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Clofazimine

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https://www.readbyqxmd.com/read/29346118/mycobacterium-avium-complex-pulmonary-disease-new-epidemiology-and-management-concepts
#1
Leah Lande, Jason George, Theodore Plush
PURPOSE OF REVIEW: The prevalence of Mycobacterium avium complex (MAC)-related pulmonary disease has been increasing because of environmental factors, changes in organism virulence, and evolving host susceptibility. Treatment is often complicated by adverse effects, development of drug resistance, and refractory disease, with recurrence rates as high as 25-45%. RECENT FINDINGS: Aerosolization of water, soil, or dusts are the likely sources of MAC-related pulmonary disease in susceptible individuals...
January 15, 2018: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/29339392/a-novel-piperazine-based-drug-lead-for-cryptosporidiosis-from-the-medicines-for-malaria-venture-open-access-malaria-box
#2
R S Jumani, K Bessoff, M S Love, P Miller, E E Stebbins, J E Teixeira, M A Campbell, M J Meyers, J A Zambriski, V Nunez, A K Woods, C W McNamara, C D Huston
Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to a need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization...
January 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29337135/defining-bedaquiline-susceptibility-resistance-cross-resistance-and-associated-genetic-determinants-a-retrospective-cohort-study
#3
Nazir A Ismail, Shaheed V Omar, Lavania Joseph, Netricia Govender, Linsay Blows, Farzana Ismail, Hendrik Koornhof, Andries W Dreyer, Koné Kaniga, Norbert Ndjeka
BACKGROUND: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ). METHODS: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960...
January 9, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29245088/-ghost-peak-of-clofazimine-a-solution-degradation-product-of-clofazimine-via-nucleophilic-substitution-by-nitrite-leaching-from-certain-glass-hplc-vials
#4
Jinsheng Lin, Zhenghuai Lin, Dan Li, Mengxue Feng, Qin Yang, Wenping Hu, Yang Han, Wenquan Zhu, Min Li, LuShan Yu
Analytical solutions of clofazimine drug substance stored in glass HPLC vials were found to undergo degradation at room temperature occasionally. At the time of each sample preparation, it was unpredictable if a particular solution would undergo such solution degradation. Once the degradation peak was observed in a particular vial, typically within 24h, it would keep growing until reaching a total yield of approximately 2%. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, followed by preparative HPLC separation and subsequent structure characterization by 1D and 2D NMR, the unknown peak was identified as a clofazimine nitrite ester...
November 26, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29216713/poly-2-oxazoline-pterostilbene-block-copolymer-nanoparticles-for-dual-anticancer-drug-delivery
#5
Matteo Romio, Giulia Morgese, Lucca Trachsel, Samuel Babity, Cristina Paradisi, Davide Brambilla, Edmondo Maria Benetti
Functional block-copolymers based on poly(2-oxazoline)s are versatile building blocks for the fabrication of dual-drug delivery nanoparticles (NPs) that show promising properties for the development of a anticancer chemotherapy. Core-shell NPs are fabricated from diblock-copolymers featuring a long and hydrophilic poly(2-methyl-2-oxazoline) (PMOXA) block, coupled to a relatively short and functionalizable poly(2-methylsuccinate-2-oxazoline) (PMestOXA) segment. The PMOXA block stabilizes the NP dispersions, whereas the PMestOXA segment is used to conjugate pterostilbene (PTS), a natural bioactive phenolic compound that is used as lipophilic model-drug and constitutes the hydrophobic core of the designed NPs...
December 7, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/29149917/treatment-outcome-with-a-short-multidrug-resistant-tuberculosis-regimen-in-nine-african-countries
#6
A Trébucq, V Schwoebel, Z Kashongwe, A Bakayoko, C Kuaban, J Noeske, S Hassane, B Souleymane, A Piubello, F Ciza, V Fikouma, M Gasana, M Ouedraogo, M Gninafon, A Van Deun, D M Cirillo, K G Koura, H L Rieder
SETTING: Nine countries in West and Central Africa. OBJECTIVE: To assess outcomes and adverse drug events of a standardised 9-month treatment regimen for multidrug-resistant tuberculosis (MDR-TB) among patients never previously treated with second-line drugs. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 9-month regimen including moxifloxacin, clofazimine, ethambutol (EMB) and pyrazinamide (PZA) throughout, supplemented by kanamycin, prothionamide and high-dose isoniazid during an intensive phase of a minimum of 4 to a maximum of 6 months...
January 1, 2018: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29145924/pharmacokinetic-interaction-between-bedaquiline-and-clofazimine-in-patients-with-drug-resistant-tuberculosis
#7
G Maartens, M J E Brill, M Pandie, E M Svensson
<h2>BACKGROUND:</h2>Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.<h2>METHODS:</h2>We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB...
November 16, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29126225/bedaquiline-resistance-its-emergence-mechanism-and-prevention
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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