scholarly journals The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Chiyun Lee ◽  
Sanjib Bhakta
Keyword(s):  
Antitubercular Activity ◽  
New Drugs ◽  
Immunomodulatory Drugs ◽  
Standard Regimen ◽  
Treatment Development ◽  
Treatment Regimens ◽  
Promising Strategy ◽  
Conventional Drug

Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.

Synthesis, biology, computational studies and in vitro controlled release of new isoniazid-based adamantane derivatives

2019 ◽  
Vol 11 (21) ◽  
pp. 2779-2802 ◽  
Author(s):  
Andria Papageorgiou ◽  
Angeliki-Sofia Foscolos ◽  
Ioannis P Papanastasiou ◽  
Marilena Vlachou ◽  
Angeliki Siamidi ◽  
...  
Keyword(s):  
Antitubercular Activity ◽  
New Drugs ◽  
In Vivo Studies ◽  
Adamantane Derivatives ◽  
Dissolution Profile ◽  
Pharmacological Test ◽  
Dynamics Simulations ◽  
Drug Resistant Strains

Aim: There is a necessity for new drugs to be more efficient than today's standard due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) Results/methodology: 12 new isoniazid-based adamantane derivatives were synthesized and tested for their antitubercular activity. The pharmacological test results and the aqueous dissolution profile of representative examples of the new molecules are in agreement with the computational results obtained from docking poses and molecular dynamics simulations on the tested compounds. Conclusion: Among their congeners, the adamantane isonicotinoyl hydrazones Ia and Ih exhibit the best antitubercular activity (MIC = 0.04 μg/ml) and the lowest cytotoxicity (selectivity index ≥2500). These results are useful for in future in vivo studies.

scholarly journals Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Andréanne Lupien ◽  
Anthony Vocat ◽  
Caroline Shi-Yan Foo ◽  
Emilyne Blattes ◽  
Jean-Yves Gillon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Exposure ◽  
Antitubercular Activity ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Content Type ◽  
Treatment Regimens

ABSTRACT The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone PBTZ169, which is currently being evaluated in phase I/II clinical trials. Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD), or sutezolid (STZ) reduced the bacterial burden by 2 logs compared to that achieved with the drugs alone, indicating synergism. MCZ also displayed synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity was found for most combinations, suggesting that MCZ could be added to different TB treatment regimens without any significant adverse effects.

scholarly journals New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

2013 ◽  
Vol 58 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Elena Salina ◽  
Olga Ryabova ◽  
Arseny Kaprelyants ◽  
Vadim Makarov
Keyword(s):  
Metabolic Activity ◽  
Latent Tuberculosis ◽  
Antitubercular Activity ◽  
New Drugs ◽  
Content Type ◽  
Phenotypic Resistance ◽  
Drug Candidates ◽  
Latently Infected

ABSTRACTFromin vivoobservations, a majority ofM. tuberculosiscells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequatein vitromodels for screening of drug candidates. We propose here a novelin vitromodel ofM. tuberculosisdormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormantM. tuberculosiscells. By means of the model ofM. tuberculosisnonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormantM. tuberculosiscells. The bactericidal effects of compounds against dormantM. tuberculosiswas confirmed by using three differentin vitromodels of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latentM. tuberculosisinfection.

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

Nanodrugs as a new approach in therapy of cardiovascular diseases and cancer with tumor-associated angiogenesis

2020 ◽  
Vol 28 ◽  
Author(s):  
Justyna Hajtuch ◽  
Karolina Niska ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Controlled Drug Release ◽  
Biological Properties ◽  
Comprehensive Information ◽  
Conventional Drug ◽  
Key Factor ◽  
Functionalized Materials

Background: Cancer along with cardiovascular diseases are globally defined as leading causes of death. Importantly, some risk factors are common to these diseases. The process of angiogenesis and platelets aggregation are observed in cancer development and progression. In recent years, studies have been conducted on nanodrugs in these diseases that have provided important information on the biological and physicochemical properties of nanoparticles. Their attractive features are that they are made of biocompatible, well-characterized and easily functionalized materials. Unlike conventional drug delivery, sustained and controlled drug release can be obtained by using nanomaterials. Methods: In this article, we review the latest research to provide comprehensive information on nanoparticle-based drugs for the treatment of cancer, cardiovascular disease associated with abnormal haemostasis, and the inhibition of tumorassociated angiogenesis. Results: The results of the analysis of data based on nanoparticles with drugs confirm their improved pharmaceutical and biological properties, which gives promising antiplatelet, anticoagulant and antiangiogenic effects. Moreover, the review included in vitro, in vivo research and presented nanodrugs with chemotherapeutics approved by Food and Drug Administration. Conclusion: By the optimization of nanoparticles size and surface properties, nanotechnology are able to deliver drugs with enhanced bioavailability in treatment of cardiovascular disease, cancer and inhibition of cancer-related angiogenesis. Thus, nanotechnology can improve the therapeutic efficacy of the drug, but there is a need for a better understanding of the nanodrugs interaction in the human body, because this is a key factor in the success of potential nanotherapeutics.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Anti-Mycobacterial Peroxides: A New Class of Agents for Development Against Tuberculosis

2020 ◽  
Vol 16 (3) ◽  
pp. 392-402
Author(s):  
Christiaan W. van der Westhuyzen ◽  
Richard K. Haynes ◽  
Jenny-Lee Panayides ◽  
Ian Wiid ◽  
Christopher J. Parkinson
Keyword(s):  
Subsequent Development ◽  
Antitubercular Activity ◽  
Organic Peroxide ◽  
New Drugs ◽  
Skeletal Myoblast ◽  
Artemisinin Derivatives ◽  
Malaria Therapy ◽  
New Class ◽  
Alternative Approach

Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.

scholarly journals Detecting apoptosis as a clinical endpoint for proof of a clinical principle

2020 ◽  
Author(s):  
Piero Zollet ◽  
Timothy E.Yap ◽  
M Francesca Cordeiro
Keyword(s):  
Drug Development ◽  
Therapeutic Response ◽  
Imaging Techniques ◽  
Brain Diseases ◽  
Promising Strategy ◽  
Sight Loss ◽  
Apoptosis Detection ◽  
Novel Therapeutic Strategies

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis, and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarize the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

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