Application of phellandrene in preparation of right ventricle targeted medicine for preventing and treating hypoxic pulmonary hypertension
By using right ventricular targeted drugs prepared with water celeryne, the problem of lack of targeted drugs for the right ventricle in the prior art was solved, and effective improvement of right ventricular function of hypoxic pulmonary hypertension was achieved, delaying the progress of the disease and improving the quality of life of patients.
Patent Information
- Application Number
- CN202510209125.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-25
- Publication Date
- 2025-05-09
AI Technical Summary
There is a lack of targeted drugs specifically targeting the right ventricle in the prior art to prevent and treat hypoxic pulmonary hypertension, resulting in inaccurate treatment effects and greater side effects.
Using celeryne as the active ingredient, a right ventricular targeted drug to prevent and treat hypoxic pulmonary hypertension was prepared. By constructing a rat model of hypoxic pulmonary hypertension, the intervention effect of celeryne on rat pulmonary hypertension was verified.
Hydraene can act directly on the right ventricle, reduce its burden, improve the compliance and contraction function of the right ventricle, thereby delaying the progress of the disease and improving the patient's exercise endurance and quality of life.
Smart Images
Figure CN119950462A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine, and particularly relates to use of phellandrene in preparing a right ventricle-targeted drug for preventing and treating hypoxic pulmonary hypertension. Background Art
[0002] With the country's high attention to the development of plateau-specific resources and plateau ecological construction, as well as the need for national defense construction, the number of people entering the plateau has increased in recent years, and acute and chronic plateau diseases have also occurred from time to time. If treatment is not timely, the mortality rate is very high. Among them, hypoxic pulmonary arterial hypertension (HPAH) is the initial link of plateau diseases such as high-altitude pulmonary edema and plateau heart disease. HPAH is characterized by pulmonary artery hyperplasia and remodeling, which leads to a specific increase in right ventricular systolic pressure (RVSP), and ultimately leads to right ventricular failure or even death. According to the international "Qinghai Diagnostic Criteria for Chronic Mountain Sickness", the diagnostic criteria for HPAH are: mean pulmonary artery pressure (mPAP)>30mmHg or pulmonary artery systolic pressure>50 mmHg. At present, the treatment of plateau hypoxic pulmonary arterial hypertension is not mature, and the main premise is to leave the hypoxic environment of the plateau. The use of drugs to intervene in acute and chronic plateau diseases is still in the research stage. At present, clinical drug treatment is mainly based on vasodilators and anti-vascular remodeling target drugs, but it is often difficult to persist in the long term due to uncertain efficacy and large side effects.
[0003] Right ventricular (RV) function is the main determinant of the prognosis of HPAH patients. During the development of pulmonary hypertension, as pulmonary artery pressure (PAP) increases, the right ventricle shows compensatory mechanisms in the early stage. As the right ventricular afterload continues to increase, the right ventricular compensatory mechanism is insufficient, leading to right ventricular decompensation, which is mainly manifested as right ventricular dilatation, increased right ventricular end-diastolic pressure, excessive fibrosis and capillary loss, leading to right heart failure (RVF) and even premature death. Hypoxia is also one of the important factors inducing pulmonary hypertension. Studies have found that pulmonary vasoconstriction (HPV) induced by high altitude hypoxia can lead to reduced right ventricular myocardial contractility, cause right ventricular remodeling, and ultimately lead to right heart failure or even death. In addition to right ventricular function damage caused by the continuous increase in right ventricular afterload, hypoxia can also directly act on the myocardium, exerting a negative inotropic effect and leading to right heart failure. Although more and more studies have shown that right ventricular function is the main prognostic factor for the morbidity and mortality of HPAH patients, there is currently no treatment for the right ventricle. Therefore, in addition to the goal of improving pulmonary vascular hemodynamics, the treatment strategy for pulmonary hypertension should focus on supporting right ventricular adaptive remodeling and / or reversing right ventricular non-adaptive remodeling. Recent studies have also pointed out that in order to improve the quality of life of HPAH patients, specific treatments for the right ventricle should be developed. Therefore, identifying the regulators of right ventricular function in pulmonary hypertension is the key to developing RV-specific treatment strategies. Summary of the invention
[0004] In order to solve the problem that there is a lack of targeted drugs specifically targeting the right ventricle for the prevention and treatment of hypoxic pulmonary hypertension in the prior art, the present invention provides the use of phellandrene in the preparation of a right ventricle-targeted drug for the prevention and treatment of hypoxic pulmonary hypertension. The present invention constructs a rat model of hypoxic pulmonary hypertension and verifies the intervention effect of phellandrene on rat pulmonary hypertension through a control experiment; HPAH rats are used as research objects, and the mean pulmonary artery pressure (mPAP), RV tissue hypertrophy index and RV tissue oxidative stress index of HPAH rats are detected to mainly study the effect of phellandrene on the right ventricular function of HPAH rats, thereby analyzing the biological effect of phellandrene on HPAH, and providing technical support for the development of right ventricle-targeted drugs for hypoxic pulmonary hypertension.
