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Neurodegenerative Disease Management Aug 2023This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of... (Review)
Review
WHAT IS THIS SUMMARY ABOUT?
This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition.
WHAT WERE THE RESULTS?
Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a 'dummy' treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped).
WHAT DO THE RESULTS MEAN?
The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS. NCT02975349 (multiple sclerosis), NCT03233230 (rheumatoid arthritis), NCT02975336 (systemic lupus erythematosus) (ClinicalTrials.gov).
Topics: Humans; Multiple Sclerosis; Pyrimidines; Lupus Erythematosus, Systemic; Arthritis, Rheumatoid
PubMed: 37345645
DOI: 10.2217/nmt-2023-0003 -
Pediatric Blood & Cancer Dec 2023Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat...
BACKGROUND
Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.
PROCEDURE
We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1-21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy-related AML (n = 1).
RESULTS
Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) C , V , T , and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m , 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m , respectively. T , V , and C , but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi).
CONCLUSIONS
Pevonedistat 20 mg/m combined with Aza-FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza-FLA combination demonstrated significant anti-leukemic activity.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Chronic Disease; Cyclopentanes; Cytarabine; Feasibility Studies; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Pyrimidines; Vidarabine
PubMed: 37710306
DOI: 10.1002/pbc.30672 -
European Journal of Medicinal Chemistry Aug 2023Salt-inducible kinases (SIKs) play a crucial role in inflammation process, acting as molecular switches that regulate the transformation of M1/M2 macrophages. HG-9-91-01...
Salt-inducible kinases (SIKs) play a crucial role in inflammation process, acting as molecular switches that regulate the transformation of M1/M2 macrophages. HG-9-91-01 is a SIKs inhibitor with potent inhibitory activity against SIKs in the nanomolar range. However, its poor drug-like properties, including a rapid elimination rate, low in vivo exposure and high plasma protein binding rate, have hindered further research and clinical application. To improve the drug-like properties of HG-9-91-01, a series of pyrimidine-5-carboxamide derivatives were designed and synthesized through a molecular hybridization strategy. The most promising compound 8h was obtained with favorable activity and selectivity on SIK1/2, excellent metabolic stability in human liver microsome, enhanced in vivo exposure and suitable plasma protein binding rate. Mechanism research showed that compound 8h significantly up-regulated the expression of anti-inflammatory cytokine IL-10 and reduced the expression of pro-inflammatory cytokine IL-12 in bone marrow-derived macrophages. Furthermore, it significantly elevated expression of cAMP response element-binding protein (CREB) target genes IL-10, c-FOS and Nurr77. Compound 8h also induced the translocation of CREB-regulated transcriptional coactivator 3 (CRTC3) and elevated the expression of LIGHT, SPHK1 and Arginase 1. Additionally, compound 8h demonstrated excellent anti-inflammatory effects in a DSS-induced colitis model. Generally, this research indicated that compound 8h has the potential to be developed as an anti-inflammatory drug candidate.
Topics: Humans; Cytokines; Inflammatory Bowel Diseases; Interleukin-10; Protein Serine-Threonine Kinases; Pyrimidines
PubMed: 37178481
DOI: 10.1016/j.ejmech.2023.115469 -
Future Oncology (London, England) Aug 2023The EPI VITRAKVI study is a retrospective study designed to place the results of the single-arm Phase I/II larotrectinib SCOUT trial into context by comparison with...
The EPI VITRAKVI study is a retrospective study designed to place the results of the single-arm Phase I/II larotrectinib SCOUT trial into context by comparison with external historical controls. Its primary objective is to compare the time to medical treatment failure between larotrectinib and the historical standard of care (chemotherapy) in patients with infantile fibrosarcoma. External historical cohorts have been selected by using objective criteria. The Inverse Probability of Treatment Weighting method will be used to adjust for potential confounding. The current publication illustrates how an external control arm study can complement data from a single-arm trial and addresses uncertainties encountered in the assessment of therapies targeting rare abnormalities where randomized controlled trials are considered not feasible. Clinical Trial Registration: NCT05236257 (ClinicalTrials.gov).
Topics: Humans; Fibrosarcoma; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Standard of Care; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic
PubMed: 37133249
DOI: 10.2217/fon-2023-0114 -
Chemical Biology & Drug Design Feb 2024The increase in the prevalence of antibiotic-resistant pathogens leads to a decrease in the number of antimicrobial agents for the treatment of infections and prompts...
The increase in the prevalence of antibiotic-resistant pathogens leads to a decrease in the number of antimicrobial agents for the treatment of infections and prompts researchers to search for new effective antimicrobial drugs. This study reports the synthesis of novel triphenylphosphonium-functionalized substituted pyrimidines and in vitro evaluation of their antibacterial and antibiofilm activity. Most of the synthesized derivatives showed high antibacterial activity (MIC = 0.39-1.56 μg/mL) against the methicillin-resistant strain of S. aureus 222. Compounds 2a and 11 exhibited a high level of antibiofilm activity against S. aureus 222 and E. coli 311. The triphenylphosphonium-containing pyrimidines 11 and 2a reduced S. aureus 222 biofilm formation by 99.1% and 95.8%, respectively. In addition, compound 2a was the most active against E. coli 311 biofilm formation (the biomass decreased by 98.4%).
