ABSTRACT
Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1â¯000â¯000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10â¯261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11â¯159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.
Subject(s)
Bosentan , Chemical and Drug Induced Liver Injury , Liver Function Tests , Phenylpropionates , Pyridazines , Humans , Phenylpropionates/therapeutic use , Phenylpropionates/adverse effects , Pyridazines/adverse effects , Pyridazines/therapeutic use , Female , Male , Middle Aged , Cross-Sectional Studies , Liver Function Tests/methods , Liver Function Tests/statistics & numerical data , United States , Bosentan/therapeutic use , Adult , Drug Labeling/standards , United States Food and Drug Administration , Antihypertensive Agents/adverse effects , Antihypertensive Agents/therapeutic use , Aged , Endothelin Receptor Antagonists/therapeutic use , Hypertension, Pulmonary/drug therapyABSTRACT
BACKGROUND: In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy. METHODS: Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition. RESULTS: Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001). CONCLUSION: In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.
Subject(s)
Antihypertensive Agents , Phenylpropionates , Pyridazines , Scleroderma, Systemic , Humans , Female , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/complications , Phenylpropionates/therapeutic use , Pyridazines/therapeutic use , Male , Middle Aged , Follow-Up Studies , Antihypertensive Agents/therapeutic use , Adult , Aged , Treatment Outcome , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/physiopathology , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathologyABSTRACT
OBJECTIVE: The objective of this study was to assess the effectiveness and safety of levosimendan as an alternative treatment for pediatric patients with decompensated heart failure unresponsive to conventional inotropes and to emphasize its role in enhancing cardiovascular stability. METHODS: A total of 15 pediatric patients with decompensated heart failure, stemming from acute fulminant myocarditis (53.3%) and post-congenital heart disease surgery complications (46.7%), received levosimendan. The evaluation focused on adverse effects, respiratory support requirements, and concurrent inotropic medication use during levosimendan treatment. Key cardiovascular parameters were assessed at 0, 6, 12, and 24 h post-levosimendan infusion. RESULTS: Levosimendan administration significantly improved key cardiovascular metrics. Left ventricular ejection fraction increased notably from 45±14.8% to 58±15.6% at 24 h (p<0.001). Systolic and diastolic blood pressures rose significantly, with systolic increasing from 79 (68-90) to 98 (89-109) mmHg and diastolic from 47 (40-57) to 66 (54-76) mmHg by 24 h (p<0.001). Heart rate decreased from 162 (111-175) to 132 (99-148) bpm (p=0.02), and lactate levels significantly decreased from 4.15 (2.3-6.5) to 1.85 (0.8-2.6) mmol/L within 6 h (p<0.001). CONCLUSION: Levosimendan demonstrates its significance in managing pediatric heart failure, indicating its safety and potential to enhance cardiac outcomes by reducing reliance on traditional inotropes.
Subject(s)
Cardiotonic Agents , Heart Failure , Hydrazones , Pyridazines , Simendan , Humans , Simendan/therapeutic use , Heart Failure/drug therapy , Cardiotonic Agents/therapeutic use , Pyridazines/therapeutic use , Pyridazines/adverse effects , Male , Female , Hydrazones/therapeutic use , Child, Preschool , Child , Treatment Outcome , Infant , Adolescent , Blood Pressure/drug effects , Myocarditis/drug therapy , Time Factors , Heart Rate/drug effects , Stroke Volume/drug effectsABSTRACT
Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real-world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)-resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib-pretreated cohort.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Australia , Male , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Female , Treatment Outcome , Aged , Adult , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Pyridazines/therapeutic use , Aged, 80 and over , Niacinamide/analogs & derivatives , PyrazolesABSTRACT
Resmetirom is an oral selective THR-ß agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.
Subject(s)
Liver Cirrhosis , Pyridazines , Uracil , Animals , Humans , Liver/metabolism , Liver/drug effects , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Mitochondria/metabolism , Mitochondria/drug effects , Pyridazines/therapeutic use , Uracil/analogs & derivativesABSTRACT
The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.
