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JAAPA : Official Journal of the... Sep 2023Acute migraine affects millions of people and is one of the most common primary care complaints in the United States. Available first-line abortive treatments are...
Acute migraine affects millions of people and is one of the most common primary care complaints in the United States. Available first-line abortive treatments are limited and vary in efficacy. Newer medications such as calcitonin gene-related peptide (CGRP) receptor antagonists may be a useful alternative. This article describes the use of ubrogepant, a new CGRP receptor antagonist, in a patient with contraindications to traditional medications used for acute migraine.
Topics: Humans; Pyridines; Pyrroles; Migraine Disorders
PubMed: 37668477
DOI: 10.1097/01.JAA.0000931424.73007.a5 -
The Lancet. Neurology May 2024Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.
METHODS
We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing.
FINDINGS
Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study.
INTERPRETATION
Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.
FUNDING
Fulcrum Therapeutics.
Topics: Adult; Female; Humans; Male; Middle Aged; Cyclopropanes; Double-Blind Method; Muscular Dystrophy, Facioscapulohumeral; Pyridines; Treatment Outcome
PubMed: 38631764
DOI: 10.1016/S1474-4422(24)00073-5 -
Sleep Medicine Oct 2023To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE/BACKGROUND
To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial.
PATIENTS/METHODS
The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study.
RESULTS
Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (∼20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%-15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups.
CONCLUSIONS
These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant.
Topics: Humans; Double-Blind Method; Pyridines; Sleep Initiation and Maintenance Disorders; Sleep; Treatment Outcome
PubMed: 37574610
DOI: 10.1016/j.sleep.2023.07.023 -
The Annals of Pharmacotherapy Jun 2024To evaluate the safety and efficacy of the novel KRAS-targeting agents, sotorasib and adagrasib, in treating -mutated non-small cell lung cancer (NSCLC). (Review)
Review
OBJECTIVE
To evaluate the safety and efficacy of the novel KRAS-targeting agents, sotorasib and adagrasib, in treating -mutated non-small cell lung cancer (NSCLC).
DATA SOURCES
A comprehensive English-based literature search of PubMed and Clinicaltrials.gov between January 2000 and July 2023 was conducted using the terms , , , , , and .
STUDY SELECTION AND DATA EXTRACTION
Relevant prescribing information, clinical trials, and treatment guidelines were evaluated.
DATA SYNTHESIS
Sotorasib and adagrasib received accelerated US Food and Drug Administration (FDA) approval following pivotal phase I/II clinical trials. Sotorasib, a first-in-class KRAS inhibitor, demonstrated an overall response rate (ORR) of 41% and a progression-free survival (PFS) of 6.3 months. In a phase III confirmatory trial, sotorasib showed significantly longer PFS compared with docetaxel (5.6 vs. 4.5 months; = 0.0017). Adagrasib produced an ORR of 42.9% and a PFS of 6.5 months. Both drugs present unique safety profiles, with common toxicities, including diarrhea, musculoskeletal pain, fatigue, and hepatotoxicity.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
With mutations being among the most common oncogenic alterations in NSCLC, sotorasib and adagrasib offer new therapeutic avenues for this previously "undruggable" target. Current treatment guidelines list sotorasib and adagrasib as second-line options in patients with confirmed -mutated NSCLC. Additional studies are required to further differentiate the safety and efficacy profiles of these 2 agents and identify their optimal place in therapy.
CONCLUSION
Sotorasib and adagrasib demonstrated promising outcomes in targeting the constitutively active KRAS G12C oncogenic driver, underscoring the need for further research to optimize their therapeutic application in this high-risk population.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Mutation; Molecular Targeted Therapy; Antineoplastic Agents; Pyridines; Pyrimidines; Piperazines
PubMed: 37700573
DOI: 10.1177/10600280231197459 -
Drug Design, Development and Therapy 2023Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of... (Review)
Review
Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease. Lasmiditan is a first-in-class agonist at the 5-HT1F serotonin receptor that does not appear to generate vasoconstriction. This article reviews the design, development, and place in therapy for lasmiditan. A narrative review of the literature using the Ovid MEDLINE database was performed. The rationale behind the development of lasmiditan and pre-clinical, proof-of-concept, Phase II, pivotal, Phase III trials and post-hoc data is covered. Additionally, the efficacy and safety of lasmiditan when compared to other acute treatments in migraine is described, including lasmiditan's side effect profile and status as a Schedule V substance. Further, head-to-head studies of lasmiditan compared with other acute treatments are required.
