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Nature Reviews. Rheumatology May 2024
Topics: Pyrimidines; Indazoles; Sulfonamides; Humans; Osteoarthritis; Nanoparticles; Angiogenesis Inhibitors
PubMed: 38503892
DOI: 10.1038/s41584-024-01104-w -
The American Journal of Case Reports Mar 2024BACKGROUND Adamantinoma is a rare low-grade malignant bone tumor, usually found in the tibial diaphysis and metaphysis, with histological similarities to mandibular...
BACKGROUND Adamantinoma is a rare low-grade malignant bone tumor, usually found in the tibial diaphysis and metaphysis, with histological similarities to mandibular ameloblastoma. The most effective treatment of recurrent adamantinoma is not yet clear. This report is of a 22-year-old woman with recurrent tibial adamantinoma treated with the tyrosine kinase inhibitor pazopanib. CASE REPORT We report the case of a 22-year-old woman who was referred to our center for a suspicious bone lesion in the right tibia. Bone biopsy findings were consistent with an adamantinoma. En bloc resection was completed successfully, with no postoperative complications. Five years later, a positive emission tomography scan revealed mildly increased tracer uptake near the area of the previous lesion and in the right inguinal lymph node. Biopsies of the lesion and inguinal lymph node confirmed recurrence of the adamantinoma. Due to abdominal and pelvic metastasis, the patient underwent surgical debulking, along with an appendectomy, right salpingo-oophorectomy, intraoperative radiation therapy, and hyperthermic intraperitoneal chemotherapy. Subsequently, the patient was placed on pazopanib for 4 months; however, her tumor continued to worsen after 4 months of chemotherapy. Currently, the patient is receiving gemcitabine and docetaxel as second-line medical therapy. CONCLUSIONS This report showed that pazopanib as standalone treatment does not appear to have promising role on patient outcomes. To the best of our knowledge, this is the second report of pazopanib in the treatment of adamantinoma.
Topics: Female; Humans; Young Adult; Adamantinoma; Ameloblastoma; Bone Neoplasms; Indazoles; Pyrimidines; Sulfonamides; Tibia
PubMed: 38486378
DOI: 10.12659/AJCR.941248 -
Drug Metabolism and Disposition: the... Apr 2024Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a...
Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, pregnane X receptor and aryl hydrocarbon receptor ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. Sulfotransferase 2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an farnesoid X receptor ligand. CYP7A1 inducers significantly increased bile acid (BA) production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery. SIGNIFICANCE STATEMENT: Kinase inhibitors, pazopanib and CP-724714, inhibit BSEP and induce CYP7A1 expression independent of small heterodimer partner (SHP) expression, leading to increased bile acid (BA) production and demonstrating clinically elevated drug-induced liver toxicity. MEK1/2 inhibitors that show BSEP-independent drug-induced liver injury (DILI) induced the CYP7A1 gene accompanied by SHP suppression. CYP7A1 induction via SHP-dependent or independent mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition. Monitoring BA production in hepatocytes can reliably detect the total effects of BA-related gene regulation for de-risking.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 11; Indazoles; Chemical and Drug Induced Liver Injury; Omeprazole; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase; Pyrimidines; Sulfonamides
PubMed: 38485279
DOI: 10.1124/dmd.124.001675 -
Cureus Feb 2024Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In...
Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In this report, we describe a case of recurrent LGESS where hormone therapy was ineffective, chemotherapy showed a partial response (PR), and pazopanib resulted in stable disease (SD). A 50-year-old patient with LGESS underwent a simple total hysterectomy and bilateral adnexectomy (pT1aN0M0, stage IA). Five years later, pelvic tumors and ascites were observed. Exploratory laparoscopy revealed bloody ascites, an 8 cm pelvic tumor, and extensive peritoneal dissemination. Nuclear atypia of the tumor cells was mild, pleomorphism and mitotic figures could not be confirmed, and necrosis was not observed. Immunostaining was positive for CD10 and estrogen receptor, negative for the BCL6 corepressor (BCOR), and showed a low Ki-67 index. Fluorescence in situ hybridization (FISH) examination of the tissue showed rearrangement of the JAZF zinc finger 1 (JAZF1) gene. Multigene panel testing revealed a homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A). Accordingly, the patient was diagnosed with recurrent LGESS and was treated with an aromatase inhibitor, followed by medroxyprogesterone acetate; both were ineffective. The patient had a PR to chemotherapy (doxorubicin/ifosfamide) and SD to pazopanib. The patient died 1.5 years after recurrence. In conclusion, we present a case of LGESS with a poor prognosis where hormone therapy was ineffective, and chemotherapy and pazopanib were both partially effective. The poor prognosis may have been associated with the CDKN2A homozygous deletion.
