Revealing the efficacy-toxicity relationship of Fuzi in treating rheumatoid arthritis by systems pharmacology

In recent decades, herbal medicines have played more and more important roles in the healthcare system in the world because of the good efficacy. However, with the increasing use of herbal medicines, the toxicity induced by herbal medicines has become a global issue. Therefore, it is needed to investigate the mechanism behind the efficacy and toxicity of herbal medicines. In this study, using Aconiti Lateralis Radix Praeparata (Fuzi) as an example, we adopted a systems pharmacology approach to investigate the mechanism of Fuzi in treating rheumatoid arthritis and in inducing cardiac toxicity and neurotoxicity. The results showed that Fuzi has 25 bioactive compounds that act holistically on 61 targets and 27 pathways to treat rheumatoid arthritis, and modulation of inflammation state is one of the main mechanisms of Fuzi. In addition, the toxicity of Fuzi is linked to 32 compounds that act on 187 targets and 4 pathways, and the targets and pathways can directly modulate the flow of Na+, Ca2+, and K+. We also found out that non-toxic compounds such as myristic acid can act on targets of toxic compounds and therefore may influence the toxicity. The results not only reveal the efficacy and toxicity mechanism of Fuzi, but also add new concept for understanding the toxicity of herbal medicines, i.e., the compounds that are not directly toxic may influence the toxicity as well.

Study of acute oral toxicity of organotin compounds containing a 2,6-di-tert-butylphenol fragment

The aim of the study was to evaluate the safety of the use of organotin compounds containing a fragment of 2,6-di-tert-butylphenol as pharmaceutical substances when administered intragastrically to Wistar outbred rats (females). Material and methods. The objects of the study were three organotin compounds: ((3,5-di-tertbutyl-4-hydroxyphenylthiolate) triphenyltin (Me-5), (3,5-di-tert-butyl-4-hydroxyphenylthiolate)trimethyltin (Me-4), bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (Me-3). Acute toxicity study were performed on 106 Wistar rats (female) weighing 190-210 g by "fixed dose" and "up and down" methods according to the OECD protocols. Results. According to the harmonized system of hazard classification and labeling of chemical products (GHS) the studied organotin compounds should be assigned to the following toxicity classes: Me-5 — IV, Me-3 — V, Me-4 — II. Average lethal dose in intragastric administration for Me-5 is LD50 = 955.0 ± 58.3 mg/kg, the value of LD50 for Me-3 is conventionally assumed to be much more than 2000 mg/kg, for Me-4 is in the range of 5 to 50 mg/kg. Discussion. The modification of tin-organic molecules in the course of directed synthesis opens broad prospects for the creation of a new class of anticancer drugs. In the course of the experimental study, the regularities of the "structure-toxicity" relationship of organic tin derivatives were revealed: the introduction of the 2,6-di-tert-butylphenol group significantly reduces toxicity compared to the corresponding initial substances; methyl derivatives are more toxic than their phenyl analogues. Compounds of GHS toxicity classes IV and V can be considered as leading candidates for promising preclinical studies in the field of experimental oncology. Conclusion. Substances of Me-3 and Me-5, which have the highest safety for intragastric use, were recommended for further study as antitumor drug agents.

Dose-Effect/Toxicity of Bupleuri Radix on Chronic Unpredictable Mild Stress and Normal Rats Based on Liver Metabolomics

Depression, one of the most prevalent psychiatric diseases, affects the quality of life of millions of people. Studies have shown that the lower polar fraction of Bupleuri Radix (PBR) elicited therapeutic effects in chronic unpredictable mild stress (CUMS) rats. In contrast, comparatively mild liver injury was observed in normal rats administered a high PBR dose. It is essential to clarify the effective and safe dose of PBR and its dose-effect/toxicity relationship. In this study, we used the CUMS model to evaluate the effects and toxicities of PBR and to decipher the dose-effect/toxicity relationship and mechanism using the liver metabonomics combined with multivariate statistical analysis. In CUMS rats, PBR improved the depression-like behaviors including reduced body growth rate, anhedonia, and locomotor activities, and markedly reduced the contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In control rats, PBR treatment altered ALT and AST from typical levels. Moreover, the effective dose range for CUMS rats was 12.6–163 g (herb)/kg, the median toxicity dose for CUMS and normal rats were 388 and 207 g (herb)/kg. The toxicological results showed that the cytokeratin-18 fragment level was increased significantly in CUMS rats given with 100 g (herb)/kg PBR. After a comprehensive analysis, the use of PBR dose was determined to be 12.6–50 g (herb)/kg. In CUMS rats, PBR could reverse amino acid metabolism, energy metabolism, sphingolipid metabolism, and β-oxidation of fatty acids to produce an anti-depressant effect in a dose-dependent manner. In control rats, two additional metabolic pathways were significantly perturbed by PBR, including glycerophospholipid metabolism and bile acid metabolism. Moreover, the comprehensive metabolic index including dose-effect index (DEI) and dose toxicity index (DTI) had a remarkable ability (ROC = 0.912, ROC = 0.878) to predict effect and toxicity. The DEI and DTI were used to determine the dose range of effect and toxicity which was shown high concordance with previous results. Furthermore, the CUMS rats possessed a higher toxicity tolerance dose of PBR which was consistent with the theory of “You Gu Wu Yun” in traditional Chinese medicine. The metabonomics techniques combined with correlation analysis could be used to discover indicators for comprehensive evaluations of efficacy and toxicity.

