Clinical efficacy analysis of butylphthalide combined with urinary kallidinogenase in treating chronic cerebral circulatory insufficiency

Abstract Objective To investigate the clinical effect of butylphthalide combined with urinary kallidinogenase in the treatment of chronic cerebral circulatory insufficiency (CCCI). Methods A total of 102 CCCI patients admitted to our hospital from October 2020 to December 2021 were retrospectively enrolled in this study. According to the different therapeutic strategy, the patients were divided into combined group (treated with butylphthalide combined with urinary kallidinogenase, n = 51) and butylphthalide group (treated with butylphthalide, n = 51). Blood flow velocity and cerebral blood flow perfusion before and after treatment between the two groups were compared. The clinical efficacy and adverse events of the two groups were analyzed. Results After treatment, the effective rate of the combined group was significantly higher than the butylphthalide group (p = .015). Before treatment, the blood flow velocity of middle cerebral artery (MCA), vertebral artery (VA), basilar artery (BA) were comparable (p > .05, respectively), while after treatment, the blood flow velocity of MCA, VA, and BA in combined group were faster than those in butylphthalide group (p < .001, respectively). Before treatment, the relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), relative mean transmit time (rMTT) of the two groups were comparable (p > .05, respectively). After treatment, rCBF and rCBV in combined group were higher than those in butylphthalide group (p < .001, respectively), and rMTT in combined group was lower than that in butylphthalide group (p = .001). The rate of adverse events in the two groups were comparable (p = .558). Conclusion Butylphthalide combined with urinary kallidinogenase can improve the clinical symptoms of CCCI patients, and the effect is promising, which is worthy of clinical application.


INTRODUCTION
The study protocol complied with the relevant requirements of the World Medical Association Declaration of Helsinki and was approved by the Ethics Committee of our hospital. Written informed consent was obtained from all patients. the presence of reduced cerebral blood flow or hypoperfusion; (7) the course of the disease was long, and the history was traced back to more than 3 months.

Diagnostic, inclusion, and exclusion criteria
Inclusion criteria: (1) those who meet the above diagnostic criteria; (2) signed the informed consent. All patients were treated continuously for 14 days.
The use of angiotensin converting enzyme inhibitors (ACEI) was prohibited 24 h before treatment and throughout the medication cycle in all cases.

Observational index
Therapeutic evaluation (Chinese Society of Neurology, of Chinese Medical Association, Cerebrovascular Group of Chinese Society of Neurology, 2015): Obvious effective: after treatment, symptoms such as headache, vertigo, and head heaviness were significantly reduced, the total score of MMSE scale was ≥27, and the CSS score was < 8.
Effective: after treatment, symptoms such as headache, vertigo, and head heaviness were significantly reduced, the total score of MMSE scale was 21-26, and the CSS score was 8-15. Ineffective: none of the above symptoms improved or even worsened significantly. Total effective rate = obvious effective + effective rate.
Cognitive function assessment: the MMSE scale total score was used to assess 7 aspects such as immediate memory, temporal orientation, and place orientation, with a total score of 0-30, normal being 27-30, cognitive dysfunction being < 27, and mild cognitive dysfunction being 21-26, the lower the score the more severe the cognitive dysfunction.
Assessment of the degree of neurological deficit: the degree of neurological deficit (CSS) score was used, including walking ability, lower extremity ability, hand muscle strength, upper extremity muscle strength, speech, facial muscle, horizontal gaze function, and consciousness, with a total score of 0-45. The higher the score, the more significant the degree of neurological impairment. Evaluation of cerebral blood flow perfusion: before and after treatment, cerebrovascular CT perfusion scan was performed at the level of region of interest (affected side), and the data of the contralateral side (healthy side) were obtained to calculate relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV) and relative mean transit time (rMTT). r value = affected side/ healthy side. rCBF between 0.9 and 1.1 was considered normal perfusion, <0.9 was considered hypoperfusion, and >1.1 was considered hyperperfusion.
Adverse events including liver and kidney injury, rash, arrhythmia, nausea, and vomiting were recorded in the two groups.

