RÉSUMÉ
The rising incidence of colorectal cancer (CRC) and gastric cancer (GC) worldwide, coupled with the limited effectiveness of current chemotherapeutic agents, has prioritized the search for new therapeutic options. Natural substances, which often exhibit cytostatic properties, hold significant promise in this area. This review evaluates the anticancer properties of three natural alkaloids-berberine, sanguinarine, and chelerythrine-against CRC and GC. In vivo and in vitro studies have demonstrated that these substances can reduce tumor volume and inhibit the epithelial-mesenchymal transition (EMT) of tumors. At the molecular level, these alkaloids disrupt key signaling pathways in cancer cells, including mTOR, MAPK, EGFR, PI3K/AKT, and NF-κB. Additionally, they exhibit immunomodulatory effects, leading to the induction of programmed cell death through both apoptosis and autophagy. Notably, these substances have shown synergistic effects when combined with classical cytostatic agents such as cyclophosphamide, 5-fluorouracil, cetuximab, and erlotinib. Furthermore, berberine has demonstrated the ability to restore sensitivity in individuals originally resistant to cisplatin GC. Given these findings, natural compounds emerge as a promising option in the chemotherapy of malignant gastrointestinal tumors, particularly in cases with limited treatment options. However, more research is necessary to fully understand their therapeutic potential.
Sujet(s)
Benzophénanthridines , Berbérine , Tumeurs colorectales , Tumeurs de l'estomac , Humains , Benzophénanthridines/pharmacologie , Benzophénanthridines/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/métabolisme , Tumeurs colorectales/anatomopathologie , Berbérine/pharmacologie , Berbérine/usage thérapeutique , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Animaux , Isoquinoléines/pharmacologie , Isoquinoléines/usage thérapeutique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiques , Alcaloïdes/pharmacologie , Alcaloïdes/usage thérapeutiqueRÉSUMÉ
Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.
Sujet(s)
Antinéoplasiques , ADN topoisomérases de type II , Isoquinoléines , Inhibiteurs de la topoisomérase-I , Inhibiteurs de la topoisomérase-II , Humains , Animaux , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/usage thérapeutique , Isoquinoléines/synthèse chimique , Isoquinoléines/pharmacocinétique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/synthèse chimique , Inhibiteurs de la topoisomérase-II/pharmacologie , Inhibiteurs de la topoisomérase-II/usage thérapeutique , Inhibiteurs de la topoisomérase-II/composition chimique , Inhibiteurs de la topoisomérase-II/synthèse chimique , Inhibiteurs de la topoisomérase-I/pharmacologie , Inhibiteurs de la topoisomérase-I/usage thérapeutique , Inhibiteurs de la topoisomérase-I/composition chimique , Inhibiteurs de la topoisomérase-I/synthèse chimique , Administration par voie orale , ADN topoisomérases de type II/métabolisme , Lignée cellulaire tumorale , Relation structure-activité , Souris , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , ADN topoisomérases de type I/métabolisme , Tests de criblage d'agents antitumoraux , Tests d'activité antitumorale sur modèle de xénogreffe , Indoles/pharmacologie , Indoles/composition chimique , Indoles/usage thérapeutique , Souris nude , Découverte de médicament , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
Background: Roxadustat is commonly used to treat renal anemia. However, the potential effects of roxadustat on metabolism and organs other than the kidneys have recently attracted increased attention. Objective: This study aimed to examine the regulatory effects of roxadustat on thyroid hormones and blood lipid metabolism in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. Methods: Eighty ESKD patients on hemodialysis and taking roxadustat were enrolled. Hemoglobin, thyroid hormones (TSH, FT3, FT4), and blood lipid profiles (TC, LDL-C, TG, HDL-C) were assessed before and after treatment. Changes in these parameters were compared, and relevant causative factors were analyzed. Results: Roxadustat significantly increased Hb, lowered TSH, FT4, TC, and LDL-C levels (all P<0.001). Patients were categorized into three groups based on post-treatment TSH inhibition percentage: Q1(≥70%), Q2(30%-70%), Q3(≤30%). Pre-treatment TSH decreased with reduced TSH inhibition (P<0.05). Post-treatment, TC, LDL-C, TSH, FT3, and FT4 increased with reduced TSH inhibition (all P<0.05).TC and LDL-C significantly decreased post-treatment in Q1 and Q2 (P<0.05). Correlation analysis showed a positive correlation between ΔTSH and pre-treatment TSH levels (r=0.732, P<0.001). The proportion of patients with ≥70% TSH inhibition increased with higher pre-treatment TSH levels (P for trend <0.05). ΔLDL-C and ΔTSH were positively correlated (r=0.278, P<0.05), with ΔTSH identified as an influencing factor in multiple linear regression (ß=0.133, 95% CI [0.042, 0.223], P<0.05). Conclusion: Roxadustat effectively improves anemia in ESKD patients while inhibiting TSH and FT4 secretion and reducing TC and LDL-C levels. Decreases in TSH levels correlate with baseline TSH levels, and lowered blood lipid levels are associated with decreased TSH levels.
