The Effects of Cinepazide Maleate in Conjunction with Edaravone on Cerebral Blood Flow and Neurofunctional Parameters in Individuals with Acute Ischemic Stroke

Abstract

Background:

This research is focused on evaluating the influence of administering cinepazide maleate and edaravone together on cerebral blood flow and neurofunctional markers in individuals who have recently suffered from an acute ischemic stroke (AIS).

Methods:

Included in this retrospective investigation were 100 patients diagnosed with AIS and treated at our medical center between the period of December 2022 and December 2023. These individuals were subsequently segregated into 2 cohorts according to the different treatments they received, consisting of 50 patients each, referred to as the control group and the observation group. Upon admission, standard treatment was initiated for all patients, alongside additional edaravone therapy for the control group, and concurrent administration of cinepazide maleate and edaravone for the observation group, for a consecutive period of 14 days. The study involved the assessment of cerebral blood flow in the middle cerebral artery (MCA) and anterior cerebral artery (ACA), in addition to the evaluation of neurofunctional markers, serum inflammatory factors, activities of daily living (ADL) scores, and National Institutes of Health Stroke Scale (NIHSS) scores. Adverse reactions were closely monitored to determine the treatment’s efficacy.

Results:

Subsequent to the treatment, augmented blood flow velocities were observed in both the MCA and ACA for both groups, particularly evident in the observation group. The observation group also demonstrated raised levels of nerve growth factor and lower levels of neuron-specific enolase and S100-β, with more notable differences when contrasted with the control group. Additionally, the observation group displayed reduced levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1, and elevated levels of interleukin-10 (IL-10), with more substantial variations as opposed to the control group. Furthermore, the observation group indicated enhanced ADL scores and diminished NIHSS scores, with more notable differences compared to the control group. The overall treatment effectiveness reached 94.00% in the observation group, markedly surpassing the 74.00% achieved in the control group.

Conclusion:

The concurrent application of cinepazide maleate and edaravone yields notable effects on cerebral blood flow and contributes to the improvement of neurofunctional capabilities in individuals dealing with AIS.

Main Points

• Combined therapy efficacy: The concurrent use of cinepazide maleate and edaravone significantly improves cerebral blood flow and neurofunctional recovery in patients with acute ischemic stroke.

• Neurofunctional improvement: The treatment combination leads to increased levels of nerve growth factor and decreased levels of neuron-specific enolase and S100-β, indicating enhanced neuronal protection and repair.

• Inflammatory response modulation: The therapy effectively reduces pro-inflammatory factors (tumor necrosis factor-alpha and monocyte chemoattractant protein-1) and increases anti-inflammatory cytokines (interleukin-10), demonstrating its role in mitigating inflammatory damage after a stroke.

• Superior clinical outcomes: The observation group showed a higher overall treatment efficacy rate (94%) compared to the control group (74%), underscoring the clinical benefit of the combined therapy.

• Improved activities of daily living (ADL): Patients receiving the combined treatment showed a more pronounced improvement in ADL scores and a greater reduction in neurological deficits as measured by NIHSS scores.

Introduction

Acute ischemic stroke (AIS) is instigated by the obstruction of cerebral blood vessels, causing a cessation of blood circulation to the brain. This pathology represents one of the foremost contributors to mortality and disability worldwide, remarkably impacting the social and financial well-being of patients and their families.^1,2 Neurological deficits resulting from AIS encompass motor dysfunction, sensory impairment, speech disturbances, and cognitive limitations, all stemming from the associated brain damage.³ Hence, a fundamental focal point in addressing AIS pertains to the essential objective of reinstating and enhancing cerebral blood flow and neurological function.^4,5

The current treatment modalities for AIS primarily encompass thrombolytic therapy and etiological interventions, yet these strategies carry inherent drawbacks and potential risks.⁶ While thrombolytic therapy can potentially reinstate cerebral blood flow, its suitability is limited to a minority of patients, and it poses the risk of severe complications, including hemorrhage.^7,8 The scope of etiological treatment primarily encompasses anticoagulation therapy and lipid-lowering therapy, with limited impact on the restoration of neurological function and cerebral blood flow in individuals experiencing AIS.^9,10