[0005] The technical solution adopted by the present invention is: The invention discloses use of phellandrene in preparing a right ventricle-targeted drug for preventing and treating hypoxic pulmonary hypertension, wherein the phellandrene is α-phellandrene.
[0006] Preferably, the phellandrene is used to improve organ indexes.
[0007] Preferably, the phellandrene is used to alleviate right ventricular function impairment caused by hypoxic pulmonary hypertension.
[0008] Preferably, the phellandrene is used to reduce mean pulmonary artery pressure.
[0009] Preferably, the phellandrene is used to reduce right ventricular hypertrophy and right heart weight index.
[0010] Preferably, the dosage of phellandrene is 50 mg / kg.
[0011] Preferably, the drug is a preparation prepared with phellandrene as the only active ingredient and pharmaceutically acceptable excipients.
[0012] Preferably, the preparation is an oral preparation.
[0013] The beneficial effects of the present invention are: Although the pathogenesis of HPAH begins in the pulmonary circulation, right ventricular dysfunction is the main cause of its increased morbidity and mortality. The 1-year, 2-year and 3-year mortality rates of HPAH patients are 8%, 16% and 21% respectively. The 5-year survival rate of patients with stable right ventricular function is >90%, but the 5-year survival rate of patients with decreased right ventricular function is <30%. After treatment, the pulmonary vascular resistance of some HPAH patients decreases, but the right ventricular function continues to decline, resulting in a poor prognosis for the patients, which may be related to the inherent characteristics and mechanisms of RV independent of afterload changes. Therefore, in-depth exploration of the mechanism leading to RV dysfunction in PAH and research on right ventricular targeted therapy are important ways to improve the prognosis and survival of HPAH patients. Under the guidance of the use of phellandrene in the preparation of right ventricular targeted drugs for the prevention and treatment of hypoxic pulmonary hypertension, the developed right ventricular targeted drugs can directly act on the right ventricle, reduce its burden, improve the compliance and contractile function of the right ventricle, thereby delaying the progression of the disease and improving the patient's exercise tolerance and quality of life. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 This is a bar chart of the effect of phellandrene on right ventricular function in HPAH rats. A and B: RV free wall thickness results in diastole and systole of HAPH rats; C and D: RV inner diameter results in diastole and systole of HAPH rats; E: pulmonary artery acceleration time (PAT) results in HPAH rats; F: pulmonary artery ejection time (PAT) results in HPAH rats; G: ratio of pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) in HPAH rats; H: tricuspid plane systolic excursion (TAPSE) results in HPAH rats; Figure 2Phellandrene improves right ventricular function in HPAH rats by echocardiograms. A and B: echocardiograms of RV free wall thickness during diastole and systole in HAPH rats; C and D: echocardiograms of RV inner diameter during diastole and systole in HAPH rats; E: echocardiograms of pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) in HPAH rats; F: echocardiograms of tricuspid plane systolic excursion (TAPSE) in HPAH rats. Figure 3 This is a bar chart analyzing the effects of phellandrene on mean pulmonary artery pressure and right ventricular remodeling in HAPH rats. A: mPAP: represents mean pulmonary artery pressure; B: RV / (LV+S): represents the ratio of right ventricular weight to left ventricle + ventricular septum; C: RV / BW: represents the ratio of right ventricular (RV) weight to body weight (BW). DETAILED DESCRIPTION
[0015] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. However, it should be understood that the protection scope of the present invention is not limited to the specific embodiments.