Sujet(s)
Glycine , Isoquinoléines , Défaillance rénale chronique , Métabolisme lipidique , Dialyse rénale , Hormones thyroïdiennes , Humains , Mâle , Femelle , Dialyse rénale/effets indésirables , Adulte d'âge moyen , Études rétrospectives , Défaillance rénale chronique/thérapie , Défaillance rénale chronique/sang , Défaillance rénale chronique/complications , Sujet âgé , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Métabolisme lipidique/effets des médicaments et des substances chimiques , Hormones thyroïdiennes/sang , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Lipides/sang , Adulte , Thyréostimuline/sangRÉSUMÉ
We aimed to compare the clinical efficacy and safety of roxadustat with erythropoiesis-stimulating agents, particularly erythropoietin (EPO), in the treatment of maintenance hemodialysis patients with renal anemia. A prospective cohort study was carried out at the Nephrology Department of the Nantong First People's Hospital and Nantong University Affiliated Hospital from December 2020 to December 2021. We compared hemoglobin (Hb) levels, serum ferritin (SF) levels, and adverse cardiovascular events between the roxadustat and EPO groups at 1, 3, and 6 months into the treatment. A total of 209 patients participated in the study, with 112 in the roxadustat group and 97 in the EPO group. At baseline, no statistically significant differences were observed between the 2 groups in terms of age, gender, weight, dialysis modality and duration, previous EPO dosage, Hb levels, SF levels, transferrin saturation, heart function classification, and blood pressure levels (Pâ >â .05). After 1 month, Hb levels in the roxadustat group were significantly higher than those in the EPO group (Pâ <â .05). However, no statistically significant differences were found between the 2 groups at 3 and 6 months (Pâ >â .05). Additionally, there were no significant differences in SF levels and the occurrence of adverse cardiovascular events between the 2 groups after treatment (Pâ >â .05). Roxadustat was superior to EPO in the initial treatment phase, while its cardiovascular safety was comparable to that of EPO.