Topics: Male; Adult; Humans; Female; Serotonin Receptor Agonists; Piperidines; Pyridines; Migraine Disorders; Treatment Outcome
PubMed: 37426628
DOI: 10.2147/DDDT.S380440 -
Expert Review of Hematology 2024Immune thrombocytopenia (ITP), a disease that commonly presents with an increased risk of bleeding, can also paradoxically produce an increased risk of thromboembolic... (Review)
Review
INTRODUCTION
Immune thrombocytopenia (ITP), a disease that commonly presents with an increased risk of bleeding, can also paradoxically produce an increased risk of thromboembolic events. The risk of thromboembolism can be associated with patient-related factors (e.g. co-morbidities, age and history of thrombosis), disease-related factors (e.g. a greater proportion of younger, more reactive platelets, and the presence of microparticles and pro-inflammatory cytokines) and treatment-related factors (e.g. splenectomy, thrombopoietin receptor agonists, and IVIg).
AREAS COVERED
Aspects of the pathophysiology of ITP and the effects of treatment are discussed with emphasis on individualizing treatment based on the patient's thromboembolic risk, treatment options and preferences.
EXPERT OPINION
An increased understanding of the pathophysiology of ITP has led to the development of new agents such as fostamatinib, a spleen tyrosine kinase inhibitor. Further research into the factors contributing to the risks for bleeding and thromboembolic events can contribute to the development of more specific therapies for ITP and allow greater individualization of therapy based on each patient's medical history and clinical status.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Aminopyridines; Morpholines; Thrombocytopenia; Pyridines; Thrombosis; Pyrimidines
PubMed: 38369947
DOI: 10.1080/17474086.2024.2318345 -
BMC Medicine Sep 2023The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral...
A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis.
BACKGROUND
The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC).
METHODS
This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCA).
RESULTS
Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCA had higher ORR and longer median progression-free survival (PFS) than those with gBRCA, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg.
CONCLUSIONS
Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; China; Mutation; Pyridines; Triple Negative Breast Neoplasms
PubMed: 37775744
DOI: 10.1186/s12916-023-03046-8 -
Environment International Apr 2024Bumblebees are among the most important wild bees for pollination of crops and securing wildflower diversity. However, their abundance and diversity have been on a...
Bumblebees are among the most important wild bees for pollination of crops and securing wildflower diversity. However, their abundance and diversity have been on a steady decrease in the last decades. One of the most important factors leading to their decline is the frequent use of plant protection products (PPPs) in agriculture, which spread into forests and natural reserves. Mixtures of different PPPs pose a particular threat because of possible synergistic effects. While there is a comparatively large body of studies on the effects of PPPs on honeybees, we still lack data on wild bees. We here investigated the influence of the frequent fungicide Cantus® Gold (boscalid/dimoxystrobin), the neonicotinoid insecticide Mospilan® (acetamiprid) and their combination on bumblebees. Cognitive performance and foraging flights of bumblebees were studied. They are essential for the provisioning and survival of the colony. We introduce a novel method for testing four treatments simultaneously on the same colony, minimizing inter-colony differences. For this, we successfully quartered the colony and moved the queen daily between compartments. Bumblebees appeared astonishingly resilient to the PPPs tested or they have developed mechanisms for detoxification. Neither learning capacity nor flight activity were inhibited by treatment with the single PPPs or their combination.
Topics: Bees; Animals; Neonicotinoids; Fungicides, Industrial; Strobilurins; Insecticides; Pyridines; Biphenyl Compounds; Niacinamide
PubMed: 38554503
DOI: 10.1016/j.envint.2024.108608 -
European Journal of Medicinal Chemistry Nov 2023Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a...
Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators.
Topics: Escherichia coli; Escherichia coli Proteins; Anti-Bacterial Agents; Pyridines; Multidrug Resistance-Associated Proteins; Carrier Proteins
PubMed: 37459793
DOI: 10.1016/j.ejmech.2023.115630 -
Bioorganic Chemistry Dec 2023The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and...
The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.
Topics: Humans; Molecular Structure; Structure-Activity Relationship; Caspase 3; Vascular Endothelial Growth Factor Receptor-2; bcl-2-Associated X Protein; Tumor Suppressor Protein p53; Apoptosis; Antineoplastic Agents; Proto-Oncogene Proteins c-bcl-2; Molecular Dynamics Simulation; Pyridines; Molecular Docking Simulation; Cell Proliferation; Drug Screening Assays, Antitumor
PubMed: 37871393
DOI: 10.1016/j.bioorg.2023.106910