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European Urology Oncology Jun 2024High-risk prostate cancer (PCa) patients frequently experience recurrence and progression after radical prostatectomy (RP). Neoadjuvant androgen deprivation therapy... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
High-risk prostate cancer (PCa) patients frequently experience recurrence and progression after radical prostatectomy (RP). Neoadjuvant androgen deprivation therapy (ADT) has not demonstrated a clear oncological benefit and is not currently recommended.
OBJECTIVE
The SUGAR trial is the first phase 2, randomised, controlled, multicentre, noncommercial, open-label study investigating single-agent perioperative darolutamide compared with the standard of care (ie, upfront RP, without neoadjuvant ADT).
DESIGN, SETTING, AND PARTICIPANTS
SUGAR aims to randomise 240 men affected by nonmetastatic PCa, with the major eligibility criteria being International Society of Urological Pathology grade group ≥4, seminal vesicle invasion at magnetic resonance imaging and/or clinically node-positive disease. Patients in the experimental arm will undergo neoadjuvant darolutamide monotherapy, RP, and adjuvant darolutamide, completing 9 mo of treatment.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint is noncurable recurrence-free survival, an innovative and clinically meaningful measure; the secondary endpoints encompass safety; recurrence-free, metastasis-free, and overall survival; pathological response; and quality of life. A predictive biomarker analysis will also be performed.
RESULTS AND LIMITATIONS
Initial data suggest that intensified neoadjuvant treatment with androgen receptor signalling inhibitors (ARSIs) is associated with a sustained pathological response and may improve outcomes, via tumour downstaging and micrometastasis eradication. ARSI monotherapy could further enhance tolerability.
CONCLUSIONS
SUGAR will provide efficacy and safety information on perioperative darolutamide monotherapy compared with upfront RP, in a contemporary high-risk PCa population undergoing surgery.
PATIENT SUMMARY
The on-going SUGAR clinical trial evaluates 9 mo of darolutamide treatment in addition to radical prostatectomy, in men affected by prostate cancer with specific high-risk characteristics. It investigates whether this hormonal treatment can lower the rates of noncurable recurrences, maintaining a favourable tolerability profile.
Topics: Humans; Male; Prostatic Neoplasms; Prostatectomy; Pyrazoles; Sulfonamides; Aged; Middle Aged; Neoadjuvant Therapy
PubMed: 37806843
DOI: 10.1016/j.euo.2023.09.020 -
The Journal of Dermatological Treatment Dec 2024
Topics: Humans; Alopecia Areata; Azetidines; Recurrence; Phenotype; Alopecia; Purines; Pyrazoles; Sulfonamides
PubMed: 38465657
DOI: 10.1080/09546634.2024.2324832 -
Veterinary Research Communications Feb 2024Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the... (Review)
Review
Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.
Topics: Animals; Dogs; Ghrelin; Receptors, Ghrelin; Growth Hormone; Piperidines; Mammals; Pyrazoles
PubMed: 37493940
DOI: 10.1007/s11259-023-10184-0 -
Haematologica Jun 2024Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite... (Comparative Study)
Comparative Study
Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Agammaglobulinaemia Tyrosine Kinase; Middle Aged; Aged; Female; Male; Protein Kinase Inhibitors; Aged, 80 and over; Adult; Pyrimidines; Treatment Outcome; Antineoplastic Agents; Pyrazoles; Tyrosine Kinase Inhibitors
PubMed: 38031799
DOI: 10.3324/haematol.2023.284150 -
JCO Precision Oncology May 2024Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.
Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.
Topics: Humans; Mutation; Neoplasms; Precision Medicine; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor
PubMed: 38709991
DOI: 10.1200/PO.24.00113 -
International Journal of Molecular... May 2024Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the... (Review)
Review
Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, mutations, and unmutated status of the immunoglobulin heavy-chain variable region () gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in or phospholipase Cγ2 (). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Leukemia, Lymphocytic, Chronic, B-Cell; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Pyrimidines; Pyrazoles; Piperidines; Adenine; Phospholipase C gamma; Antineoplastic Agents; Mutation
PubMed: 38791284
DOI: 10.3390/ijms25105246 -
Inflammopharmacology Feb 2024The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α...
The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using H NMR, C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.
Topics: Humans; Arachidonate 5-Lipoxygenase; Molecular Docking Simulation; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor Inhibitors; Thiophenes; Ligands; Spectroscopy, Fourier Transform Infrared; Anti-Inflammatory Agents; Analgesics; Cyclooxygenase 2; Pyrazoles; Neoplasms; Cyclooxygenase 2 Inhibitors; Molecular Structure; Edema; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37985602
DOI: 10.1007/s10787-023-01364-0 -
Journal of Agricultural and Food... Jan 2024Fipronil, classified as a phenylpyrazole insecticide, is utilized to control agricultural, public health, and veterinary pests. Notably, its unique ecological fate... (Review)
Review
Fipronil, classified as a phenylpyrazole insecticide, is utilized to control agricultural, public health, and veterinary pests. Notably, its unique ecological fate involves degradation to toxic metabolites, which poses the risk of contamination in water and foodstuffs and potential human exposure through the food chain. In response to these concerns, there is a pressing need to develop analytical methodologies for detecting fipronil and its metabolites. This review provides a concise overview of the mode of action, metabolism, and toxicology of fipronil. Additionally, various detection strategies, encompassing antibody-based immunoassays and emerging analytical techniques, such as fluorescence assays based on aptamer/molecularly imprinted polymer/fluorescent probes, electrochemical sensors, and Raman spectroscopy, are thoroughly reviewed and discussed. The focus extends to detecting fipronil and its metabolites in crops, fruits, vegetables, animal-derived foods, water, and bodily fluids. This comprehensive exploration contributes valuable insights into the field, aiming to foster the development and innovation of more sensitive, rapid, and applicable analytical methods.
Topics: Animals; Humans; Insecticides; Pyrazoles; Immunoassay; Water
PubMed: 38252458
DOI: 10.1021/acs.jafc.3c07428 -
The Journal of Investigative Dermatology Oct 2023Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory...
Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4 T cells, CD8 T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.
Topics: Mice; Animals; Janus Kinase Inhibitors; CD8-Positive T-Lymphocytes; Dermatitis, Allergic Contact; Pyrazoles; Disease Models, Animal
PubMed: 37028703
DOI: 10.1016/j.jid.2023.03.1667 -
American Journal of Respiratory and... Jun 2024Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented...
Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.
Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Nasal swabs from 13 children with CF and at least one allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Proportions of -positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.
Topics: Humans; Cystic Fibrosis; Child; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Male; Homeostasis; Benzodioxoles; Aminophenols; Quinolones; Indoles; Drug Combinations; Quinolines; Pyrazoles; Pyrroles; Nasal Mucosa; Pyridines
PubMed: 38259174
DOI: 10.1164/rccm.202310-1836OC