Roxadustat Versus Erythropoietin: The Comparison of Efficacy in Reversing Ventricular Remodeling in Dialysis Patients with Anaemia.

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.

Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials.

BACKGROUND: Chronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD. METHODS: We conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA). RESULTS: A total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP < ULN group, 524 patients from 4 studies were incorporated into the analysis. All patients received roxadustat as the primary intervention. The pooled results revealed no significant difference in ΔHb between patients with CRP ≥ ULN and CRP < ULN at baseline (Mean Difference: 0.00, 95% Confidence Interval: -0.32 to 0.33, P = 0.99). Moreover, within the CRP ≥ ULN group, three studies involving 1399 patients compared the efficacy of roxadustat and erythropoiesis-stimulating agents (ESAs). The results indicated no significant difference in ΔHb between patients treated with ESAs and HIF-PHIs (Mean Difference: 0.24, 95% Confidence Interval: -0.08 to 0.56, P = 0.14). In terms of medication dosage, an increase in ESA dose over time was observed across various studies, particularly evident in the CRP ≥ ULN group, while the dose of roxadustat remains constant over time and is not influenced by the baseline levels of CRP. CONCLUSIONS: Our systematic review demonstrates that roxadustat exhibits similar efficacy across different CRP levels. Moreover, within the CRP ≥ ULN group, roxadustat can maintain efficacy comparable to ESA without the necessity for dose escalation. TRIAL REGISTRATION: CRD42023396704.

Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction.

Cancer immunotherapy has revolutionized clinical advances in a variety of cancers. Due to the low immunogenicity of the tumor, only a few patients can benefit from it. Specific microtubule inhibitors can effectively induce immunogenic cell death and improve immunogenicity of the tumor. A series of isoquinoline derivatives based on the natural products podophyllotoxin and diphyllin were designed and synthesized. Among them, F10 showed robust antiproliferation activity against four human cancer cell lines, and it was verified that F10 exerted antiproliferative activity by inhibiting tubulin and V-ATPase. Further studies indicated that F10 is able to induce immunogenic cell death in addition to apoptosis. Meanwhile, F10 inhibited tumor growth in an RM-1 homograft model with enhanced T lymphocyte infiltration. These results suggest that F10 may be a promising lead compound for the development of a new generation of microtubule drugs.

Duvelisib: A comprehensive profile.

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

Comparative analysis of roxadustat efficacy between maintenance hemodialysis and peritoneal dialysis patients.

BACKGROUND: This study evaluated the comparative efficacy of roxadustat for renal anemia between patients on maintenance hemodialysis (HD) and peritoneal dialysis (PD). MATERIALS AND METHODS: 93 maintenance dialysis patients who regularly followed up from August 2015 to June 2021 were enrolled. Despite receiving a therapeutic dose ≥ 12,000 U/week of erythropoiesis-stimulating agents (E+SA) in the past 12 weeks, this had not worked very well. Subjects were assigned to the HD group (n = 60) or the PD group (n = 33) based on their dialysis treatment modality. All patients received oral roxadustat and were followed up for 24 weeks, after which their hemoglobin, serum iron, transferrin saturation, and ferritin were tested. RESULTS: We observed that the hemoglobin level of PD patients was significantly increased from 76.1 ± 15.7 g/L to 106 ± 23.8 g/L (p < 0 .001), while it significantly increased from 73.8 ± 12.9 g/L to 100.7 ± 20.2 g/L (p < 0.001) in the HD patients. After 1 and 3 months of roxadustat treatment, the hemoglobin level and its change in the PD group was significantly higher compared to that in the HD group despite the higher dose of roxadustat in the latter group. In addition, roxadustat was noted to reduce cholesterol levels and stabilize serum iron levels in parallel with improving hemoglobin levels. CONCLUSION: Roxadustat can effectively increase the hemoglobin level of maintenance dialysis patients, even in those with low erythropoietin response or erythropoietin resistance, and, more importantly, its efficacy in PD patients was more significant.

