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https://www.readbyqxmd.com/read/29126225/bedaquiline-resistance-its-emergence-mechanism-and-prevention
#1
Thi Van Anh Nguyen, Richard M Anthony, Anne-Laure Bañuls, Dinh Hoa Vu, Jan-Willem C Alffenaar
Bedaquiline, a new anti-tuberculosis drug, has already been used in more than 50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This paper aims to review currently identified mechanisms of resistance, the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from the compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance...
November 8, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29122712/development-of-plga-nanoparticles-loaded-with-clofazimine-for-oral-delivery-assessment-of-formulation-variables-and-intestinal-permeability
#2
Luíse L Chaves, Sofia A Costa Lima, Alexandre C C Vieira, Luísa Barreiros, Marcela A Segundo, Domingos Ferreira, Bruno Sarmento, Salette Reis
The use of polymeric nanoparticles as delivery systems is a promising tool to overcome drawbacks related to low aqueous solubility of drugs, which limit their in vivo bioavailability. The aim of this study was to decrease clofazimine (CLZ) toxicity using experimental design to formulate CLZ loaded in PLGA nanoparticles (NPs-CLZ) through a Plackett-Burman design (PBD). A screening PBD was constructed with twelve formulations involving six variables among process and formulation parameters and the selected responses were particle size, polydispersity index (PDI), association efficiency (AE) and drug loading (DL)...
November 6, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29091204/molecular-mechanisms-of-clofazimine-resistance-in-mycobacterium-tuberculosis
#3
Wing Wai Yew, Dachao Liang, Denise P Chan, Wanliang Shi, Ying Zhang
No abstract text is available yet for this article.
October 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29066849/chemotherapeutic-efficacies-of-a-clofazimine-and-diminazene-aceturate-combination-against-piroplasm-parasites-and-their-at-rich-dna-binding-activity-on-babesia-bovis
#4
Bumduuren Tuvshintulga, Mahmoud AbouLaila, Thillaiampalam Sivakumar, Dickson Stuart Tayebwa, Sambuu Gantuya, Khandsuren Naranbaatar, Aki Ishiyama, Masato Iwatsuki, Kazuhiko Otoguro, Satoshi Ōmura, Mohamad Alaa Terkawi, Azirwan Guswanto, Mohamed Abdo Rizk, Naoaki Yokoyama, Ikuo Igarashi
Recently, we reported that clofazimine (CF) has an anti-piroplasm activity, but it could not completely eliminate parasites in the host. The currently available anti-piroplasm drug, diminazene aceturate (DA), has sometimes been reported to have toxic side effects. In the present study, we evaluated the combination treatment with CF and DA against piroplasms both in vitro and in vivo. Additionally, mRNA level and DNA amounts were analyzed in CF‒ and DA‒treated Babesia bovis by a qPCR. The CF-DA combination had additive effects on Babesia bovis, B...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29061760/combinations-of-respiratory-chain-inhibitors-have-enhanced-bactericidal-activity-against-mycobacterium-tuberculosis
#5
Bryan J Berube, Tanya Parish
As an obligate aerobe Mycobacterium tuberculosis uses its electron-transport chain (ETC) to produce energy via oxidative phosphorylation. This pathway has recently garnered a lot of attention and is a target for several new anti-mycobacterials. We tested the respiratory adaptation of M. tuberculosis to phenoxy alkyl benzimidazoles (PABs), compounds proposed to target QcrB, a component of the cytochrome bc1 complex. We show M. tuberculosis is able to reroute its ETC to provide temporary resistance to PABs. However, combination treatment of PAB with agents targeting other components of the electron-transport chain overcomes this respiratory flexibility...
October 23, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29047275/excipient-free-pulmonary-delivery-and-macrophage-targeting-of-clofazimine-via-air-jet-micronization
#6
Ashlee D Brunaugh, Syed Umer Jan, Silvia Ferrati, Hugh D C Smyth
Clofazimine (CFZ) is highly active against mycobacterium, including resistant Mycobacterium tuberculosis, but its therapeutic efficacy via the oral route is limited by severe adverse effects, poor aqueous solubility, and slow onset of action. Pulmonary delivery of CFZ is an attractive alternative to target mycobacterium-harboring alveolar macrophages. This study explores the use of air jet milling to develop a respirable, cost-effective CFZ formulation. Jet milled CFZ was readily dispersed from an off-the-shelf dry powder inhaler without the need for additional excipients or carrier particles...
