Therapy of Suppressing Yang and Astringing Yin for the Treatment of Cancer-Related Insomnia

Capsules , etc., for the treatment of insomnia are not very powerful for relaxing the mind. For more complex CRI, the clinical effect of these medicines is not satisfactory and it lacks high-quality methods and support by medical evidence. 1 Professor Zheng Yuling is the instructor of the sixth batch of national Chinese medicine experts in the succession of academic experience, Qihuang scholar, and an expert with special allowance of the State Council. Professor Zheng has long been engaged in medical treatment, teaching, and scienti ﬁ c research of malignant tumors with integrative Abstract The pathogenesis of cancer-related insomnia (CRI) mainly includes, ﬁ rst, the ﬂ ow of cancerous toxin leading to the disorder of visceral qi; second, cancer-related radiotherapy and chemotherapy belonging to “ exogenous pathogenic factors ” to a certain extent, which can further aggravate visceral disorders. The therapeutic principle of Chinese medicine is to tranquilize the mind on the basis of regulating viscera, suppressing yang, and astringing yin. On this theoretical basis, Professor Zheng Yuling created a representative prescription of Zhenjing Anshen Granules which can achieve the co-regulation of the heart, liver, and kidney, tranquilizing the mind and nourishing the blood. Clinically, the selection of prescriptions and medicines needs to be considered due to factors such as different treatment stages and differences in patients ’ constitutions.

medicine. With rich clinical experience and remarkable curative effects, she has gradually developed unique academic thoughts in clinical practice: taking traditional Chinese medicine thinking as the root, protecting healthy qi as the basis, and simultaneous purging and tonifying it as the principle with comprehensive syndrome differentiation and treatment as the purpose.
CRI belongs to the category of "insomnia" in Chinese medicine. In Discussion on Great Perplexity of Spiritual Pivot (Ling Shu Da: Huo Lun): "Defensive qi cannot flow into the yin phase…remains in the yang phase, then yang qi is full. When yang qi is full, the yin in the Yangqiao channel becomes excessive. Since the defensive qi cannot flow into the yin phase, yin qi is deficient. That is why the patient cannot sleep." According to Questions and Answers of Spiritual Pivot (Ling Shu: Kou Wen), it records "When yang qi is exhausted, yin qi will be predominant and therefore people close their eyes to sleep. When yin qi is exhausted, yang qi will be predominant and therefore people keep awake." The disease location of CRI is mainly in the heart and closely related to the kidney, liver, spleen, stomach, gallbladder, etc. 7,8 The pathogenesis includes imbalance between the heart and the kidney, disharmony between the spleen and stomach, liver-qi stagnation, and deficiency of both the heart and spleen, etc. 9 Professor Zheng Yuling believes that the pathogenesis of CRI is nothing more than the imbalance of yin and yang and visceral disorder, especially the heart, liver, and kidney. The core pathogenesis is the overflight of the mind and the imbalance between the liver and the kidney. If the heart fails to dominate the spirit, the mind will be unease and lead to insomnia. If the liver fails to store the soul, the soul will be restless. If the kidney fails to store will, the will may not hide but become uneasy. Professor Zheng Yuling holds that CRI is different from general insomnia. On the one hand, cancer patients suffer from the flow of cancerous toxin and disorder of visceral qi internally; on the other hand, cancer-related radiotherapy and chemotherapy belong to "exogenous pathogenic factors to a certain extent," which can further aggravate visceral disorders. Therefore, Professor Zheng Yuling believes that the therapeutic principle of Chinese medicine is to tranquilize the mind on the basis of regulating viscera, suppressing yang and astringing yin. Based on this theoretical basis, she created the representative prescription of Zhenjing Anshen Granules which has been applied clinically for many years and achieved good effects. Now, her experience in the clinical application of Zhenjing Anshen Granules in the treatment of CRI is expounded as follows.