[0016] Embodiment 1: Experimental process: 1. Experimental animals: 8-week-old healthy male Sprague-Dawley (SD) rats weighing 200±20 g were purchased from the Animal Experiment Center of Xi'an Jiaotong University (Experimental Animal License No. SCXK (Shaanxi) 2023-002) and raised in a hypoxic environment for 4 weeks. The α-phellandrene used in the experiment was a purchased α-phellandrene standard.
[0017] 2. Experimental instruments: Electronic balance: SHANGPING (YP601N), anesthesia machine air pump (model: R510-29) purchased from Shenzhen Ruiwode Life Science Technology Co., Ltd., small animal ultrasound imaging system (model: Vevo 3100LT), low-pressure oxygen chamber (model: DYC-300) purchased from Guizhou Fenglei.
[0018] 3. Construction of pulmonary hypertension model: Rats in the blank control group were raised in a normoxic environment (Xi'an) for 28 days; rats in the experimental group were modeled in a hypoxic and hypobaric oxygen chamber (Guizhou Fenglei Oxygen Chamber Co., Ltd., Guizhou Fenglei Oxygen Chamber, dyc-300) and raised in an environment with a simulated altitude of 4500 meters for 28 days. From the first day of entering the chamber, different doses of phellandrene (50 mg / kg / d, 25 mg / kg / d and 12.5 mg / kg / d) 1 mL were given by gavage; rats in the positive control group (sildenafil group) were given sildenafil (30 mg / kg / d); there were 10 experimental rats in each group.
[0019] 4. Measurement of right ventricular function in rats: The rats were anesthetized by intraperitoneal injection of 20% ulanose at a volume of 0.8 mL / 0.1 kg according to their body weight. The MS250 probe (16 MHz and 21 MHz) was used to detect the relevant indices of right ventricular function in rats. Right ventricular inner diameter (RVID), right ventricular free wall systole (RVFWs) and right ventricular free wall diastole (RVFWd) were measured in two-dimensional mode. Tricuspid annular plane systolic excursion (TAPSE). Pulmonary artery acceleration time (PA-AT) and pulmonary artery ejection time (PA-ET) were measured by pulse wave Doppler images at the pulmonary artery annulus in the parasternal short axis view. Cardiac output (CO) was measured by Doppler echocardiography, and the measured echocardiographic parameters were quantified and analyzed using Vevo LAB 5.6.0.
[0020] 5. Determination of mean pulmonary artery pressure: 20% ulexol was injected into the rats at a volume of 8 ml / kg for anesthesia, and the mPAP of rats in each group was measured using a pressure signal acquisition system. The specific operation is as follows: (1) Preparation: sufficient fresh heparin (0.1%), a polyvinylidene catheter with a diameter of 0.28 mm, a small curved hook at one end of the catheter and a mark 3 cm above the end, and the other end connected to a physiological recorder; (2) Anesthetizing rats: Anesthetize with 20% urea sodium, observe after stabilization for 5 minutes, and fix the rat on a horizontal board when its breathing is stable and its limbs do not respond to pinching; (3) Inserting the catheter: Gently use hemostatic forceps to lift the fur on the rat's neck, cut the neck skin, and separate the rat's external jugular vein using blunt separation. Cut a "V"-shaped opening in the middle of the vein, insert the curved catheter end into the "V"-shaped opening, and gently insert the catheter to the 3 cm mark.
