The present study aimed to establish an LC-MS/MS method for the quantification of tiamulin in minipig plasma and to further conduct a pharmacokinetic comparison of different formulations. The plasma samples were extracted with acetonitrile (meloxicam as internal standard), separated on a C18 column, and quantified by multiple reaction monitoring mode (ESI+). Sanyuan minipigs were used as experimental animals. Plasma samples were collected after intravenous injection (10 mg/kg) and intragastric administration (20 mg/kg). The method showed good linearity, with intra- and inter-batch RSD of 1.00%–8.13% and RE within ±15%. The extraction recovery, matrix effect and stability of the analytical methods met the relevant requirements. Tiamulin fumarate active pharmaceutical ingredient was intravenously administered, with c0 of about (4383.73±2676.78) ng/mL, AUC0-t of about (4803.50±965.68) h·ng/mL, t1/2 of about (4.66±1.68) h, and CL of about (2.14±0.46) L/(kg·h). Three tiamulin formulations were intragastrically administered, with cmax of (552.00±328.55), (545.00±136.97) and (590.60±237.02) ng/mL, tmax of (1.47±0.68), (0.69±0.75) and (0.72±0.72) h, and F of 24.85%, 15.28% and 16.97%, respectively. The validated method meets the requirements for biological sample analysis and is applicable for the pharmacokinetic evaluation of tiamulin formulations in minipigs.

BACKGROUND: Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI assistance. METHODS: An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo . We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo . RESULTS: AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis. CONCLUSION AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
Animals ; Glaucoma/metabolism* ; Neuroprotective Agents/pharmacology* ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Artificial Intelligence ; Retinal Ganglion Cells/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Male

Objective To observe the analgesic effects of different concentrations of ropivacaine combined with ultrasound-guided nerve stimulation for continuous femoral nerve block(CFNB)in elderly female patients undergoing total knee arthroplasty(TKA).Methods A total of 90 female patients scheduled for TKA at the First People's Hospital of Huzhou from March 2023 to February 2024 were selected as the research subjects,they were randomly divided into three groups(A,B,C)using a random number table,with 30 cases in each group.Different concentrations of ropivacaine(20ml)were administered for muscle relaxant block before general anesthesia:Group A received 0.150％ropivacaine,group B received 0.250％ropivacaine,and group C received 0.375％ropivacaine.Postoperatively,analgesia pumps with the corresponding concentration of local anesthetic were set at 5ml/h for 72h.Intraoperative hemodynamic changes were recorded,postoperative visual analog pain scores(VAS)during rest,active,and continuous passive functional training,time to first ambulation,popliteal discomfort,muscle strength grading,and adverse reactions were assessed.Results VAS scores during active functional training at 24h,48h,and 72h among three groups showed statistically significant differences(P<0.05),with group C having significantly lower VAS scores than groups A and B(P<0.05).VAS scores for passive training at 72h also showed significant differences,with group C scoring significantly lower than groups A and B(P<0.05).The proportion of patients taking more than 24h to ambulate for the first time and proportion experiencing popliteal discomfort differed among the groups,with group C having significantly fewer cases than groups A and B.Muscle strength in all groups was greater than grade 3 from 24h to 72h postoperatively.Conclusion CFNB with 0.375％ropivacaine has a good postoperative analgesic effect for TKA and does not increase incidence of side effects.