Interpretation of the Meaning of Zhenjing Anshen Granules ()
The composition of the Zhenjing Anshen Granules includes Sheng Muli (unprocessed Concha Ostreae), Zhenzhumu (Concha Margaritiferae Usta), Chao Suanzaoren (fried Semen Ziziphi Spinosae), Zhi Yuanzhi (processed Radix Polygalae), Shouwuteng (Caulis Polygoni Multiflori), and Dengxincao (Medulla Junci). Sheng Muli (unprocessed Concha Ostreae), the king medicine in the prescription, is salty in flavor and slightly cold in property, pertaining to the kidney, liver, and gallbladder meridians, with the effects of tranquilizing the mind, suppressing yang and astringing yin. Zhenzhumu (Concha Margaritiferae Usta) is salty in flavor and cold in nature, pertaining to the heart and liver meridians, with effects of calming the mind, soothing the liver and suppressing yang. Combined with Sheng Muli (unprocessed Concha Ostreae), it has stronger effects of tranquilizing the mind, suppressing yang and astringing yin. Chao Suanzaoren (fried Semen Ziziphi Spinosae) is sour and sweet in flavor and mild in property, pertaining to the liver, heart, and gallbladder meridians, and has the effects of nourishing the heart, tonifying the liver, calming the heart, and tranquilizing the mind. They are minister medicines. The combination of the king medicine and the minister medicines ensures the calm of heart and mind, coordinating yin and yang and enriching liver blood. Zhi Yuanzhi (processed Radix Polygalae) is pungent and bitter in flavor and warm in property, pertaining to the lung, heart, and kidney meridians, and has the effects of tranquilizing the mind, benefiting the intelligence, and communicating with the heart and kidney. In combination with Zhenzhumu (Concha Margaritiferae Usta), they can regulate both the heart and the kidney and achieve the balance between water and fire. Besides, this medicine enters the kidney meridian and has the effects of resolving phlegm and promoting resuscitation; Shouwuteng (Caulis Polygoni Multiflori), as the assistant medicine, is sweet in flavor and mild in property, pertaining to the liver and heart meridians, and has the effects of nourishing blood and calming the mind. In combination with Chao Suanzaoren (fried Semen Ziziphi Spinosae), it can nourish blood and tonify the liver and restrict the coldness of the king and minister medicines. Dengxincao (Medulla Junci), the guiding medicine, is slightly astringent in flavor, can enter the heart meridian, and has the effects of clearing heart fire, calming the mind, promoting urination, and guiding the fire to move downward. It can "induce pathogens to go out of the body". 10 The abovementioned six medicines are complementary to each other with the combination of deficiency and excess and usage of cold and heat medicines for co-regulation of the heart, liver, and kidney, tranquilizing the mind with heavy medicines and nourishing blood so as to achieve the calming effects of the mind, suppressing yang and astringing yin.
the twelve officials will be in danger and cannot function well." The heart is the master of the five Zang organs and six Fu organs and it is the monarch organ. It stores spirit, which dominates all spiritual activities and consciousness of the human body. 11 Failure of the storage of the spirit will cause uneasiness of the mind as well as soul and poor sleep quality. 7 Therefore, storing and tranquilizing the mind should be the major therapy. The liver stores blood and the blood houses the soul . 12 The mind and soul will be separated due to liver blood deficiency and malnourishment or chronic illness and anxiety; depressed anger impairs the liver, resulting in the depression of liver qi, restlessness, and insomnia, so regulating the liver and nourishing blood is a common treatment. The kidney is the water organ, while the heart is the fire organ. The integration of the two achieves the balance between yin and yang, water and fire. If the mind is overflying or the kidney water is insufficient, water and fire fail to coordinate; it will lead to disharmony between yin and yang. Therefore, regulating the kidney is also a common treatment method which is helpful to suppress the mind. Zou et al 13 collected sedative and tranquilizing prescriptions containing marine Chinese medicines, created a database through the Chinese medicine inheritance auxiliary platform, and conducted data mining on their medicine frequency, prescription rules, and new prescription analysis. The results showed that the core medicine pair of sedative prescriptions containing marine Chinese medicines includes Muli (Concha Ostreae), Zhenzhumu (Concha Margaritiferae Usta), and Suanzaoren (Semen Ziziphi Spinosae). The highfrequency medicines are in the following order: Suanzaoren (Semen Ziziphi Spinosae), Zhenzhumu (Concha Margaritiferae Usta), Muli (Concha Ostreae), and Yuanzhi (Radix Polygalae), which are highly compatible with the composition of the prescription. Thus, the scientific nature of the composition of the sedative and tranquilizing prescription is also verified.

