-
Life (Basel, Switzerland) Nov 2023Febuxostat, initially developed as a xanthine oxidase inhibitor to address hyperuricemia in gout patients, has evolved into a versatile therapeutic agent with... (Review)
Review
Febuxostat, initially developed as a xanthine oxidase inhibitor to address hyperuricemia in gout patients, has evolved into a versatile therapeutic agent with multifaceted applications. This review provides a comprehensive overview of febuxostat's mechanism of action, its effectiveness in gout management, its cardiovascular safety profile, renal and hepatic effects, musculoskeletal applications, safety considerations, and emerging research prospects. Febuxostat's primary mechanism involves selective inhibition of xanthine oxidase, resulting in reduced uric acid production. Its pharmacokinetics require personalized dosing strategies based on individual characteristics. In gout management, febuxostat offers a compelling alternative, effectively lowering uric acid levels, relieving symptoms, and supporting long-term control, especially for patients intolerant to allopurinol. Recent studies have demonstrated its cardiovascular safety, and it exhibits minimal hepatotoxicity, making it suitable for those with liver comorbidities. Febuxostat's potential nephroprotective effects and kidney stone prevention properties are noteworthy, particularly for gout patients with renal concerns. Beyond gout, its anti-inflammatory properties hint at applications in musculoskeletal conditions and a broader spectrum of clinical contexts, including metabolic syndrome. Emerging research explores febuxostat's roles in cardiovascular health, neurological disorders, rheumatoid arthritis, and cancer therapy, driven by its anti-inflammatory and antioxidative properties. Future directions include personalized medicine, combination therapies, mechanistic insights, and ongoing long-term safety monitoring, collectively illuminating the promising landscape of febuxostat's multifaceted therapeutic potential.
PubMed: 38004339
DOI: 10.3390/life13112199 -
Biomedicine & Pharmacotherapy =... Nov 2023Colorectal cancer (CRC) is a globally prevalent malignancy with a high potential for metastasis. Existing cancer treatments have limitations, including drug resistance... (Review)
Review
Colorectal cancer (CRC) is a globally prevalent malignancy with a high potential for metastasis. Existing cancer treatments have limitations, including drug resistance and adverse effects. Researchers are striving to develop effective therapies to address these challenges. Impressively, contemporary research has discovered that many natural products derived from foods, plants, insects, and marine invertebrates can suppress the progression, metastasis, and invasion of CRC. In this review, we conducted a comprehensive search of the CNKI, PubMed, Embase, and Web of Science databases from inception to April 2023 to evaluate the efficacy of natural products targeting mitochondria to fight against CRC. Mitochondria are intracellular energy factories involved in cell differentiation, signal transduction, cell cycle regulation, apoptosis, and tumorigenesis. The identified natural products have been classified and summarized based on their mechanisms of action. These findings indicate that natural products can induce apoptosis in colorectal cancer cells by inhibiting the mitochondrial respiratory chain, ROS elevation, disruption of mitochondrial membrane potential, the release of pro-apoptotic factors, modulation of the Bcl-2 protein family to facilitate cytochrome c release, induction of apoptotic vesicle activity by activating the caspase protein family, and selective targeting of mitochondrial division. Furthermore, diverse apoptotic signaling pathways targeting mitochondria, such as the MAPK, p53, STAT3, JNK and AKT pathway, have been triggered by natural products. Natural products such as diosgenin, allopurinol, and clausenidin have demonstrated low toxicity, high efficacy, and multi-targeted properties. Mitochondria-targeting natural products have great potential for overcoming the challenges of CRC therapy.
PubMed: 37713992
DOI: 10.1016/j.biopha.2023.115473 -
The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Gout; Gout Suppressants; Hyperuricemia
PubMed: 37871112
DOI: 10.58347/tml.2023.1688c -
The American Journal of Medicine Jun 2024
Topics: Humans; Allopurinol; Liver Cirrhosis
PubMed: 38821688
DOI: 10.1016/j.amjmed.2024.01.032 -
Arthritis & Rheumatology (Hoboken, N.J.) Apr 2024Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement.
METHODS
Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence.
RESULTS
Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence.
CONCLUSIONS
Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.
Topics: Humans; Allopurinol; Uric Acid; Febuxostat; Gout Suppressants; Goals; Quality of Life; Treatment Outcome; Gout; Diuretics
PubMed: 37842953
DOI: 10.1002/art.42731 -
American Journal of Kidney Diseases :... Jun 2024We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with...
