doi:10.1128/mbio.01586-16

Cited by 154 publications

(115 citation statements)

References 80 publications

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“…Goldie and Coldman's seminal results in the 1980s demonstrated that this strategy reduces the emergence of resistance in cancer cells, maximising the probability of remission [149][150][151][152]. A similar approach has been successfully applied to the management of several diseases, ranging from HIV [153] and TB [154] to rheumatoid arthritis [155]. It is curious that HD, a disease genotypically present at birth, takes decades to manifest clinically.…”

Section: Resultsmentioning

confidence: 99%

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Jensen

Barker

2019

JHD

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To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss diseasemodifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early onbefore it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processese.g. huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.To date, no disease-modifying therapy exists for Huntington's disease (HD), despite considerable financial investment [1]. Roche pharmaceutics, however, believe that IONIS-HTTRx, a promising new drug candidate, bucks this trend; their milestone payment to IONIS follows completion of a phase 1/2 study of IONIS-HTTRx, an antisense oligonucleotide (ASO), in 46 patients with early-stage HD. The drug was safe and well tolerated, and resulted in dose-dependent reductions in huntingtin protein (HTT) in the cerebrospinal fluid (CSF) of treated participants [2]. Roche anticipate that results of a trial designed to assess clinical efficacy will prove definitive, accelerating FDA-approval of IONIS-HTTRx. Other global leaders in therapeutics -Spark, Voyager, and UniQurehave followed suit with programs targeting the mutant huntingtin (muHTT) mRNA, representing a shift in optimism affording by targeting the 'root cause' of the disease -HTT gene expression [3].Despite a shift in approachfrom downstream to upstream targetsdrug development in HD has adopted a common mentality: searching for a single agent which selectively targets one aspect of HD pathology which would then be universally effective in this condition, regardless of when in the disease course it is administered and in what type of patient [4]. Although such a therapy has proven elusive, the selection of candidate disease-modifying therapies has been grounded in mechanistic insights into HD pathogenesis ( fig. 1). Two potential explanations for such low rates of clinical success have received less consideration, and stem from adopting this mentality. Reason one: combination therapy has been disregardedTo date, it has been assumed that manipulating a single pathogenic process will be sufficient to halt disease progression. Initial attempts at disease modification focussed on counteracting one of the downstream effects of muHTT thought to be a key contributor to neuronal death: mitochondrial dysfunction [5], excitotoxicity [6...

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Section: Resultsmentioning

confidence: 99%

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Jensen

Barker

2019

JHD

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“…Drug repurposing is a useful strategy to accelerate the drug development process due to lower costs, reduced risk and decreased time to availability of preclinical data [89]. In studies pioneering the concept, rational combination chemotherapy was developed for tuberculosis and other bacterial infections [90]. Nowadays, its use has been extended for chemotherapy of cancer, acquired immune deficiency syndrome (AIDS) [91] and for malaria [92,93].…”

Section: Chemotherapy Against Schistosomiasis and Opisthorchiasismentioning

confidence: 99%

“…Nowadays, its use has been extended for chemotherapy of cancer, acquired immune deficiency syndrome (AIDS) [91] and for malaria [92,93]. The major goals of combination chemotherapy are to minimize and/or to delay the appearance of drug resistance [90][91][92], and to achieve an additive/synergistic effect that could translate in reduced doses of drugs and/or minimized side effects [90]. Ideally for opisthorchiasis and schistosomiasis, the combined drugs would exhibit a divergent mechanism of action of PZQ and/or target the immature parasite to enhance cure and eggs reduction rates as well as pathologies associated with infection and thereby improve the chemotherapy [65].…”

Section: Chemotherapy Against Schistosomiasis and Opisthorchiasismentioning

confidence: 99%

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

2020

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Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as Group 1 biological carcinogen and it has been postulated that parasites produce oxysterol and estrogen-like metabolites that might be considered as initiators of infection-associated carcinogenesis. Chemotherapy for these helminthic infections relies on a single drug, praziquantel, (PZQ) that mainly targets the parasite. Additionally, PZQ has some major drawbacks as inefficacy against juvenile form and alone it is not capable to counteract pathologies associated to infections or prevent carcinogenesis. There is an urgent need to develop novel therapeutic approaches that not only target the parasite but also improve the pathologies associated to infection, and ultimately, counteract or/and prevent the carcinogenesis processes. Repurposing the drug in combination of compounds with different modes of action is a promising strategy to find novel therapeutics approaches against these helminthic infections and its pathologies. Here, we emphasized that using antioxidants either alone or combined with anthelmintic drugs could ameliorate tissue damage, infection-associated complications, moreover, could prevent the development of cancer associated to infections. Hence, antioxidants represent a potential adjuvant approach during treatment to reduce morbidity and mortality. Despite the success of some strategies, there is a long way to go to implement novel therapies for schistosomiasis.

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“…Tuberculosis (TB), caused by an aerobic, acid-fast bacillus, that is, Mycobacterium tuberculosis (M. tuberculosis), to humans, and it is still a major public health problem worldwide (Kerantzas and Jacobs 2017). For many decades, it has continued to pose a significant threat to human health (WHO 2017).…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Tuberculosis: Nanodiagnostics Approaches

Gupta

Singh

2020

NanoBioMedicine

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Tuberculosis (TB) remains one of the most devastating infectious diseases worldwide. The burden of TB is alarmingly high in developing countries, where diagnosis latent TB infection (LTBI), Extra-pulmonary tuberculosis (EPTB), drug-resistant tuberculosis (DR-TB), HIV-associated TB, and paediatric TB is still a challenge. This is mainly due to delayed or misdiagnosis of TB, which continues to fuel its worldwide epidemic. The ideal diagnostic test is still unavailable, and conventional methods remain a necessity for TB diagnosis, though with poor diagnostic ability. The nanoparticles have shown potential for the improvement of drug delivery, reducing treatment frequency and diagnosis of various diseases. The engineering of antigens/antibody nanocarriers represents an exciting front in the field of diagnostics, potentially flagging the way toward development of better diagnostics for TB. This chapter discusses the presently available tests for TB diagnostics and also highlights the recent advancement in the nanotechnology-based detection tests for M. tuberculosis.

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Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application

Cited by 154 publications

References 80 publications

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

Diagnosis of Tuberculosis: Nanodiagnostics Approaches

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