Muli (Concha Ostreae)
In modern pharmacology, it has been proved that Muli (Concha Ostreae) has anti-tumor, anti-oxidation, anti-fatigue, and immune-enhancement pharmacological effects. 14 Studies have confirmed that it contains a small amount of amino acids that have anticonvulsant and sedative effects. 15 Since it has anti-tumor, sedative, softening, and dispelling effects and strong sedative power as well as stable, safe, and non-toxic medicine properties, it is the king medicine in this prescription.

Zhenzhumu (Concha Margaritiferae Usta)
According to Compendium of Materia Medica (Ben Cao Gang Mu), "it can calm the mind and soul." Disturbance of the soul will lead to difficulty in sleeping. Modern pharmacological studies have shown that Zhenzhumu (Concha Margaritiferae Usta) is rich in a variety of trace elements, which can inhibit nerve and skeletal muscle excitement, thereby exerting sedative and hypnotic effects. Liu et al 16 and other studies have shown that its hypnotic effect is related to the promotion of central 5-HT secretion. In addition, Zhenzhumu (Concha Margaritiferae Usta) also has an antidepressant effect, 17 and the proteins in it inhibit tyrosine hydroxylase and interrupt the dopamine synthesis pathway, thereby down-regulating the level of norepinephrine. 18 CRI is often associated with mental illnesses such as depression. Zhenzhumu (Concha Margaritiferae Usta) has multiple effects. By regulating these accompanying diseases, it has multiple effects on insomnia, so it is a minister medicine.

Suanzaoren (Semen Ziziphi Spinosae)
In Explanation of Medicinals from Changsha (Chang Sha Yao Jie), it says "It can calm the heart and remove restlessness, astringe mind and soul, ensure sleep sound." In Miscellaneous Records of Famous Physicians (Ming Yi Bie Lu), it was recorded that "it mainly treats insomnia due to restlessness. It can make people strong and healthy." The classics of the past dynasties all show that Suanzaoren (Semen Ziziphi Spinosae) has good effects of nourishing the heart and calming the mind. Modern pharmacological studies have also shown that Suanzaoren (Semen Ziziphi Spinosae) has various effects of tranquilization, myocardial protection, and anti-anxiety, anti-tumor, and anti-depression. 19 Its main effective components are saponins and flavonoids; the main mechanism is to inhibit central excitement, regulate neurotransmitters, and cytokines. 20 Because of its strong power of nourishing the heart and calming the mind, it can increase the effect of the king medicine to soothe the mind as well as tonify liver deficiency and nourish liver blood, so it is the minister medicine.

Yuanzhi (Radix Polygalae)
In Shen Nong's Materia Medica (Shen Nong Ben Cao Jing), it records that "it can unblock the nine orifices…improves memory, will and physical strength." In Treatise on Medicinal Properties (Yao Xing Lun), it records that "it can relieve forgetfulness and calms the soul…remove dreaminess." In ancient classics, Yuanzhi (Radix Polygalae) has the functions of calming the mind and fright, resuscitating, and improving intelligence. Modern pharmacology proves that Yuanzhi (Radix Polygalae) has the brain-protective, sedative and hypnotic, anti-tumor, anti-anxiety, and anti-depression effects. 21 Studies in recent years have also confirmed its anti-tumor activity. It is especially suitable for the treatment of "chemobrain," which can inhibit the release of neuroinflammatory factors and improve nerve damage, memory, and cognition. 22 Research by Li et al 23 showed that the antidepressant effects of Yuanzhi (Radix Polygalae) are related to the interference with the reuptake of monoamine neurotransmitters. Yuanzhi (Radix Polygalae) has anti-anxiety, anti-depression, anti-tumor, sedative, and hypnotic effects and is safe and non-toxic. Therefore, it is used as assistant medicine for the king and minister medicines.

