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Journal of Cardiothoracic and Vascular... Apr 2024
Topics: Humans; Hemorrhage; Blood Coagulation; Pyridones; Pyrazoles; Anticoagulants; Atrial Fibrillation; Stroke
PubMed: 38368165
DOI: 10.1053/j.jvca.2024.01.019 -
Expert Opinion on Pharmacotherapy 2023Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or... (Review)
Review
INTRODUCTION
Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or macrovascular events. Characteristic aquagenic pruritus and fatigue can have a substantial impact on quality of life. Over time, a minority will transform into more aggressive conditions such as post-PV myelofibrosis or acute myeloid leukemia. The JAK1 and 2 inhibitor Ruxolitinib has been approved for the treatment of PV after the failure of first-line therapies. Other JAK inhibitors have not been extensively tested in PV.
AREAS COVERED
In this article, we describe how PV is diagnosed and conventional treatments before moving to cover the status of JAK inhibitors as a therapeutic option for this disease and other novel therapies following a literature review.
EXPERT OPINION
Ruxolitinib when used for PV delivers control of blood counts and reduces disease-related symptoms. Recent data have also suggested that treatment with Ruxolitinib can improve event-free survival and may be associated with disease modification. Adverse effects of Ruxolitinib such as the increased risk of infection and squamous cell skin cancers, most likely to be linked to immunosuppression and prior lines of therapies, require careful consideration.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Quality of Life; Pyrazoles; Nitriles; Janus Kinase 2
PubMed: 37343285
DOI: 10.1080/14656566.2023.2228688 -
International Journal of Molecular... Aug 2023Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They... (Review)
Review
Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives have been synthesized and evaluated for their anticancer potential against various cancer cell lines. Structure-activity relationship studies have shown that appropriate substitution on different positions of the pyrazole ring can significantly enhance anticancer efficacy and tumor selectivity. It is noteworthy that many pyrazole derivatives have demonstrated multiple mechanisms of anticancer action by interacting with various targets including tubulin, EGFR, CDK, BTK, and DNA. Therefore, this review summarizes the current understanding on the structural features of pyrazole derivatives and their structure-activity relationships with different targets, aiming to facilitate the development of potential pyrazole-based anticancer drugs. We focus on the latest research advances in anticancer activities of pyrazole compounds reported from 2018 to present.
Topics: Antineoplastic Agents; Pyrazoles; Cell Line; Structure-Activity Relationship; Tubulin
PubMed: 37628906
DOI: 10.3390/ijms241612724 -
Lung Cancer (Amsterdam, Netherlands) May 2024Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic... (Review)
Review
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
Topics: Humans; Lactams; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Pyrazoles; Lung Neoplasms; Protein Kinase Inhibitors; Lactams, Macrocyclic; Anaplastic Lymphoma Kinase; Drug-Related Side Effects and Adverse Reactions; Antineoplastic Agents; Disease Management
PubMed: 38554546
DOI: 10.1016/j.lungcan.2024.107535 -
Ophthalmic Plastic and Reconstructive...
Topics: Humans; Vitiligo; Pyrazoles; Eyelids; Nitriles; Pyrimidines
PubMed: 37450618
DOI: 10.1097/IOP.0000000000002461 -
Future Medicinal Chemistry Aug 2023Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent... (Review)
Review
Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent need for the development of novel potent chemical entities. Azoles, particularly pyrazole, could interact with different biological targets and exhibit diverse biological properties including anticancer activity. Many clinically used anticancer agents own an azole moiety, demonstrating that azoles are privileged and pivotal templates in the discovery of novel anticancer chemotherapeutics. The present article is an attempt to highlight the recent advances in pyrazole-azole hybrids with anticancer potential and discuss the structure-activity relationships, covering articles published from 2018 to present, to facilitate the rational design of more effective anticancer candidates.
Topics: Humans; Azoles; Structure-Activity Relationship; Antineoplastic Agents; Neoplasms; Pyrazoles
PubMed: 37610862
DOI: 10.4155/fmc-2023-0138 -
Current Hematologic Malignancy Reports Jun 2024Summarize best practices for management of patients with early myelofibrosis (MF). (Review)
Review
PURPOSE OF REVIEW
Summarize best practices for management of patients with early myelofibrosis (MF).
RECENT FINDINGS
Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms. The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease.
Topics: Humans; Primary Myelofibrosis; Disease Management; Pyrazoles; Pyrimidines; Nitriles; Janus Kinase Inhibitors; Practice Guidelines as Topic
PubMed: 38441783
DOI: 10.1007/s11899-024-00729-8 -
Targeted Oncology Jul 2023Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.
A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.
BACKGROUND
Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.
OBJECTIVE
The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.
PATIENTS AND METHODS
Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle.
RESULTS
Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified).
CONCLUSION
Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT02482311; registered June 2015.
Topics: Female; Humans; Triple Negative Breast Neoplasms; Pyrimidinones; Pyrazoles; Ovarian Neoplasms; Small Cell Lung Carcinoma; Lung Neoplasms
PubMed: 37278879
DOI: 10.1007/s11523-023-00965-7 -
Clinical Cancer Research : An Official... Jan 2024In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after...
In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee-assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% [95% confidence interval (CI), 41-59], and the complete response rate was 13% (95% CI, 7-20), with an estimated median duration of response of 8.3 months. The most common nonhematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Pyrazoles; Protein Kinase Inhibitors; Fatigue
PubMed: 37624619
DOI: 10.1158/1078-0432.CCR-23-1272 -
Pest Management Science Dec 2023Fertilizers and pesticides are commonly used simultaneously in agriculture. However, the effects of common fertilizers on the dissipation, enantioselectivity, and...
BACKGROUND
Fertilizers and pesticides are commonly used simultaneously in agriculture. However, the effects of common fertilizers on the dissipation, enantioselectivity, and metabolites of the chiral insecticide fipronil in soil are yet to be reported.
RESULT
An enantioselective method for detecting fipronil enantiomers and their metabolites in different soil matrices was developed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The results showed that organic and compound fertilizers significantly decreased the degradation of S- and R-fipronil, whereas phosphate and microbial fertilizers slightly reduced fipronil dissipation. The half-life values for S- and R-fipronil were 43.3 and 28.9 days, 99.0 and 63.0 days, 69.3 and 43.3 days, 46.2 and 30.1 days, and 43.3 and 31.5 days, respectively, in the control and the four fertilizer treatments, respectively. The enantioselectivity of fipronil enantiomers occurred and R-fipronil exhibited preferential degradation with an enantiomeric fraction (EF) of 0.4900-0.6238 in all treatments; but the four tested fertilizers decreased enantioselectivity with EF values changed from 0.4970 to 0.6238 in the control to 0.4900-0.6171 in fertilizer treatments. Two metabolites, fipronil sulfone and sulfide, were produced, and their amounts increased with culture time in all treatments. Fertilization reduced the content of fipronil sulfide and sulfone but hardly reduced the total amount of fipronil and its metabolites.
CONCLUSION
Fertilizers affect the environmental behavior of fipronil in the soil. Fertilization alters the soil bacterial community, which may be an important factor. This influence is relatively complicated and should be comprehensively considered in the environmental risk assessment of pesticides. © 2023 Society of Chemical Industry.
Topics: Soil; Fertilizers; Chromatography, Liquid; Tandem Mass Spectrometry; Pesticides; Sulfides; Fertilization; Pyrazoles
PubMed: 37615248
DOI: 10.1002/ps.7737