Absorption, metabolism, and excretion of [¹⁴C]-sebetralstat (KVD900) following a single oral dose in healthy male participants

Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Six healthy male participants received one dose of 600 mg (540 µCi) [14C]-sebetralstat. Plasma concentrations of sebetralstat and levels of total radioactivity in plasma, urine, and faeces were determined. Metabolite profiles of radioactivity were generated, and major metabolites structurally characterised.Radioactivity was rapidly absorbed and was excreted with a mean of 95.8% (63.4% faeces; 32.4% urine) recovered by 216 h. Sebetralstat was the major drug-related component in urine and faeces, although metabolism predominated overall (main metabolites: M19 (des-[methoxy-fluoro-methylpyridine]-sebetralstat), M10 (N-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine O-desmethyl-sebetralstat), and M34 (pyridine dioxy-dihydro-sebetralstat)). Sebetralstat was the main radiolabelled component in plasma (mean of 64.1% of the total radioactivity AUC0–24), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was >10% of the plasma radioactivity AUC0–24, in one participant it comprised a mean of 0–24. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed vs. that in humans.Given these findings and the lack of pharmacological activity of M19, it was concluded that there was no unique or disproportionate circulating metabolite in humans. Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Six healthy male participants received one dose of 600 mg (540 µCi) [14C]-sebetralstat. Plasma concentrations of sebetralstat and levels of total radioactivity in plasma, urine, and faeces were determined. Metabolite profiles of radioactivity were generated, and major metabolites structurally characterised. Radioactivity was rapidly absorbed and was excreted with a mean of 95.8% (63.4% faeces; 32.4% urine) recovered by 216 h. Sebetralstat was the major drug-related component in urine and faeces, although metabolism predominated overall (main metabolites: M19 (des-[methoxy-fluoro-methylpyridine]-sebetralstat), M10 (N-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine O-desmethyl-sebetralstat), and M34 (pyridine dioxy-dihydro-sebetralstat)). Sebetralstat was the main radiolabelled component in plasma (mean of 64.1% of the total radioactivity AUC0–24), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was >10% of the plasma radioactivity AUC0–24, in one participant it comprised a mean of 0–24. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed vs. that in humans. Given these findings and the lack of pharmacological activity of M19, it was concluded that there was no unique or disproportionate circulating metabolite in humans.</p

Image2_RNA 5-Methylcytosine Regulators Contribute to Metabolism Heterogeneity and Predict Prognosis in Ovarian Cancer.JPEG

5-Methylcytosine (m5C) is an abundant and highly conserved modification in RNAs. The dysregulation of RNA m5C methylation has been reported in cancers, but the regulatory network in ovarian cancer of RNA m5C methylation-related genes and its implication in metabolic regulation remain largely unexplored. In this study, RNA-sequencing data and clinical information of 374 ovarian cancer patients were downloaded from The Cancer Genome Atlas database, and a total of 14 RNA m5C regulators were included. Through unsupervised consensus clustering, two clusters with different m5C modification patterns were identified with distinct survivals. According to enrichment analyses, glycosaminoglycan and collagen metabolism–related pathways were specifically activated in cluster 1, whereas fatty acid metabolism–related pathways were enriched in cluster 2, which had better overall survival (OS). Besides the metabolism heterogeneity, the higher sensitivity to platinum and paclitaxel in cluster 2 can further explain the improved OS. Ultimately, a least absolute shrinkage and selection operator prediction model formed by ALYREF, NOP2, and TET2 toward OS was constructed. In conclusion, distinct m5C modification pattern exhibited metabolism heterogeneity, different chemotherapy sensitivity, and consequently survival difference, providing evidence for risk stratification.</p

Forest plot of MPV values and the presence of psoriasis.

Forest plot of MPV values and the presence of psoriasis.</p

Image3_RNA 5-Methylcytosine Regulators Contribute to Metabolism Heterogeneity and Predict Prognosis in Ovarian Cancer.JPEG

5-Methylcytosine (m5C) is an abundant and highly conserved modification in RNAs. The dysregulation of RNA m5C methylation has been reported in cancers, but the regulatory network in ovarian cancer of RNA m5C methylation-related genes and its implication in metabolic regulation remain largely unexplored. In this study, RNA-sequencing data and clinical information of 374 ovarian cancer patients were downloaded from The Cancer Genome Atlas database, and a total of 14 RNA m5C regulators were included. Through unsupervised consensus clustering, two clusters with different m5C modification patterns were identified with distinct survivals. According to enrichment analyses, glycosaminoglycan and collagen metabolism–related pathways were specifically activated in cluster 1, whereas fatty acid metabolism–related pathways were enriched in cluster 2, which had better overall survival (OS). Besides the metabolism heterogeneity, the higher sensitivity to platinum and paclitaxel in cluster 2 can further explain the improved OS. Ultimately, a least absolute shrinkage and selection operator prediction model formed by ALYREF, NOP2, and TET2 toward OS was constructed. In conclusion, distinct m5C modification pattern exhibited metabolism heterogeneity, different chemotherapy sensitivity, and consequently survival difference, providing evidence for risk stratification.</p

Forest plot of RDW values and the presence of psoriasis.