Statistical analysis
The enumeration data were expressed as constituent ratio, and the chisquare test or exact probability method was used to compare the rates between groups. Measurement data conforming to normal distribution were expressed as mean ± standard deviation, and compared using t test. Measurement data with skewed distribution were expressed as M (Q1-Q3), and the comparison between the two groups was analyzed by Wilcoxon nonparametric test. p < .05 was considered significant difference. All statistical analyses were performed using IBM SPSS Statistics 22.0 software (IBM SPSS Statistics).

Baseline characteristics
There were 51 cases in both groups. The course of disease in combined group was 8.9 ± 1.7 months, while that in butyphthalide group was 8.8 ± 1.8 months. There was no significant difference in gender, age, course of disease, comorbidity, smoking, alcohol drinking, and educational background between the two groups (all p > .05). See Table 1.

Comparison of clinical efficacy
The numbers of obvious effective, effective, ineffective in combined group were 34, 16, and 1, respectively. And the numbers of above indicators in butyphthalide group were 19, 23, and 7, respectively. The total effective rate were 98.04% vs. 86.27% (p = .015). Total effective rate in combined group was higher than that in butyphthalide group.

Adverse events
One case (1/51, 1.96%) in combined group suffered facial fever during the treatment, and the symptom lasted for about 10 min and then relieved, without stopping the drug or giving other treatments. In butyphthalide group, there was 1 case of nausea, 1 patient's heart rate increased and blood pressure decreased. After adjusting fluid velocity, the patient's symptoms improved and blood pressure increased, no recurrence of discomfort later. The incidence of adverse events in butyphthalide group was 3.92% (2/51). There was no significant difference of adverse events incidence between the two groups (χ 2 = 0.343, p = .558).

DISCUSSION
CCCI is a common disease in neurology. Its etiology is related to blood pressure level, arterial thrombosis, vascular function, blood flow velocity, blood viscosity, cardiac output (Hynes et al., 2019). According to the data of the World Health Organization, CCCI patients have a significantly higher risk of progressing to serious cardiovascular events within 1-5 years than normal people, and can easily induce cognitive impairment and even dementia. Therefore, CCCI is also considered as a pre-stroke state (Yu et al., 2022). CCCI has certain reversibility.
Timely administration of effective treatment strategy and drugs can effectively prevent progressive stroke or dementia, and play a positive role in improving the prognosis of patients. Butylphthalide is a new class I drug launched in China in recent years, which can help patients improve brain energy metabolism and microcirculation . Butylphthalide has the following pharmacological mechanisms (Ding et al., 2020): Urinary kallidinogenase can be converted into kinin and vasodilator in vivo, selectively dilating the arterioles of ischemic brain tissue, and increasing the blood flow to the brain and the level of hemoglobin in the cerebral blood, thereby improving the blood supply and oxygen supply of the ischemic brain tissue. Also, it can upregulate the expression of vascular endothelial growth factor, promote vascular endothelial growth factor, promote angiogenesis, increase cerebral blood flow reserve, and improve the effect of hypoperfusion (Ni et al., 2021). So far, research on urinary kallidinogenase mainly focuses on cerebral infarction (Dong et al., 2020;Ni et al., 2021), but few studies on CCCI are available. The results of this study showed that after treatment, the total effective rate of the combined group was significantly higher than that of the butylphthalide group, suggesting that butylphthalide combined with urinary kallidinogenase could effectively relieve the clinical symptoms of CCCI patients, and the effect was obvious. As one of the most important organs, the brain consumes 20% of the total oxygen consumption of the human body. It needs sufficient blood supply to support the normal activities. A decrease in cerebral blood flow affects the supply of oxygen to brain cells, leading to changes in brain function. CCCI is not focal cerebral ischemia, in which the blood supply to the brain is only slowly reduced rather than completely blocked. With the increase of patients' age, the tolerance of brain tissue to ischemia and hypoxia is significantly reduced, and the autoregulation function of cerebral blood vessels is significantly weakened. Even slight changes in cerebral blood supply will greatly affect cerebral blood flow and trigger CCCI (Wu, 2017). A previous study found that the abnormal cerebral blood flow in CCCI patients is as high as 97.96% (Liu et al., 2017). Therefore, active and effective measures should be given to improve the blood flow velocity, which is of great clinical significance. Cheng et al. (2016) pointed out that butylphthalide can significantly improve cerebral blood flow velocity in CCCI patients. Pan et al. (2020) revealed that butylphthalide injection has a definite therapeutic effect on acute cerebral infarction, which effectively alleviating the symp-