Topics: Pyrimidines; Staphylococcus aureus; Escherichia coli; Structure-Activity Relationship; Microbial Sensitivity Tests; Anti-Bacterial Agents; Anti-Infective Agents; Biofilms; Methicillin-Resistant Staphylococcus aureus; Organophosphorus Compounds
PubMed: 38355145
DOI: 10.1111/cbdd.14483 -
BMJ Open Aug 2023This study aimed to conduct a thorough analysis of fluid retention-associated adverse events (AEs) associated with BCR::ABL inhibitors.
Fluid retention-associated adverse events in patients treated with BCR::ABL1 inhibitors based on FDA Adverse Event Reporting System (FAERS): a retrospective pharmacovigilance study.
OBJECTIVES
This study aimed to conduct a thorough analysis of fluid retention-associated adverse events (AEs) associated with BCR::ABL inhibitors.
DESIGN
A retrospective pharmacovigilance study.
SETTING
Food and Drug Administration Adverse Event Reporting System (FAERS) database for BCR::ABL inhibitors was searched from 1 January 2004 to 30 September 2021.
MAIN OUTCOME MEASURES
Reporting OR (ROR) and 95% CI were used to detect the signals. ROR was calculated by dividing the odds of fluid retention event reporting for the target drug by the odds of fluid retention event reporting for all other drugs. The signal was considered positive if the lower limit of 95% CI of ROR was >1. The analysis was run only considering coupled fluid retention events/BCR::ABL inhibitors with at least three cases.
RESULTS
A total of 97 823 reports were identified in FAERS. Imatinib had the most fluid retention signals, followed by dasatinib and nilotinib, while bosutinib and ponatinib had fewer signals. Periorbital oedema (ROR=24.931, 95% CI 22.404 to 27.743), chylothorax (ROR=161.427, 95% CI 125.835 to 207.085), nipple swelling (ROR=48.796, 95% CI 26.270 to 90.636), chylothorax (ROR=35.798, 95% CI 14.791 to 86.642) and gallbladder oedema (ROR=77.996, 95% CI 38.286 to 158.893) were the strongest signals detected for imatinib, dasatinib, nilotinib, bosutinib and ponatinib, respectively. Pleural effusion, pericardial effusion and pulmonary oedema were detected for all BCR::ABL inhibitors, with dasatinib having the highest RORs for pleural effusion (ROR=37.424, 95% CI 35.715 to 39.216), pericardial effusion (ROR=14.146, 95% CI 12.649 to 15.819) and pulmonary oedema (ROR=11.217, 95% CI 10.303 to 12.213). Patients aged ≥65 years using dasatinib, imatinib, nilotinib or bosutinib had higher RORs for pleural effusion, pericardial effusion and pulmonary oedema. Patients aged ≥65 years and females using imatinib had higher RORs for periorbital oedema, generalised oedema and face oedema.
CONCLUSIONS
This pharmacovigilance study serves as a clinical reminder to physicians to be more vigilant for fluid retention-associated AEs with BCR::ABL inhibitors.
Topics: Female; Humans; United States; Dasatinib; Imatinib Mesylate; Pharmacovigilance; Pulmonary Edema; Retrospective Studies; Chylothorax; Pericardial Effusion; Pyrimidines; Pleural Effusion; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 37536976
DOI: 10.1136/bmjopen-2022-071456 -
Targeted Oncology May 2024Futibatinib (LYTGOBI) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor... (Review)
Review
Futibatinib (LYTGOBI) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20 mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.
Topics: Humans; Cholangiocarcinoma; Bile Duct Neoplasms; Neoplasm Metastasis; Pyrimidines; Pyrazoles; Pyrroles
PubMed: 38724820
DOI: 10.1007/s11523-024-01059-8 -
Acta Haematologica 2024
Topics: Humans; Primary Myelofibrosis; Benzamides; Pyrimidines
PubMed: 38467116
DOI: 10.1159/000538289 -
Bioorganic & Medicinal Chemistry Jul 2023A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic...
A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.
Topics: Ribonuclease H, Human Immunodeficiency Virus; Reverse Transcriptase Inhibitors; Ribonuclease H; Pyrimidines; Antiparasitic Agents; Structure-Activity Relationship
PubMed: 37336083
DOI: 10.1016/j.bmc.2023.117376 -
Journal of Medicinal Chemistry Aug 2023Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has been confirmed to protect against...
Structure-Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury.
Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has been confirmed to protect against AKI, suggesting that SIRT5 inhibitors might be a promising therapeutic approach for AKI. Herein, structural optimization was performed on our previous compound (IC = 3.0 μM), and a series of 2,4,5-trisubstituted pyrimidine derivatives have been synthesized. The structure-activity relationship (SAR) analysis led to the discovery of three nanomolar level SIRT5 inhibitors, of which the most potent compound (IC = 310 nM) was demonstrated to be a substrate-competitive and selective inhibitor. Importantly, significantly alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice. Further studies revealed that regulated protein succinylation and the release of proinflammatory cytokines in the kidneys of septic AKI mice. Collectively, these results highlighted that targeting SIRT5 has a therapeutic potential against septic AKI.
Topics: Animals; Mice; Acute Kidney Injury; Kidney; Pyrimidines; Sepsis; Sirtuins; Structure-Activity Relationship
PubMed: 37556731
DOI: 10.1021/acs.jmedchem.3c01031