Songling Xuemaikang in Hypertension and Insomnia Evaluation（SHINE）

Songling Xuemaikang Capsules in Hypertension and Insomnia Evaluation：a Randomized，Double-blind，Placebo-controlled Multicenter Study

To evaluate the effect of Songling Xuemaikang Capsules on reducing 24-hour mean blood pressure in patients with hypertension accompanied by insomnia.

Disease Background： Hypertension is one of the major chronic non-communicable diseases in China, with an extremely severe epidemic situation, imposing a heavy burden on public health and the national medical system. According to the latest data, the weighted prevalence of hypertension among adults aged ≥18 years in China was 27.5% in 2018. A survey from 2012 to 2015 showed that the awareness, treatment, and control rates of hypertension among people aged over 18 years were 51.6%, 45.8%, and 16.8%, respectively. Healthy sleep includes sufficient sleep duration and good sleep quality. Healthy sleep is associated with a lower risk of hypertension, and with a lower incidence of coronary heart disease and stroke in hypertensive patients. Short sleep duration increases the risk of hypertension, and insomnia is associated with cardiovascular mortality and all-cause mortality. A meta-analysis conducted in 2024 included 32 sleep studies in China involving more than 370,000 participants, assessed by the Pittsburgh Sleep Quality Index (PSQI) with a cutoff score of 4-7 (68.8% of studies used a cutoff of 7 for sleep abnormality). The prevalence of poor sleep quality was found to be 19.0% (95% CI: 15.8%-22.8%). The proportion of sleep problems in the hypertensive population is higher than that in the general population. A meta-analysis published in 2020 included 24 studies involving 13,920 participants, revealing that the prevalence of sleep difficulty in hypertensive individuals was as high as 52.5% (95% CI: 46.1%-58.9%), compared with 32.5% (95% CI: 19.0%-49.7%) in healthy controls. The odds ratio (OR) of sleep difficulty in hypertensive patients was 2.66 (95% CI: 1.80-3.93).

There is a complex pathophysiological link between hypertension accompanied by insomnia, rather than coincidental overlap. Numerous studies have confirmed that insomnia is an independent risk factor for the development and progression of hypertension. Chronic insomnia can elevate blood pressure and heart rate and increase the risk of hypertension through mechanisms such as activating the sympathetic nervous system, disrupting hypothalamic-pituitary-adrenal (HPA) axis function, and promoting inflammatory responses. A meta-analysis showed that the relative risk (RR) of incident hypertension in individuals with insomnia was approximately 1.21. Conversely, hypertension itself and its therapeutic drugs may also cause or worsen insomnia. Hypertensive patients often experience impaired sleep quality due to nocturnal blood pressure fluctuations, excessive sympathetic activation, anxiety, or side effects of certain antihypertensive agents .

Therefore, the Chinese Guidelines for the Prevention and Treatment of Hypertension (2024 Revised Edition) provides specific and practical recommendations for the management of sleep duration and quality, including screening for sleep disorders and blood pressure in targeted populations, and proposes specific measures such as cognitive behavioral therapy for insomnia, hypnotic medications, and reducing diuretic use at night. However, in clinical practice, concerns regarding long-term adherence to cognitive behavioral therapy for insomnia and the safety of long-term use of sedative-hypnotic drugs still compromise the synergistic management of hypertension accompanied by insomnia. Thus, the selection of a medication that can lower blood pressure and improve insomnia simultaneously is of great clinical value.

Drug Background： Songling Xuemaikang Capsule is an exclusive product of Chengdu Kanghong Pharmaceutical Co., Ltd., approved for marketing on February 12, 1996. Its formula consists of Pini Massonianae Folium (fresh pine needle), Puerariae Lobatae Radix (kudzu root), and Concha Margaritifera Usta (nacre powder). Its functions and indications are: calming the liver and suppressing yang, tranquilizing the heart and calming the nerves. It is used for headache, dizziness, irritability, palpitations, and insomnia caused by hyperactivity of liver yang; it is also indicated for hypertension and primary hyperlipidemia with the above symptoms.