Phase I safety and efficacy study of autophagy inhibition with hydroxychloroquine to augment the antiproliferative and biological effects of preoperative palbociclib plus letrozole for estrogen receptor-positive, HER2-negative metastatic breast cancer (MBC).

1067 Background: Endocrine therapy with a CDK4/6 inhibitor is standard of care for patients (pts) with estrogen-receptor-positive (ER+), HER2-negative MBC, yet resistance ultimately develops. We have shown that low doses of palbociclib activates autophagy, which reverses initial G1 cell cycle arrest. High concentrations of palbociclib induce senescence, but these are off target effects of the drug. The autophagy inhibitor hydroxychloroquine (HCQ) induces senescence at a lower (i.e. on-target) continuous dosing of palbociclib, in in vitro and in vivo models. This strategy is being tested in a phase I/II trial (NCT03774472). Results from the phase I portion are reported here. Methods: The phase I part of this study uses a dose escalation 3+3 design testing HCQ, 400, 600 and 800 mg daily (6 pts at 800 mg) with continuously dosed palbociclib at 75 mg and letrozole 2.5 mg daily. Dose limiting toxicity (DLT) includes any study drug-related grade ≥ 3 nonhematological (lab) toxicity. Responding pts may continue on therapy beyond 8 weeks for up to 52 weeks. Primary objective is to determine safety, tolerability and the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives are overall tumor response and time to progression. Eligible pts are ≥18 years of age, postmenopausal (ovarian suppression allowed) with ER+/HER2-negative MBC, ECOG performance status score of ≤1 and with adequate renal, hepatic, and hematologic function. Response is assessed per RECIST v1.1. Results: Between 9/24/18 and 12/15/20, 14 pts were evaluable for safety. Median age was 41 with Asian (1, 7.1%), Black (2, 14.3%) White (11, 78.6%) patients enrolled. No DLTs were observed. One pt progressed during the DLT period and 2 withdrew consent (one during the DLT period); two pts were replaced for DLT assessment. Reasons for coming off study were grade 3 skin toxicity (1), per protocol at 8 weeks (non-measurable or pt/physician preference, 9), and (2) full duration treatment at 50 and 52 weeks. Adverse events (AEs) of grade ≥3 were hematologic (29), metabolism/nutrition (2), musculoskeletal/ connective tissue (1), and skin/subcutaneous tissue (3), with no serious AEs reported. The percent of palbociclib doses held per pt due to neutrophil level ranged from 0-37.5% with no apparent relation to HCQ dose. Best response was partial (2) stable (11); and progression (1). For measurable disease, tumor decreases of 11%, 12%, 21%, 26%, 30%, 55% and increase in 1 pt by 55% were seen. Conclusions: This phase I study showed acceptable safety and no HCQ dose-toxicity relationship. The RP2D of HCQ is 800 mg/day with continuous dosing palbociclib at 75 mg/day and letrozole at 2.5 mg/day. The phase 2 trial will proceed in the neoadjuvant setting, with Ki67 proliferative index response as the primary endpoint. Clinical trial information: NCT03774472 .

Correlation between the structure and skin permeability of compounds

A three-descriptor quantitative structure–activity/toxicity relationship (QSAR/QSTR) model was developed for the skin permeability of a sufficiently large data set consisting of 274 compounds, by applying support vector machine (SVM) together with genetic algorithm. The optimal SVM model possesses the coefficient of determination R2 of 0.946 and root mean square (rms) error of 0.253 for the training set of 139 compounds; and a R2 of 0.872 and rms of 0.302 for the test set of 135 compounds. Compared with other models reported in the literature, our SVM model shows better statistical performance in a model that deals with more samples in the test set. Therefore, applying a SVM algorithm to develop a nonlinear QSAR model for skin permeability was achieved.