Sujet(s)
Anémie , Hémoglobines , Isoquinoléines , Dialyse rénale , Humains , Mâle , Femelle , Dialyse rénale/effets indésirables , Anémie/traitement médicamenteux , Anémie/étiologie , Adulte d'âge moyen , Études prospectives , Isoquinoléines/usage thérapeutique , Isoquinoléines/effets indésirables , Isoquinoléines/administration et posologie , Hémoglobines/analyse , Hémoglobines/métabolisme , Sujet âgé , Érythropoïétine/usage thérapeutique , Antianémiques/usage thérapeutique , Antianémiques/effets indésirables , Antianémiques/administration et posologie , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Ferritines/sang , Résultat thérapeutiqueRÉSUMÉ
RATIONALE: Pharmacological mechanism of Roxadustat in the treatment of renal anemia. PATIENT CONCERNS: To investigate the efficacy and safety of combined Roxadustat and erythropoiesis stimulator (ESA) treatment of renal anemia in hemodialysis patients with secondary hyperparathyroidism. DIAGNOSES: A retrospective analysis was conducted on hemodialysis patients with renal anemia and secondary hyperparathyroidism treated with ESAs alone, who were admitted to our hospital from March 2022 to December 2022. INTERVENTIONS: The patients were treated with Roxadustat combined with ESAs for 3 months, during which oral iron supplementation was given, and the changes in Hb levels and laboratory-related indicators before and after the combined treatment were analyzed. OUTCOMES: The results showed that a total of 13 patients received combination therapy, with a significant increase in Hb compared to ESAs alone (tâ =â -3.955, Pâ =â .002). The Hb qualification rate was 38.46%, and the ∆Hb response rate was 76.92%. The parathyroid hormone significantly decreased with a statistically significant difference (Zâ =â -2.062b, Pâ =â .039). Hemoglobin (RBC), total iron binding capacity, and serum ferritin (male) were significantly increased compared to ESAs alone. Total cholesterol and low-density lipoprotein were significantly lower than ESAs alone. The differences in the changes in the above indicators were statistically significant (Pâ <â .05). There was no statistically significant difference in changes in other laboratory-related indicators (Pâ >â .05). No adverse reactions were observed during the combined treatment of 13 patients. LESSONS SUBSECTIONS: The combination of Roxadustat and ESAs can effectively improve renal anemia in hemodialysis patients with secondary hyperparathyroidism, as well as improve indicators of hyperparathyroidism and blood lipid levels with high levels of safety. This combined treatment thus provides a new and safe treatment method for these patients.
Sujet(s)
Anémie , Association de médicaments , Antianémiques , Hyperparathyroïdie secondaire , Isoquinoléines , Dialyse rénale , Humains , Mâle , Femelle , Dialyse rénale/effets indésirables , Études rétrospectives , Hyperparathyroïdie secondaire/traitement médicamenteux , Hyperparathyroïdie secondaire/étiologie , Adulte d'âge moyen , Anémie/traitement médicamenteux , Anémie/étiologie , Antianémiques/usage thérapeutique , Antianémiques/administration et posologie , Sujet âgé , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Isoquinoléines/effets indésirables , Hémoglobines/analyse , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Résultat thérapeutique , Adulte , Ferritines/sangRÉSUMÉ
Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. METHODS: We evaluated roxadustat's impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.
Sujet(s)
Glycine , Sous-unité alpha du facteur-1 induit par l'hypoxie , Isoquinoléines , Souris de lignée C57BL , Infarctus du myocarde , Remodelage ventriculaire , Animaux , Infarctus du myocarde/traitement médicamenteux , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/métabolisme , Souris , Remodelage ventriculaire/effets des médicaments et des substances chimiques , Glycine/analogues et dérivés , Glycine/pharmacologie , Glycine/usage thérapeutique , Mâle , Femelle , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Isoquinoléines/pharmacologie , Isoquinoléines/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiques , Chimiokine CXCL12/métabolisme , Chimiokine CXCL12/génétique , Myocarde/anatomopathologie , Myocarde/métabolismeRÉSUMÉ
Background: Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week). Methods: The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO. Results: The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased. Conclusion: Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism.
Sujet(s)
Anémie , Érythropoïétine , Glycine , Antianémiques , Isoquinoléines , Dialyse rénale , Humains , Mâle , Femelle , Anémie/traitement médicamenteux , Anémie/étiologie , Antianémiques/usage thérapeutique , Antianémiques/administration et posologie , Études rétrospectives , Adulte d'âge moyen , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Sujet âgé , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Glycine/administration et posologie , Association de médicaments , Hémoglobines/métabolisme , Hémoglobines/analyse , Résistance aux substances/effets des médicaments et des substances chimiques , Insuffisance rénale chronique/thérapie , Insuffisance rénale chronique/complications , Insuffisance rénale chronique/sang , Adulte , Protéines recombinantes/administration et posologie , Protéines recombinantes/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Mini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation. METHODS: Molecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo. RESULTS: Pixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety. CONCLUSION: These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic.
Sujet(s)
Antinéoplasiques , Apoptose , Isoquinoléines , Composant-2 du complexe de maintenance des minichromosomes , Tumeurs de l'ovaire , Animaux , Femelle , Humains , Souris , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiques , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Réplication de l'ADN/effets des médicaments et des substances chimiques , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/usage thérapeutique , Souris nude , Composant-2 du complexe de maintenance des minichromosomes/métabolisme , Simulation de docking moléculaire , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/anatomopathologie , Tumeurs de l'ovaire/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.
Sujet(s)
Indazoles , Tumeurs de l'ovaire , Pipéridines , Humains , Femelle , Indazoles/effets indésirables , Indazoles/administration et posologie , Pipéridines/administration et posologie , Pipéridines/effets indésirables , Pipéridines/usage thérapeutique , Adulte d'âge moyen , Sujet âgé , Tumeurs de l'ovaire/traitement médicamenteux , Adulte , Inhibiteurs de poly(ADP-ribose) polymérases/effets indésirables , Inhibiteurs de poly(ADP-ribose) polymérases/administration et posologie , Inhibiteurs de poly(ADP-ribose) polymérases/usage thérapeutique , Isoquinoléines/administration et posologie , Isoquinoléines/effets indésirables , Isoquinoléines/usage thérapeutique , Chimiothérapie de maintenanceRÉSUMÉ
BACKGROUND: To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors. METHODS: This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups. RESULTS: A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success. CONCLUSION: Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.
Sujet(s)
Glaucome à angle ouvert , Pression intraoculaire , Isoquinoléines , Mitomycine , Sulfonamides , Trabéculectomie , Humains , Trabéculectomie/méthodes , Mâle , Pression intraoculaire/effets des médicaments et des substances chimiques , Études prospectives , Femelle , Glaucome à angle ouvert/chirurgie , Glaucome à angle ouvert/traitement médicamenteux , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Sujet âgé , Sulfonamides/usage thérapeutique , Sulfonamides/administration et posologie , Mitomycine/usage thérapeutique , Mitomycine/administration et posologie , Adulte d'âge moyen , rho-Associated Kinases/antagonistes et inhibiteurs , Résultat thérapeutique , Agents alcoylants/administration et posologie , Agents alcoylants/usage thérapeutiqueRÉSUMÉ
OBJECTIVES: To compare the efficacy and safety of hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHis), a novel agent for management of anemia in chronic kidney disease (CKD), between transplant recipients and nontransplant individuals. METHODS: A retrospective analysis was conducted on nondialysis-dependent CKD stage 3 to 5 patients treated with the HIF-PHi roxadustat or daprodustat at a single institution. Patients were categorized as kidney transplant recipients (KTRs) and non-KTRs. Efficacy outcomes (hemoglobin and creatinine levels) and safety profiles (rate of adverse events [AEs], descriptions, and discontinuations due to AEs) were assessed 3 months before and 6 months after HIF-PHi initiation within and then between the groups. RESULTS: The study comprised 82 patients (KTR: 43, non-KTR: 39). Median ages significantly differed between the KTR (52.7 years) and non-KTR (82.9 years) groups (P < .001). Roxadustat was predominantly used in the KTR group (88.4%), while daprodustat was used in the non-KTR group (94.9%, P < .001). Both groups exhibited significant increases in Hb levels at 1, 3, and 6 months post-HIF-PHi initiation (P for trend, <.001), with a relative increase in Hb level at 6 months of 16% for KTRs and 13% for non-KTRs. Creatinine levels showed no significant changes over 6 months. Although no difference was observed in drug discontinuation due to AEs, the KTR group experienced a significantly higher rate of thrombotic events (18.6 vs 2.6%, P = .049). CONCLUSIONS: HIF-PHis demonstrate comparable efficacy for managing anemia in CKD, regardless of transplant status. However, heightened vigilance for thrombosis events is necessary during follow-up for KTRs.
Sujet(s)
Transplantation rénale , Humains , Transplantation rénale/effets indésirables , Femelle , Adulte d'âge moyen , Études rétrospectives , Mâle , Anémie/traitement médicamenteux , Insuffisance rénale chronique , Sujet âgé , Inhibiteurs de prolyle hydroxylases/usage thérapeutique , Hypoxia-inducible factor-proline dioxygenases/antagonistes et inhibiteurs , Sujet âgé de 80 ans ou plus , Adulte , Résultat thérapeutique , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Glycine/effets indésirables , Isoquinoléines/usage thérapeutique , Isoquinoléines/effets indésirables , Receveurs de transplantationRÉSUMÉ
Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain ß-amyloid (Aß) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aß deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances.
