Research Progress on the Experimental Model and Underlying Mechanistic Studies of Tension-Type Headaches.

PURPOSE OF REVIEW: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH. RECENT FINDINGS: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.

[Expert consensus on clinical application of Lixuwang~® Xuesaitong Soft Capsules].

Lixuwang~® Xuesaitong Soft Capsules(referred to as "Xuesaitong Soft Capsules") have the effects of promoting blood circulation, resolving blood stasis, and dredging meridians and collaterals. They are widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases in clinical practice. Through years of clinical observation, they have shown significant efficacy in ischemic stroke, coronary heart disease, and other diseases, and have been recommended by multiple guidelines, consensus statements, and monographs. Based on the summary of clinical application experience by doctors and existing evidence-based research, following the Technical Specifications for Consensus Development of Chinese Patent Medicine by Clinical Experts issued by Standardization Office of the Chinese Association of Traditional Chinese Medicine, a nominal group method was used to reach 19 recommended opinions/consensus suggestions. This document proposes the timing of medication, syndrome differentiation for medication, therapeutic effects, dosage and administration, treatment duration, economic considerations, and safety considerations in the use of Xuesaitong Soft Capsules for the treatment of ischemic stroke and angina pectoris in coronary heart disease. It is intended for doctors in internal medicine, encephalopathy(neurology), cardiovascular medicine, geriatrics, emergency medicine, general practice, and traditional Chinese medicine departments of various medical institutions, as well as pharmacists in hospitals and pharmacies, as a medication reference when using Xuesaitong Soft Capsules. It is hoped that the widespread application of this consensus can improve the clinical efficacy of Xuesaitong Soft Capsules in the treatment of ischemic stroke and coronary heart disease, promote rational drug use, and reduce medication risks. This consensus has been reviewed and published by the China Association of Traditional Chinese Medicine, with the identification number GS/CACM 323-2023.

[Evidence mapping of clinical research on traditional Chinese medicine in treatment of diabetic foot].

The present study comprehensively summarized the clinical randomized controlled trials(RCTs) and systematic reviews/Meta-analyses of traditional Chinese medicine(TCM) in the treatment of diabetic foot by evidence mapping and clarified the distribution of evidence in this field.CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, and Web of Science were searched for clinical RCTs and systematic reviews on TCM in the treatment of diabetic foot published in the past ten years.The evidence was analyzed and displayed in the form of text combined with figures and tables.AMSTAR was used for the quality evaluation of systematic reviews.A total of 1 037 clinical RCTs and 20 systematic reviews/Meta-analyses were included.The overall publishing trend was stable, and the scale of RCTs was small.TCM interventions for diabetic foot mainly included external application and foot bath.Much attention was paid to the outcome indicators including total effective rate, ankle brachial index(ABI), and TCM syndromes, while less attention to neuropathy scores, emotional psychology, and long-term prognosis.The overall quality of systematic reviews was low, and the majority of studies indicated that TCM had potential efficacy in treating diabetic foot, and there was still a lack of clear clinical evidence of efficacy.TCM has both advantages and problems in the treatment of diabetic foot.At present, there is still a lack of high-quality research, suggesting that more large-sample, multi-center RCTs should be launched in the future, and the quality of related systematic reviews/Meta-analyses should be improved to fully explore and give full play to the advantages of TCM in the treatment of diabetic foot, and promote the development of the clinical and evidence-based medicine of TCM in the treatment of diabetic foot.

[Network Meta-analysis of oral or nasal feeding with Chinese patent medicine in treatment of hypertensive intracerebral hemorrhage].

