Comparative pharmacokinetic study of Anisodamine Hydrobromide tablets and injection in septic acute lung injury rats.

Aim: We aimed to establish a sensitive LC-MS/MS method to analyze the pharmacokinetics of Ani HBr tablets and injection. Methods: Around 10 mmNH4Ac containing 0.1% formic acid and acetonitrile were used as the mobile phase. Acute lung injury in septic and normal rats, respectively, were administered Ani HBr tablets at doses of 12.5, 25 and 50 mg/kg and injection at doses of 4, 8 and 16 mg/kg, followed by extraction of the drugs from plasma using ethyl acetate for subsequent analysis. Results & conclusion: The method met the requirements for biological analysis. Ani HBr tablets absorbed slowly in rats with disease, tail vein administration was a more promising approach for treating septic acute lung injury.

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Anisodamine hydrobromide ameliorates acute lung injury via inhibiting pyroptosis in murine sepsis model.

OBJECTIVE: Sepsis can have severe implications on lung function, leading to acute lung injury (ALI), a major contributor to sepsis-related mortality. Anisodamine hydrobromide (Ani HBr), a bioactive constituent derived from the root of Scopolia tangutica Maxim, a plant endemic to China, has demonstrated efficacy in treating septic shock. We aim to explore whether Ani HBr can alleviate sepsis-triggered ALI and elucidate the fundamental mechanisms involved. MATERIALS AND METHOD: The protective effects of Ani HBr were assessed in two models: in vitro, lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and in vivo, cecal ligation puncture (CLP)-induced sepsis. To measure the cell viability of RAW264.7 cells after Ani HBr treatment, we used the CCK-8 assay. We quantified the levels of pro-inflammatory cytokines expression using ELISA. We also measured the expression of pyrotosis indicators by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. RESULTS: Our study demonstrates that Ani HBr can alleviate pulmonary edema, bleeding, and excessive inflammation induced by CLP. Additionally, it exhibits protective effects against cytotoxicity induced by LPS in RAW264.7 macrophage cells. Furthermore, Ani HBr downregulates the mRNA and protein levels of NLRP3, Caspase-1, GSDMD, IL-18, and IL-1ß in both animal models and cell cultures, thereby inhibiting pyroptosis in a similar mechanism to AC-YVAD-CMK (AYC)'s blockade of Caspase-1. Moreover, Ani HBr suppresses the production and release of proinflammatory cytokines. CONCLUSION: These findings suggest that Ani HBr could serve as a protective agent against sepsis-induced ALI by suppressing pyroptosis.

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Anisodamine hydrobromide ameliorates cardiac damage after resuscitation.

The microcirculation is correlated with the prognosis of patients with cardiac arrest and changes after resuscitation. In the present study, the effects of anisodamine hydrobromide (AH) on microcirculation was investigated and its potential mechanisms were explored. A total of 24 pigs were randomly grouped into three groups (n=8): Sham, Saline and AH group. After pigs were anesthetized, intubated and mechanically ventilated, ventricular fibrillation was induced by electrical stimulation. After 8 min, cardiopulmonary resuscitation was given to the restoration of spontaneous circulation (ROSC). Arteriovenous blood was collected at baseline and 0, 1, 2, 4 and 6 h after ROSC to measure blood gas and cytokines. Perfused vessel density (PVD) and microvascular flow index (MFI) were measured to reflect the microcirculation. Continuous cardiac output and global ejection fraction were measured to indicate hemodynamics. Compared with Sham group, PVD and MFI in the intestines and the sublingual regions decreased significantly after resuscitation. The microcirculation recovered faster in the AH group than the SA group. The decrease of intestinal microcirculatory blood flow was closely related to the decrease of sublingual microcirculatory blood flow. The cardiac function was impaired after resuscitation, and a decrease of IFN-γ as well as IL-2 and an increase of IL-4 as well as IL-10 suggested the immune imbalance. The microcirculation changes in sublingual regions were closely related to the changes in intestines. AH could improve the immune imbalance after resuscitation and was beneficial to the recovery of cardiac function.

Influence of Microcirculatory Dysfunction on Myocardial Injury after Cardiopulmonary Resuscitation.