A phase 3b, multicenter, open-label, single-arm study of roxadustat within a US dialysis organization: The DENALI study.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in-center or home dialysis. METHODS: Eligible patients received open-label roxadustat, dosed three times weekly for 24 weeks, with an optional extension of ≤1 year. Initial dosing depended on erythropoiesis-stimulating agent (ESA) dose at screening for patients receiving ESAs (≥6 weeks) and weight-based for those not (total <6 weeks). Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed. FINDINGS: Of 281 patients screened, 203 were treated and 201 included in the full analysis set. Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period. Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis. Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24. Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL. Prespecified subgroup analyses were consistent with primary analyses. Dosing adherence was 94%. Overall, 3.0% of patients received a red blood cell transfusion at up to Week 24. TEAEs and TESAEs were reported by 71.4% and 25.6% of patients, respectively. The most frequently reported TESAEs were COVID-19 (n = 5; 2.5%), and acute myocardial infarction, pneumonia, and sepsis (each n = 4; 2.0%). DISCUSSION: Roxadustat effectively achieved and/or maintained mean Hb levels ≥10.0 g/dL in patients receiving dialysis. The feasibility of incorporating oral roxadustat into dialysis organizations was successfully demonstrated with high dosing adherence. No new safety signals were identified.

A clinical study on roxadustat for anemia in diabetic nephropathy: a 8-week study.

PURPOSE: The development of roxadustat is a standard treatment for renal anemia, and multiple clinical trials have proved its safety and efficacy. However, less information is available from trials of the population with diabetic nephropathy (DN). This study aimed to determine whether roxadustat is effective for treating DN. METHODS: This was a single-center, retrospective, institutional review board-approved cohort study. The patients with DN were chosen and given roxadustat or erythropoietin (EPO) for 8 weeks. The mean hemoglobin (Hb) level after 8 weeks of treatment served as the primary outcome. Alterations in the iron index and lipid levels were considered secondary objectives. Sub-group analysis was performed to observe the impact of inflammation and glycemic status on Hb. RESULTS: A total of 80 patients were enrolled, 40 in each group. After 8 weeks of treatment, the Hb levels in the roxadustat group were higher than those in the control group. The number of patients who achieved Hb response was higher in the roxadustat group than in the control group (77.5% versus 27.5%; P < 0.001). In addition to lowering total cholesterol and low-density lipoprotein cholesterol, roxadustat decreased ferritin and elevated total iron-binding capacity. Compared to the control group, roxadustat was more beneficial for patients with an inflammatory condition and poor glycemic control. CONCLUSIONS: Roxadustat treatment remarkably corrected anemia in patients with DN, and its effectiveness was unaffected by inflammation or glycemic control levels. In addition, roxadustat can also reduce a patient's blood lipid level and enhance the body's use of iron. CLINICAL TRIAL REGISTRATION: ChiCTR2200057232.

Palonosetron for prevention of delayed chemotherapy-induced nausea and vomiting in pediatric patients: a meta-analysis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are common adverse events in patients undergoing emetogenic chemotherapy. Palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), has demonstrated non-inferiority to first-generation 5-HT3 RAs for CINV in pediatric patients. Although palonosetron has a long half-life and prolonged antiemetic action, its efficacy against delayed CINV in pediatric patients is not well understood. Therefore, this meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy of palonosetron for delayed CINV in pediatric patients. METHODS: A literature search of MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science databases was performed. A meta-analysis was performed using forest plots, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. A funnel plot was constructed to explore publication bias. RESULTS: The literature search retrieved 842 records, of which 23 full-text articles were assessed, including six RCTs. Meta-analysis of four RCTs that reported on the complete response (CR: defined as no emesis and no rescue medication) rate for delayed CINV revealed that palonosetron was statistically superior to first-generation 5-HT3 RAs (RR = 1.21 [95% CI 1.09-1.35]; p < 0.01). Although the number of studies included was small, no publication bias was observed in the funnel plots. In addition, the CR rate for overall and acute CINV was also significantly higher for palonosetron (RR = 1.25 [95% CI 1.01-1.54]; p = 0.04 and RR = 1.06 [95% CI 1.01-1.12]; p = 0.03, respectively). CONCLUSION: Palonosetron is effective in the prophylaxis of delayed CINV in pediatric patients.

Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway.

Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and mortality. Liensinine, a major isoquinoline alkaloid, is extracted from the green embryos of mature Nelumbonaceae seeds. It has been reported to have an inhibitory effect on tumors. However, the effects of liensinine on ALI have not been reported to-date. The aim of this study was to explore the inhibitory effects of liensinine on lipopolysaccharide (LPS)-induced ALI and its possible mechanism. We found that liensinine significantly reduced LPS-induced ALI and reduced the production of inflammatory factors IL-6, IL-8, and TNF-α. In addition, liensinine blocked autophagic flux and increased the number of autophagosomes by upregulating LC3-II/I and p62 protein levels. More importantly, pretreatment with the early stages autophagy inhibitor 3-Methyladenine (3-MA) can reverse the inhibitory effects of liensinine on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway is involved in LPS-induced autophagy regulated by liensinine in ALI. In summary, this study suggests that liensinine inhibits the production of inflammatory factors in LPS-induced ALI by regulating autophagy via the PI3K/AKT/mTOR pathway, which may provide a new therapeutic strategy to alleviate ALI.

