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Advances in Therapy Sep 2022Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting β-agonist [LABA], and long-acting muscarinic antagonist... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting β-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD.
METHODS
This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible).
RESULTS
The NMA was informed by five trials reporting FEV at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6).
CONCLUSION
The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines
PubMed: 35849317
DOI: 10.1007/s12325-022-02231-0 -
Journal of Clinical Oncology : Official... May 2021Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a...
PURPOSE
Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in -mutant cells.
METHODS
This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with -mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).
RESULTS
Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only mutations by next-generation sequencing had higher rates of CR (69% 25%; = .006). Responding patients had significant reductions in variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 7.5 months; = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).
CONCLUSION
Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with -mutant MDS and oligoblastic AML.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Biomarkers, Tumor; Female; Humans; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Quinuclidines; Tumor Suppressor Protein p53
PubMed: 33449813
DOI: 10.1200/JCO.20.02341 -
Journal of the American Chemical Society Jan 2020We accidentally found that YM-53601, a known small-molecule inhibitor of squalene synthase (SQS), selectively depletes SQS from mammalian cells upon UV irradiation....
We accidentally found that YM-53601, a known small-molecule inhibitor of squalene synthase (SQS), selectively depletes SQS from mammalian cells upon UV irradiation. Further analyses indicated that the photodepletion of SQS requires its short peptide segment located at the COOH terminus. Remarkably, when the 27 amino acid peptide was fused to green fluorescent protein or unrelated proteins at either the NH or COOH terminus, such fusion proteins were selectively depleted when the cells were treated with both YM-53601 and UV exposure. Product analysis and electron spin resonance experiments suggested that the UV irradiation promotes homolytic C-O bond cleavage of the aryl ether group in YM-53601. It is likely that the radical species generated from UV-activated YM-53601 abstract hydrogen atoms from the SQS peptide, leading to the photolysis of the entire protein. The pair of the SQS peptide and YM-53601 discovered in the present study paves the way for the design of a new small-molecule-controlled optogenetic tool.
Topics: Farnesyl-Diphosphate Farnesyltransferase; HEK293 Cells; Humans; Peptides; Photolysis; Quinuclidines
PubMed: 31899620
DOI: 10.1021/jacs.9b09178 -
Haematologica Feb 2022APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the...
APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.
Topics: Cell Death; Ferroptosis; Humans; Leukemia, Myeloid, Acute; Quinuclidines
PubMed: 33406814
DOI: 10.3324/haematol.2020.259531 -
International Journal of Chronic... 2022Triple therapy (TT; inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β-agonist) is recommended for patients with chronic obstructive pulmonary...
PURPOSE
Triple therapy (TT; inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β-agonist) is recommended for patients with chronic obstructive pulmonary disease (COPD) at risk of exacerbation, although the optimum timing of TT initiation remains unclear. This study evaluated the impact of prompt versus delayed initiation of single-inhaler TT (fluticasone furoate, umeclidinium, and vilanterol [FF/UMEC/VI]) following a COPD exacerbation.
PATIENTS AND METHODS
This retrospective cohort study used data from the IQVIA PharMetrics Plus database. Patients initiating FF/UMEC/VI following a COPD exacerbation between September 18, 2017 and September 30, 2019 (exacerbation = index date) were categorized as prompt (within 30 days of index) or delayed (31-180 days after index) FF/UMEC/VI initiators. Patients were aged ≥40 years at index, had ≥12 months' continuous health insurance coverage before index (baseline), and ≥6 months' coverage after index (follow-up). Patients with a COPD exacerbation or claim for FF/UMEC/VI during baseline were excluded. Inverse probability weighting was used to adjust for differences in baseline characteristics between cohorts. Exacerbations (overall, moderate, and severe), healthcare costs, and readmissions were evaluated during follow-up.
RESULTS
A total of 1904 patients (prompt: 529; delayed: 1375) were included. After weighting, baseline characteristics were well balanced between cohorts. Patients in the prompt cohort had significantly lower rates per person-year (PPY) of overall (0.98 vs 1.23; rate ratio [RR] [95% CI] = 0.79 [0.65-0.94], p = 0.004), moderate (0.86 vs 1.03; RR [95% CI] = 0.84 [0.69-0.99], p = 0.038), and severe (0.11 vs 0.20; RR [95% CI] = 0.57 [0.37-0.79], p = 0.002) exacerbations, compared with delayed initiators. Mean all-cause and COPD-related healthcare costs were significantly lower among prompt initiators (all-cause: $26,107 vs $32,400 PPY, p = 0.014; COPD-related: $12,694 vs $17,640 PPY, p = 0.002).
CONCLUSION
Prompt initiation of FF/UMEC/VI following a moderate or severe COPD exacerbation was associated with significant reductions in exacerbations and healthcare costs relative to delayed initiation.
Topics: Administration, Inhalation; Adult; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies
PubMed: 35281476
DOI: 10.2147/COPD.S337668 -
Journal of Clinical Oncology : Official... Jan 2022We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting.... (Comparative Study)
Comparative Study
PURPOSE
We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.
PATIENTS AND METHODS
Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate).
RESULTS
Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( < .001) and 0.3% versus 3.6% ( < .001), respectively.
