Songling Xuemaikang in Hypertension and Insomnia Evaluation（SHINE）

Disease Background： Hypertension is one of the major chronic non‐communicable diseases inChina, with an extremely severe epidemic situation, imposing a heavy burden on publichealth and the national medical system. According to the latest data, the weightedprevalence of hypertension among adults aged ≥18 years in China was 27.5% in 2018. Asurvey from 2012 to 2015 showed that the awareness, treatment, and control rates ofhypertension 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 isassociated with a lower risk of hypertension, and with a lower incidence of coronaryheart disease and stroke in hypertensive patients. Short sleep duration increases therisk of hypertension, and insomnia is associated with cardiovascular mortality andall‐cause mortality. A meta‐analysis conducted in 2024 included 32 sleep studies in Chinainvolving 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 sleepabnormality). 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 higherthan that in the general population. A meta‐analysis published in 2020 included 24studies involving 13,920 participants, revealing that the prevalence of sleep difficultyin hypertensive individuals was as high as 52.5% (95% CI: 46.1%‐58.9%), compared with32.5% (95% CI: 19.0%‐49.7%) in healthy controls. The odds ratio (OR) of sleep difficultyin 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 anindependent risk factor for the development and progression of hypertension. Chronicinsomnia can elevate blood pressure and heart rate and increase the risk of hypertensionthrough mechanisms such as activating the sympathetic nervous system, disruptinghypothalamic‐pituitary‐adrenal (HPA) axis function, and promoting inflammatory responses.A meta‐analysis showed that the relative risk (RR) of incident hypertension inindividuals with insomnia was approximately 1.21. Conversely, hypertension itself and itstherapeutic drugs may also cause or worsen insomnia. Hypertensive patients oftenexperience impaired sleep quality due to nocturnal blood pressure fluctuations, excessivesympathetic activation, anxiety, or side effects of certain antihypertensive agents .Therefore, the Chinese Guidelines for the Prevention and Treatment of Hypertension (2024Revised Edition) provides specific and practical recommendations for the management ofsleep duration and quality, including screening for sleep disorders and blood pressure intargeted populations, and proposes specific measures such as cognitive behavioral therapyfor insomnia, hypnotic medications, and reducing diuretic use at night. However, inclinical practice, concerns regarding long‐term adherence to cognitive behavioral therapyfor insomnia and the safety of long‐term use of sedative‐hypnotic drugs still compromisethe synergistic management of hypertension accompanied by insomnia. Thus, the selectionof a medication that can lower blood pressure and improve insomnia simultaneously is ofgreat clinical value.Drug Background： Songling Xuemaikang Capsule is an exclusive product of Chengdu KanghongPharmaceutical Co., Ltd., approved for marketing on February 12, 1996. Its formulaconsists of Pini Massonianae Folium (fresh pine needle), Puerariae Lobatae Radix (kudzuroot), 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 byhyperactivity of liver yang; it is also indicated for hypertension and primaryhyperlipidemia with the above symptoms.The sovereign drug of Songling Xuemaikang Capsule is Pinus massoniana Lamb. (Massonpine), a plant of the Pinus genus in the Pinaceae family. It is widely distributed in thehumid eastern subtropical regions of China and extends to the northern tropics. In thelower 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". Theneedles are in bundles of two, lanceolate, 12‐20 cm long, soft and flexible, with resincanals marginal; young leaves are green, and fallen leaves are brown. When dried, a longand narrow groove appears in the center, showing the leaf characteristics. The surface issmooth, dull green, light and crisp, with a slight odor, astringent and bitter taste, andwarm nature. Compendium of Materia Medica records: "Long‐term administration of pineneedles cures all diseases, calms the five zang‐organs, promotes hair growth, resistscold and heat, endures wind and rain, lightens the body and replenishes qi, preserves theinterior and prolongs life without grain." Pine needle enters the heart and livermeridians, with effects of dispelling wind and drying dampness, killing parasites andrelieving itching, activating blood circulation and calming the nerves. It is commonlyused for influenza, rheumatic arthralgia, traumatic swelling and pain, hypertension,hyperlipidemia, neurasthenia, eczema, etc. Modern pharmacological studies have shown thatproanthocyanidins and shikimic acid in pine needle exert antihypertensive,lipid‐lowering, antioxidant, antipyretic, analgesic, anti‐inflammatory, and sedativeeffects.Kudzu root is the dried root