Subject(s)
Hematopoietic Stem Cell Transplantation , Imidazoles , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Pyridazines , Humans , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Pyridazines/therapeutic use , Adolescent , Imidazoles/therapeutic use , Young Adult , Immunotherapy , Recurrence , Transplantation, HomologousSubject(s)
Liver Cirrhosis , Non-alcoholic Fatty Liver Disease , Pyridazines , Humans , Clinical Trials, Phase III as Topic , Fatty Liver/complications , Fatty Liver/drug therapy , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/drug therapy , Pyridazines/therapeutic use , Thyroid Hormone Receptors beta/agonists , Uracil/analogs & derivativesSubject(s)
Cardiotonic Agents , Hydrazones , Mitral Valve , Pyridazines , Simendan , Ventricular Dysfunction, Right , Humans , Simendan/therapeutic use , Ventricular Dysfunction, Right/drug therapy , Pyridazines/therapeutic use , Hydrazones/therapeutic use , Mitral Valve/surgery , Cardiotonic Agents/therapeutic useSubject(s)
Imatinib Mesylate , Imidazoles , Pyridazines , Humans , Pyridazines/therapeutic use , Pyridazines/adverse effects , Imatinib Mesylate/therapeutic use , Imidazoles/therapeutic use , Imidazoles/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Philadelphia Chromosome , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapyABSTRACT
INTRODUCTION: The treatment outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have improved with various tyrosine kinase inhibitors (TKIs) and bispecific T-cell engagers. Although allogeneic stem cell transplantation (allo-SCT) is the standard treatment for young patients with Ph+ALL, its role remains debatable in the era of TKIs and blinatumomab. AREAS COVERED: There are some issues regarding Ph+ALL. First, do young patients require intensive chemotherapy (IC) in the era of multitarget agents? Second, which TKI is preferred for frontline therapy? Third, should allo-SCT be performed in patients achieving complete remission with ponatinib and IC? Fourth, can chemo-free treatment lead to a cure without allo-SCT? We searched relevant literature from the last 30 years on PubMed; reviewed the role of chemo-free therapies and combinations of ponatinib and IC; and assessed the necessity of allo-SCT in young patients with Ph+ALL. EXPERT OPINION: Allo-SCT may not be needed, even in young patients with Ph+ALL treated with ponatinib-based IC or combined ponatinib and blinatumomab as frontline therapy. When adopting a ponatinib-based chemo-minimized regimen for induction, allo-SCT is needed with posttransplant ponatinib maintenance. Continuous exposure to ponatinib at pre- or post-transplant is regarded as one of the most important factor for the success of treatment.
Subject(s)
Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Transplantation, Homologous , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Hematopoietic Stem Cell Transplantation/methods , Protein Kinase Inhibitors/therapeutic use , Antibodies, Bispecific/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pyridazines/therapeutic use , Treatment Outcome , Molecular Targeted Therapy , Combined Modality Therapy , ImidazolesABSTRACT
Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.
Subject(s)
Antineoplastic Agents , Imatinib Mesylate , Imidazoles , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Pyridazines , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Fusion Proteins, bcr-abl/genetics , Imatinib Mesylate/therapeutic use , Imatinib Mesylate/adverse effects , Imidazoles/therapeutic use , Imidazoles/adverse effects , Imidazoles/administration & dosage , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Progression-Free Survival , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Pyridazines/therapeutic use , Pyridazines/adverse effects , Remission Induction , AdolescentABSTRACT
Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including T315I-mutated disease, which is resistant to first- and second-generation TKIs. Ponatinib was approved for T315I-mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph-positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I-mutated CML and Ph-positive ALL. The response-based dosing of ponatinib in chronic phase CML (CP-CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib-based therapy also resulted in significantly better outcomes in frontline Ph-positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third-generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph-positive ALL.