The sovereign drug of Songling Xuemaikang Capsule is Pinus massoniana Lamb. (Masson pine), a plant of the Pinus genus in the Pinaceae family. It is widely distributed in the humid eastern subtropical regions of China and extends to the northern tropics. In the lower Yangtze River basin, it occurs below 700 m above sea level; in the middle reaches, below 1,100-1,200 m; and in western China, below 1,500 m. The needle of Pinus massoniana, also known as pine hair, is slender and needle-shaped, hence called "pine needle". The needles are in bundles of two, lanceolate, 12-20 cm long, soft and flexible, with resin canals marginal; young leaves are green, and fallen leaves are brown. When dried, a long and narrow groove appears in the center, showing the leaf characteristics. The surface is smooth, dull green, light and crisp, with a slight odor, astringent and bitter taste, and warm nature. Compendium of Materia Medica records: "Long-term administration of pine needles cures all diseases, calms the five zang-organs, promotes hair growth, resists cold and heat, endures wind and rain, lightens the body and replenishes qi, preserves the interior and prolongs life without grain." Pine needle enters the heart and liver meridians, with effects of dispelling wind and drying dampness, killing parasites and relieving itching, activating blood circulation and calming the nerves. It is commonly used for influenza, rheumatic arthralgia, traumatic swelling and pain, hypertension, hyperlipidemia, neurasthenia, eczema, etc. Modern pharmacological studies have shown that proanthocyanidins and shikimic acid in pine needle exert antihypertensive, lipid-lowering, antioxidant, antipyretic, analgesic, anti-inflammatory, and sedative effects.

Kudzu root is the dried root of Pueraria lobata (Willd.) Ohwi (Fabaceae), originating mainly from the Himalayan region of China and currently distributed in most parts of China, especially in hot southern areas. It was first recorded in Shennong's Classic of Materia Medica: "Kudzu root mainly treats thirst, high fever, vomiting, various impediments, raises yin qi, and relieves various toxins." The Pharmacopoeia of the People's Republic of China (2020 Edition) states that kudzu root is sweet, pungent, and cool in nature, acting on the spleen, stomach, and lung meridians. It has the effects of relieving muscles and reducing fever, promoting fluid production and quenching thirst, promoting eruption, elevating yang and stopping diarrhea, unblocking collaterals, and relieving alcoholism. Clinically, it is used for exterior fever with headache, stiff neck and back, incomplete measles, heat dysentery, diarrhea, dizziness and headache, apoplectic hemiplegia, chest stuffiness and heart pain, and alcohol-induced injury. Modern pharmacological studies have found that the active ingredients of kudzu root include isoflavonoids (daidzin, daidzein, puerarin, etc.), kudzuosides, coumarins, triterpenoids, alkaloids, and other compounds. Its modern pharmacological effects include antipyretic, lipid-lowering, hypoglycemic, antihypertensive, and antiarrhythmic actions. Puerarin in kudzu root can directly dilate blood vessels, reduce peripheral resistance, and exert a significant antihypertensive effect, effectively relieving the "neck tightness" symptom in hypertensive patients. It also improves microcirculation, resists arrhythmia and platelet aggregation, and lowers blood glucose and lipids, with anti-hypoxia and antioxidant effects.

Concha Margaritifera is the shell of Hyriopsis cumingii (Lea), Cristaria plicata (Leach) (Unionidae), or Pteria martensii (Dunker) (Pteriidae). Hyriopsis cumingii is mainly produced in Hebei, Jiangsu, Anhui, Zhejiang, etc.; Cristaria plicata is distributed in most parts of China; Pteria martensii is mainly produced in Hepu, Guangxi. Concha Margaritifera was first recorded in Supplement to Materia Medica of the Tang Dynasty: "Ground rotten shell powder taken orally treats regurgitation and phlegm retention in the chest and heart", indicating its effects of drying dampness and resolving phlegm, regulating qi and harmonizing the stomach. The Pharmacopoeia of the People's Republic of China (2020 Edition) records that Concha Margaritifera is cold and salty in nature, acting on the liver and heart meridians, with effects of calming the liver and suppressing yang, tranquilizing and calming convulsions, and improving eyesight and removing nebula. It is used for headache, dizziness, palpitations, insomnia, red eyes with nebula, and blurred vision. Zhang Bingcheng's Notes to Materia Medica states: "Tranquilizing the heart and calming palpitations, it treats mania and epilepsy due to phlegm confusion, enters the liver and improves eyesight", demonstrating its tranquilizing effect. Nacre powder is a fine powder prepared from the nacre layer of Concha Margaritifera after removing the middle and outer layers. Modern pharmacological studies have shown that Concha Margaritifera is rich in trace elements such as calcium, iron, sodium, and potassium, which inhibit the excitation of nerves and skeletal muscles, mainly affecting the rapid eye movement (REM) sleep stage, and may also indirectly influence sleep by regulating other physiological functions and metabolic balance. Jiang Shanshan et al. established an insomnia rat model by electrical stimulation and evaluated it with polysomnography. The results showed that, compared with synthetic sedative-hypnotics and heart-nourishing and nerve-calming herbs, heavy tranquilizing herbs represented by magnetite and cinnabar prolonged total sleep time in insomnia rats, mainly extending slow-wave sleep I, slow-wave sleep II, and REM sleep stages, with more significant effects. Liu Tong et al. established a mouse insomnia model with para-chlorophenylalanine (PCPA), and evaluated the sedative-hypnotic effect by observing spontaneous activity, measuring adrenocorticotropic hormone (ACTH) in serum by ELISA, and calculating brain weight and brain coefficient. Experiments confirmed that Concha Margaritifera exerted sedative and hypnotic effects in mice, and its oligopeptide components may be one of the material bases for efficacy, acting by regulating ACTH. Liu Dong et al.found that the active fractions of Concha Margaritifera increased the concentration of 5-hydroxytryptamine (5-HT), which may be related to the brain 5-HT synthetase inhibitor PCPA, ultimately achieving sedative and hypnotic effects.

