Comments on Chinese Medicine Research Papers Published in The Lancet

 Tiejun Tang    

A recent research paper published in the internationally renowned medical journal The Lancet titled "Traditional Chinese Medicine FYTF-919 (Zhongfeng Xingnao Oral Prescription) for the Treatment of Acute Cerebral Hemorrhage: A Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial" ^[1] concluded that the efficacy of the traditional Chinese medicine (TCM) prescription, Zhongfeng Xingnao Oral Prescription, was no different from that of a placebo, and it could not improve the functional prognosis, survival rate, or quality of life of patients with cerebral hemorrhage. This conclusion could easily mislead readers into thinking that traditional Chinese medicine is ineffective in treating cerebral hemorrhage, causing a negative impact on the reputation of TCM and provoking strong responses from the TCM community both domestically and internationally.

But is it really true that traditional Chinese medicine is ineffective in treating cerebral hemorrhage? No! The conclusions of this study only show that the specific prescription used in the trial is ineffective, and they cannot be generalized to all traditional Chinese medicines. The main issue with the negative research results lies in the selection of the prescription.

Zhongfeng Xingnao Oral Prescription contains four ingredients: Hongshen, Sanqi, Chuanxiong, and Dahuang. My opinion is using Chuanxiong in the treatment of acute cerebral hemorrhage is fundamentally incorrect.

The Chinese Pharmacopoeia records that Chuanxiong is pungent, warm, and acts on the liver, gallbladder, and pericardium meridians. It is known for promoting blood circulation, dispelling wind, and relieving pain. It is typically used for irregular menstruation, dysmenorrhea, abdominal pain due to lumps, stabbing chest and rib pain, swelling and pain from injuries, and headaches. In clinical practice, Chuanxiong is recognized for its ability to promote blood circulation and remove blood stasis, making it an important medicine for treating headaches. Modern pharmacological studies have confirmed that the main active ingredient of Chuanxiong is ligustrazine. The pharmacological effects of Chuanxiong and ligustrazine have been hotly researched, with over 1,000 articles available on PubMed when searching for "Chuanxiong" or "ligustrazine" (1022 and 1608 papers, respectively). In 2024 lone, there were 96 and 115 studies published on the topic.

Recent studies on Chuanxiong’s effect on coagulation and blood rheology reveal some concerning findings:

1. One study using network pharmacology found that Chuanxiong can inhibit TF (tissue factor) procoagulant activity and reduce TF mRNA and protein expression in EA.hy926 cells in a dose-dependent manner via the PI3K/Akt/NF-κB signaling pathway ^[2].
2. Another study using affinity ultrafiltration mass spectrometry (AUF-MS) identified 21 active components from Chuanxiong, with ferulic acid, chlorogenic acid, and isochlorogenic acid A being potential antithrombin agents. The conclusion was that Chuanxiong is a Chinese herbal medicine with good anticoagulant effects ^[3].
3. A third study using a microfluidic chip model of normal and stenotic arteries showed that ligustrazine inhibits platelet aggregation and activation by reducing the binding of von Willebrand factor (vWF) to the GPIb/IX/V complex, partly inhibiting platelet aggregation through the P2Y12-ADP receptor pathway ^[4].

Ligustrazine has effects such as inhibiting platelet aggregation, dilating blood vessels, reducing blood viscosity, and anticoagulation. It is mainly used in the treatment of ischemic stroke and can be employed for rehabilitation in hemorrhagic stroke. However, it is obviously unsuitable for use in the acute stage of cerebral hemorrhage, as its anticoagulant properties could worsen bleeding.

In contrast, Western medicine uses hemostatic drugs such as aprotinin, 6-aminocaproic acid, and tranexamic acid in treating acute cerebral hemorrhage to correct coagulation dysfunction and prevent the expansion of the bleeding area. Although the clinical effect of hemostatic drugs is not ideal, they remain one of the routine treatments for acute cerebral hemorrhage. The effect of ligustrazine on coagulation is completely opposite to that of hemostatic agents.

Traditional Chinese medicine (TCM) holds that "blood that leaves the vessel is stagnant," and there are indeed reports of using blood-activating and blood-stasis-removing methods to treat cerebral hemorrhage. However, this is generally applied in the recovery period, not in the acute phase. TCM often uses Sanqi (Panax notoginseng), which has both blood-activating and hemostatic effects, in such treatments. The two ingredients, Chuanxiong and Dahuang, in this particular prescription both promote blood circulation, which does not align with the TCM principles of syndrome differentiation and treatment. This discrepancy likely led to the negative research results in the study.

For treating acute cerebral hemorrhage, TCM must follow the principle of syndrome differentiation. For example:

• Angong Niuhuang Wan clears heat, resolves phlegm, and opens the orifices, suitable for phlegm-heat blocking type stroke.
• Shenfu Tang is used for yang qi exhaustion syndrome.
• Shengmai San is used for qi and yin deficiency syndrome.

There is no single prescription that can effectively treat all types of strokes.

Furthermore, scientific research on TCM must respect the inherent principles of TCM. It cannot simply replicate the Western medical research model, as this approach would lead to biased conclusions.

References:

1. Jianwen Guo. Traditional Chinese Medicine FYTF-919 (Zhongfeng Xingnao Oral Prescription) for the Treatment of Acute Intracerebral Hemorrhage: A Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial. The Lancet, 2024 Nov; Volume 404, Issue 10468, Pages 2187-2196.
2. Shasha He. "Exploring the Mechanism of Chuanxiong Rhizoma Against Thrombosis Based on Network Pharmacology, Molecular Docking and Experimental Verification." Molecules, 2023 Sep 19; 28(18): 6702.
3. Chencun Huang. "Screening of Anti-Thrombin Active Components from Ligusticum Chuanxiong by Affinity-Ultrafiltration Coupled with HPLC-Q-Orbitrap-MS." Phytochemical Analysis, 2023 Jun; 34(4): 443-452.
4. Tiancong Zhang. "Application of Microfluidic Chip Technology to Study the Inhibitory Effect of Tetramethylpyrazine on Platelet Aggregation, Activation, and Phosphatidylserine Exposure Mediated by Pathological High Shear Rate." Blood Coagul Fibrinolysis, 2023 Jan 1; 34(1): 47-60.