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Pharmacotherapy Apr 2022Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the... (Review)
Review
Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%-74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3-5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%-67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.
Topics: Anticoagulants; Drug Interactions; Humans; Platelet Aggregation Inhibitors; Rifabutin; Rifampin; Rifamycins; Warfarin
PubMed: 35152432
DOI: 10.1002/phar.2672 -
The Nursing Clinics of North America Jun 2019Drug-resistant tuberculosis (TB) is one of the greatest challenges facing the elimination of TB. In the United States, persons born outside the United States account for... (Review)
Review
Drug-resistant tuberculosis (TB) is one of the greatest challenges facing the elimination of TB. In the United States, persons born outside the United States account for 70% of new TB cases. Nucleic acid amplification testing has greatly reduced the amount of time needed for diagnosis of TB, down to 1 to 2 days, compared with waiting 21 days for culture results. The shorter treatment regimen for latent TB infection with weekly isoniazid and rifabutin for 12 weeks provides treatment as effective as the traditional daily isoniazid for 6 months, but with better adherence from patients.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Early Diagnosis; Humans; Isoniazid; Latent Tuberculosis; Practice Guidelines as Topic; Rifabutin; United States
PubMed: 31027661
DOI: 10.1016/j.cnur.2019.02.008 -
Natural Product Reports Sep 2022Covering: 2011 to 2021Structural division of natural naphthalenoid ansamycins, regarding the type of the core and length of the ansa chain, and their biosynthetic... (Review)
Review
Covering: 2011 to 2021Structural division of natural naphthalenoid ansamycins, regarding the type of the core and length of the ansa chain, and their biosynthetic pathways in microorganisms are discussed. The great biosynthetic plasticity of natural naphthalenoid ansamycins is reflected in their structural variety due to the alterations within ansa bridge or naphthalenoid core portions. A comparison between the biological potency of natural and semisynthetic naphthalenoid ansamycins was performed and discussed in relation to the molecular targets in cells. The antibacterial potency of naphthalenoid ansamycins seems to be dependent on the ansa chain length and conformational flexibility - the higher flexibility of the ansa chain the better biological outcome is noted.
Topics: Anti-Bacterial Agents; Lactams, Macrocyclic; Molecular Conformation
PubMed: 35244668
DOI: 10.1039/d2np00002d -
European Journal of Medicinal Chemistry Dec 2022Triene-ansamycins such as ansatrienins and cytotrienins are characterized by three conjugated double bond motifs within a 21-membered benzenoid ansamycins. Their... (Review)
Review
Triene-ansamycins such as ansatrienins and cytotrienins are characterized by three conjugated double bond motifs within a 21-membered benzenoid ansamycins. Their structural diversity exists in the different substituents in the C-11 or C-13 side chain or in the 3-amino-5-hydroxy benzoic acid moiety. More complex derivatives have been reported with fused ring systems which may be produced via intramolecular cycloaddition between phenol and triene. The biosynthetic gene clusters and biosynthetic pathway of ansatrienins and cytotrienins have been characterized. Based on biosynthetic knowledge, a series of structural analogs has been prepared by genomic manipulation. Triene-ansamycins exhibit significant anticancer activity. The structure-activity relationships and biological targets have been investigated. This mini-review presents a comprehensive survey of triene-ansamycins, which covers natural occurrence, biological activity, biosynthesis, structural derivatization, structure-activity relationships, and biological targets from 1967 to 2022. Eighty triene-ansamycins have been reported.