CONCLUSION
FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.
Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Double-Blind Method; Drug Combinations; Female; Humans; Isoquinolines; Japan; Male; Middle Aged; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Pyridines; Quinuclidines; Time Factors; Treatment Outcome; Vomiting
PubMed: 34793245
DOI: 10.1200/JCO.21.01315 -
Annals of Oncology : Official Journal... Mar 2006Important progress in the prophylaxis of chemotherapy-induced acute and delayed emesis has been achieved but some fundamental needs still remain that requires new,... (Review)
Review
BACKGROUND
Important progress in the prophylaxis of chemotherapy-induced acute and delayed emesis has been achieved but some fundamental needs still remain that requires new, efficacious antiemetic drugs.
METHODS
A critical review of the results of published studies of aprepitant, a new NK1 receptor antagonist, and of palonosetron, a 5-HT3 receptor antagonist with a longer half-life.
RESULTS
Aprepitant combined with dexamethasone and a 5-HT3 antagonist significantly increased the control of acute emesis with respect to dexamethasone and a 5-HT3 antagonist alone after cisplatin and moderately emetogenic chemotherapy. For cisplatin nausea, aprepitant combined with dexamethasone significantly increased the control of delayed emesis with respect to dexamethasone alone, while for moderately emetogenic chemotherapy aprepitant is superior to a 5-HT3 antagonist in the control of delayed emesis. Palonosetron showed superior or similar efficacy to ondansetron and dolasetron in patients submitted to moderately emetogenic chemotherapy and similar efficacy to ondansetron in patients submitted to cisplatin.
CONCLUSIONS
More studies are necessary comparing aprepitant alone or combined with dexamethasone with respect to the recommended antiemetic drugs for the prevention of delayed emesis induced by cisplatin and moderately emetogenic chemotherapy as well as for palonosetron combined with dexamethasone with respect to other 5-HT3 antagonists combined with dexamethasone.
Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Dexamethasone; Drug Therapy, Combination; Humans; Isoquinolines; Medical Oncology; Morpholines; Nausea; Neoplasms; Palonosetron; Quinuclidines; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Vomiting
PubMed: 16608997
DOI: 10.1093/annonc/mdj936 -
Journal of Clinical Oncology : Official... May 2021-mutated () myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20%...
PURPOSE
-mutated () myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.
PATIENTS AND METHODS
This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R MDS and AML patients.
RESULTS
Fifty-two patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( < .01) and higher age ( = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.
CONCLUSION
In this very high-risk population of MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mutation; Myelodysplastic Syndromes; Quinuclidines; Tumor Suppressor Protein p53
PubMed: 33600210
DOI: 10.1200/JCO.20.02342 -
International Journal of Molecular... Aug 2021At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an... (Review)
Review
At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.
Topics: Animals; Cognition Disorders; Humans; Muscarinic Agonists; Neurodegenerative Diseases; Neuropharmacology; Pharmaceutical Preparations; Quinuclidines; Thiophenes
PubMed: 34445613
DOI: 10.3390/ijms22168908 -
Drug Design, Development and Therapy 2018Penehyclidine hydrochloride (PHC) is an anticholinergic drug manufactured in China. It is used widely in clinics as a reversal agent in cases of organic phosphorus... (Review)
Review
BACKGROUND
Penehyclidine hydrochloride (PHC) is an anticholinergic drug manufactured in China. It is used widely in clinics as a reversal agent in cases of organic phosphorus poisoning and as a preanesthetic medication. Compared with other anticholinergic agents, PHC confers substantial advantages. Here, in this review, we focus on its important clinical effects for organic phosphorus poisoning, preanesthetic medication, and the protective effects on certain visceral organs.
MATERIALS AND METHODS
Our bibliographic sources include the PubMed and China National Knowledge Infrastructure (CNKI) databases, updated in March 2018. To assess the data in detail, we used the search terms "penehyclidine hydrochloride," "preanesthetic medication," and "organic phosphorus." Papers were restricted to those published in the English and Chinese languages, and to "paper" and "review" as the document type.
RESULTS
PHC can effectively antagonize the symptoms of central and peripheral poisoning caused by organophosphorus poisoning. As a preanesthetic medication, it can not only effectively reduce mucus secretion and vascular infiltration but can also relax airway smooth muscles, dilate bronchioles in pulmonary conditions such as bronchiectasis, and increase pulmonary dynamic compliance. It can also prevent reflexive actions of the vagus nerve caused by excessive acetylcholine release such as abnormal airway contraction. Furthermore, it can strengthen sedation, bidirectionally regulate heart rate, and effectively inhibit respiratory secretions. In recent studies, PHC was shown to also have protective effects on various organs, such as the heart, lungs, brain, kidneys, intestines, and liver.
CONCLUSION
PHC has beneficial pharmacological properties used in the treatment of organophosphorus poisoning and as a preanesthetic medication for its few side effects. It also has protective effects on multiple organs, suggesting that PHC has extensive clinical application value which is worth further research. This review should be of help to those intending to research these topics further.
Topics: Animals; Cholinergic Antagonists; Humans; Organophosphate Poisoning; Preanesthetic Medication; Quinuclidines
PubMed: 30323561
DOI: 10.2147/DDDT.S177435