PubMed: 38481894
DOI: 10.7759/cureus.54066 -
European Journal of Clinical... Jun 2024Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a...
The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.
PURPOSE
Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers.
METHODS
A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them.
RESULT
The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062).
CONCLUSION
Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.
Topics: Humans; Carcinoma, Renal Cell; Indazoles; Male; Female; Kidney Neoplasms; Sunitinib; Middle Aged; Aged; Sulfonamides; Pyrimidines; Adrenergic beta-Antagonists; Receptors, Vascular Endothelial Growth Factor; Progression-Free Survival; Adult; Aged, 80 and over; Retrospective Studies; Antineoplastic Agents
PubMed: 38478093
DOI: 10.1007/s00228-024-03668-8 -
Cureus Feb 2024Leptomeningeal carcinomatosis (LMC) from renal cell carcinoma (RCC) is rare. There is no established treatment strategy for LMC, and the prognosis is extremely poor. We...
Leptomeningeal carcinomatosis (LMC) from renal cell carcinoma (RCC) is rare. There is no established treatment strategy for LMC, and the prognosis is extremely poor. We describe a case of LMC from RCC treated with local CyberKnife radiotherapy (CKR) and systemic therapy with pazopanib. The patient was a 63-year-old man with brain metastases from right RCC. Surgery and CKR were performed for the brain metastases, and the lesions were subsequently controlled. The patient developed isolated lesions in the pituitary stalk, right internal auditory canal, left ventricular choroid plexus (CP), left facial nerve, and medulla oblongata after the surgery and CKR for brain metastases. We diagnosed LMC and treated the patient with systemic therapy with pazopanib. We performed local therapy with CKR for lesions of the pituitary stalk, right internal auditory canal, left facial nerve, and medulla oblongata. The CP lesion was not treated with CKR because the lesion tended to shrink after systemic therapy with pazopanib. There were no symptoms due to LMC until the end of life and no adverse events due to CKR. Ten years and five months after the nephrectomy for RCC, one year and four months after the initial CKR for brain metastases, and nine months after the diagnosis of LMC, the patient died due to pleural effusion from lung metastases. Our case suggests that CKR combined with pazopanib may be effective as a palliative treatment for LMC from RCC.
PubMed: 38476802
DOI: 10.7759/cureus.54025 -
AAPS PharmSciTech Mar 2024Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of...
Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of lipid-based formulations (LbFs) resulted in reduced PAZ loading due to solid-state mediated low liposolubility. This study aims to enhance our understanding of PAZ crystallinity by synthesizing a lipophilic salt and phospholipid complex and investigating its impact on the drug loading in LbFs. The synthesized pazopanib lipophilic salt and phospholipid complex were extensively characterized. The solid form of pazopanib docusate (PAZ-DOC) and pazopanib phospholipid complex (PAZ-PLC) indicates a reduction in characteristic diffraction peaks of crystalline PAZ. The lipid formulations were prepared using synthesized PAZ-DOC and PAZ-PLC, where PAZ-DOC demonstrated six fold higher drug solubility than the commercial salt form and twice that of the PAZ-PLC due to differences in the crystallinity. Further, the impact of salt and complex formation was assessed on the aqueous drug solubilization using lipolysis and multimedia dissolution experiments. Moreover, the LbFs showed notably faster dissolution compared to the crystalline PAZ and marketed tablet. In terms of in vivo pharmacokinetics, the PAZ-DOC LbF exhibited a remarkable 11-fold increase in AUC value compared to the crystalline PAZ and a 2.5-fold increase compared to Votrient. Similarly, PAZ-PLC LbF showed an approximately nine fold increase in drug exposure compared to the crystalline PAZ, and a 2.2-fold increase compared to Votrient. These findings suggest that disrupting the crystallinity of drugs and incorporating them into LbF could be advantageous for enhancing drug loading and overcoming limitations related to drug absorption.