Forest plot of RDW values and the presence of psoriasis.</p

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Image1_RNA 5-Methylcytosine Regulators Contribute to Metabolism Heterogeneity and Predict Prognosis in Ovarian Cancer.JPEG

5-Methylcytosine (m5C) is an abundant and highly conserved modification in RNAs. The dysregulation of RNA m5C methylation has been reported in cancers, but the regulatory network in ovarian cancer of RNA m5C methylation-related genes and its implication in metabolic regulation remain largely unexplored. In this study, RNA-sequencing data and clinical information of 374 ovarian cancer patients were downloaded from The Cancer Genome Atlas database, and a total of 14 RNA m5C regulators were included. Through unsupervised consensus clustering, two clusters with different m5C modification patterns were identified with distinct survivals. According to enrichment analyses, glycosaminoglycan and collagen metabolism–related pathways were specifically activated in cluster 1, whereas fatty acid metabolism–related pathways were enriched in cluster 2, which had better overall survival (OS). Besides the metabolism heterogeneity, the higher sensitivity to platinum and paclitaxel in cluster 2 can further explain the improved OS. Ultimately, a least absolute shrinkage and selection operator prediction model formed by ALYREF, NOP2, and TET2 toward OS was constructed. In conclusion, distinct m5C modification pattern exhibited metabolism heterogeneity, different chemotherapy sensitivity, and consequently survival difference, providing evidence for risk stratification.</p

Image_2_The Efficacy of Berberine-Containing Quadruple Therapy on Helicobacter Pylori Eradication in China: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.pdf

BackgroundBerberine-containing quadruple therapy (adding berberine to the standard triple therapy) is being used to treat Helicobacter pylori infection, but the effects in randomized controlled trials (RCTs) are still controversial. Therefore, a meta-analysis is needed to estimate the efficacy and safety of berberine-containing quadruple therapy on Helicobacter pylori eradication.MethodsTen databases were searched to find the available literature. RCTs about the efficacy and safety of berberine-containing quadruple therapy on Helicobacter pylori eradication were included. The data of Helicobacter pylori eradication rate, peptic ulcer healing rate, relieving rate of clinical symptoms and adverse events were extracted to appraise the net change with a fixed or randomized effect model.ResultsA total of 13 articles were included in the analysis. Pooled results showed that the addition of berberine in standard triple therapy significantly improved Helicobacter pylori eradication rate (RR 1.22; 95% CI 1.16 to 1.27; I2 = 12%), increased the peptic ulcer healing rate (RR 1.15; 95% CI 1.10 to 1.19; I2 = 44%), relieved the clinical symptoms (RR 1.11; 95% CI 1.06 to 1.17; I2 = 44%) and reduced the incidence of side events (RR 0.65; 95% CI 0.53 to 0.80; I2 = 58%) comparing to the standard triple therapy.ConclusionsThe analysis showed that the addition of berberine in standard triple therapy could improve Helicobacter pylori eradication rate and clinical symptom remission rate, accelerate ulcer healing, and reduce adverse events, which is very beneficial to clinical work in China.</p

Subgroup analysis of MPV in psoriasis.

Subgroup analysis of MPV in psoriasis.</p

Image_4_The Efficacy of Berberine-Containing Quadruple Therapy on Helicobacter Pylori Eradication in China: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.pdf

BackgroundBerberine-containing quadruple therapy (adding berberine to the standard triple therapy) is being used to treat Helicobacter pylori infection, but the effects in randomized controlled trials (RCTs) are still controversial. Therefore, a meta-analysis is needed to estimate the efficacy and safety of berberine-containing quadruple therapy on Helicobacter pylori eradication.MethodsTen databases were searched to find the available literature. RCTs about the efficacy and safety of berberine-containing quadruple therapy on Helicobacter pylori eradication were included. The data of Helicobacter pylori eradication rate, peptic ulcer healing rate, relieving rate of clinical symptoms and adverse events were extracted to appraise the net change with a fixed or randomized effect model.ResultsA total of 13 articles were included in the analysis. Pooled results showed that the addition of berberine in standard triple therapy significantly improved Helicobacter pylori eradication rate (RR 1.22; 95% CI 1.16 to 1.27; I2 = 12%), increased the peptic ulcer healing rate (RR 1.15; 95% CI 1.10 to 1.19; I2 = 44%), relieved the clinical symptoms (RR 1.11; 95% CI 1.06 to 1.17; I2 = 44%) and reduced the incidence of side events (RR 0.65; 95% CI 0.53 to 0.80; I2 = 58%) comparing to the standard triple therapy.ConclusionsThe analysis showed that the addition of berberine in standard triple therapy could improve Helicobacter pylori eradication rate and clinical symptom remission rate, accelerate ulcer healing, and reduce adverse events, which is very beneficial to clinical work in China.</p