| Objective: As an acute cerebral circulatory disorder,ischemic stroke has a very high rate of disability and fatality.The key to the treatment of ischemic stroke is to use thrombolytic drugs as soon as possible after the occurrence of the disease,followed by the use of neuroprotective agents to repair the damaged nerve function and reduce the occurrence probability and malignant degree of sequelae.In recent years,molecular pathological studies have found that vascular occlusion caused by stroke triggers a signal cascade process called “Stroke cascade”,which is the main cause of nerve cell death.Various neuroprotective agents currently in the stage of research and development or clinical application only block a certain part of the “Stroke cascade”.Since the pathogenesis of ischemic nerve injury is complicated,blocking a single pathway cannot completely inhibit the pathological damage process.The cocktail therapy is more reasonable,that is,according to the progress of the disease,the combined use of multi-target drugs to regulate the ischemic injury cascade,jointly block the pathological damage mechanism of cerebral ischemia,and protect the brain function.The aim of this study is to assess the effectiveness,safety,economy and rationality of neuroprotective agents in combination with a view to provide an individualized medication plan for the clinical rational use of neuroprotective agents in the treatment of ischemic stroke.Methods: Ⅰ Real-world analysis: a total of 213 patients who were hospitalized for acute ischemic stroke in the Department of Neurology,Zhongda Hospital,Southeast University,from January 2017 to December 2018 and received combined treatment of N-butylphthalide injection(NBP),Edaravone injection(EDA)and Monosialic acid tetrahexosylganglioside injection(GM-1)within 24 hours were collected.According to the combination of neuroprotective agents within the diagnosis and treatment time,the patients were separated into two groups: N-butylphthalide + Edaravone group(NBP+EDA group)and N-butylphthalide + Edaravone + Monosialic acid tetrahexosylganglioside group(NBP+EDA+GM-1 group).The patients were selected by frequency matching method to match the general condition data,past medical history and main treatment plans of the patients.The improvement of clinical neurological impairment and the level of functional disability were determined according to the changes of NIHSS and mRs.The criteria for judging the overall clinical efficacy were determined according to the percentage of reduced NIHSS score after treatment.The adverse drug reaction monitoring system of the Ministry of Pharmacy was used to observe whether the patients had serious adverse reactions reported at home and abroad.The cost was confirmed according to the Chinese pharmacoeconomic evaluation guidelines,and the direct medical costs of patients during hospitalization were collected and analyzed.Pharmacoeconomic analysis was performed according to the therapeutic effect of the patients and the cost-effectiveness ratio and incremental cost-effectiveness ratio were calculated.Ⅱ Metabonomics analysis: randomly selected in the Department of Neurology,Zhongda Hospital,Southeast University,from July 2019 to November 2019,was admitted for acute ischemic stroke.A total of 195 patients with ischemic stroke were treated with four neuroprotective agents: N-butylphthalide injection(NBP),Edaravone injection(EDA),Monosialic acid tetrahexosylganglioside injection(GM-1)and Troxerutin injection(TRO)within 24 hours.All patients were clinically confirmed.At the same time,fifty-three persons who experienced health examination in Zhongda hospital were chosen as the normal control group.Stroke patients are admitted to the hospital through the green channel to receive auxiliary examinations such as blood glucose,electrolytes,renal function,emergency blood routine,coagulation function,and urinalysis.The plasma and urine samples are used as samples before treatment.After 7 days of standardized stroke unit treatment with the respective specific admission time as the starting point,the patient’s blood routine and thromboelastogram will be tested again before discharge(the 5th day of admission),and the patient’s mid-morning urine will be collected,and this plasma and urine will be treated as the patient’s post-treatment samples,and the NIHSS score and mRs score and related biochemical indexes were collected at the same time.All the samples were analyzed by UPLC-Q-TOF/MS.Metabolites were identified and semi-quantitatively analyzed by metabonomics analysis software MS-DIAL,Massbank and human metabolic group database.Principal component analysis(PCA)model and orthogonal partial least square discriminant(OPLS-DA)model were constructed by SIMCA and Metaboanalyst 4.0 software respectively to find differential biomarkers and potential metabolic pathways,and finally clinical and biological explanations were carried out.Results: 1)The NIHSS score and mRS score were decreased in both the two drugs combination group and the three drugs combination group(P < 0.001),and the combined use of three drugs in conventional treatment has a more significant effect on reducing the NIHSS score(P < 0.001),but there was no significant difference in the overall clinical efficacy between the two drugs combination group and the three drugs combination group(P > 0.001).The direct medical cost in the two-drug combination group was significantly lower than that in the three-drug combination group(P < 0.001).The difference mainly came from the drug cost(P < 0.05)and examination fee(P < 0.05).The cost-effectiveness analysis showed that it is completely worthwhile for the increased cost of the three-drug combination group.The three-drug combination group was further divided into four subgroups,by minimum cost analysis,it was found that N-butylphthalide injection,Edaravone injection and Monosialic acid tetrahexosylganglioside injection combined with Mecobalamin injection and Citicoline sodium capsule were the most effective and economical.2)Metabolic disorders in patients with ischemic stroke were observed in plasma and urine metabonomics.The combination of neuroprotective agents may be involved in the regulation of energy metabolism(glycolysis,pentose phosphate pathway,TCA cycle),lipid metabolism(glycerol phospholipid metabolism,fatty acid oxidation),amino acid metabolism(aromatic amino acid metabolism,glutamic acid metabolism,β-alanine metabolism)and other metabolism(urea cycle)in stroke patients.Conclusion: The neurological deficit and the recovery level of neurological function in patients with ischemic stroke treated with neuroprotective agents have been improved.The effective rate and markedly effective rate of the three-drug combination group was higher than that of the two-drug combination group,but the economy of the regimen was lower.Further analysis of the three-drug combination subgroup showed that N-butylphthalide injection,Edaravone injection and Monosialic acid tetrahexosylganglioside injection combined with Mecobalamin injection and Citicoline sodium capsule were the most effective and economical.There are changes in energy metabolism,lipid metabolism,amino acid metabolism and other metabolism in patients with ischemic stroke after combined treatment with neuroprotective agents.This provides a new strategy for the application of plasma and urine metabolic markers in the stratification of patients with ischemic stroke,and is of great significance for understanding the pathogenesis of stroke patients and determining appropriate individualized treatment. |
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