Subject(s)
Fusion Proteins, bcr-abl , Imidazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Pyridazines , Humans , Pyridazines/therapeutic use , Pyridazines/adverse effects , Imidazoles/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents/therapeutic use , Drug Resistance, NeoplasmABSTRACT
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML), but are endowed with negative effects on endothelial function. OBJECTIVES: We aimed to characterize endothelial function in patients with CML treated with various TKIs. PATIENTS AND METHODS: A total of 48 patients diagnosed with chronicphase CML treated with TKIs, such as imatinib, bosutinib, nilotinib, ponatinib, and asciminib were included. Endothelial function was assessed in the brachial artery and microcirculation based on flowmediated dilation (FMD), reactive hyperemia peripheral arterial tonometry (RHPAT) and flowmediated skin fluorescence (FMSF). RESULTS: Reactive hyperemia index, FMD, reactive hyperemia response (RHR), normoxia oscillatory index, and hyperemic response index did not differentiate between the group of patients with low / moderate risk in the Systematic Coronary Risk Estimation 2 (SCORE2), SCORE2Older Persons (SCORE2OP), and those with high / very high risk scores. Among the patients with low / intermediate risk based on the SCORE2 algorithm, some had lower (below the first quartile) values of the endothelial parameters, reflecting impaired endothelial function, as compared with the high / very high risk patient population. Lower values of the endothelial function parameters were associated with overall longterm treatment with TKIs or ponatinib. Importantly, endothelial function assessed by FMSF (RHR) negatively correlated with total duration of TKI treatment, also after adjustment for age. CONCLUSIONS: Endothelial function in CML patients treated with TKIs was not related to cardiovascular risk based on SCORE2/SCORE2OP algorithms but correlated with CMLspecific factors, including duration of TKI treatment. FMSFbased assessment of skin microcirculation was a sensitive method for detecting the vascular effects of TKIs.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Male , Female , Middle Aged , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Aged , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Adult , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Algorithms , Cardiovascular Diseases/chemically induced , Pyridazines/therapeutic use , Risk AssessmentSubject(s)
Blast Crisis , Imidazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Mutation , Pyridazines , Pyridazines/therapeutic use , Pyridazines/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Imidazoles/therapeutic use , Imidazoles/administration & dosage , Humans , Blast Crisis/genetics , Blast Crisis/drug therapy , Blast Crisis/pathology , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mice , Fusion Proteins, bcr-abl/genetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Niacinamide/analogs & derivatives , PyrazolesSubject(s)
Imidazoles , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Pyridazines , Recurrence , Humans , Pyridazines/therapeutic use , Pyridazines/adverse effects , Pyridazines/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Imidazoles/therapeutic use , Imidazoles/adverse effects , Imidazoles/administration & dosage , Male , Female , Middle Aged , Aged , Adult , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effectsABSTRACT
ABSTRACT: Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 min, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.
Subject(s)
Diaphragm , Hydrazones , Pyridazines , Sepsis , Simendan , Humans , Simendan/therapeutic use , Sepsis/drug therapy , Sepsis/physiopathology , Diaphragm/drug effects , Diaphragm/physiopathology , Male , Female , Middle Aged , Pyridazines/therapeutic use , Hydrazones/therapeutic use , Aged , Single-Blind Method , Adult , Blood Gas AnalysisSubject(s)
Cardiotonic Agents , Heart Failure , Myocardial Contraction , Simendan , Humans , Simendan/therapeutic use , Simendan/pharmacology , Pilot Projects , Myocardial Contraction/physiology , Myocardial Contraction/drug effects , Male , Female , Cardiotonic Agents/therapeutic use , Cardiotonic Agents/pharmacology , Heart Failure/physiopathology , Heart Failure/drug therapy , Heart Failure/therapy , Aged , Middle Aged , Treatment Outcome , Pyridazines/therapeutic useABSTRACT
INTRODUCTION: Selective tyrosine kinase inhibitors are proven effective in patients with non-small lung cancer (NSCLC) with a MET exon 14 skipping mutation. CASE PRESENTATION: The patient developed a metastatic lung adenocarcinoma with a MET exon 14 skipping mutation. She was treated with a first 1b MET inhibitor, Capmatinib, but had to stop the drug because of major hepatotoxicity. A few months later, she started Tepotinib, another 1b MET inhibitor with this time, no sign of hepatotoxicity. DISCUSSION: Adverse events are frequent with 1b MET inhibitors. However, there is a wide interpatient variability. Absence of cross-toxicity between Capmatinib and Tepotinib is misunderstood but can be explained by slight differences in phamarcodynamics and pharmacokinetics. Practitionners have to be warned about severe adverse events to stop or change the drug if necessary. CONCLUSION: This is the first case showing the absence of cross-toxicity between 1b MET inhibitors.