Recently, new medications such as cinepazide maleate and edaravone have been incorporated into AIS treatment. Cinepazide maleate operates as a mild calcium antagonist, enhancing endogenous adenosine effectiveness and refining microcirculation by suppressing the transmembrane movement of Ca²⁺ into the smooth muscle cells of blood vessels, ultimately inducing vasodilation and diminishing blood viscosity. This mechanism facilitates the augmentation of cerebral blood flow, improves the utilization of glucose by brain cells, optimizes cellular nutrition and energy metabolism, and fortifies the brain tissue’s ability to combat ischemia and hypoxia, thus safeguarding brain cell function.^11,12 Conversely, edaravone is a neuroprotective agent with a range of action mechanisms, encompassing antioxidant, anti-inflammatory, and anti-apoptotic properties that support the protection and repair of compromised neurons.^13,14

As such, the core focus of this investigation is to explore the efficacy of utilizing a combined therapy approach using cinepazide maleate and edaravone on cerebral blood flow and markers linked to neurological function in individuals affected by AIS.

Material and Methods

General Information

The study retrospectively included 100 individuals diagnosed with AIS and treated at the hospital between December 2022 and December 2023, subsequently segregated into 2 cohorts known as the control and observation groups according to the different treatments they received, comprising 50 patients each. Male and female distribution in the observation group stood at 28 and 22, respectively, with ages ranging from 41 to 81 (63.22 ± 5.87) years. Likewise, the control group encompassed 27 males and 23 females, aged 41-84 (63.22 ± 5.96) years. The comparative analysis revealed no noteworthy distinctions in general characteristics between the 2 cohorts (P > .05). In this study, 100 patients diagnosed with AIS from West China Hospital voluntarily participated in the survey and provided written consent. The study was approved by the Ethics Committee of West China Hospital of Sichuan University (Approval Number: EC2022-121).

Criteria for inclusion: (1) individuals meeting the diagnostic criteria detailed in the initial care recommendations for patients with AIS¹⁵; (2) clinical diagnosis of AIS based on cranial magnetic resonance imaging or computed tomography results; (3) symptom onset occurring within 72 hours; and (4) willingness and consent from individuals and their families to take part in the investigation.

Exclusion criteria: (1) individuals with hemorrhagic stroke or cerebral bleeding; (2) individuals with severe diabetes or cardiac conditions; and (3) patients with profound dementia or psychiatric disorders.

According to the pre-experimental data and relevant statistical methods for estimation, it is expected that at least 40 patients are needed in each group to ensure that under the set test level (α = 0.05) and test power (1−β= 0.80), the differences in the main observation indicators (such as cerebral blood flow velocity, neurological function indicators, inflammatory factor levels, etc.) between the 2 groups can be detected. To draw more robust conclusions, it was finally determined that include 50 patients would be included in each group, with a total of 100 patients participating in the study.

Upon admission, routine care was administered to patients in both groups, incorporating blood pressure regulation, intracranial pressure management, lipid-lowering therapy, glycemic control, fluid balance maintenance, antiplatelet medication, electrolyte supplementation, and symptomatic support therapy. Additional therapy with edaravone (Manufacturer: Nanjing Xian Sheng Dong Yuan Pharmaceutical Co., Ltd.; Batch No.: 20141121; Specification: 20 mL:30 mg) was administered to the control group. The 30 mg edaravone injection was diluted with 100 mL of 0.9% saline solution and given to the patients through intravenous drip twice a day. The observation group was administered a combined regimen consisting of edaravone and cinepazide maleate (Manufacturer: Beijing Sihuan Pharmaceutical Co., Ltd.; Batch no.: 20141203; Specification: 10 mL:0.32 g × 2/vial). In conjunction with the edaravone injection, 320 mg of cinepazide maleate injection was mixed with saline or 5% glucose solution and given by intravenous drip once daily. Both patient groups underwent continuous treatment for 14 days.