In summary, the combination of fresh pine needle and kudzu root not only dissolves turbidity and lowers lipids to purify blood and improve blood viscosity, but also activates blood circulation and removes blood stasis to restore vascular elasticity and ameliorate vascular aging, thereby regulating blood pressure by improving hemorheology and peripheral vascular resistance. Combined with nacre powder, it synergistically calms the liver and suppresses yang, tranquilizes the heart and calms the nerves, and improves symptoms such as headache, dizziness, irritability, palpitations, and insomnia.

Study Objectives： On the basis of healthy lifestyle management for hypertension and using a matching placebo of Songling Xuemaikang Capsule as the control, this study will evaluate the efficacy of Songling Xuemaikang Capsule in patients with hypertension accompanied by insomnia by assessing 24-hour ambulatory blood pressure, polysomnography, sleep and anxiety scales, and other measurements. Specifically, it will characterize its effects on 24-hour mean blood pressure, daytime and nighttime blood pressure reduction, blood pressure stability, sleep architecture, and symptom improvement, in order to evaluate the therapeutic efficacy of Songling Xuemaikang Capsule in this population.

Inclusion Criteria:

1. Age 18-79 years (inclusive), male or female;

2. Meet diagnostic criteria for essential hypertension, and satisfy one of the following conditions:

   Grade 1 hypertension with no antihypertensive drugs in the past 2 weeks; Receiving stable treatment with one standard-dose chemical antihypertensive agent for at least 4 weeks, with blood pressure（BP）140-159/90-99 mmHg, and is willing to maintain the treatment regimen without adjustment;

3. Insomnia Serverity Index (ISI) score ≥ 8, symptoms occur for at least 3 nights per week and have persisted for no less than 3 months;

4. No sedative-hypnotic drugs have been taken within the preceding one month;

5. Is able to complete scale assessments independently;

6. Is willing and able to comply with all examinations and observations specified in the protocol; Has provided written informed consent.

Exclusion Criteria:

1. Severe hypertension (mean SBP ≥ 180 mmHg and/or mean DBP ≥ 110 mmHg); malignant hypertension, hypertensive emergency, hypertensive crisis, hypertensive encephalopathy, etc.
2. Suspected secondary hypertension (renal parenchymal hypertension, renovascular hypertension, obstructive sleep apnea, primary aldosteronism or other endocrine hypertension, drug-induced hypertension, monogenic hypertension, etc.);
3. Clinically significant laboratory abnormalities at screening: ALT > 1.5 × ULN, AST > 1.5 × ULN, or Serum creatinine ≥ 2.0 mg/dL;
4. Chronic gastrointestinal disorders accompanied by frequent abdominal pain or diarrhea, or history of gastrointestinal surgery that may impair drug absorption;
5. A history of allergic diathesis or hypersensitivity to any component of the investigational product;
6. Pregnant females，or those with a positive pregnancy test at screening, women planning pregnancy during the study, lactating women, or fertile women without adequate contraception protection;
7. Clinically severe and unstable hepatic, renal, hematologic disease, malignant tumor, or unilateral/bilateral renal artery stenosis;
8. Documented psychiatric disorder, or GAD-7 score ≥ 10 or PHQ-9 score ≥ 10;
9. Insomnia due to hyperthyroidism, restless legs syndrome, narcolepsy, sleep-related movement disorders, etc.;
10. Insomnia due to neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, epilepsy, etc.);
11. Acute stroke;
12. Confirmed diagnosis of OSA or STOP-BANG score ≥ 5;
13. Night shift or rotating shift workers;
14. Suspected or confirmed alcohol or drug abuse/dependence;
15. Participation in another clinical trial within 3 months prior to screening; Any other condition deemed by the investigator to render the subject unsuitable for the trial.