The effect of oral or nasal feeding with Chinese patent medicine on hypertensive intracerebral hemorrhage was systematically evaluated by using the method of network Meta-analysis. Four Chinese databases(CNKI, VIP, Wanfang, CBM), three English databases(Medline, EMbase, Cochrane Library) and ClinicalTrials.gov were retrieved through computers. According to the inclusion criteria and exclusion criteria, randomized controlled trials(RCTs) of Chinese patent medicine combined with Western medicine in the treatment of hypertensive intracerebral hemorrhage were screened out according to the inclusion criteria and exclusion criteria. The Cochrane bias risk assessment tool was used to evaluate the quality of the included studies, and Stata 16.0 software was used to analyze the outcome indicators. A total of 3 888 literatures were retrieved, and 30 studies involving 6 kinds of Chinese patent medicines were finally included. The total sample size was 2 758 cases, including 1 401 cases in the treatment group and 1 357 cases in the control group. According to the results of network Meta-analysis,(1)in terms of improving the degree of nerve function defect, the order of Chinese patent medicines was conventional Western medicine combined with Xiaoyukang Capsules>combined with Tongxinluo Capsules>combined with Naoxuekang Oral Liquid>combined with Naoxueshu Oral Liquid>combined with Angong Niuhuang Pills>conventional Western medicine;(2)in terms of reducing the amount of residual cerebral hematoma, the order of Chinese patent medicines was conventional Western medicine combined with Naoxueshu Oral Liquid>combined Xiaoyukang Capsules>combined Naoxuekang Oral Liquid>conventional Western medicine;(3)in terms of improving ability of daily living, the order of Chinese patent medicines was conventional Western medicine combined with Shenzhi Huoxue Capsules>combined with Angong Niuhuang Pills>combined with Naoxueshu Oral Liquid>conventional Western medicine;(4)in terms of improving total effective rate, the order of Chinese patent medicines was conventional Western medicine combined with Naoxueshu Oral Liquid>combined with Xiaoyukang Capsules>combined with Angong Niuhuang Pills=combined with Naoxuekang Oral Liquid>combined Tongxinluo Capsules>conventional Western medicine treatment. The results showed that in addition to conventional Western medicine therapy, the combined use with Chinese patent medicine can improve the clinical efficacy in the treatment of hypertensive intracerebral hemorrhage. However, due to the differences in the number and quality of various Chinese patent medicines included in the studies, and the lack of direct comparison of Chinese patent medicines, the ranking results still need to be verified by multi center, large-sample-size randomized double-blind trials in the future, so as to provide more reliable evidence support for clinical drug use.

[Outcome indicators in randomized controlled trials on traditional Chinese medicine intervention for tension-type headache in recent five years].

To evaluate the application of outcome indicators in randomized controlled trials(RCTs) concerning the treatment of tension-type headache(TTH) with traditional Chinese medicine(TCM) in recent five years, so as to provide a basis for the study of core outcome set(COS) for TCM intervention in TTH. The RCTs on TCM treatment of TTH in recent five years were systematically retrieved from CNKI, Wanfang, VIP, CBM, EMbase, PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov and China Clinical Trial Registry. After literature screening, data extraction and evaluation of the risk of bias, the outcome indicators in the included RCTs were subjected to qualitative analysis. The preliminary search yielded 19 042 articles, and 10 983 were left after the elimination of duplication. Finally, 52 RCTs(48 in Chinese and 4 in English) were included for qualitative analysis. The outcome indicators of RCTs included in this study were classified into seven domains: TCM syndrome, symptom and sign, physical and chemical detection, quality of life, long-term prognosis, economic evaluation, and safety event. The findings demonstrated that headache characteristic index in the symptom and sign domain was the index with the highest reporting frequency and reporting rate. Seventeen RCTs used TCM syndrome score as the outcome indicator. Further analysis revealed that there existed such problems in research design as non-distinction between primary and secondary outcome indicators, great difference in the adopted measurement tools for outcome indicators, and the neglect of measurement time of outcome indicators. Moreover, the syndrome indicators reflecting TCM advantages, objective evaluation indicators, safety and health-economic indicators were lacking. These limitations have affected the quality and reliability of RCTs on TTH treatment with TCM. It is suggested that the efficacy and characteristics of TCM should be combined into current clinical research, and the COS in RCTs regarding TCM treatment of TTH should be established according to internationally recognized standard procedures.

[Systematic review and Meta-analysis of efficacy and safety of gastrodin in treatment of tension-type headache].

