keyword
https://read.qxmd.com/read/38490104/female-mice-display-sex-specific-differences-in-cerebrovascular-function-and-subarachnoid-haemorrhage-induced-injury
#1
JOURNAL ARTICLE
Danny D Dinh, Hoyee Wan, Darcy Lidington, Steffen-Sebastian Bolz
BACKGROUND: In male mice, a circadian rhythm in myogenic reactivity influences the extent of brain injury following subarachnoid haemorrhage (SAH). We hypothesized that female mice have a different cerebrovascular phenotype and consequently, a distinct SAH-induced injury phenotype. METHODS: SAH was modelled by pre-chiasmatic blood injection. Olfactory cerebral resistance arteries were functionally assessed by pressure myography; these functional assessments were related to brain histology and neurobehavioral assessments...
March 14, 2024: EBioMedicine
https://read.qxmd.com/read/38474016/comprehensive-assessment-of-cftr-modulators-therapeutic-efficiency-for-n1303k-variant
#2
JOURNAL ARTICLE
Anna Efremova, Nataliya Kashirskaya, Stanislav Krasovskiy, Yuliya Melyanovskaya, Maria Krasnova, Diana Mokrousova, Nataliya Bulatenko, Elena Kondratyeva, Oleg Makhnach, Tatiana Bukharova, Rena Zinchenko, Sergey Kutsev, Dmitry Goldshtein
p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K- CFTR function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K- CFTR function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients...
February 27, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38402082/effectiveness-of-lumacaftor-ivacaftor-initiation-in-children-with-cystic-fibrosis-aged-2-through-5-years-on-disease-progression-interim-results-from-an-ongoing-registry-based-study
#3
JOURNAL ARTICLE
Claire Kim, Mark Higgins, Lingyun Liu, Nataliya Volkova, Anna Zolin, Lutz Naehrlich
BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR)...
February 23, 2024: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://read.qxmd.com/read/38398574/organic-synthesis-and-current-understanding-of-the-mechanisms-of-cftr-modulator-drugs-ivacaftor-tezacaftor-and-elexacaftor
#4
REVIEW
Filipa C Ferreira, Camilla D Buarque, Miquéias Lopes-Pacheco
The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators-small molecules acting on the basic molecular defect in CF-have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445)...
February 10, 2024: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38384849/airway-inflammation-accelerates-pulmonary-exacerbations-in-cystic-fibrosis
#5
JOURNAL ARTICLE
Theodore G Liou, Natalia Argel, Fadi Asfour, Perry S Brown, Barbara A Chatfield, David R Cox, Cori L Daines, Dixie Durham, Jessica A Francis, Barbara Glover, My Helms, Theresa Heynekamp, John R Hoidal, Judy L Jensen, Christiana Kartsonaki, Ruth Keogh, Carol M Kopecky, Noah Lechtzin, Yanping Li, Jerimiah Lysinger, Osmara Molina, Craig Nakamura, Kristyn A Packer, Robert Paine, Katie R Poch, Alexandra L Quittner, Peggy Radford, Abby J Redway, Scott D Sagel, Rhonda D Szczesniak, Shawna Sprandel, Jennifer L Taylor-Cousar, Jane B Vroom, Ryan Yoshikawa, John P Clancy, J Stuart Elborn, Kenneth N Olivier, Frederick R Adler
Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators...
March 15, 2024: IScience
https://read.qxmd.com/read/38310629/lumacaftor-ivacaftor-population-pharmacokinetics-in-pediatric-patients-with-cystic-fibrosis-a-first-step-toward-personalized-therapy
#6
JOURNAL ARTICLE
Naïm Bouazza, Saïk Urien, Frantz Foissac, Laure Choupeaux, Gabrielle Lui, Léo Froelicher Bournaud, Steeve Rouillon, Yi Zheng, Emmanuelle Bardin, Nathalie Stremler, Katia Bessaci, Tiphaine Bihouee, Emmanuelle Coirier-Duet, Christophe Marguet, Eric Deneuville, Muriel Laurans, Philippe Reix, Michèle Gerardin, Marie Mittaine, Ralph Epaud, Caroline Thumerelle, Laurence Weiss, Romain Berthaud, Michaela Semeraro, Jean-Marc Treluyer, Sihem Benaboud, Isabelle Sermet-Gaudelus
BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability...
February 4, 2024: Clinical Pharmacokinetics
https://read.qxmd.com/read/38289650/assessing-the-labeling-information-on-drugs-associated-with-suicide-risk-systematic-review
#7
REVIEW
Soo Min Jeon, HyunJoo Lim, Hyo-Bin Cheon, Juhee Ryu, Jin-Won Kwon
BACKGROUND: Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide. OBJECTIVE: We aimed to systematically review case reports on DIS to provide evidence-based drug information. METHODS: We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded...