of Pueraria lobata (Willd.) Ohwi (Fabaceae), originatingmainly from the Himalayan region of China and currently distributed in most parts ofChina, especially in hot southern areas. It was first recorded in Shennong's Classic ofMateria Medica: "Kudzu root mainly treats thirst, high fever, vomiting, variousimpediments, raises yin qi, and relieves various toxins." The Pharmacopoeia of thePeople's Republic of China (2020 Edition) states that kudzu root is sweet, pungent, andcool in nature, acting on the spleen, stomach, and lung meridians. It has the effects ofrelieving muscles and reducing fever, promoting fluid production and quenching thirst,promoting eruption, elevating yang and stopping diarrhea, unblocking collaterals, andrelieving alcoholism. Clinically, it is used for exterior fever with headache, stiff neckand 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 rootinclude isoflavonoids (daidzin, daidzein, puerarin, etc.), kudzuosides, coumarins,triterpenoids, alkaloids, and other compounds. Its modern pharmacological effects includeantipyretic, 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 "necktightness" symptom in hypertensive patients. It also improves microcirculation, resistsarrhythmia and platelet aggregation, and lowers blood glucose and lipids, withanti‐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 mainlyproduced in Hebei, Jiangsu, Anhui, Zhejiang, etc.; Cristaria plicata is distributed inmost parts of China; Pteria martensii is mainly produced in Hepu, Guangxi. ConchaMargaritifera was first recorded in Supplement to Materia Medica of the Tang Dynasty:"Ground rotten shell powder taken orally treats regurgitation and phlegm retention in thechest and heart", indicating its effects of drying dampness and resolving phlegm,regulating qi and harmonizing the stomach. The Pharmacopoeia of the People's Republic ofChina (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 andsuppressing yang, tranquilizing and calming convulsions, and improving eyesight andremoving nebula. It is used for headache, dizziness, palpitations, insomnia, red eyeswith nebula, and blurred vision. Zhang Bingcheng's Notes to Materia Medica states:"Tranquilizing the heart and calming palpitations, it treats mania and epilepsy due tophlegm confusion, enters the liver and improves eyesight", demonstrating itstranquilizing effect. Nacre powder is a fine powder prepared from the nacre layer ofConcha Margaritifera after removing the middle and outer layers. Modern pharmacologicalstudies 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 indirectlyinfluence sleep by regulating other physiological functions and metabolic balance. JiangShanshan et al. established an insomnia rat model by electrical stimulation and evaluatedit with polysomnography. The results showed that, compared with syntheticsedative‐hypnotics and heart‐nourishing and nerve‐calming herbs, heavy tranquilizingherbs 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 moresignificant effects. Liu Tong et al. established a mouse insomnia model withpara‐chlorophenylalanine (PCPA), and evaluated the sedative‐hypnotic effect by observingspontaneous activity, measuring adrenocorticotropic hormone (ACTH) in serum by ELISA, andcalculating brain weight and brain coefficient. Experiments confirmed that ConchaMargaritifera exerted sedative and hypnotic effects in mice, and its oligopeptidecomponents may be one of the material bases for efficacy, acting by regulating ACTH. LiuDong et al.found that the active fractions of Concha Margaritifera increased theconcentration of 5‐hydroxytryptamine (5‐HT), which may be related to the brain 5‐HTsynthetase inhibitor PCPA, ultimately achieving sedative and hypnotic effects.In summary, the combination of fresh pine needle and kudzu root not only dissolvesturbidity and lowers lipids to purify blood and improve blood viscosity, but alsoactivates blood circulation and removes blood stasis to restore vascular elasticity andameliorate vascular aging, thereby regulating blood pressure by improving hemorheologyand peripheral vascular resistance. Combined with nacre powder, it synergistically calmsthe liver and suppresses yang, tranquilizes the heart and calms the nerves, and improvessymptoms such as headache, dizziness, irritability, palpitations, and insomnia.Study Objectives： On the basis of healthy lifestyle management for hypertension and usinga matching placebo of Songling Xuemaikang Capsule as the control, this study willevaluate the efficacy of Songling Xuemaikang Capsule in patients with hypertensionaccompanied by insomnia by assessing 24‐hour ambulatory blood pressure, polysomnography,sleep and anxiety scales, and other measurements. Specifically, it will characterize itseffects on 24‐hour mean blood pressure, daytime and nighttime blood pressure reduction,blood pressure stability, sleep architecture, and symptom improvement, in order toevaluate the therapeutic efficacy of Songling Xuemaikang Capsule in this population.