[0021] 6. Determination of organ index and right ventricular hypertrophy index: (1) The heart, lungs, liver, spleen, and kidneys of the rats were removed in turn, and the excess tissues and water were filtered out and weighed. The organ index of each organ was calculated: organ index = organ mass (g) / body mass (g) × 100%; (2) RV tissue sampling: Use 20% ulose at a dose of 0.8 mL / 0.1 kg to anesthetize the rats, open the abdominal cavity, and expose the rat heart and lung tissues; separate the heart tissue and lung tissue, gently remove the heart tissue, weigh and record. Carefully separate the right ventricle along the ventricular septum, weigh and record; calculate the right ventricular hypertrophy index and right ventricular weight index according to the following formulas: Right ventricular hypertrophy index = right ventricle / left ventricle + ventricular septum (RV / LV+S); Right ventricular mass index = right ventricle / rat body weight (RV / BW).
[0022] 7. Statistical analysis: SPSS26.0 software was used for statistical analysis. All data were expressed as mean ± standard deviation (x ̅ ± s). The data were in accordance with normal distribution and analyzed by one-way analysis of variance. The test level was α = 0.05, and P ≤ 0.05 was considered statistically significant. # indicates the Hypoxia group compared with the Control group, and * indicates the phellandrene intervention group (12.5 mg / kg / d, 25 mg / kg / d and 50 mg / kg / d) and the Sildenafil group compared with the hypoxia model group.
[0023] Experimental results: 1. Effects of phellandrene on right ventricular function in HPAH rats In order to study the effect of phellandrene on the right ventricular function of HPAH rats, the present invention used non-invasive echocardiography to detect the indicators related to the right ventricular function of HPAH rats. The results showed that under hypoxic conditions, the right ventricular free wall thickness (RVFW-D, RVFW-S) of HPAH rats increased compared with the normoxic group. After intervention with phellandrene and sildenafil, the right ventricular free wall thickness (RVFW-D, RVFW-S) of rats decreased compared with the hypoxic model group (P<0.05, Figure 1 A. Figure 1 B and Figure 2 A. Figure 2 B, Table 1). Under hypoxic conditions, the right ventricular internal diameters (RVID-D, RVID-S) of HPAH rats were increased compared with those in the normoxic group. After intervention with phellandrene and sildenafil, the right ventricular internal diameters (RVID-D, RVID-S) of rats were decreased compared with those in the hypoxic model group (P<0.05, Figure 1 C. Figure 1 D and Figure 2 C. Figure 2D, Table 1). In the hypoxia model group, the pulmonary artery acceleration time (PAT) value of HPAH rats was lower than that of the control group, and the pulmonary artery ejection time (PET) value was higher than that of the control group. In the phellandrene intervention group, the PAT value of HPAH rats was higher than that of the model group, and the PET value was lower (P<0.05, Figure 1 E. Figure 1 F and Figure 2 E, Table 2). PAT / PET in the hypoxia model group was higher than that in the control group. After intervention with phellandrene, PAT / PET was higher than that in the model group. The high-dose group (50 mg / kg) had the best effect (P<0.05, Figure 1 G, Table 2). The TAPSE of HPAH rats in the hypoxia model group was decreased, while the TAPSE of phellandrene (25.0 mg / kg, 50.0 mg / kg) and sildenafil intervention was increased compared with the hypoxia model group (P<0.05, Figure 1 H and Figure 2 F, Table 1); Table 1 Effects of phellandrene on right ventricular function in rats exposed to hypoxia for 28 days (x±s) Control Hypoxia Hyp+12.5mg / kg Hyp+25.0mg / kg Hyp+50.0mg / kg Sildenafil n 5 5 5 5 5 5 RVFW-D (mm) 0.67±0.06 <![CDATA[1.26±0.20 # ]]> 1.02±0.14* 0.92±0.03* 0.92±0.05* 0.95±0.06* RVFW-S (mm) 1.06±0.11 <![CDATA[1.94±0.16 # ]]> 1.67±0.05* 1.56±0.05* 1.44±0.15* 1.55±0.16* RVID-D (mm) 1.62±0.13 <![CDATA[2.40±0.22 # ]]> 1.91±0.2* 2.00±0.04* 1.66±0.32* 1.76±0.33* RVID-S (mm) 1.05±0.14 <![CDATA[1.55±0.31 # ]]> 1.20±0.14* 0.99±0.11* 1.11±0.19* 0.91±0.11* PAT (ms) 32.7±2.48 <![CDATA[24.05±1.26 # ]]> 27.38±0.65* 31.24±2.20* 34.09±1.98* 26.84±2.42* PET (ms) 81.11±2.98 <![CDATA[88.41±5.10 # ]]> 82.26±1.60* 76.88±2.77* 78.3±4.57* 87.57±2.44* PAT / PET 0.4±0.04 <![CDATA[0.27±0.02 # ]]> 0.33±0.01* 0.41±0.03* 0.44±0.01* 0.31±0.02* TAPSE (mm) 4.15±0.17 <![CDATA[3.08±0.59 # ]]> 3.06±0.42 4.26±0.11* 3.82±0.31* 4.01±0.31* RVOT VTI (mm) 46.30±2.59 <![CDATA[35.08±1.28 # ]]> 43.84±1.55* 41.51±0.91* 43.78±2.44* 46.60±4.08*
[0024] 2. Effect of phellandrene on mean pulmonary artery pressure in HAPH rats from Figure 1 It can be seen that compared with the control group, the mPAP of the rats in the hypoxia model group was significantly increased; the mPAP of the sildenafil group was lower than that of the hypoxia model group; the mPAP level in 1 mL of the 12.5 mg / kg / d phellandrene intervention group was reduced, and the mPAP level in 1 mL of the 25 mg / kg / d and 50 mg / kg / d phellandrene intervention groups was increased (P<0.05, Figure 3 A).
[0025] 3. Effects of phellandrene on various organ parameters in HPAH rats Before hypoxia treatment, the SD rats in each group were in good spirits and had good vitality. After hypoxia treatment, as the hypoxia time increased, the vitality of the experimental rats gradually weakened. As shown in Table 2, after the end of the experiment, the lung and spleen weights of the rats in the hypoxia model group increased, while the body weight, liver and kidney weights decreased compared with the control group ( # P<0.05, Table 2); Compared with the hypoxia model group, after intervention with phellandrene, the lung-to-body ratio of rats decreased, the liver index increased, the spleen index of rats in the medium-dose and high-dose groups decreased, and the body weight and kidney index increased (*P<0.05, Table 2); After intervention with sildenafil, except for the increase in liver index compared with the model group, there was no difference in other organ indices. After intervention with phellandrene, the improvement of body weight and organ indices of HPAH rats had a certain biological effect on the reduction of their pulmonary artery pressure; Table 2 Effects of phellandrene on body weight and organ-body ratios of rats exposed to hypoxia for 28 days (x±s) Blank control group Model Group Sildenafil Low dose group Medium dose group High dose group Number of animal cases 10 10 9 9 10 10 Weight (g) 270.4±16.13 <![CDATA[222±17.99 ＃ ]]> 217.56±10.08 224.22±20.47 225.70±31.44* 234.3±21.95* Lung to body ratio (mg / g) 1.65±0.14 <![CDATA[2.01±0.20 ＃ ]]> 2.05±0.26 1.80±0.2* 1.84±0.29* 1.80±0.33* Liver to body ratio (mg / g) 9.97±1.42 <![CDATA[7.09±0.72 ＃ ]]> 8.08±0.82^ 8.38±1.01* 8.66±1.31* 8.88±1.33* Spleen to body ratio (mg / g) 0.45±0.05 <![CDATA[0.53±0.15 ＃ ]]> 0.51±0.10 0.55±0.18 0.49±0.13* 0.43±0.22* Kidney to body ratio (mg / g) 2.03±0.13 <![CDATA[1.64±0.14 ＃ ]]> 1.60±0.14 1.65±0.14 1.67±0.28* 1.69±0.15* Note: Rats in the blank control group were kept in a normoxic environment for 28 days; rats in the hypoxia model group were exposed to hypoxic conditions (equivalent to an altitude of 4500 meters) for 4 weeks; sildenafil group: rats in the positive control group were given sildenafil (30 mg / kg / d); rats in the hypoxia + phellandrene intervention group (50 mg / kg / d, 25 mg / kg / d and 12.5 mg / kg / d) 1 mL were intervened for 4 weeks during modeling in a hypobaric oxygen chamber; the results are expressed as mean ± SD, # indicates the hypoxia model group compared with the control group, * indicates the phellandrene intervention group compared with the hypoxia model group, and ^ indicates the sildenafil group compared with the hypoxia model group.
