-
Drugs Jul 2022Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the... (Review)
Review
Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the treatment of hypertrophic cardiomyopathy (HCM) and diseases of diastolic dysfunction. In April 2022, mavacamten was approved for use in the USA in the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms. This article summarizes the milestones in the development of mavacamten leading to this first approval for the treatment of adults with symptomatic NYHA class II-III obstructive HCM.
Topics: Adult; Benzylamines; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Humans; Uracil
PubMed: 35802255
DOI: 10.1007/s40265-022-01739-7 -
Drugs in Context 2023Tinea pedis is one of the most common superficial fungal infections of the skin, with various clinical manifestations. This review aims to familiarize physicians with... (Review)
Review
BACKGROUND
Tinea pedis is one of the most common superficial fungal infections of the skin, with various clinical manifestations. This review aims to familiarize physicians with the clinical features, diagnosis and management of tinea pedis.
METHODS
A search was conducted in April 2023 in PubMed Clinical Queries using the key terms 'tinea pedis' OR 'athlete's foot'. The search strategy included all clinical trials, observational studies and reviews published in English within the past 10 years.
RESULTS
Tinea pedis is most often caused by and . It is estimated that approximately 3% of the world population have tinea pedis. The prevalence is higher in adolescents and adults than in children. The peak age incidence is between 16 and 45 years of age. Tinea pedis is more common amongst males than females. Transmission amongst family members is the most common route, and transmission can also occur through indirect contact with contaminated belongings of the affected patient. Three main clinical forms of tinea pedis are recognized: interdigital, hyperkeratotic (moccasin-type) and vesiculobullous (inflammatory). The accuracy of clinical diagnosis of tinea pedis is low. A KOH wet-mount examination of skin scrapings of the active border of the lesion is recommended as a point-of-care testing. The diagnosis can be confirmed, if necessary, by fungal culture or culture-independent molecular tools of skin scrapings. Superficial or localized tinea pedis usually responds to topical antifungal therapy. Oral antifungal therapy should be reserved for severe disease, failed topical antifungal therapy, concomitant presence of onychomycosis or in immunocompromised patients.
CONCLUSION
Topical antifungal therapy (once to twice daily for 1-6 weeks) is the mainstay of treatment for superficial or localized tinea pedis. Examples of topical antifungal agents include allylamines (e.g. terbinafine), azoles (e.g. ketoconazole), benzylamine, ciclopirox, tolnaftate and amorolfine. Oral antifungal agents used for the treatment of tinea pedis include terbinafine, itraconazole and fluconazole. Combined therapy with topical and oral antifungals may increase the cure rate. The prognosis is good with appropriate antifungal treatment. Untreated, the lesions may persist and progress.
PubMed: 37415917
DOI: 10.7573/dic.2023-5-1 -
Journal of the American College of... Jun 2020Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.
OBJECTIVES
MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.
METHODS
The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6.
RESULTS
Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009).
CONCLUSIONS
Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).
Topics: Adult; Aged; Benzylamines; Biomarkers; Cardiomyopathy, Hypertrophic; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Uracil
PubMed: 32466879
DOI: 10.1016/j.jacc.2020.03.064 -
Autophagy Jun 2020Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator PPARGC1A (peroxisome proliferator...
UNLABELLED
Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator PPARGC1A (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) regulates mitochondrial biogenesis, reducing senescence of vascular smooth muscle cells (VSMCs); however, it is unknown whether autophagy mediates PPARGC1A-protective effects on senescence. Using VSMCs, we identified the autophagy receptor SQSTM1/p62 (sequestosome 1) as a major regulator of autophagy and senescence of VSMCs. Abnormal autophagosomes were observed in VSMCs in aortas of mice. VSMCs in culture presented reductions in LC3-II levels; in autophagosome number; and in the expression of SQSTM1 (protein and mRNA), LAMP2 (lysosomal-associated membrane protein 2), CTSD (cathepsin D), and TFRC (transferrin receptor). Reduced SQSTM1 protein expression was also observed in aortas of mice and was upregulated by PPARGC1A overexpression, suggesting that SQSTM1 is a direct target of PPARGC1A. Inhibition of autophagy by 3-MA (3 methyladenine), spautin-1 or (autophagy related 5) siRNA stimulated senescence. Rapamycin rescued the effect of siRNA in , but not in VSMCs, suggesting that other targets of MTOR (mechanistic target of rapamycin kinase), in addition to autophagy, also contribute to senescence. siRNA increased senescence basally and in response to AGT II (angiotensin II) and zinc overload, two known inducers of senescence. Furthermore, gene deficiency mimicked the phenotype of depletion by presenting reduced autophagy and increased senescence and . Thus, PPARGC1A upregulates autophagy reducing senescence by a SQSTM1-dependent mechanism. We propose SQSTM1 as a novel target in therapeutic interventions reducing senescence.