Shouwuteng (Caulis Polygoni Multiflori)
Shouwuteng (Caulis Polygoni Multiflori) is also known as Yejiaoteng (Caulis Polygoni Multiflori). In Orthodox Interpretation of the Materia Medica (Ben Cao Zheng Yi), it records that "Yejiaoteng (Caulis Polygoni Multiflori) can be used to improve poor sleep at night, so it can guide yang into yin. It reconciles yin and yang, which is beneficial and harmless." Yejiaoteng (Caulis Polygoni Multiflori), as the name suggests, can induce yin and yang to intersect. Concordance between yin and yang ensures sound sleep. Modern pharmacology shows that it has various effects such as regulating the nervous system, improving sleep, anti-oxidation, immune regulation, etc., and confirms that its extracts may increase the contents of Ca 2þ -Mg 2þ -ATPase, Na þ -K þ -ATPase and improve the ultrastructure of mitochondria to treat insomnia. 24 Since it can communicate the upper and the lower parts and induce the concordance between yin and yang, it is the assistant medicine.

Dengxincao (Medulla Junci)
In Explanation of the Material Medical Classic (Ben Cao Jing Jie), it records that "it is cold in nature which can clear heat, sweet in flavor which can transform qi, relieve the stagnation and purging fire." In Compendium of Materia Medica (Ben Cao Gang Mu), it says, "it can reduce heart fire and promote qi circulation." It is light and clear in nature, going straight downward, guiding the heat of the heart and lung from top to the bottom. It has the effect of inducing heat downward, tranquilizing the mind, and eliminating restlessness for insomnia due to hyperactive heart fire. Modern pharmacology shows that Dengxincao (Medulla Junci) has sedative, antioxidant, and antibacterial pharmacological effects. 25 Wang et al 26 confirmed the sedative effect of its ethyl acetate extract through research. It can pave a way for the pathogens to go out, so it is the assistant and guiding medicine in the prescription.

Clinical Application Experience of Zhenjing Anshen Granules
CRI is a concomitant disease with cancer. Its pathogenesis is the absence of mind and liver and kidney disorder. However, cancer is quite complicated. Due to factors such as different treatment stages and differences in constitutions of the patients, the selections of prescriptions and medicines should be differentiated. Since the composition of this prescription is simple and with special effects, it is often applied with other prescriptions to cure both the symptoms and the root causes.

Application Experience in Different Treatment Stages of Tumor
Tumor belongs to the category of "accumulation" in Chinese medicine. In Required Readings from the Medical Ancestors (Yi Zong Bi Du), the accumulations were divided into three stages, the primary stage, the middle stage, and the final stage, and it formulated the therapeutic methods for each stage. As it says, "in the primary stage, healthy qi is not severely impaired and the pathogenic qi is not deep, then purgation can be applied; in the middle stage, the invasion is relatively longer and the pathogenic qi relatively deep and healthy qi rather deficient, then tonification and purgation should be applied simultaneously; in the final stage, long-term pathogenic invasion leads to bullying of pathogenic qi to weak healthy qi, tonification should be applied." Therefore, overall syndrome differentiation should be performed in addition to the treatment of insomnia for CRI patients. Based on the state of healthy qi in the patient and the depth of pathogenic factors, different therapeutic principles such as tonification, purgation or integrated tonification, and purgation should be applied. Besides, with the intervention of modern medicine, the therapies for tumor is becoming increasingly diverse and different therapies produce different effects on the body. Therefore, flexible compatibility should be made according to different therapies in clinical practice.

Insomnia during Operation
After surgery, healthy qi declines, primordial qi is greatly impaired, and qi and blood become deficient. The treatment method should be reinforcing healthy qi on the basis of Zhenjing Anshen prescription , Shiquan Dabu decoction , Shuyu pill , and Dihuang Yinzi combination.