[Objective]To investigate LI Dongyuan's theory of"any deficiency of spleen and stomach is a disease of the blood"and provide reference for modern clinical practice.[Methods]Taking Discussion on Internal and External Injuries,Treatise on Spleen and Stomach,Orchid Chamber of Secrets and Invention of Medicine as references,it starts from the connotation of"any deficiency of spleen and stomach is a disease of the blood",and explores the etiology and pathogenesis of the diseases,the theoretical construction and the clinical application respectively.[Results]Taking Inner Canon of Yellow Emperor and Zhongjing's academic thought as the source,absorbing CHENGs' and ZHU Xi's ideas of science.Being inspired by his teacher ZHANG Yuansu,and driven by his own clinical practice,LI Dongyuan put forward the academic thought of"any deficiency of spleen and stomach is a disease of the blood".From the Treatise on Spleen and Stomach-Treatise on the Prosperity and Decline of Spleen and Stomach,"any deficiency of spleen and stomach is a disease of the blood",which is a pathological state caused by the deficiency of spleen and stomach Qi and the weakness of elevation due to the disorders of emotions and moods,overwork and overdose,and uncontrolled diets,there fore causes insufficient blood production and too much blood consumption,and then leads to the deficiency of blood and Yin,and the essence of which is the disordered ascending,descending,floating and sinking of the human body's Qi.In treatment,LI Dongyuan always based on regulating blood,to restore the body's Qi,and harmonize Qi and blood as the goal,with"blood replenishment must have Yang Qi,Qi and blood double tonic""rising Yang must be in response to the time of the day,and make good use of the wind herbs""relieving heat must protect the Yin and blood,moderation in attacking and destroying".[Conclusion]Exploring this theory can help to view the relationship between Qi and blood from a new perspective,better grasp LI Dongyuan's academic thinking,and provide reference for the treatment of spleen and stomach diseases and blood diseases.

Objective To observe the analgesic effects of different concentrations of ropivacaine combined with ultrasound-guided nerve stimulation for continuous femoral nerve block(CFNB)in elderly female patients undergoing total knee arthroplasty(TKA).Methods A total of 90 female patients scheduled for TKA at the First People's Hospital of Huzhou from March 2023 to February 2024 were selected as the research subjects,they were randomly divided into three groups(A,B,C)using a random number table,with 30 cases in each group.Different concentrations of ropivacaine(20ml)were administered for muscle relaxant block before general anesthesia:Group A received 0.150％ropivacaine,group B received 0.250％ropivacaine,and group C received 0.375％ropivacaine.Postoperatively,analgesia pumps with the corresponding concentration of local anesthetic were set at 5ml/h for 72h.Intraoperative hemodynamic changes were recorded,postoperative visual analog pain scores(VAS)during rest,active,and continuous passive functional training,time to first ambulation,popliteal discomfort,muscle strength grading,and adverse reactions were assessed.Results VAS scores during active functional training at 24h,48h,and 72h among three groups showed statistically significant differences(P<0.05),with group C having significantly lower VAS scores than groups A and B(P<0.05).VAS scores for passive training at 72h also showed significant differences,with group C scoring significantly lower than groups A and B(P<0.05).The proportion of patients taking more than 24h to ambulate for the first time and proportion experiencing popliteal discomfort differed among the groups,with group C having significantly fewer cases than groups A and B.Muscle strength in all groups was greater than grade 3 from 24h to 72h postoperatively.Conclusion CFNB with 0.375％ropivacaine has a good postoperative analgesic effect for TKA and does not increase incidence of side effects.

[Objective]To investigate LI Dongyuan's theory of"any deficiency of spleen and stomach is a disease of the blood"and provide reference for modern clinical practice.[Methods]Taking Discussion on Internal and External Injuries,Treatise on Spleen and Stomach,Orchid Chamber of Secrets and Invention of Medicine as references,it starts from the connotation of"any deficiency of spleen and stomach is a disease of the blood",and explores the etiology and pathogenesis of the diseases,the theoretical construction and the clinical application respectively.[Results]Taking Inner Canon of Yellow Emperor and Zhongjing's academic thought as the source,absorbing CHENGs' and ZHU Xi's ideas of science.Being inspired by his teacher ZHANG Yuansu,and driven by his own clinical practice,LI Dongyuan put forward the academic thought of"any deficiency of spleen and stomach is a disease of the blood".From the Treatise on Spleen and Stomach-Treatise on the Prosperity and Decline of Spleen and Stomach,"any deficiency of spleen and stomach is a disease of the blood",which is a pathological state caused by the deficiency of spleen and stomach Qi and the weakness of elevation due to the disorders of emotions and moods,overwork and overdose,and uncontrolled diets,there fore causes insufficient blood production and too much blood consumption,and then leads to the deficiency of blood and Yin,and the essence of which is the disordered ascending,descending,floating and sinking of the human body's Qi.In treatment,LI Dongyuan always based on regulating blood,to restore the body's Qi,and harmonize Qi and blood as the goal,with"blood replenishment must have Yang Qi,Qi and blood double tonic""rising Yang must be in response to the time of the day,and make good use of the wind herbs""relieving heat must protect the Yin and blood,moderation in attacking and destroying".[Conclusion]Exploring this theory can help to view the relationship between Qi and blood from a new perspective,better grasp LI Dongyuan's academic thinking,and provide reference for the treatment of spleen and stomach diseases and blood diseases.