Observation Indicators

Transcranial Doppler ultrasound was employed to evaluate the blood flow in the middle cerebral artery (MCA) and anterior cerebral artery (ACA) both prior to and following the 14-day treatment period. Furthermore, neurofunctional markers were assessed using ELISA to detect the levels of nerve growth factor (NGF), neuron-specific enolase (NSE), and S100-β in fasting serum samples obtained from patients both pre-treatment and post-treatment. Evaluation of serum inflammatory factors encompassed the measurement of monocyte chemotactic protein-1 (MCP-1) and interleukin-10 (IL-10) levels using ELISA, and tumor necrosis factor-alpha (TNF-α) levels using turbidimetry in the previously mentioned serum samples. The functional capacities in performing activities of daily living (ADL) and the severity of neurologic deficits as quantified by the NIHSS score were appraised before and after the treatment. The recording of any adverse reactions was diligently carried out.

Evaluation of Therapeutic Efficacy

The criteria for evaluating therapeutic efficacy were as follows: markedly effective: patients experienced a substantial amelioration in signs of cerebral infarction, coupled with a considerable decrease in serum TNF-α, MCP-1, and related markers. Effective: patients witnessed notable alleviation in symptoms of AIS, and associated complications exhibited marked improvement. Ineffective: clinical symptoms did not alleviate, and there was an observable elevation in the levels of relevant serum factors. The total effective rate = (markedly effective cases + effective cases)/total number × 100%.

Statistical Analysis

The data were processed using SPSS 25.0 (IBM SPSS Corp.; Armonk, NY, USA) software. National Institutes of Health Stroke Scale scores and other numerical data are expressed as (mean ± SD) and analyzed by t-test. This is because these data are continuous. Through conducting normality tests, it was found that they basically meet the normal distribution assumption. Differences in these measures before and after treatment and between the 2 groups were assessed by a paired sample t-test, and comparisons of differences between groups were made by an independent sample t-test. Categorical data are expressed as [n (%)] and compared by chi-square test. P < .05 is considered statistically significant.

Results

Cerebral Blood Flow Velocity

Following treatment, an elevation was evident in the blood flow velocities of both the MCA and ACA in both groups (P < .05), with the observation group demonstrating a more pronounced increase (P < .05) (Table 1).

Table 1.

Comparisons of Cerebral Blood Flow Velocity (Mean ± SD, cm/s)

Items	Group (n)	Before	After	P	Difference
MCA	Observation (50)	42.43 ± 4.85	53.46 ± 5.66	<.001	11.23 ± 1.35
	Control (50)	43.28 ± 5.00	49.02 ± 5.55	<.001	5.64 ± 0.61
P					<.001
ACA	Observation (50)	34.91 ± 5.08	48.44 ± 6.47	<.001	14.17 ± 1.38
	Control (50)	34.84 ± 4.43	41.36 ± 5.22	<.001	6.53 ± 0.58
P					<.001

Neurofunctional Indicator Levels

Post-treatment, both groups experienced an increase in NGF levels and a decrease in NSE and S100-β levels, with the changes appearing notably more prominent in the observation group in comparison to the control group (P < .05) (Table 2).

Table 2.

Comparisons of Neurofunctional Indicator Levels (Mean ± SD, cm/s)

Items	Group (n)	Before	After	P	Difference
NGF (μg/mL)	Observation (50)	118.65 ± 12.00	145.11 ± 14.75	<.001	26.73 ± 2.55
	Control (50)	116.60 ± 12.70	132.85 ± 14.45	<.001	15.44 ± 1.62
P					<.001
NSE (μg/L)	Observation (50)	54.76 ± 8.40	35.41 ± 6.58	<.001	−18.33 ± 1.98
	Control (50)	52.65 ± 7.62	41.60 ± 6.78	<.001	−10.64 ± 0.91
P					<.001
S100-β (μg/L)	Observation (50)	0.94 ± 0.27	0.35 ± 0.10	<.001	−0.67 ± 0.08
	Control (50)	0.93 ± 0.20	0.53 ± 0.14	<.001	−0.41 ± 0.05
P					<.001

Serum Inflammatory Indicator Levels

Following treatment, both groups experienced reductions in TNF-α and MCP-1 levels, along with an elevation in IL-10 levels. These changes were notably more pronounced in the observation group compared to the control group (P < .05) (Table 3).