Objective: This study aimed to examine the effects of microcirculatory dysfunction and 654-1 intervention after cardiopulmonary resuscitation on myocardial injury. Methods: Landrace pigs were divided into a sham operation group (S group, n= 6), ventricular fibrillation control group (VF-C group, n= 8) and 654-1 intervention group (VF-I group, n= 8). Hemodynamics was recorded at baseline, at recovery of spontaneous circulation (ROSC), and 1 h, 2 h, 4 h and 6 h thereafter. Sidestream dark field (SDF) technology was used to evaluate and monitor the microcirculation flow index, total vessel density, perfusion vessel ratio, De-Backer score, and perfusion vessel density in animal viscera at various time points. Results: After administration of 654-1 at 1.5 h post-ROSC, the hemodynamics in the VF-I group, as compared with the VF-C group, was significantly improved. The visceral microcirculation detected by SDF was also significantly improved in the VF-I group. As observed through electron microscopy, significantly less myocardial tissue injury was present in the VF-I group than the VF-C group. Conclusion: Administration of 654-1 inhibited excessive inflammatory by improving the state of visceral microcirculation.

Protection of intestinal immune barrier against ischemia/reperfusion injury in a swine model using anisodamine hydrobromide

Abstract Intestinal ischemia/reperfusion (I/R) causes barrier impairment and bacterial influx. This study explored the protective effects of anisodamine hydrobromide (AH) on intestinal I/R injury caused by cardiopulmonary resuscitation (CPR) after cardiac arrest (CA). After successful CPR, minipigs were randomly divided into two groups (n = 8): saline and AH (4 mg/kg), and then treated with saline or AH via central venous injection, respectively. The same procedures without ventricular fibrillation initiation were conducted in the Sham group (n = 8). Levels of interferon gamma (IFN-γ) and interleukin 4 (IL-4) were measured at different time points (0, 0.5, 1, 2, 4, and 6 h) in serum and 6 h in gut associated lymphoid tissues (GALTs) after the return of spontaneous circulation (ROSC) to evaluate changes in the proportion of T-helper type 1 (Th1) and T-helper type 2 (Th2). Moreover, the positive culture rates of GALTs were examined to evaluate bacterial translocation. AH treatment markedly alleviated aberrant arterial blood gas and hemodynamics as well as intestinal macroscopic and morphological changes after CPR. Moreover, AH treatment significantly increased IFN-γ and decreased IL-4 in both serum and GALTs. Furthermore, AH treatment dramatically decreased positive bacterial growth in GALTs. AH treatment mitigated immunosuppression caused by intestinal I/R and protected the intestinal immune barrier against bacterial translocation, thereby reducing the risk of secondary intestinal infection

Coronary microvascular dysfunction: An important interpretation on the clinical significance of transient ischemic dilation of the left ventricle on myocardial perfusion imaging.

PURPOSE: To further investigate the clinical significance of transient ischemic dilation (TID) on myocardial perfusion imaging (MPI) by analyzing the effect of anisodamine hydrobromide (a drug that can effectively ameliorate microcirculation) on the patients with isolated TID and the findings of previous literatures. METHODS: Total 107 patients with isolated TID (TID value≥1.11) were randomly divided into group A (n = 36; intravenous administration of anisodamine hydrobromide), group N (n = 36; intravenous administration of isosorbide dinitrate), and group C (n = 35; intravenous administration of normal saline). MPI and treadmill exercise test (TET) were performed again after 14-day course of intervention. Pre- and post-intervention frequencies of symptom were recorded. RESULTS: In group A, after intervention of anisodamine hydrobromide, the summed stress score (SSS) and TID value on MPI significantly decreased than those before intervention (P < 0.001), the durations of exercise (DEs) and metabolic equivalents (METs) in TET notably ascended (P < 0.001), as well as the symptom remarkably improved. In group N and group C, there were no significant differences in SSS, TID value, DEs, METs, and frequencies of symptom between pre- and post-intervention (P > 0.05). No significant improvement of symptoms in group N before and after treatment. CONCLUSIONS: TID with perfusion defect may usually predict a possibility of severe and extensive coronary artery disease (CAD). An isolated TID should be considered as a likelihood of coronary microvascular dysfunction (CMD). TET and coronary CT angiography (cCTA) are extremely helpful for the antidiastole on CAD and CMD. The administration of anisodamine hydrobromide might be an optional treatment for the patients with isolated TID.