Insomnia during Chemotherapy
Sometimes it is accompanied by gastrointestinal reactions such as vomiting, nausea, poor appetite, etc., due to disharmony in the middle energizer, transport failure by the spleen, and upward flow of stomach qi. 27 It is recommended to apply the methods of strengthening the spleen, harmonizing the stomach, and changing the direction of the flow in a descending manner; Jianpi pill , Xuanfu Daizhe decoction , and Dingxiang Touge decoction can be combined for this. When accompanied by fatigue and low leukocyte, the disease is located in bone marrow, spleen and kidney ,with the main syndromes of spleen deficiency, qi and blood deficiency and spleen and kidney deficiency. 28 At this time, the methods of strengthening the spleen and kidney combined with tonifying qi and blood should be applied with the combination of Shiquan Dabu decoction , Liuwei Dihuang decoction , Bazhen decoction , and Shengyu decoction .

Insomnia at the Stage of Radiotherapy
Radiotherapy belongs to the pathogen of "heat toxin" which consumes yin fluid and disturbs the mind. It should be treated by the combined methods of clearing heat, nourishing yin, and generating body fluid with the combination of Shashen Maidong decoction , Qingwei powder , Zhuye Shigao decoction , Baihu decoction , and Shengmai drink .

Application Experience in Treating Cancer Patients with Different Constitutions
When the external pathogenic factor meets deficient healthy qi, the disease will occur. The occurrence of malignant tumor is closely related to the patient's constitution, and malignant tumor is a kind of wasting disease which depletes the body's healthy qi. The growth of tumor requires the nourishment of yin blood, body fluid, and the promotion of yang qi, which will cause the deficiency of qi, blood, yin, and yang over time.

Experience in Treating Cancer Patients with Accompanying Symptoms
CRI can be seen in a variety of cancers. Insomnia is the main symptom, but the accompanying symptoms are often different depending on the type of cancer. For instance, pleural effusion is often seen in lung cancer; poor appetite, abdominal distension, and bloody stool are common in gastric cancer; dry stools are common in pancreatic cancer; emotional depression, vexation, and irritability are common in breast cancer; and dizziness and headaches are often seen in brain cancer. In clinical practice, insomnia should be treated as the main symptom, along with the accompanying symptoms of cancer. For those with pleural effusion, add Zexie