November 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29042210/the-physicochemical-basis-of-clofazimine-induced-skin-pigmentation
#7
Mikhail D Murashov, Vernon LaLone, Phillip M Rzeczycki, Rahul K Keswani, Gi S Yoon, Sudha Sud, Walajapet Rajeswaran, Scott Larsen, Kathleen A Stringer, Gus R Rosania
Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug's red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation...
October 14, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29038265/verapamil-increases-the-bioavailability-and-efficacy-of-bedaquiline-but-not-clofazimine-in-a-murine-model-of-tuberculosis
#8
Jian Xu, Rokeya Tasneen, Charles A Peloquin, Deepak V Almeida, Si-Yang Li, Kala Barnes-Boyle, Yu Lu, Eric Nuermberger
Drug efflux pumps play an important role in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine and other drugs against Mycobacterium tuberculosis has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and clofazimine against M...
October 16, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#9
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29026393/in-vitro-investigation-of-clofazimine-analogues-for-antiplasmodial-cytotoxic-and-pro-oxidative-activities
#10
E M Makgatho, E F Mbajiorgu
BACKGROUND: Tetramethyl-piperidine-substituted, B4119 and B4158 have been shown to exhibit antiplasmodial activity. OBJECTIVES: The in vitro antiplasmodial, cytotoxic and oxidative activities of clofazimine and its analogues, all TMP (tetramethylpiperidyl)-substituted phenazines except B669, were evaluated in this study. METHODS: The antiplasmodial activity of the compounds against RB-1 and pfUP10 laboratory strains of Plasmodium falciparum was investigated by flow cytometry...
March 2017: African Health Sciences
https://www.readbyqxmd.com/read/28930155/identification-of-agents-active-against-methicillin-resistant-staphylococcus-aureus-usa300-from-a-clinical-compound-library
#11
Hongxia Niu, Rebecca Yee, Peng Cui, Lili Tian, Shuo Zhang, Wanliang Shi, David Sullivan, Bingdong Zhu, Wenhong Zhang, Ying Zhang
Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat for effective treatment of several difficult-to-treat infections in humans. To identify potential new treatment options for MRSA infections, we screened a clinical compound library consisting of 1524 compounds using a growth inhibition assay in 96-well plates. We identified 34 agents which are either bacteriostatic or bactericidal against log-phase clinical MRSA strain USA300. Among them, 9 candidates (thonzonium, cetylpyridinium, trilocarban, benzododecinium, bithionol, brilliant green, chlorquinaldol, methylbenzethonium and green violet) are known antiseptics, 11 candidates are known antibiotics currently recommended for the treatment of MRSA...
September 20, 2017: Pathogens
https://www.readbyqxmd.com/read/28929769/design-and-solidification-of-fast-releasing-clofazimine-nanoparticles-for-treatment-of-cryptosporidiosis
#12
Yingyue Zhang, Jie Feng, Simon A McManus, Hoang D Lu, Kurt D Ristroph, Eugene J Cho, Ellen L Dobrijevic, Hak-Kim Chan, Robert K Prud'homme
Clofazimine, a lipophilic (log P = 7.66) riminophenazine antibiotic approved by the US Food and Drug Administration (FDA) with a good safety record, was recently identified as a lead hit for cryptosporidiosis through a high-throughput phenotypic screen. Cryptosporidiosis requires fast-acting treatment as it leads to severe symptoms which, if untreated, result in morbidity for infants and small children. Consequently, a fast-releasing oral formulation of clofazimine in a water-dispersible form for pediatric administration is highly desirable...
October 2, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28880343/granuloma-faciale-treatment-a-systematic-review
#13
Claudia Lindhaus, Peter Elsner
Granuloma faciale is an uncommon benign chronic dermatosis characterized by reddish-brown to violaceous asymptomatic plaques appearing predominantly on the face. The pathogenesis of granuloma faciale remains unclear, and it is frequently unresponsive to therapy. This systematic review aims to summarize all recent publications on the management of granuloma faciale. The publications are mainly individual case reports, small case series and a few retrospective studies. Treatment options included topical, intralesional and systemic corticosteroids, topical pimecrolimus and tacrolimus, topical and systemic dapsone, systemic hydroxychloroquine, clofazimine, and tumour necrosis factor-alpha inhibitors...
September 7, 2017: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/28869943/targeting-the-potassium-channel-kv1-3-kills-glioblastoma-cells
#14
Elisa Venturini, Luigi Leanza, Michele Azzolini, Stephanie Kadow, Andrea Mattarei, Michael Weller, Ghazaleh Tabatabai, Michael J Edwards, Mario Zoratti, Cristina Paradisi, Ildikò Szabò, Erich Gulbins, Katrin Anne Becker
BACKGROUND/AIMS: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells...
