Pyrotinib combined with trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer: a single-arm exploratory phase II trial.

PURPOSE: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC. METHODS: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety. RESULTS: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed. CONCLUSION: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

Toxicity reduction and water expelling effect preservation of Shizaotang after its toxic members processing with vinegar on rats with malignant pleural effusions.

ETHNOPHARMACOLOGICAL RELEVANCE: Shizaotang (SZT), consisted of Euphorbia kansui S.L.Liou ex S.B.Ho (EK), Euphorbia pekinensis Rupr. (EP), Daphne genkwa Sieb. et Zucc. (DG，fried) and Ziziphus jujuba Mill. (ZJ), is usually used for treating malignant pleural effusions (MPE), but the toxicity of EK and EP limits its clinical safe application. It was reported that vinegar processing can reduce the toxicity of EK and EP. Whether EK and EP processing with vinegar can cause the reduced toxicity and retained pharmacological effects of SZT, it still remains unknown. AIM OF THE STUDY: We aimed to evaluate whether using vinegar processed EK and EP would reduce toxicity and preserve water expelling effect of SZT. MATERIALS AND METHODS: Network pharmacology and qualitative analysis of SZT/VSZT were used to construct compound-target-pathway network of their effects and toxicity. Pleural fluid weight, urine volume, uric electrolyte, pH, pro-inflammatory cytokines in pleural fluid, serum Renin-Angiotensin-Aldosterone System (RAAS), anti-diuretic hormone (ADH) and intestinal aquaporin 8 (AQP8) protein were used to evaluate the effect mechanisms involved in rats experiments. And liver damage, oxidative damage and HE staining (liver, stomach, and intestine) were used to determine the toxicity. RESULTS: Network pharmacology analysis reviewed inflammation-related pathways of the effect and toxicity of SZT/VSZT: VEGF-PI3K-AKT pathway inhibited MPE by changing the vasopermeability; PI3K-Akt/Mitogen-activated protein kinase (MAPK)/TNF-NF-κB signaling pathway inhibited MPE by up-regulating expression of AQP8 protein. In vivo experiments displayed that SZT/VSZT could reduce pleural fluid, increase urine volume, lower pro-inflammatory cytokines levels and up-regulate AQP8 protein expression significantly (P < 0.05, P < 0.01). In addition, disorders on electrolyte (Na+, K+ and Cl-) and pH were ameliorated (P < 0.05, P < 0.01). The levels of RAAS and ADH were significantly dose-dependently called back (P < 0.01). These findings were partly consistent with the results of network pharmacology analysis. Results of toxicity experiments demonstrated that SZT and VSZT exhibited certain toxicity on normal rats, and VSZT had lower toxicity than that of SZT. Interestingly, SZT and VSZT exerted alleviation effect to the liver damage and oxidative damage on model rats. CONCLUSION: SZT/VSZT improved MPE by regulating associated inflammation pathways. Besides, compared to SZT, VSZT showed lower toxicity and equivalent expelling MPE effect. This study may provide scientific basis for guiding the clinical application of SZT.

A new mixed inhibitor of adenosine deaminase produced by endophytic Cochliobolus sp. from medicinal plant seeds.

Medicinal plants have been studied for potential endophytic interactions and numerous studies have provided evidence that seeds harbor diverse microbial communities, not only on their surfaces but also within the embryo. Adenosine deaminase (ADA) is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Therefore, in this study, 20 types of medicinal plant seeds were used to screen endophytic fungi with tissue homogenate and streak. In addition, 128 morphologically distinct endophyte strains were isolated and their ADA inhibitory activity determined by a spectrophotometric assay. The strain with the highest inhibitory activity was identified as Cochliobolus sp. Seven compounds were isolated from the strain using a chromatography method. Compound 3 showed the highest ADA inhibitory activity and was identified as 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, based on the results of 1H and 13C NMR spectroscopy. The results of molecular docking suggested that compound 3 binds to the active site and the nonspecific binding site of the ADA. Furthermore, we found that compound 3 is a mixed ADA inhibitor. These results indicate that endophytic strains are a promising source of ADA inhibitors and that compound 3 may be a superior source for use in the preparation of biologically active ADA inhibitor compounds used to treat cancer.

Reynoutria Japonica from Traditional Chinese Medicine: A Source of Competitive Adenosine Deaminase Inhibitors for Anticancer.

BACKGROUND: Adenosine deaminase (ADA) is an important enzyme in purine metabolism and is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Traditional Chinese Herbal Medicine (TCHM) is widely used alone or in combination with chemotherapy to treat cancer, due to its ability to deliver a broad variety of bioactive secondary metabolites as promising sources of novel organic natural agents. OBJECTIVE: In the present study, 29 varieties of medicinal plants were screened for the presence of ADA inhibitors. RESULTS: Extracts from Reynoutria japonica, Glycyrrhiza uralensis, Lithospermum erythrorhizon, Magnolia officinalis, Gardenia jasminoides, Stephania tetrandra, Commiphora myrrha, Raphanus sativus and Corydalis yanhusuo demonstrated strong ADA inhibition with rates greater than 50%. However, Reynoutria japonica possessed the highest ADA inhibitory activity at 95.26% and so was used in our study for isolating the ADA inhibitor to be further studied. Eight compounds were obtained and their structures were identified. The compound H1 had strong ADA inhibitory activity and was deduced to be emodin by 1H and 13C-NMR spectroscopic analysis with an IC50 of 0.629 mM. The molecular docking data showed that emodin could bind tightly to the active site of ADA. Our results demonstrated that emodin displayed a new biological activity which is ADA inhibitory activity with high cytotoxic activity against K562 leukemia cells. The bioactivity of cordycepin was significantly increased when used in combination with emodin. CONCLUSION: Emodin may represent a good candidate anti-cancer therapy and adenosine protective agent.

Pyruvate in oral rehydration salt improves hemodynamics, vasopermeability and survival after burns in dogs.

BACKGROUND: To investigate whether pyruvate-enriched oral rehydration solution (Pyr-ORS), compared with citrate-enriched ORS (Cit-ORS), improves hemodynamics and organ function by alleviating vasopermeability and plasma volume loss during intra-gastric fluid rehydration in dogs with severe burn. METHODS: Forty dogs subjected to severe burn were randomly divided into four groups (n=10): two oral rehydrated groups with Pyr-ORS and Cit-ORS (group PR and group CR), respectively, according to the Parkland formula during the first 24h after burns. Other two groups were the intravenous (IV) resuscitation (group VR) with lactated Ringer's solution with the same dosage and no fluid rehydration (group NR). During the next 24h, all groups received the same IV infusion. The hemodynamics, plasma volume, vasopermeability and water contents and function of various organs were determined. Plasma levels of vascular endothelial growth factor (VEGF) and platelet activating factor (PAF) were detected by ELISA. RESULTS: Hemodynamics parameters were significantly improved in group PR superior to group CR after burns. Levels of VEGF and PAF were significantly lower in group PR than in group CR. Organ function parameters were also greatly preserved in group PR, relative to groups CR and NR. Lactic acidosis was fully corrected and survival increased in group PR (50.0%), compared to group CR (20.0%). CONCLUSION: Pyr-ORS was more effective than Cit-ORS in improving hemodynamics, visceral blood perfusion and organ function by alleviating vasopermeability-induced visceral edema and plasma volume loss in dogs with severe burn.