Dachaihu decoction ameliorates septic intestinal injury via modulating the gut microbiota and glutathione metabolism as revealed by multi-omics.

Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance. We further found that the combination of EPO with romiplostim, a thrombopoietin receptor agonist that can stimulate the expansion of hematopoietic stem cells, can treat EPO-resistance. In this study, we performed interspecies pharmacodynamic (PD) scaling of this combination therapy for human dose prediction. The pharmacokinetic parameters of both rHuEPO and romiplostim in humans were obtained from previous studies. The PD parameters obtained in rats were scaled to humans using allometric equations. The relationship between PD parameters of the megakaryocyte lineage from rats, monkeys, and humans was in agreement with those from the literature on allometric scaling. The PD response was translated to humans based on allometric scaling and agreed with the observed data. These parameters were used to simulate hemoglobin and platelet response in humans. RHuEPO 50 IU/kg thrice weekly and romiplostim 1 μg/kg once every 4 weeks from the second week is the recommended combination dosing regimen according to the model prediction. Our work successfully scaled the PD of rHuEPO and romiplostim monotherapy from rats to humans. The predicted dosing regimen of each drug in the combination therapy is less intensive than the approved starting dose of each drug, which supports additional evaluations of the combination therapy in humans.

https://www.mdpi.com/1999-4923/15/2/344/pdf?version=1674460243

Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia

Fecal microbiota transplantation holds the secret to youth

Modifications of Ganoderma lucidum spores into digestive-tissue highly adherent porous carriers with selective affinity to hydrophilic or hydrophobic drugs.

Neo-adjuvant chemotherapy (NACT) is utilized in locally advanced oral cancers to reduce the tumor burden and downstage the tumor to be amenable for definitive surgical management. Its long-term results compared to upfront surgical resection was not encouraging. Immunotherapy has now been used not only in recurrence and metastatic setting but also in the locally advanced tumor management regimens. The purpose of this concept paper is to bring forward the rationale to use a fixed low-dose immunotherapy agent as a potentiator to the standard NACT regimen and recommend their future investigation in oral cancer management.

Low-dose immunotherapy as a potentiator to increase the response with neo-adjuvant chemotherapy in oral cancers

https://doi.org/10.1016/j.apsb.2022.10.016

Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice

Pharmacokinetics, absorption and transport mechanism for ginseng polysaccharides.

Clearance as an Early Indicator of Efficacy for Therapeutic Monoclonal Antibodies: Circumventing Dose Selection Challenges in Oncology

Erythropoietin (EPO) and thrombopoietin (TPO) have long been known to promote erythropoiesis and megakaryopoiesis, respectively. However, the fate-changing role of EPO and TPO on megakaryocyte-erythroid progenitors (MEPs) to develop along the erythroid versus megakaryocyte lineage remains unclear. We have previously shown that EPO may have a fate-changing role because EPO treatment could induce progenitor cells depletion and result in EPO resistance. Therefore, we hypothesize that a combination of romiplostim, a TPO receptor agonist that could stimulate the expansion of progenitors, with EPO can treat EPO resistance. Using rats with anemia due to chronic kidney disease, we demonstrated that romiplostim synergized with EPO to promote red blood cells production whereas EPO inhibited platelet production in a dose-dependent manner to reduce the risk of thrombosis. Corroborating findings from in vivo, in vitro experiments demonstrated that romiplostim expanded hematopoietic stem cells and stimulated megakaryopoiesis whereas EPO drove the progenitors toward an erythroid fate. We further developed a novel pharmacokinetic-pharmacodynamic model to quantify the effects of EPO and romiplostim on megakaryopoiesis and erythropoiesis simultaneously. The modeling results demonstrated that EPO increased the differentiation rate of MEPs into burst-forming unit-erythroid cells up to 22-fold, indicating that the slight increase of MEPs induced by romiplostim could be further amplified and recruited by EPO to promote erythropoiesis. The data herein support that romiplostim in combination with EPO can treat EPO resistance. SIGNIFICANCE STATEMENT This study clarified that erythropoietin (EPO) drives the fate of megakaryocyte-erythroid progenitors (MEPs) toward the erythroid lineage, thus reducing their megakaryocyte (MK) lineage commitment, whereas romiplostim, a thrombopoietin receptor agonist, stimulates megakaryopoiesis through the MK-committed progenitor and MEP bifurcation pathways simultaneously. These findings support an innovative combination of romiplostim and EPO to treat EPO-resistant anemia because the combination therapy further promotes erythropoiesis compared to EPO monotherapy and inhibits platelet production compared to romiplostim monotherapy.

Xiaoqing Fan

Papers

Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice

Pharmacokinetics, absorption and transport mechanism for ginseng polysaccharides.

Clearance as an Early Indicator of Efficacy for Therapeutic Monoclonal Antibodies: Circumventing Dose Selection Challenges in Oncology

Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors

Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia