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Hepatology (Baltimore, Md.) Jan 2022Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity.
APPROACH AND RESULTS
In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models.
CONCLUSIONS
Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.
Topics: Aminopyridines; Animals; Benzimidazoles; Biopsy; Coenzyme A Ligases; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction
PubMed: 34510514
DOI: 10.1002/hep.32148 -
ESMO Open Dec 2022Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments'... (Review)
Review
BACKGROUND
Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available.
METHODS
We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib.
RESULTS
A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients.
CONCLUSIONS
Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.
Topics: Female; Humans; Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Quality of Life; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors
PubMed: 36399953
DOI: 10.1016/j.esmoop.2022.100629 -
The Journal of Experimental Medicine Apr 2023We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and...
We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients.
Topics: Animals; Mice; Programmed Cell Death 1 Receptor; Aminopyridines; Purines; Melanoma
PubMed: 36688919
DOI: 10.1084/jem.20220729 -
Clinical Cancer Research : An Official... May 2021Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-positive (ROS1) non-small cell lung cancer (NSCLC) is crizotinib...
PURPOSE
Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-positive (ROS1) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1 NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1 disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.
EXPERIMENTAL DESIGN
Biopsies from patients with ROS1 NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.
RESULTS
From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, mutations were identified in 38% and 46%, respectively. G2032R was the most commonly occurring mutation in approximately one third of cases. Additional mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1 causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1, ROS1, and ROS1 were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified amplification (4%), G12C (4%), amplification (4%), mutation (4%), and mutation (4%).
CONCLUSIONS
mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Aminopyridines; Antigens, Differentiation, B-Lymphocyte; Biopsy; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens Class II; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Models, Molecular; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Structure-Activity Relationship; Young Adult
PubMed: 33685866
DOI: 10.1158/1078-0432.CCR-21-0032 -
Platelets Dec 2023Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune... (Review)
Review
Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.
Topics: Humans; Aminopyridines; COVID-19; Oxazines; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic; Pyridines; Syk Kinase
PubMed: 36331249
DOI: 10.1080/09537104.2022.2131751 -
JNCI Cancer Spectrum Jul 2023The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or... (Review)
Review
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs and overall survival for ribociclib and abemaciclib. Results in early breast cancer are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review nonclinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects.
Topics: Female; Humans; Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4
PubMed: 37369022
DOI: 10.1093/jncics/pkad045 -
Current Neuropharmacology 2019Cerebellar ataxia is a frequent and often disabling syndrome severely impairing motor functioning and quality of life. Patients suffer from reduced mobility, and... (Review)
Review
Cerebellar ataxia is a frequent and often disabling syndrome severely impairing motor functioning and quality of life. Patients suffer from reduced mobility, and restricted autonomy, experiencing an even lower quality of life than, e.g., stroke survivors. Aminopyridines have been demonstrated viable for the symptomatic treatment of certain forms of cerebellar ataxia. This article will give an outline of the present pharmacotherapy of different cerebellar disorders. As a current key-therapy for the treatment of downbeat nystagmus 4-aminopyridine (4-AP) is suggested for the treatment of downbeat nystagmus (5-10 mg Twice a day [TID]), a frequent type of persisting nystagmus, due to a compromise of the vestibulo-cerebellum. Studies with animals have demonstrated, that a nonselective blockage of voltage-gated potassium channels (mainly Kv1.5) increases Purkinje- cell (PC) excitability. In episodic ataxia type 2 (EA2), which is frequently caused by mutations of the PQ-calcium channel, the efficacy of 4-AP (5-10 mg TID) has been shown in a randomized controlled trial (RCT). 4-AP was well tolerated in the recommended dosages. 4-AP was also effective in elevating symptoms in cerebellar gait ataxia of different etiologies (2 case series). A new treatment option for cerebellar disease is the amino-acid acetyl-DL-leucine, which has significantly improved cerebellar symptoms in three case series. There are on-going randomized controlled trials for cerebellar ataxia (acetyl-DL-leucine vs placebo; ALCAT), cerebellar gait disorders (SR-form of 4-AP vs placebo; FACEG) and EA2 (sustained-release/SR-form of 4-AP vs acetazolamide vs placebo; EAT2TREAT), which will provide new insights into the pharmacological treatment of cerebellar disorders.
Topics: Aminopyridines; Animals; Cerebellar Ataxia; Cerebellar Diseases; Humans; Leucine
PubMed: 30182858
DOI: 10.2174/1570159X16666180905093535 -
Neurology(R) Neuroimmunology &... May 2021As an antagonist of voltage-gated potassium (Kv) channels, 4-aminopyridine (4-AP) is used as symptomatic therapy in several neurologic disorders. The improvement of... (Review)
Review
As an antagonist of voltage-gated potassium (Kv) channels, 4-aminopyridine (4-AP) is used as symptomatic therapy in several neurologic disorders. The improvement of visual function and motor skills and relieve of fatigue in patients with MS have been attributed to 4-AP. Its prolonged release formulation (fampridine) has been approved for the symptomatic treatment of walking disability in MS. The beneficial effects were explained by the blockade of axonal Kv channels, thereby enhancing conduction along demyelinated axons. However, an increasing body of evidence suggests that 4-AP may have additional properties beyond the symptomatic mode of action. In this review, we summarize preclinical and clinical data on possible neuroprotective features of 4-AP.
Topics: 4-Aminopyridine; Animals; Humans; Inflammation; Multiple Sclerosis; Neuroprotective Agents; Potassium Channel Blockers; Signal Transduction
PubMed: 33653963
DOI: 10.1212/NXI.0000000000000976 -
Chest Jul 2015
Topics: Albuterol; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Bronchodilator Agents; Female; Humans; Male; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives
PubMed: 26149564
DOI: 10.1378/chest.15-0837 -
Current Oncology (Toronto, Ont.) Jun 2023The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment... (Review)
Review
The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment evidence base is challenging. In this narrative review, we provide best-practice recommendations for the first-line treatment of HR+/HER2- advanced breast cancer in Canada based on relevant literature, clinical guidelines, and our own clinical experience. Due to statistically significant improvements in overall survival and progression-free survival, ribociclib + aromatase inhibitor is our preferred first-line treatment for de novo advanced disease or relapse ≥12 months after completion of adjuvant endocrine therapy and ribociclib or abemaciclib + fulvestrant is our preferred first-line treatment for patients experiencing early relapse. Abemaciclib or palbociclib may be used when alternatives to ribociclib are needed, and endocrine therapy can be used alone in the case of contraindication to CDK4/6 inhibitors or limited life expectancy. Considerations for special populations-including frail and fit elderly patients, as well as those with visceral disease, brain metastases, and oligometastatic disease-are also explored. For monitoring, we recommend an approach across CDK4/6 inhibitors. For mutational testing, we recommend routinely performing ER/PR/HER2 testing to confirm the subtype of advanced disease at the time of progression and to consider and testing for select patients. Where possible, engage a multidisciplinary care team to apply evidence in a patient-centric manner.
Topics: Humans; Aged; Female; Breast Neoplasms; Neoplasm Recurrence, Local; Aminopyridines
PubMed: 37366894
DOI: 10.3390/curroncol30060411