New trends in the practical use of isoquinoline alkaloids as potential drugs applicated in infectious and non-infectious diseases.

In the last years, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding permanently. Isoquinoline alkaloids have always attracted scientific interest due to either their positive or negative effects on human organism. The present review describes research on isoquinoline alkaloids isolated from different plant species. Alkaloids are one of the most important classes of plant derived compounds among these isoquinoline alkaloids possess varied biological activities such as anticancer, antineurodegenerative diseases, antidiabetic, antiinflammatory, antimicrobial, and many others. The use of plants against different disorders is entrenched in traditional medicine around the globe. Recent progress in modern therapeutics has stimulated the use of natural products worldwide for various ailments and diseases. The review provides a collection of information on the capabilities of some isoquinoline alkaloids, its potential for the treatment of various diseases and is designed to be a guide for future research on different biologically active isoquinoline alkaloids and plant species containing them. The authors are aware that they were not able to cover the whole area of the topic related to biological activity of isoquinoline alkaloids. This review is intended to suggest directions for further research and can also help other researchers in future studies.

What role will ensifentrine play in the future treatment of chronic obstructive pulmonary disease patients? Implications from recent clinical trials.

Data from the phase III ENHANCE clinical trials provide compelling evidence that ensifentrine, an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor, can provide additional benefit to existing treatments in patients with chronic obstructive pulmonary disease and represents a 'first-in-class' drug having bifunctional bronchodilator and anti-inflammatory activity in a single molecule. Ensifentrine, generally well tolerated, can provide additional bronchodilation when added to muscarinic receptor antagonists or ß2-agonists and reduce the exacerbation risk. This information allows us to consider better the possible inclusion of ensifentrine in the future treatment of chronic obstructive pulmonary disease. However, there is less information on whether it provides additional benefit when added to inhaled corticosteroid or 'triple therapy' and, therefore, when this drug is best utilized in clinical practice.

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties/airflow limitations. The airflow limitation is not completely reversible and is associated with a state of chronic inflammation of lung tissue. Treatment of the disease is still heavily dependent on the use of medications called bronchodilators and corticosteroids. However, corticosteroids have little-to-no impact on the underlying inflammation in most COPD patients. Therefore, innovative anti-inflammatory approaches are required. In this context, single molecules that are capable of simultaneously inducing bronchodilation, relaxing the muscles in the lungs and widening the airways (bronchi), and anti-inflammatory activity are a highly intriguing possibility for treating COPD. One approach is to develop drugs that can simultaneously inhibit enzymes called phosphodiesterase (PDE)3 and PDE4. Enzymes are proteins that help speed up metabolism, or the chemical reactions in our bodies. PDE4 inhibitors are intracellular enzymes (work inside the cell) expressed in most inflammatory cells, even in neutrophils (a type of white blood cells), which are involved in the pathogenesis of COPD, where an infection turns into a disease. However, its inhibition does not produce severe bronchodilator effects, which is instead obtained by inhibiting PDE3, the PDE isoenzyme (a different form of the same enzyme) that is predominantly expressed in airway smooth muscle cells. A treatment called ensifentrine is a dual PDE3/4 inhibitor (inhibits both PDE3 and PDE4). Two recent phase III studies (ENHANCE-1 and ENHANCE-2) have shown that it induces significant bronchodilation and reduces the risk of COPD worsening, exerting an anti-inflammatory effect. Data from the ENHANCE studies also showed the benefit of adding ensifentrine to treatment with bronchodilators. Certainly, the drug represents a useful therapeutic option, but further clinical studies are needed to be able to correctly position ensifentrine in the context of regular COPD treatment.

Roxadustat treatment for erythropoiesis-stimulating agent-hyporesponsive anemia in maintenance hemodialysis patients.