Table 3.

Comparisons of Serum Inflammatory Indicator Levels (Mean ± SD, mg/L)

Items	Group (n)	Before	After	P	Difference
TNF-α	Observation (50)	17.84 ± 3.67	6.73 ± 1.38	<.001	−11.12 ± 1.25
	Control (50)	17.69 ± 3.50	12.21 ± 1.75	<.001	−5.45 ± 0.46
P					<.001
IL-10	Observation (50)	11.00 ± 2.33	17.51 ± 4.08	<.001	6.56 ± 0.57
	Control (50)	11.40 ± 2.26	14.87 ± 2.52	<.001	3.54 ± 0.41
P					<0.001
MCP-1	Observation (50)	7.25 ± 1.32	3.60 ± 0.57	<.001	−3.67 ± 0.38
	Control (50)	7.47 ± 1.24	5.08 ± 0.96	<.001	−2.51 ± 0.26
P					<.001

Activities of Daily Living and National Institutes of Health Stroke Scale Scores

Subsequent to treatment, both groups experienced an increase in ADL scores and a decrease in NIHSS scores, with the changes being more noticeable in the observation group as opposed to the control group (P < .05) (Figure 1).

Figure 1.

A. Changes in activities of daily living (ADL) scores before and after treatment. Both groups exhibited significant increases in ADL scores following treatment, with the observation group showing a more noticeable improvement compared to the control group (P < .05). B. Changes in National Institutes of Health Stroke Scale (NIHSS) scores before and after treatment. Both groups showed significant decreases in NIHSS scores after treatment, with the observation group experiencing a greater reduction compared to the control group (P < .05).

Clinical Efficacy

The total effective rate for the observation group stood at 94.00%, substantially surpassing the 74.00% for the control group, with a statistically substantial variance (P < .05) (Table 4).

Table 4.

Curative Effect

Group (n)	Markedly Effective	Effective	Ineffective	Total Effective Rate
Observation (50)	34 (68.00)	13 (26.00)	3 (6.00)	47 (94.00)
Control (50)	25 (50.00)	12 (24.00)	13 (26.00)	37 (74.00)
P				.006

Adverse Reactions

During the treatment, 1 case of nausea and vomiting and 1 case of fever occurred in the observation group, and 1 case of headache, 1 case of rash, and 1 case of fever occurred in the control group. After symptomatic treatment, these complications did not cause treatment interruption. There was no significant difference in the incidence of adverse reactions between the 2 groups (P > .05).

Discussion

In recent times, there has been a notable rise in cases of cerebrovascular diseases. The modification of blood constituents due to damage in brain tissue results in the onset of cerebral artery atherosclerosis, leading to the roughening and constriction of arterial lumens, ultimately inducing pathological transformations within the cerebral arterial wall. Emboli are transported to the brain via the bloodstream, resulting in blockages and infarctions within the cerebral vasculature.¹⁶

Following a cerebral infarction, the ischemia and hypoxia of brain tissue result in extensive cell necrosis, leading to diminished blood flow velocities in the MCA and ACA, which demonstrates severe impairment of brain function.¹⁷ The study’s outcomes revealed that subsequent to treatment, there was a rise in blood flow velocities within the MCA and ACA for both groups, with a notably more substantial increase noted in the observation group in comparison to the control group. This indicates the capacity for combined therapy to considerably improve cerebral blood flow perfusion and enhance cerebral hemodynamics. In clinical practice, improving cerebral blood flow is crucial for the prognosis of AIS patients and helps to reduce the deterioration of neurological function caused by insufficient blood perfusion and improve the recovery potential of patients.