Objective To investigate how opioid-free anesthesia affects the occurrence of emergence agitation(EA)during recovery after transurethral resection of prostate(TURP).Methods A total of 78 patients undergoing TURP from May 2023 to June 2024 in the First People's Hospital of Huzhou were selected as the study subjects.Patients were assigned to two groups using a random number table method,group F received fentanyl(3μg/kg)+propofol(2mg/kg),and group LY received esketamine(0.3mg/kg)+propofol(2mg/kg),39 cases in each group.EA was assessed every 5 minutes following the removal of the laryngeal mask,and pain levels were measured using the visual analog score(VAS).Mean arterial pressure(MAP)and heart rate(HR)were recorded at admission(T0),immediately after laryngeal mask insertion(T1),3 minutes after(T2),6 minutes after(T3),and 9 minutes after(T4).Data on rescue analgesia,operation time,recovery time,and adverse reactions during recovery,such as agitation,nausea,vomiting,hypoxemia,nightmares,and hallucinations were also recorded.Results Compared to group F,incidence of postoperative EA,highest VAS score,and extubation time in group LY were lower(P＜0.05).The highest sedation score in group LY was greater than that in group F(P＜0.05).The comparison of HR and MAP at each time point between two groups showed statistically significant differences from T1 to T4(P＜0.05).Conclusion The opioid-free anesthesia regimen reduces incidence of EA and postoperative pain scores in TURP patients without increasing adverse reactions during recovery.

Objective To investigate how opioid-free anesthesia affects the occurrence of emergence agitation(EA)during recovery after transurethral resection of prostate(TURP).Methods A total of 78 patients undergoing TURP from May 2023 to June 2024 in the First People's Hospital of Huzhou were selected as the study subjects.Patients were assigned to two groups using a random number table method,group F received fentanyl(3μg/kg)+propofol(2mg/kg),and group LY received esketamine(0.3mg/kg)+propofol(2mg/kg),39 cases in each group.EA was assessed every 5 minutes following the removal of the laryngeal mask,and pain levels were measured using the visual analog score(VAS).Mean arterial pressure(MAP)and heart rate(HR)were recorded at admission(T0),immediately after laryngeal mask insertion(T1),3 minutes after(T2),6 minutes after(T3),and 9 minutes after(T4).Data on rescue analgesia,operation time,recovery time,and adverse reactions during recovery,such as agitation,nausea,vomiting,hypoxemia,nightmares,and hallucinations were also recorded.Results Compared to group F,incidence of postoperative EA,highest VAS score,and extubation time in group LY were lower(P＜0.05).The highest sedation score in group LY was greater than that in group F(P＜0.05).The comparison of HR and MAP at each time point between two groups showed statistically significant differences from T1 to T4(P＜0.05).Conclusion The opioid-free anesthesia regimen reduces incidence of EA and postoperative pain scores in TURP patients without increasing adverse reactions during recovery.

Chronic spontaneous urticaria (CSU) is characterized by recurrent wheals with severe itching, and greatly affects the life quality of patients. The European guideline on chronic urticaria recommends the anti-IgE monoclonal antibody omalizumab as the only third-line therapy for patients with CSU whose condition can not be controlled by high doses of antihistamines. Although a lot of researches have shown that omalizumab is effective and safe for the treatment of CSU, its therapeutic mechanisms have not yet been fully elucidated. This review summarizes therapeutic mechanisms of omalizumab in the treatment of CSU, and indices for predicting and monitoring its clinical efficacy.