OBJECTIVE: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a prevalent problem affecting hemodialysis (HD) patients. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. We explored the ability of roxadustat to increase the hemoglobin (Hb) concentration in ESA-hyporesponsive patients undergoing HD and assessed its effect on iron metabolism and inflammation. METHODS: This prospective study included 30 patients with ESA-hyporesponsive anemia who had been undergoing stable dialysis. All patients received roxadustat three times per week for 24 weeks. The primary endpoint was the mean change in Hb from baseline to the average level over weeks 20 to 24. Iron metabolism markers, C-reactive protein, interleukin (IL)-6, and safety were also assessed. RESULTS: At week 24, roxadustat treatment resulted in a 2.5 ± 1.3 g/dL increase in the Hb level. In total, 28 of 30 patients (93.3%) had an Hb level increase of more than 1.0 g/dL from baseline. Seventeen patients (56.7%) met the endpoint, with a mean Hb level of at least 10.0 g/dL. Iron metabolism and IL-6 levels were also improved. CONCLUSIONS: Oral roxadustat is effective for ESA-hyporesponsive anemia in maintenance HD patients and may also improve iron metabolism and IL-6 levels.

Evaluating the effect of Roxadustat on ventricular repolarization in patients undergoing peritoneal dialysis.

BACKGROUND: Roxadustat is a novel oral medication used to treat anemia in CKD patients. Several studies have shown that Roxadustat can alleviate anemia in CKD patients by increasing hemoglobin levels and regulating iron metabolism. We aimed to evaluate the effect of Roxadustat on ventricular repolarization in PD patients. This study may provide a new integrated approach to the assessment and treatment of CKD. METHODS: The present prospective cohort study enrolled 65 CKD patients who were treated with Roxadustat and 31 CKD patients who received conventional therapy between January 2021 and June 2022. All patients were examined for ECG in the absence of clinical symptoms and compared the ECG indicators. Demographic and clinical data of all patients were collected. All data used SPSS 18.0 for statistical analyses. RESULTS: The T peak-to-end (Tpe) of PD patients in the Roxadustat group was remarkably slower than that of patients in the conventional group. Additionally, the Tpe/QT ratio in the conventional group was significantly elevated than that in the Roxadustat group. The results of logistic regression analysis showed that Tpe (95%CI 1.191 ~ 2.141, P = 0.002) and Roxadustat treatment (95%CI 1.357 ~ 42.121, P = 0.021) were the risk factors of PD patients with high Tp-e/QT ratio. CONCLUSION: In summary, we found that Roxadustat could improve ventricular repolarization in peritoneal dialysis patients, which indicated a potential cardiovascular protective effect of Roxadustat. This study might provide a new integrated approach to the assessment and treatment of CKD.

Development of a health economic model to evaluate the cost-effectiveness of roxadustat in treating anemia associated with non-dialysis-dependent chronic kidney disease.

BACKGROUND: Treatment for anemia of chronic kidney disease (CKD) largely consists of erythropoiesis-stimulating agents (ESAs) with iron supplementation. Although ESAs are well-established and efficacious, their use has been associated with considerable economic and humanistic burdens. Roxadustat, an oral medication, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that targets multiple causes of CKD and has a similar efficacy and safety profile to ESAs. The cost-effectiveness of this treatment, however, has yet to be investigated. OBJECTIVE: The study objective was to develop a health economic model to evaluate the cost-effectiveness of roxadustat compared with ESAs for treating anemia of non-dialysis-dependent (NDD) CKD. METHODS: A cohort-based model was developed for a hypothetical cohort of 1,000 patients with anemia of NDD CKD, incorporating eight health states, representing the hemoglobin level of each patient. The model was informed by individual patient-level data from the roxadustat global phase 3 clinical trial program. Total and incremental costs as well as quality-adjusted life-years (QALYs) associated with roxadustat versus ESAs were estimated from the perspective of the UK National Health Service. Sensitivity analyses were performed to assess the robustness of the model. Analyses exploring alternative scenarios were also conducted. RESULTS: On a per-person basis, over 1,000 simulations, roxadustat was found to be on average less costly (-£32) and more effective (+0.01 QALYs) than ESAs, with a dominant incremental cost-effectiveness ratio. The probability of cost-effectiveness at a £20,000 per QALY willingness-to-pay threshold from the UK perspective was 67%. CONCLUSION: The model developed may be a useful instrument that, alongside expert clinical opinion, can inform clinical and policy decision-making regarding treatment of anemia of NDD CKD. The model highlights the cost-effectiveness of roxadustat, as well as its potential to have a meaningful impact in reducing the burden of anemia of NDD CKD.