Topics: Lactams, Macrocyclic; Multigene Family; Biosynthetic Pathways
PubMed: 36240545
DOI: 10.1016/j.ejmech.2022.114815 -
Natural Product Reports Sep 2022Covering: 2011 to 2021The structural division of ansamycins, including those of atypical cores and different lengths of the ansa chains, is presented. Recently... (Review)
Review
Covering: 2011 to 2021The structural division of ansamycins, including those of atypical cores and different lengths of the ansa chains, is presented. Recently discovered benzenoid and atypical ansamycin scaffolds are presented in relation to their natural source and biosynthetic routes realized in bacteria as well as their muta and semisynthetic modifications influencing biological properties. To better understand the structure-activity relationships among benzenoid ansamycins structural aspects together with mechanisms of action regarding different targets in cells, are discussed. The most promising directions for structural optimizations of benzenoid ansamycins, characterized by predominant anticancer properties, were discussed in view of their potential medical and pharmaceutical applications. The bibliography of the review covers mainly years from 2011 to 2021.
Topics: Lactams, Macrocyclic; Pharmaceutical Preparations; Rifabutin; Structure-Activity Relationship
PubMed: 35262153
DOI: 10.1039/d2np00004k -
Nature Reviews. Clinical Oncology Jan 2021
Topics: Aminopyridines; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles; Receptor Protein-Tyrosine Kinases
PubMed: 33262501
DOI: 10.1038/s41571-020-00458-w -
The Journal of Infectious Diseases Oct 2020
Topics: Animals; Foreign Bodies; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Rats; Rifabutin; Rifampin
PubMed: 32914842
DOI: 10.1093/infdis/jiaa403 -
Archives of Pharmacal Research Sep 2015Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is involved in the folding, activation, and stabilization of numerous oncogenic proteins. It... (Review)
Review
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is involved in the folding, activation, and stabilization of numerous oncogenic proteins. It has become an attractive therapeutic target, especially for eradicating malignant cancers and overcoming chemotherapy resistance. The Hsp90 family in mammalian cells is composed of four major homologs: Hsp90α, Hsp90β, 94-kDa glucose-regulated protein (Grp94), and TNF receptor-associated protein 1 (Trap1). Hsp90α and Hsp90β are mainly localized in the cytoplasm, while Grp94 and Trap1 reside in the endoplasmic reticulum and the mitochondria, respectively. Additionally, some Hsp90 s are secreted from the cytoplasm, commonly called extracellular Hsp90. Interestingly, each Hsp90 isoform is localized in a particular organelle, possesses a unique biological function, and participates in various physiological and pathological processes. To inhibit the organelle-specific Hsp90 chaperone function, there have been significant efforts to accumulate Hsp90 inhibitors in particular cellular compartments. This review introduces current studies regarding the delivery of Hsp90 inhibitors to subcellular organelles, particularly to the extracellular matrix and the mitochondria, and discusses their biological insights and therapeutic implications.
Topics: Animals; Benzoquinones; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Organelles; Triazoles
PubMed: 26195286
DOI: 10.1007/s12272-015-0636-1 -
Cancer Discovery Jun 2018The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK...
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, -ethyl--nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single mutations. In similar screens with EML4-ALK containing single resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies. Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. .
Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Ethylnitrosourea; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Exome Sequencing; Xenograft Model Antitumor Assays
PubMed: 29650534
DOI: 10.1158/2159-8290.CD-17-1256 -
Cold Spring Harbor Perspectives in... Jul 2016Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive... (Review)
Review
Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive prosthetic joint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDS patients in treating mycobacterial infections TB and Mycobacterium avium complex (MAC), having fewer drug-drug interactions that interfere with AIDS medications. Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (peptic ulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment for TB. Rifaximin is a monotherapeutic agent to treat gastrointestinal (GI) disorders, such as hepatic encephalopathy, irritable bowel syndrome, and travelers' diarrhea. Rifaximin is confined to the GI tract because it is not systemically absorbed on oral dosing, achieving high local concentrations, and showing anti-inflammatory properties in addition to its antibacterial activity. Resistance issues are unavoidable with all the rifamycins when the bioburden is high, because of mutations that modify RNA polymerase.
Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Rifabutin; Rifampin; Rifamycins; Rifaximin; Tuberculosis
PubMed: 27270559
DOI: 10.1101/cshperspect.a027011