RATIONALE & OBJECTIVE
We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD).
STUDY DESIGN
Prespecified sub cohort analysis of a randomized controlled trial.
SETTING
& Participants: A sub study of the STOP Gout trial in participants with CKD. CKD was defined as an eGFR 30-59 mL/min/1.73 m at baseline.
EXPOSURE
Trial participants with CKD and gout and serum urate (sUA) concentration ≥6.8 mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal sUA of <6.0 mg/dl (<5.0 mg/dl with tophi) (Phase 1) and maintained during weeks 25-48 (Phase 2). Gout flare was assessed between weeks 49-72 (Phase 3).
OUTCOME
Gout flare between weeks 49-72 (Phase 3) was the primary outcome. Secondary outcomes included sUA goal achievement and ULT dosing at end of Phase 2, and serious adverse events (SAEs).
ANALYTICAL APPROACH
Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm.
RESULTS
351 of 940 participants (37.3%) had CKD; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; p=0.02) despite similar attainment of sUA goal (79% vs. 81%; p=0.6) by the end of Phase 2. Acute kidney injury (AKI) was more common in participants with stage 3 CKD randomized to allopurinol compared to febuxostat.
LIMITATIONS
Limited power to assess infrequent safety events, largely male, older population.
CONCLUSIONS
Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.
PubMed: 38906504
DOI: 10.1053/j.ajkd.2024.04.017 -
The Journal of Rheumatology Jun 2024Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we... (Review)
Review
Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management.
Topics: Allopurinol; Humans; Gout; Gout Suppressants; Treatment Failure; Uric Acid
PubMed: 38490676
DOI: 10.3899/jrheum.2024-0144 -
Clinical Pharmacology : Advances and... 2023Allopurinol is a commonly used medication that lowers uric acid production which is essential for gout treatment and prevention. Although many patients tolerate...
Allopurinol is a commonly used medication that lowers uric acid production which is essential for gout treatment and prevention. Although many patients tolerate allopurinol therapy without severe complications; Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are life-threatening delayed hypersensitivity reactions that have been reported especially among Asian and African American patients. We describe a case of allopurinol-induced SJS in a 95-year-old Asian female. The patient started allopurinol 13 days prior to presenting to the emergency room (ER). On day 10 of therapy, the patient developed a diffuse erythematous desquamating rash which prompted her to visit the ER after 3 days from the rash onset. This case report describes a rare fatal hypersensitivity reaction that requires rapid identification and treatment in a multi-disciplinary setting.
PubMed: 37811521
DOI: 10.2147/CPAA.S427714 -
Journal of Experimental & Clinical... Sep 2023Hypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key...
BACKGROUND
Hypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear.
METHODS
RNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo.
RESULTS
The expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively.
CONCLUSIONS
Collectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Allopurinol; Cisplatin; Esophageal Neoplasms; Guanosine Triphosphate; Tumor Microenvironment; Vascular Endothelial Growth Factor A; STAT3 Transcription Factor; Carrier Proteins; Membrane Proteins
PubMed: 37752569
DOI: 10.1186/s13046-023-02821-y -
Clinical Medicine Insights. Cardiology 2024The association between hyperuricemia and cardiovascular diseases has been studied for many years. Research has shown a link between high uric acid levels and increased... (Review)
Review
The association between hyperuricemia and cardiovascular diseases has been studied for many years. Research has shown a link between high uric acid levels and increased risk of including coronary artery disease hypertension and other cardiovascular conditions. Urate-lowering therapy, particularly with xanthine oxidase inhibitors like allopurinol, has shown promising results in reducing blood pressure in individuals with hyperuricemia and hypertension. Clinical trials and studies have demonstrated significant reductions in both systolic and diastolic blood pressure with urate-lowering treatment. Urate-lowering treatment has shown a favorable effect on reducing systolic blood pressure and major adverse cardiovascular events in patients with previous cardiovascular disease. In terms of cardiovascular safety, clinical trials have indicated that xanthine oxidase inhibitors such as febuxostat are non-inferior to allopurinol and do not increase the risk of death or serious adverse events. Overall, these findings highlight the importance of managing hyperuricemia and utilizing urate-lowering therapy to mitigate the adverse cardiovascular effects associated with elevated uric acid levels.
PubMed: 38529322
DOI: 10.1177/11795468241239542