Following an AIS, the rise in NGF levels is instrumental in the repair and differentiation of neurons.¹⁸ Neuron-specific enolase is an essential marker of neural cell damage, and its presence in the cerebrospinal fluid serves as a remarkable indicator of hypoxic injuries to cerebral tissue.¹⁹ Furthermore, S100-β acts as a chemical marker of brain tissue damage, contributing to the regulation of intracellular and extracellular calcium ions, the facilitation of nerve tissue growth and regeneration.²⁰ The study identified an increase in NGF levels and a decrease in NSE and S100-β levels in the observation group post-treatment compared to the control group. These variations were notably more observable in the observation group, indicating that the combined treatment positively influences the enhancement and restoration of neurologic function. For AIS patients, the recovery of nerve function is directly related to the improvement of their motor, sensory, cognitive and other functions, enabling them to better return to daily life and social activities.

Monocyte chemoattractant protein-1 and TNF-α play crucial roles as inflammatory factors, with their levels increasing during inflammatory responses, thus triggering the aggregation of monocytes in the brain and resulting in embolism. In contrast, IL-10 inhibits the release of inflammatory mediators from macrophages and enhances the release of anti-inflammatory factors. After treatment, a noteworthy decline in TNF-α and MCP-1 levels and a considerable rise in IL-10 levels were noted in the observation group. These shifts were more pronounced in the observation group, indicating that combined therapy effectively restrains the emergence and progression of inflammatory responses, mitigates the release of inflammatory factors and associated damage, and encourages the production of anti-inflammatory elements. However, it is important to note that the finding of a significant reduction in TNF-α levels may be attributed to the combined effect of cinepazide maleate and edaravone in the study. Interestingly, Chen et al²¹ did not observe any differences in the levels of TNF-α before and after the treatment with edaravone in AIS patients. This discrepancy could potentially arise from differences in sample characteristics (age, gender, underlying diseases, time from symptom onset to treatment), treatment regimens (drug dosage, treatment duration, concomitant medications), and study design (prospective or retrospective). Regarding other studies on these 2 medications, there are also some conflicting data. For example, in some investigations, the specific mechanisms and the extent of the improvement in neurological function by cinepazide maleate were not entirely consistent with the findings, and in terms of the regulation of the inflammatory response by edaravone, there were also certain discrepancies in the magnitude and time course of the changes in specific inflammatory factors.²² These differences suggest that when interpreting and applying research results, multiple factors need to be considered comprehensively, and further large-scale, multicenter, and well-designed studies are required to clarify the efficacy and mechanisms of action of these drugs, so as to better guide clinical practice.

Additionally, the observation group exhibited an elevation in ADL scores and a reduction in NIHSS scores, with more visible alterations compared to the control group. This suggests that combined therapy effectively contributes to the recuperation and enhancement of patients’ daily activities and the amelioration of their neurological capacity. On the whole, the total effective rate of treatment for the observation group was 94.00%, notably surpassing the 74.00% for the control group, indicating the beneficial efficacy of the combined therapy involving cinepazide maleate and edaravone in managing AIS. In clinical application, this means that patients can recover their independent living ability faster, reduce their dependence on others, reduce the burden on families and society, and also help to improve the mental health and life confidence of patients.

However, it is pivotal to recognize the constraints within the study, encompassing the retrospective nature of the design and the limitations related to substantiating these findings and delving deeper into the optimal utilization of combined therapy and its mechanisms of action.

In closing, the investigation points to the positive influence of the combined therapy involving cinepazide maleate and edaravone on cerebral blood flow and neurologic function in individuals with AIS. The combination therapy enhances cerebral hemodynamics and facilitates the restoration and rehabilitation of neurologic function, while also regulating inflammatory reactions.

Funding Statement

The authors declared that this study has received no financial support.

Data Availability Statement:

All experimental data included in this study can be obtainedby contacting the first author if needed.