Sujet(s)
Maladie d'Alzheimer , Modèles animaux de maladie humaine , Troubles de la mémoire , Souris transgéniques , Antagonistes des récepteurs des orexines , Privation de sommeil , Animaux , Privation de sommeil/complications , Privation de sommeil/traitement médicamenteux , Souris , Antagonistes des récepteurs des orexines/pharmacologie , Antagonistes des récepteurs des orexines/usage thérapeutique , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/complications , Troubles de la mémoire/traitement médicamenteux , Troubles de la mémoire/étiologie , Isoquinoléines/pharmacologie , Isoquinoléines/usage thérapeutique , Précurseur de la protéine bêta-amyloïde/génétique , Acétamides/pharmacologie , Acétamides/usage thérapeutique , Mâle , Peptides bêta-amyloïdes/métabolisme , Apprentissage/effets des médicaments et des substances chimiques , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/étiologie , Récepteurs des orexines/métabolisme , Préséniline-1/génétiqueRÉSUMÉ
Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.
Sujet(s)
Antiémétiques , Aprépitant , Carboplatine , Dexaméthasone , Étoposide , Nausée , Palonosétron , Vomissement , Aprépitant/usage thérapeutique , Aprépitant/administration et posologie , Carboplatine/administration et posologie , Carboplatine/usage thérapeutique , Carboplatine/effets indésirables , Humains , Dexaméthasone/administration et posologie , Dexaméthasone/usage thérapeutique , Palonosétron/administration et posologie , Palonosétron/usage thérapeutique , Mâle , Étoposide/administration et posologie , Étoposide/usage thérapeutique , Antiémétiques/administration et posologie , Antiémétiques/usage thérapeutique , Femelle , Adulte d'âge moyen , Vomissement/induit chimiquement , Vomissement/prévention et contrôle , Sujet âgé , Nausée/induit chimiquement , Nausée/prévention et contrôle , Études rétrospectives , Adulte , Association de médicaments , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Quinuclidines/administration et posologie , Quinuclidines/usage thérapeutique , Morpholines/administration et posologie , Morpholines/usage thérapeutique , Antinéoplasiques/administration et posologie , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Isoquinoléines/administration et posologie , Isoquinoléines/usage thérapeutique , Résultat thérapeutiqueRÉSUMÉ
Roxadustat, recently approved, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. This article reviews main features and possible effects by activation of pathway sequences HREs.
Sujet(s)
Anémie , Humains , Anémie/traitement médicamenteux , Anémie/étiologie , Isoquinoléines/usage thérapeutique , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Glycine/usage thérapeutique , Glycine/analogues et dérivés , Thérapie moléculaire ciblée , Inhibiteurs de prolyle hydroxylases/usage thérapeutique , Inhibiteurs de prolyle hydroxylases/pharmacologie , Facteurs de transcription à motif basique hélice-boucle-hélice/antagonistes et inhibiteurs , Facteurs de transcription à motif basique hélice-boucle-hélice/métabolismeRÉSUMÉ
In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.