Typical Cases
Hong, 62 years old, female, from Zhengzhou City of Henan Province, went to see the doctor on November 1, 2020. The patient was diagnosed with clear cell carcinoma of the right ovary in February 2020 with the symptom of postmenopausal vaginal bleeding, and she then underwent radical surgery and adjuvant chemotherapy. Chief complaints included lower limb swelling and insomnia after post-operative chemotherapy of ovarian cancer. Current symptoms were mild swelling of both lower limbs, which worsened after walking; poor sleep quality, waking up easily at night and difficulty in falling asleep again; ordinary spirit, relatively normal appetite, and normal urination and defecation. The color of the tongue was pale and dark with thin, white, and greasy coating. Western medicine diagnosis reported (1) lower limb edema after post-operative chemotherapy of ovarian cancer and (2) insomnia. TCM diagnosis reported (1) edema, syndrome differentiation: deficiency of qi and blood, internal retention of water, and dampness; (2) mass; and (3) insomnia. The therapeutic principle included benefiting qi and harmonizing nutrient phase, warming yang and promoting diuresis. Following prescription was selected: Shuyu pill On the second visit (February 9, 2021), the effects of the prescription were found to be good: the strength increased and fatigue and edema were alleviated compared with the previous visit. Current symptoms were normal appetite, with weight gain by 10 kg in the past 3 months; the sleep quality was still poor, with the symptoms of difficulty in falling asleep, sleeping less than 5 hours at night, light sleep, dreaminess and awaking easily; unsmooth defecation, with slight leakage of urine; the color of the tongue was light red with thin and white coating, and the pulse was taut and slippery. Western medicine diagnosis reported insomnia after post-operative chemotherapy of ovarian cancer. TCM diagnosis reported insomnia. Syndrome differentiation indicated floating mind and liver and kidney disorder. The following prescription was se- On the third visit (February 28, 2021), after taking the upper prescription, sleep quality got improved slightly and defecation was smoother than before, with swollen hands and feet accompanied by hot sensation and sweating, and irascibility. The sleep quality was still poor and it was still difficult to fall asleep, with light sleep, waking up easily, and dreaminess, but it improved after taking the medicines. Appetite, urination, and defecation relatively normalized, and the tongue and pulse conditions were the same as reported earlier. Syndrome differentiation indicated restlessness due to liver depression and spleen deficiency. The therapeutic principle included soothing the liver and invigorating the spleen and tranquilizing the mind. One the fourth visit (March 21, 2021), the effects of the upper prescription were found to be good: sleep quality improved considerably; defecation became smoother than before; the swelling of the hands and feet, hot sensation and sweating, and excessive breaking wind were all alleviated compared with the previous visit. Current symptoms were heavy right leg, edema, irritable temper, nausea, relatively normal appetite and sleep of 6 to 7 hours duration, and normal sleeping depth, sleep was more stable than before and symptoms of light sleep and easy waking up disappeared, with relatively normal urination and defecation and mild urine leakage. The tongue was light red with thin and white coating, and the pulse was slippery and moist. This was treated by adding 30 g of Yiyiren (Semen Coicis) to the former prescription.
On the fifth visit (April 18, 2021), the effects were good; sleep continued to improve and became basically normal; the swelling and discomfort of the hands and feet, the hot sensation and sweating, and excessive breaking wind improved compared with the previous visit. Current symptoms were heavy and swelling right leg, relatively normal appetite, basically normal sleep at night, and normal urination and defecation; the tongue and pulse conditions were the same as before. TCM diagnosis indicated edema. Syndrome differentiation indicated disharmony between liver and spleen, qi stagnation, and water retention. The therapeutic principles include harmonizing the liver and spleen, nourishing blood, and inducing diuresis. The following prescription was selected modified Danggui Shaoyao powder . The components of medicines were 15 g of Baishao (Radix Paeoniae Alba), 15 g of Chuanxiong (Rhizoma Chuanxiong), 30 g of Danggui (Radix Angelicae Sinensis), 15 g of Fuling (Poria), 12 g of Zexie (Rhizoma Alismatis), 30 g of Xiakucao (Spica Prunellae), 12 g of Baizhu (Rhizoma Atractylodis Macrocephalae), 30 g of Yiyiren (Semen Coicis), and 15 g of Ezhu (Rhizoma Curcumae).

Conclusion
The symptom of insomnia in cancer patients not only negatively impacts their immune function, heart function, and blood sugar regulation but also aggravates the condition of the cancer patients, reduces their confidence in fighting against diseases, decreases the quality of life, and increases early mortality. 29 The treatment of insomnia is symptomatic and can also improve the quality of life of cancer patients and enhance the tolerance of anti-tumor treatments through sleep adjustment. Professor Zheng Yuling created Zhenjing Anshen Granules by summing up her own clinical experience, combining it with modern pharmacological research, repeatedly exploring in the clinical practice, and adopting the method of suppressing yang and astringing yin, which can significantly improve CRI. This prescription has been used since September 10, 2017. So far, approximately 200 patients have taken this prescription. With regular follow-ups, it has shown good therapeutic effects on insomnia caused by anxiety, fear, and depression that occur during the course of cancer or cancer treatment. For moderate and severe insomnia caused by other diseases, it also has obvious curative effect, with an effectivity rate of 77%. At present, this prescription has been approved for national invention patent and the hospital preparations are also in process. In the future, Professor Zheng Yuling's team will use animal experiments, pharmacological and toxicological methods, clinical observations, and more other objective methods to study this prescription at multiple levels and aspects, and carry out in-depth explorations of its action mechanism and molecular pathways to benefit more patients.