Topics: Phospholipids; Biological Availability; Drug Compounding; Indazoles; Sodium Chloride; Dioctyl Sulfosuccinic Acid; Solubility; Administration, Oral; Pyrimidines; Sulfonamides
PubMed: 38472682
DOI: 10.1208/s12249-024-02780-3 -
Oncogene May 2024Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying...
Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying mechanisms driving this heterogeneity is essential for developing effective therapeutic strategies. This study revealed that ubiquitin B (UBB) is downregulated in ccRCC, which adversely affects the survival of ccRCC patients. UBB exerts regulatory control over vascular endothelial growth factor A (VEGFA) by directly interacting with specificity protein 1 (SP1), consequently exerting significant influence on angiogenic processes. Subsequently, we validated that DNA methyltransferase 3 alpha (DNMT3A) is located in the promoter of UBB to epigenetically inhibit UBB transcription. Additionally, we found that an unharmonious UBB/VEGFA ratio mediates pazopanib resistance in ccRCC. These findings underscore the critical involvement of UBB in antiangiogenic therapy and unveil a novel therapeutic strategy for ccRCC.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Sp1 Transcription Factor; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Down-Regulation; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Animals; Pyrimidines; Indazoles; DNA Methyltransferase 3A; Sulfonamides; Mice; Ubiquitin; DNA (Cytosine-5-)-Methyltransferases; Drug Resistance, Neoplasm; Promoter Regions, Genetic; Female; Male; Angiogenesis
PubMed: 38467852
DOI: 10.1038/s41388-024-03003-6 -
BMC Urology Mar 2024In the past few years, there has been a continuous rise in the occurrence of renal cell carcinoma (RCC), with RCC recurrence becoming the primary factor behind... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In the past few years, there has been a continuous rise in the occurrence of renal cell carcinoma (RCC), with RCC recurrence becoming the primary factor behind fatalities. Despite numerous clinical trials, the impact of different medications on the long-term survival of patients with RCC after surgery remains uncertain. This network meta-analysis aimed to evaluate the impact of various medications on the survival and safety of drugs in individuals with RCC following nephrectomy.
METHODS
We conducted a thorough search in various databases, including CNKI, WAN FANG DATA, VIP, Web of Science, Cochrane Library (CENTRAL), PubMed, Scopus, and Embase, for articles published prior to June 2, 2023. This meta-analysis incorporated randomized controlled trials (RCTs).
RESULTS
The analysis included 17 studies with 14,298 participants. The findings from the disease-free survival (DFS) analysis indicated that pembrolizumab demonstrated efficacy in enhancing DFS among patients with RCC following nephrectomy when compared to the placebo group (HR = 0.83, 95%CI 0.70 to 0.99). None of the drugs included in the study significantly improved overall survival (OS) and recurrence-free survival (RFS) after nephrectomy. For adverse events (AEs), sorafenib, pazopanib, sunitinib, and nivolumab plus ipilimumab interventions showed a higher incidence of adverse events compared with placebo.
CONCLUSION
The network meta-analysis yielded strong evidence indicating that pembrolizumab could potentially enhance DFS in patients with RCC following nephrectomy, surpassing the effectiveness of a placebo.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Network Meta-Analysis; Chemotherapy, Adjuvant; Neoplasm Recurrence, Local; Nephrectomy
PubMed: 38454397
DOI: 10.1186/s12894-024-01441-8 -
Scientific Reports Mar 2024To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs)... (Observational Study)
Observational Study
To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.
Topics: Aged; Humans; Male; Anilides; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Electrolytes; Indazoles; Kidney Neoplasms; Pharmacovigilance; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; United States; United States Food and Drug Administration; Female; Middle Aged
PubMed: 38454105
DOI: 10.1038/s41598-024-56335-4