Sujet(s)
Glycine , Isoquinoléines , Syndromes myélodysplasiques , Humains , Syndromes myélodysplasiques/traitement médicamenteux , Sujet âgé , Mâle , Méthode en double aveugle , Femelle , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Adulte d'âge moyen , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Glycine/administration et posologie , Sujet âgé de 80 ans ou plus , Résultat thérapeutique , Adulte , Transfusion d'érythrocytesRÉSUMÉ
Some aplastic anemia(AA) patients only have partial hematological responses after immunosuppressive therapy. Failure to achieve complete normalization of blood counts, particularly hemoglobin, will reduce their quality of life. This open-label pilot study was conducted to evaluate the efficacy and safety of roxadustat in this setting. A total of 14 patients with AA who had inadequate erythroid response after immunosuppressive therapy were included in the study. The primary efficacy endpoint was hemoglobin response at week 8 after roxadustat treatment. The median duration of roxadustat therapy was 14 (4-30) weeks, with 12 patients receiving roxadustat for ≥ 8 weeks. At week 8, nine patients (9/14, 64.3%) had their hemoglobin rising for at least 15 g/L, with two patients (2/14, 14.3%) achieving normal hemoglobin levels. By the last follow-up, hemoglobin responses were observed in 10 patients (10/14, 71.4%), with 4 patients(4/14, 28.6%) having normal hemoglobin levels. Roxadustat was tapered or discontinued in four responded patients; one relapsed after 12 weeks of tapering, and three maintained their response. Four patients (4/14, 28.6%) experienced mild adverse effects during therapy. Roxadustat is safe and well tolerated by patients with AA. Treatment with the hypoxia-inducible factor prolyl hydroxylase inhibitor improves hemoglobin levels in AA patients with inadequate erythroid responses.
Sujet(s)
Anémie aplasique , Glycine , Isoquinoléines , Humains , Mâle , Femelle , Adulte , Adulte d'âge moyen , Projets pilotes , Isoquinoléines/usage thérapeutique , Isoquinoléines/effets indésirables , Isoquinoléines/administration et posologie , Anémie aplasique/traitement médicamenteux , Anémie aplasique/sang , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Glycine/effets indésirables , Sujet âgé , Hémoglobines/analyse , Résultat thérapeutique , Jeune adulte , Données préliminaires , AdolescentRÉSUMÉ
Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.
Sujet(s)
Anémie , Isoquinoléines , Syndromes myélodysplasiques , Humains , Anémie/étiologie , Anémie/traitement médicamenteux , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Hypoxia-inducible factor-proline dioxygenases/antagonistes et inhibiteurs , Isoquinoléines/usage thérapeutique , Isoquinoléines/administration et posologie , Syndromes myélodysplasiques/traitement médicamenteux , Inhibiteurs de prolyle hydroxylases/usage thérapeutique , Études rétrospectivesRÉSUMÉ
Objective: To evaluate the efficacy and safety of roxadustat in patients with refractory non-severe aplastic anemia (NSAA) . Methods: The clinical data of patients with refractory NSAA who had been treated with roxadustat continuously for at least 3 months and followed up for more than 6 months at Peking Union Medical College Hospital from October 2020 to August 2022 were retrospectively collected. The demographic information, clinical data, treatment efficacy, adverse reactions, and outcomes were evaluated, and the factors influencing efficacy were analyzed. Results: A total of 41 patients were included. The male-to-female ratio was 16â¶25, and the median age was 52 (18-84) years. The median duration of roxadustat treatment was 5 (3-20) months, and the median follow-up was 15 (6-26) months. Hematologic improvement-erythroid (HI-E) was 12.2%, 29.3%, 46.3%, 43.9%, and 30.3% at 1, 2, 3, 6, and 12 months, respectively. The rate of transfusion independence was 28.5%, 38.1%, and 33.3% at 3, 6, and 12 months, respectively. Hemoglobin returned to normal in some patients after treatment with roxadustat. The incidence of adverse events was 22%, all of which were grade â -â ¡ and recoverable. No factors that could affect HI-E were identified. By the end of follow-up, 45% of the patients relapsed, with a median time to relapse of 7 (3-12) months. No clonal evolution was observed, and one patient died. Conclusion: Roxadustat effectively improved anemia with good tolerance in patients with refractory NSAA.
Sujet(s)
Anémie aplasique , Glycine , Isoquinoléines , Humains , Mâle , Femelle , Anémie aplasique/traitement médicamenteux , Adulte d'âge moyen , Adulte , Études rétrospectives , Sujet âgé , Adolescent , Isoquinoléines/usage thérapeutique , Isoquinoléines/effets indésirables , Glycine/analogues et dérivés , Glycine/usage thérapeutique , Glycine/effets indésirables , Résultat thérapeutique , Sujet âgé de 80 ans ou plus , Jeune adulteRÉSUMÉ
BACKGROUND/AIMS: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. METHODS: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. RESULTS: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. CONCLUSION: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.