Effect of Roxadustat on Thyroid Function in Patients With Renal Anemia.

CONTEXT: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, a recently developed class of drugs for treatment of anemia in chronic kidney disease (CKD), is reported to have a structure unlike that of other HIF-PH inhibitors but similar to that of triiodothyronine and bind to the thyroid hormone receptor in vitro. However, reports on the effects of roxadustat on thyroid function are limited and not detailed, and it remains unknown whether other HIF-PH inhibitors also affect thyroid function. OBJECTIVE: To compare the effect of roxadustat with daprodustat, another HIF-PH inhibitor, on thyroid function in patients with renal anemia in CKD. METHODS: This retrospective observational study included a total of 26 patients with anemia in CKD who were treated with roxadustat or daprodustat; thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured before and after treatment with the drugs. RESULTS: After initiation of roxadustat, TSH showed a significant decrease (2.4732 [1.7858-4.9016] µIU/mL before treatment and 0.659 [0.112-2.005] µIU/mL after treatment, P < .05); FT4 showed a significant decrease (0.93 [0.84-1.05] ng/dL before treatment and 0.70 [0.53-0.85] ng/dL after treatment, P < .01). After daprodustat initiation, neither TSH nor FT4 showed a significant change (TSH: 3.044 [1.853-4.171] µIU/mL before treatment and 2.893 [1.866-4.894] µIU/mL after treatment, P = .635; FT4 was 0.93 [0.81-1.00] ng/dL before treatment and 0.97 [0.87-1.05] ng/dL after treatment, P = .328). CONCLUSION: Roxadustat decreases TSH and FT4 levels while daprodustat does not.

A phase 3b, multicenter, open-label, single-arm study of roxadustat (ASPEN): Operational learnings within United States dialysis organizations.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations. METHODS: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed. FINDINGS: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%). DISCUSSION: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations.

Long-term efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma achieving a complete response with pixantrone.

INTRODUCTION: The prognosis of diffuse large B-cell lymphoma (DLBCL) patients with refractory or multiply relapsed (R/R) disease is disappointing. Pixantrone is currently approved as third or fourth line regimen, with encouraging results, even if long-term follow-up data are limited. METHODS: In this post-hoc analysis of our observational study, we retrospectively investigated disease outcome and clinical characteristics of 16 R/R DLBCL patients who achieved a complete response with pixantrone. RESULTS: Pixantrone was administered as third or fourth line in 12/16 (75%) and 4/16 (25%) cases. After a median follow-up of 24 months, 14/16 patients (87.5%) were alive (causes of death were progressive disease and secondary acute myeloid leukemia, one case each). Median progression-free survival was 23.8 months, median duration of response was 17.8 months and median overall survival (OS) was not reached (2-years OS was 84%). A significant proportion of patients achieved a long-lasting response >12 months (7/16 cases). Response to prior therapy did not influence long-term remission after pixantrone. CONCLUSION: In this real-life experience, pixantrone demonstrated long-term efficacy in a cohort of R/R DLBCL cases who had previously received at least two prior regimens; many of whom had characteristics associated with poor prognosis.

Design, synthesis, and biological evaluation of 1-styrenyl isoquinoline derivatives for anti-hepatocellular carcinoma activity and effect on mitochondria.

In this study, 18 derivatives of 1-styrene-isoquinoline were designed and synthesized from resveratrol and isoquinoline. The IC50 of compound 1c against Huh7 and SK-Hep-1 cells were 2.52 µM and 4.20 µM, respectively. Mice were treated with 650 mg/kg compound 1c, and the survival status of mice was good. Further studies showed that compound 1c could inhibit cell proliferation by arresting the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration and invasion by regulating epithelial-mesenchymal transition (EMT). It is worth noting that numbers of studies have pointed that resveratrol can trigger mitochondrial apoptosis to induce apoptosis of cancer cells. Therefore, we investigated the mechanism of compound 1c induced apoptosis of Huh7 and SK-Hep-1 cells. The results indicated that compound 1c could regulate the expression of proteins which are related to mitochondrial apoptosis pathway and inhibit the phosphorylation of PI3K/Akt/mTOR signaling pathway. In addition, compound 1c could inhibit the growth of Huh7-xenografts, and perform a tumor inhibitory rate of 41.44% when administered 30 mg/kg once a day. This work provides a potential anti-hepatocellular carcinoma compound that warrants further investigation.