September 1, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/28843822/clofazimine-protects-against-mycobacterium-tuberculosis-dissemination-in-the-cns-following-an-aerosol-challenge-in-a-murine-model
#15
Sooraj Baijnath, Chivonne Moodley, Bongani Ngcobo, Sanil D Singh, Hendrik G Kruger, Per I Arvidsson, Tricia Naicker, Alexander Pym, Thavendran Govender
BACKGROUND: Tuberculosis (TB) has been the scourge of the human race for many decades, claiming countless number of lives along the way. This is further complicated by the ability of Mycobacterium tuberculosis (M.tb) to infect extra-pulmonary sites, more specifically the brain. These forms of TB are difficult to treat due to the problems associated with drug delivery across the blood brain barrier (BBB). Linezolid (LZD and clofazimine (CFZ) are two of the more promising anti-TB antibiotics in recent times...
August 23, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28833263/quantitative-analysis-of-clofazimine-lamprene%C3%A2-an-antileprosy-agent-in-human-dried-blood-spots-using-liquid-chromatography-tandem-mass-spectrometry
#16
Wenkui Li, John Doherty, Yunlin Fu, Jimmy Flarakos
An LC-MS/MS method was developed and validated for bioanalysis of clofazimine in human DBS samples in support of a clinical study on multidrug-resistant tuberculosis in developing countries. The validated assay dynamic range was from 10.0 to 2000 ng/mL using a 1/8″ DBS punch. The accuracy and precision of the assay were ±11.0 % (bias) and ≤13.5% (CV) for the LLOQs (10.0 ng/mL) and ± 15% (bias) and ≤ 15% (CV) for all other QC levels. The assay was proved to be free from the possible impact due to spot size and storage temperature (e...
August 19, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28826448/clinical-significance-of-qt-prolonging-drug-use-in-patients-with-mdr-tb-or-ntm-disease
#17
H-Y Yoon, K-W Jo, G B Nam, T S Shim
SETTING: Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. OBJECTIVE: To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. METHODS: We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin)...
September 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28819600/extensively-drug-resistant-tuberculosis-of-the-lumbar-spine-in-a-six-year-old-child-a-case-report
#18
Siddharth Sanjay Shah, Aakanksha Arvind Goregaonkar, Arvind Balkrishna Goregaonkar
INTRODUCTION: The emergence of extensively drug-resistant tuberculosis (XDR-TB) is a challenging paradigm shift faced by the TB control programs worldwide today. The treatment is further compounded with unique management difficulties faced in pediatric patients. Treatment of XDR-TB requires prolonged chemotherapy with second-line drugs which offer lesser potency and increased risk of drug-related side effects. We present a case of spinal XDR-TB in a child, managed with extended second-line antitubercular chemotherapy (ATT)...
March 2017: Journal of Orthopaedic Case Reports
https://www.readbyqxmd.com/read/28781126/targeting-mycobacterium-tuberculosis-sensitivity-to-thiol-stress-at-acidic-ph-kills-the-bacterium-and-potentiates-antibiotics
#19
Garry B Coulson, Benjamin K Johnson, Huiqing Zheng, Christopher J Colvin, Robert J Fillinger, Elizabeth R Haiderer, Neal D Hammer, Robert B Abramovitch
Mycobacterium tuberculosis (Mtb) must sense and adapt to immune pressures such as acidic pH during pathogenesis. The goal of this study was to isolate compounds that inhibit acidic pH resistance, thus defining virulence pathways that are vulnerable to chemotherapy. Here, we report that the compound AC2P36 selectively kills Mtb at acidic pH and potentiates the bactericidal activity of isoniazid, clofazimine, and diamide. We show that AC2P36 activity is associated with thiol stress and causes an enhanced accumulation of intracellular reactive oxygen species at acidic pH...
August 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28776518/fighting-tuberculosis-by-drugs-targeting-nonreplicating-mycobacterium-tuberculosis-bacilli
#20
REVIEW
Angelo Iacobino, Giovanni Piccaro, Federico Giannoni, Alessandro Mustazzolu, Lanfranco Fattorini
Current tuberculosis (TB) treatment requires 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) + INH for latent TB. The lungs of patients with active and latent TB contain heterogeneous mixtures of cellular and caseous granulomas harboring Mycobacterium tuberculosis bacilli ranging from actively replicating (AR) to nonreplicating (NR), phenotypically drug-resistant stages. Several in vitro models to obtain NR cells were reported, including exposure to hypoxia, nutrient starvation, acid + nitric oxide, and stationary phase...
July 2017: International Journal of Mycobacteriology
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