January 30, 2024: JMIR Public Health and Surveillance
https://read.qxmd.com/read/38281825/subtherapeutic-triazole-concentrations-as-result-of-a-drug-drug-interaction-with-lumacaftor-ivacaftor
#8
JOURNAL ARTICLE
T J L Smeets, H van der Sijs, H M Janssens, E J Ruijgrok, B C M de Winter
Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles...
January 27, 2024: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://read.qxmd.com/read/38218661/elexacaftor-tezacaftor-ivacaftor-improves-chronic-rhinosinusitis-detected-by-magnetic-resonance-imaging-in-children-with-cystic-fibrosis-on-long-term-therapy-with-lumacaftor-ivacaftor
#9
JOURNAL ARTICLE
Lena Wucherpfennig, Johanna K Z Becker, Felix Wuennemann, Monika Eichinger, Angelika Seitz, Ingo Baumann, Mirjam Stahl, Simon Y Graeber, Shengkai Zhao, Jaehi Chung, Jens-Peter Schenk, Abdulsattar Alrajab, Hans-Ulrich Kauczor, Marcus A Mall, Olaf Sommerburg, Mark O Wielpütz
INTRODUCTION: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied...
January 12, 2024: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://read.qxmd.com/read/38173511/plasma-levels-of-chemokines-decrease-during-elexacaftor-tezacaftor-ivacaftor-therapy-in-adults-with-cystic-fibrosis
#10
JOURNAL ARTICLE
Dirk Westhölter, Johannes Pipping, Jonas Raspe, Mona Schmitz, Sivagurunathan Sutharsan, Svenja Straßburg, Matthias Welsner, Christian Taube, Sebastian Reuter
BACKGROUND: Cystic fibrosis (CF) is associated with dysregulated immune responses, exaggerated inflammation and chronic infection. CF transmembrane conductance regulator (CFTR) modulator therapies directly target the underlying protein defects and resulted in significant clinical benefits for people with CF (pwCF). This study analysed the effects of triple CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) on CF-associated inflammation, especially systemic chemokines. METHODS: A bead-based immunoassay was used to quantify proinflammatory chemokines (IL-8, IP-10, Eotaxin, TARC, RANTES, MIP-1α, MIP-1β, MIP-3α, MIG, ENA-78, GROα, I-TAC) in plasma samples from pwCF collected before, at three, and at six months after starting ETI therapy...
January 15, 2024: Heliyon
https://read.qxmd.com/read/38139828/in-silico-and-in-vitro-evaluation-of-the-mechanism-of-action-of-three-vx809-based-hybrid-derivatives-as-correctors-of-the-f508del-cftr-protein
#11
JOURNAL ARTICLE
Debora Baroni, Naomi Scarano, Alessandra Ludovico, Chiara Brandas, Alice Parodi, Dario Lunaccio, Paola Fossa, Oscar Moran, Elena Cichero, Enrico Millo
Cystic fibrosis (CF), the most common autosomal recessive fatal genetic disease in the Caucasian population, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that regulates salt and water transport across a variety of secretory epithelia. Deletion of phenylalanine at position 508, F508del, the most common CF-causing mutation, destabilises the CFTR protein, causing folding and trafficking defects that lead to a dramatic reduction in its functional expression...
December 8, 2023: Pharmaceuticals
https://read.qxmd.com/read/38105411/cyclic-diacyl-thioureas-enhance-activity-of-corrector-lumacaftor-on-f508del-cftr
#12
JOURNAL ARTICLE
Andrea Spallarossa, Nicoletta Pedemonte, Emanuela Pesce, Enrico Millo, Elena Cichero, Camillo Rosano, Matteo Lusardi, Erika Iervasi, Marco Ponassi
Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del-CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6i displayed the most marked enhancing effect and acylthioureas 6d and 6f were also able to improve efficacy of Lumacaftor...
December 17, 2023: ChemMedChem
https://read.qxmd.com/read/38075767/synthesis-and-evaluation-of-ivacaftor-derivatives-with-reduced-lipophilicity
#13
JOURNAL ARTICLE
Melissa Iazzi, Phillip Junor, Jitesh Doshi, Saujanya Acharya, Roxana Sühring, Russell D Viirre, Gagan D Gupta
Mutations in the unique ATP-binding cassette anion channel, the cystic fibrosis conductance regulator (CFTR), lead to the inherited fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel gating of CFTR by stabilizing its open state and has been approved as monotherapy for CF patients with CFTR gating mutations (e.g., G551D) and as part of combination therapy with lumacaftor for CFTR folding mutations (e.g., ΔF508). However, in the latter context, ivacaftor may destabilize folding-rescued ΔF508-CFTR and membrane-associated proteins and attenuate lumacaftor pharmacotherapy...