The efficacy of gastrodin as a Chinese herbal medicine extract in the treatment of tension-type headache has been confirmed. This paper systematically reviewed the efficacy and safety of gastrodin in the treatment of tension-type headache, aiming to provide a new choice for the treatment of this disease. In this study, four Chinese databases, four English databases and two trial registries were searched from the date of establishment to September 2020. The related randomized controlled trials(RCTs) were screened out according to the predetermined criteria. The bias risk assessment tool developed by Cochrane collaboration was used to evaluate the quality of the reports. RevMan 5.4.1 was used for Meta-analysis, and GRADE system for the evidence-based evaluation on the quality of outcome indicators. A total of 177 articles were retrieved and 8 articles were finally included for analysis, with a total sample size of 1 091 cases, which included 565 cases in the treatment group and 526 cases in the control group. The overall quality of included stu-dies was not high. The results of Meta-analysis are as follows:(1)In terms of headache frequency, gastrodin group was better than wes-tern medicine group(MD=-2.90, 95%CI[-3.76,-2.03], P<0.000 01).(2)In terms of number of abnormal blood vessels in TCD, gastrodin group was better than western medicine group(MD=-88.96, 95%CI[-102.36,-75.55], P<0.000 01).(3)In terms of effective rate, gastrodin group was better than western medicine group(RR=1.47, 95%CI[1.29, 1.68], P<0.000 01). The results of subgroup analysis are as follows:(1)Effective rate based on age, for the patients upper age limit 40-46 years old, gastro-din group was better than western medicine group(RR=1.69, 95%CI[1.50, 1.90], P<0.000 01); for the patients upper age limit 55-60 years old, gastrodin group was better than western medicine group(RR=1.27, 95%CI[1.16, 1.38], P<0.000 01).(2)Effective rate based on dosage form, both the gastrodin capsules and injection groups were better than western medicine group(RR_(capsules)=1.42, 95%CI[1.08, 1.88], P=0.01; RR_(injection)=1.50, 95%CI[1.26, 1.77], P<0.000 01). GRADE evaluation showed that the above outcomes had low quality of evidence. Only one article detailed the occurrence of adverse reactions and thus the present study cannot make a positive conclusion on the safety of gastrodin in the treatment of tension-type headache. The small number and low quality of the included reports affected the reliability of the results. In the future, more high-quality randomized controlled trails are needed to improve the evaluation on the efficacy and safety of gastrodin in the treatment of tension-type headache.

[Systematic review and Meta-analysis of efficacy and safety of Toutongning Capsules in treatment of tension-type headache].

This study aims to systematically evaluate the clinical efficacy and safety of Toutongning Capsules in the treatment of tension-type headache(TTH), so as to provide a corresponding basis for clinical treatment. Eight commonly used medical research databases and two clinical trial registration systems were retrieved with the time interval from the establishment of the database or system to November 2020. The randomized controlled trials of Toutongning Capsules in the treatment of TTH were screened out according to the pre-set criteria. The quality of the included papers was evaluated by the bias risk assessment tool in Cochrane Reviewers Handbook 6.1 and the data were statistically analyzed by RevMan v5.4 provided by Cochrane collaboration. A total of 13 studies were included and the quality of methodology was generally low. Meta-analysis showed that Toutongning Capsules assisted with western medicine therapy can effectively reduce the pain intensity(MD_(VAS)=-1.94,95%CI[-2.50,-1.38],P<0.000 01;MD_(NRS)=-0.83,95%CI[-0.86,-0.80],P<0.000 01), headache duration(SMD=-0.98,95%CI[-1.17,-0.79],P<0.000 01), headache frequency(MD=-1.01,95%CI[-1.16,-0.85],P<0.000 01), headache index(MD=-11.13,95%CI[-12.10,-10.16],P<0.000 01), anxiety and depression scale score(MD_(HAMA)=-4.02,95%CI[-6.58,-1.46],P=0.002;MD_(HAMD)=-2.67,95%CI[-4.04,-1.29],P=0.000 1), while Toutongning Capsules as monotherapy only reduced the headache score(MD=-2.24,95%CI[-2.97,-1.51],P<0.000 01). The available clinical studies demonstrate that Toutongning Capsules combined with western medicine in the treatment of TTH can improve the related outcome indicators, but the clinical safety and efficacy of Toutongning Capsules alone remain unclear. Due to the small number and low quality of the included studies, large-sample, multi-center, high-quality and strictly designed randomized controlled trials are still needed to verify the clinical efficacy in the future.