[0026] 4. Effect of phellandrene on right ventricular hypertrophy index in HPAH rats After pulmonary hypertension occurs, the heart's pumping function declines and the right ventricular structure undergoes remodeling, causing compensatory hypertrophy of the right ventricle. The right ventricular weight index (RV / BW) and the right ventricular hypertrophy index (RV / LV+S) reflect the compensatory hypertrophy of the right ventricle under pulmonary hypertension. After the rats were treated in a hypobaric oxygen chamber for 28 days, the right ventricular hypertrophy index of HPAH rats was measured. The results showed that the RV / BW and RV / LV+S ratios in the hypoxia model group were higher than those in the control group (P<0.05, Figure 3 B. Figure 3 C and Table 3). The RV / BW and RV / LV+S ratios in the phellandrene and sildenafil intervention group were lower than those in the model group (P<0.05, Figure 3 B. Figure 3 C and Table 3). This suggests that the use of a hypobaric oxygen chamber to simulate the low-pressure and low-oxygen environment at an altitude of 4500 meters significantly increased pulmonary artery pressure and formed pathological hypertrophy of the right ventricle; Table 3 Effects of phellandrene on physiological parameters of SD rats exposed to hypoxia for 28 days (x±s) Parameters Control Hypoxia Hyp+12.5mg / kg Hyp+25.0mg / kg Hyp+50.0mg / kg Sildenafil RV / (LV+S) 0.52±0.07 <![CDATA[4.70±0.55 # ]]> <![CDATA[0.43±0.06 * ]]> <![CDATA[0.42±0.08 * ]]> <![CDATA[0.37±0.05 * ]]> <![CDATA[0.40±0.05 * ]]> RV / BW 0.72±0.09 <![CDATA[4.44±0.81 # ]]> <![CDATA[0.84±0.10 * ]]> <![CDATA[0.99±0.12 * ]]> <![CDATA[1.10±0.20 * ]]> <![CDATA[0.84±0.06 * ]]>
[0027] Although the present invention has been described in detail in the embodiments through general explanations, specific implementation methods and experiments, modifications or improvements can still be made without departing from the core of the present invention, and all belong to the scope of protection required by the present invention.
Claims
1. Use of phellandrene in preparing a right ventricle-targeted drug for preventing and treating hypoxic pulmonary hypertension, wherein the phellandrene is α-phellandrene.
2. The use according to claim 1, characterized in that: The phellandrene is used for improving organ indexes.
3. The use according to claim 1, characterized in that: The phellandrene is used for alleviating right ventricular function damage caused by hypoxic pulmonary hypertension.
4. The use according to claim 1, characterized in that: The phellandrene is used to reduce mean pulmonary artery pressure.
5. The use according to claim 1, characterized in that: The phellandrene is used to reduce right ventricular hypertrophy and right heart weight index.
6. The use according to claim 1, characterized in that: The dosage of phellandrene is 50 mg / kg.
7. The use according to any one of claims 1 to 5, characterized in that: The medicine is a preparation prepared by taking phellandrene as the only active ingredient and adding pharmaceutically acceptable auxiliary materials.
8. The use according to claim 6, characterized in that: The preparation is an oral preparation.