December 5, 2023: ACS Omega
https://read.qxmd.com/read/38024720/spectral-analysis-on-cuba-lumacaftor-cubane-as-benzene-bioisosteres-of-lumacaftor
#14
JOURNAL ARTICLE
Dongdong Wang, Xiaohong Lyu, Mengtao Sun, Yongqiang Liang
In this paper, we theoretically investigate the electronic structure and physical properties of cuba-lumacaftor, cubane as benzene bioisosteres of lumacaftor, stimulated by recent experimental reports [Wiesenfeldt M. P.; Nature2023, 618, 513-518]. The permanent electric dipole moments of cuba-lumacaftor in neutral, acidic, and alkaline environments are significantly enlarged than that of lumacaftor, significantly promoting the interaction between cuba-lumacaftor and surrounding polar solvent environments and resulting in pH-independent high solubility and pharmacological activity...
November 14, 2023: ACS Omega
https://read.qxmd.com/read/37983082/corrector-therapies-with-or-without-potentiators-for-people-with-cystic-fibrosis-with-class-ii-cftr-gene-variants-most-commonly-f508del
#15
REVIEW
Matthew Heneghan, Kevin W Southern, Jared Murphy, Ian P Sinha, Sarah J Nevitt
BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function - faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF...
November 20, 2023: Cochrane Database of Systematic Reviews
https://read.qxmd.com/read/37908398/nationwide-lung-function-monitoring-from-infancy-in-newborn-screened-children-with-cystic-fibrosis
#16
JOURNAL ARTICLE
Rikke M Sandvik, Marika N Schmidt, Christian M Voldby, Frederik F Buchvald, Hanne V Olesen, Jørgen Olsen, Maja V Kragh, Sune L M Rubak, Tacjana Pressler, Paul D Robinson, Per M Gustafsson, Marianne Skov, Kim G Nielsen
BACKGROUND: Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor...
September 2023: ERJ Open Research
https://read.qxmd.com/read/37813637/m-protein-from-dengue-virus-oligomerizes-to-pentameric-channel-protein-in-silico-analysis-study
#17
JOURNAL ARTICLE
Ayesha Zeba, Kanagaraj Sekar, Anjali Ganjiwale
The Dengue virus M protein is a 75 amino acid polypeptide with two helical transmembranes (TM). The TM domain oligomerizes to form an ion channel, facilitating viral release from the host cells. The M protein has a critical role in the virus entry and life cycle, making it a potent drug target. The oligomerization of the monomeric protein was studied using ab initio modeling and molecular dynamics (MD) simulation in an implicit membrane environment. The representative structures obtained showed pentamer as the most stable oligomeric state, resembling an ion channel...
September 2023: Genomics & Informatics
https://read.qxmd.com/read/37787417/use-of-cftr-modulators-in-special-populations-part-1-pregnancy-and-lactation
#18
REVIEW
Joseph Elijah, Linda J Fitzgerald, Hanna Phan
Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use...
October 3, 2023: Pediatric Pulmonology
https://read.qxmd.com/read/37728222/use-of-cftr-modulators-in-special-populations-part-2-severe-lung-disease
#19
REVIEW
Joseph Elijah, Linda J Fitzgerald, Hanna Phan
Safety and efficacy data surrounding cystic fibrosis transmembrane regulator (CFTR) modulator administration for people with CF (pwCF) and severe lung disease elect has remained unclear as a result of exclusion from key trials. A scoping review of English language articles from the period of 1 January 2012, to 31 July 2023 was conducted utilizing PubMed and EmBase databases with the following terms: "severe lung disease" OR "advanced lung disease" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use...
September 20, 2023: Pediatric Pulmonology
https://read.qxmd.com/read/37712606/real-life-experience-with-a-generic-formulation-of-lumacaftor-ivacaftor-in-patients-with-cystic-fibrosis-homozygous-for-the-phe508del-cftr-mutation
#20
JOURNAL ARTICLE
Alejandro Teper, Silvina Lubovich, Viviana Rodríguez, Silvina Zaragoza, Ezequiel Rodríguez, Facundo García Bournissen
INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation...
September 15, 2023: Pediatric Pulmonology
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