Registration of intervention trials of Traditional Chinese Medicine for four neurological diseases on Chinese Clinical Trial Registry and ClinicalTrials.gov: a narrative review.

OBJECTIVE: To analyze the current status of clinical trial registration of Traditional Chinese Medicine (TCM) for the treatment of neurological diseases. METHODS: Interventional clinical trials of TCM treatment for ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, tension-type headache before September 22, 2020 on the platform of Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov were searched. Two researchers independently selected the literature and extracted data. RESULTS: A total of 180 interventional clinical trials were included for analysis. Out of 180 trials, 127 were from ChiCTR and 53 from ClinicalTrials.gov. The countries primary sponsoring the included trials were China (176, 97.8%), and the common categories of primary sponsors were hospital (131, 72.8%). Among the study design, the largest proportion of allocation was randomized (172, 95.6%), interventional model assignment was parallel (163, 90.6%), masking was double blind 49 (27.2%), and the sample size was ≤ 400 (144, 80.0%). The trials were most carried out at a single center (102, 56.7%). Among the included studies, 112 (62.2%) registered on ChiCTR attached the ethical approval documents. In terms of trial stages, 50 (27.7%) studies were in phase IV. The mostly used intervention was Chinese herbal medicines (99, 55%), acupuncture (68, 37.8%) was the second. By searching the registration number on China National Knowledge Infrastructure Database and PubMed, 38 (21.1%) registered trials were published, including 25 protocol studies and 14 research results with one (NCT02275949) published both the protocol and the results. CONCLUSIONS: Irregular and inadequate reporting, untimely update and publication, insufficient information on traditional medicine unique characteristics, and lack of international collaborations are the problems existing in the interventional clinical registration trials of traditional medicine treatment on neurological diseases. More efforts need to be made from the above aspects to standardize and improve the registration of traditional medicine trials.

[Keutel syndrome with tracheal stenosis as the major symptom: case report and literature review].

OBJECTIVE: To investigate the clinical characteristics, diagnosis and therapy of Keutel syndrome, and thereby to minimize the misdiagnosis. METHOD: Data of a case of Keutel syndrome diagnosed at the Provincial Hospital Affiliated to Shandong University were analyzed and related literature were reviewed. RESULT: An 8-month-26-day-old boy was presented with inspiratory and expiratory stridor and wheezing after movement on lung auscultation. His craniofacial appearance was characterized by midfacial hypoplasia with a broad depressed nasal bridge. The nose was small and flat. A grade 2-3/6 systolic murmur was heard between the second and third ribs at left edge of the sternum. The end phalanges of his fingers were thickened. Chest radiograph showed tracheobronchial cartilage calcification and tracheobronchial stenosis. Echocardiographic examination revealed the right pulmonary stenosis. With endoscopic surgery, antiobstructive and antibiotic therapy clinical symptoms were improved. Three weeks later he died of lung reinfection after he was discharged from our hospital. English literature search with "Keutel syndrome" as the key word at "PubMed" showed 22 articles covering 26 patients, and the clinical symptoms were hearing loss (91%), persistent respiratory symptoms (68%), recurrent otitis media/sinusitis (67%), growth development delay (52%) in turn, and signs were brachytelephalangism (100%), low nasal bridge (95%), midfacial hypoplasia (93%), cardiac murmur (69%), and auxiliary examinations showed abnormal cartilage calcification (100%), pulmonary arterial stenosis (72%), tracheobronchial stenosis (50%). CONCLUSION: The diagnosis of Keutel syndrome should be considered in patients with brachytelephalangism, abnormal cartilage calcification, peripheral pulmonary stenosis, and midfacial hypoplasia. Tracheal stenosis was main clinical manifestation in part of patients.