ABBREVIATIONS
3-MA: 3 methyladenine; ACTA2/SM-actin: actin, alpha 2, smooth muscle, aorta; ACTB/β-actin: actin beta; AGT II: angiotensin II; ATG5: autophagy related 5; BECN1: beclin 1; CAT: catalase; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); Chl: chloroquine; CTSD: cathepsin D; CYCS: cytochrome C, somatic; DHE: dihydroethidium; DPBS: Dulbecco's phosphate-buffered saline; EL: elastic lamina; EM: extracellular matrix; FDG: fluorescein-di-β-D-galactopyranoside; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; γH2AFX: phosphorylated H2A histone family, member X, HDCFDA: 2',7'-dichlorodihydrofluorescein diacetate; LAMP2: lysosomal-associated membrane protein 2; MASMs: mouse vascular smooth muscle cells; MEF: mouse embryonic fibroblast; NBR1: NBR1, autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; MTOR: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid derived 2, like 2; NOX1: NADPH oxidase 1; OPTN: optineurin; PFA: paraformaldehyde; PFU: plaque-forming units; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; Ptdln3K: phosphatidylinositol 3-kinase; RASMs: rat vascular smooth muscle cells; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SIRT1: sirtuin 1; Spautin 1: specific and potent autophagy inhibitor 1; SQSTM1/p62: sequestosome 1; SOD: superoxide dismutase; TEM: transmission electron microscopy; TFEB: transcription factor EB; TFRC: transferrin receptor; TRP53/p53: transformation related protein 53; TUBG1: tubulin gamma 1; VSMCs: vascular smooth muscle cells; WT: wild type.
Topics: Animals; Aorta; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Benzylamines; Brain; Cathepsin D; Cellular Senescence; Lysosomal-Associated Membrane Protein 2; Lysosomes; Male; Methylcholanthrene; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Myocytes, Smooth Muscle; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Quinazolines; RNA, Small Interfering; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Transferrin; Sequestosome-1 Protein; Sirolimus; Up-Regulation
PubMed: 31441382
DOI: 10.1080/15548627.2019.1659612 -
Protein & Cell Oct 2021Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases....
Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Benzothiazoles; Benzylamines; Cell Line, Tumor; Chaperone-Mediated Autophagy; Disease Models, Animal; Gene Expression Regulation; HEK293 Cells; HSC70 Heat-Shock Proteins; HeLa Cells; Humans; I-kappa B Kinase; Isoenzymes; MAP Kinase Kinase Kinases; Male; Metformin; Mice; Mice, Transgenic; Neurons; Neuroprotective Agents; PC12 Cells; Phenylurea Compounds; Quinazolines; Rats; Signal Transduction
PubMed: 34291435
DOI: 10.1007/s13238-021-00858-3 -
Drug Design, Development and Therapy 2023Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Calcium Channel Blockers
PubMed: 37064432
DOI: 10.2147/DDDT.S368590 -
European Heart Journal Nov 2023Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic... (Review)
Review
Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction.
Topics: Adult; Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Heart; United States; Uracil
PubMed: 37804245
DOI: 10.1093/eurheartj/ehad637 -
Journal of the American College of... Dec 2021EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM).
OBJECTIVES
The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures.
METHODS
Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory.
RESULTS
More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m vs 41 ± 14 mL/m; mean change from baseline of -7.5 mL/m [95% CI: -9.0 to -6.1 mL/m] vs -0.09 mL/m [95% CI: -1.6 to 1.5 mL/m]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04).
CONCLUSIONS
Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).
Topics: Aged; Benzylamines; Biomarkers; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Double-Blind Method; Echocardiography; Exercise Tolerance; Female; Heart; Humans; Male; Middle Aged; Uracil
PubMed: 34915982
DOI: 10.1016/j.jacc.2021.09.1381 -
Science Advances Feb 2021Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable...
Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.
Topics: Adaptor Proteins, Signal Transducing; Basic Helix-Loop-Helix Transcription Factors; Benzylamines; CRISPR-Cas Systems; Humans; Ikaros Transcription Factor; Oncogene Proteins; Proteolysis; Quinazolines; Thalidomide; Transcription Factors
PubMed: 33547076
DOI: 10.1126/sciadv.abd6263 -
Molbank Jun 2023()-(+)-3,5-dinitro--(1-phenylethyl)benzothioamide is a potential chiral solvating agent (CSA) for the spectral resolution of enantiomers via H NMR spectroscopy. The...
()-(+)-3,5-dinitro--(1-phenylethyl)benzothioamide is a potential chiral solvating agent (CSA) for the spectral resolution of enantiomers via H NMR spectroscopy. The single enantiomer of was synthesized from commercially available ()-(+)-a-methylbenzylamine in two steps with 85% yield.
PubMed: 38274708
DOI: 10.3390/m1650