CN111557959A

CN111557959A - Medicinal preparation for improving immunity

Info

Publication number: CN111557959A
Application number: CN202010520062.0A
Authority: CN
Inventors: 张建波; 徐克沂
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-06-09
Filing date: 2020-06-09
Publication date: 2020-08-21

Abstract

The invention provides a pharmaceutical preparation for improving immunity, which comprises the following raw materials: the total ginsenoside is ginsenoside Rg1 extracted from Notoginseng radix monomer. The medicinal preparation provided by the invention has a treatment effect on people with poor immune reconstitution and can increase the number of CD4+ T lymphocytes. Therefore, the preparation can improve and regulate the human immunity, reduce the occurrence of diseases, reduce the hyperlipemia and reduce the cardiovascular diseases, can be used as an auxiliary medicament for AIDS, and can also be used for health care and disease prevention of common people and treatment and immunoregulation of hyperlipemia people.

Description

Medicinal preparation for improving immunity

Technical Field

The invention relates to the technical field of medicines, in particular to a pharmaceutical preparation for improving immunity.

Background

Acquired immunodeficiency syndrome (AIDS) is a serious infectious disease caused by the Human Immunodeficiency Virus (HIV). HIV is a retrovirus, and the reverse transcription process is a process of synthesizing proviral DNA by using viral RNA as a template under the action of viral reverse transcriptase. Antiretroviral drugs are a class of drugs used to treat retroviral (primarily HIV) infections. Although long-term antiretroviral therapy (ART) is effective in inhibiting HIV-1 replication, increasing the number of CD4+ T lymphocytes in peripheral blood, and reconstituting immune function in patients, the number of CD4+ T lymphocytes in about 20% of HIV/AIDS patients cannot be restored to normal levels, and we refer to such patients as immune reconstitution (INR). Such patients are more likely to develop AIDS or cause non-AIDS related diseases such as cardiovascular diseases, liver and kidney diseases, etc., than patients with good immune reconstitution, resulting in increased mortality. How to judge the immune reconstruction failure, determine the occurrence mechanism of the immune reconstruction failure and formulate an effective clinical treatment scheme is an important ring on the current approach to overcoming AIDS. Poor immune reconstitution is caused by a number of factors. Clinically, poor immune reconstitution is mostly caused by aging, increased apoptosis and senescence of T lymphocytes, increased level of immune activation and disturbance of inflammatory factor level. In particular to the toxic and side effects of the AIDS antiviral drugs such as dyslipidemia and fat metabolism abnormality, which often cause other complications of AIDS and lead to death.

Disclosure of Invention

The invention aims to solve the defects of the prior art and provide a pharmaceutical preparation capable of increasing the number of CD4+ T lymphocytes of a person with poor immune reconstitution.

A pharmaceutical preparation for improving immunity comprises the following raw materials: total ginsenoside and monomer extract Rg1 of Notoginseng radix.

Further, in the pharmaceutical preparation for improving immunity, the mass ratio of the total ginsenoside to the panax notoginseng monomer extract Rg1 is 3: 1.

Furthermore, the pharmaceutical preparation for improving immunity further comprises pharmaceutically acceptable auxiliary materials, and is prepared into pharmaceutically acceptable dosage forms.

Panax notoginseng belongs to Araliaceae Panax, is a root herbaceous plant, is mainly produced in Yunnan province of China, has pharmacological activity in the aspects of immune system, cardiovascular system, nervous system, tumor resistance, aging resistance and the like through modern pharmacological research, contains Rb1, Rg1, Re, Rd and R1 as the main components of total saponins of Panax notoginseng clinically used at present, and is widely applied to cardiovascular system diseases, tumors and organ interstitial diseases.

Rg1 extracted from Notoginseng radix monomer has strong immunoregulation and antiinflammatory activity, and has strong effect in balancing ion metabolism disorder.

Has the advantages that:

the medicinal preparation provided by the invention has a treatment effect on people with poor immune reconstitution and can increase the number of CD4+ T lymphocytes. Therefore, the preparation can improve and regulate human immunity, reduce the occurrence of diseases, reduce hyperlipidemia and reduce cardiovascular diseases, can be used as an auxiliary medicine for AIDS, and can also be used for health care and disease prevention of common people and treatment and immunoregulation of hyperlipidemia people.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention forms a new compound preparation by 150mg of total ginsenoside and 50mg of Rg1, and is used for treating cardiovascular diseases caused by immunosuppression, immune transition activation and abnormal fat metabolism.

According to the pharmaceutical preparation provided by the invention, the extraction of the Rg1 and the total ginsenoside is carried out by using a mature and commonly used alcohol reflux extraction method at present, volatile alcohols such as industrial methanol and industrial ethanol are used as organic solvents, the leachate is heated and distilled, the organic solvents are cooled by a condensing tube after being volatilized, and the organic solvents are returned to a container until the effective components are completely extracted. The optimal conditions are as follows: soaking Notoginseng radix or Ginseng radix coarse powder in 8 times of 50% ethanol for 40 min, and extracting under reflux for 2 times each for 2 hr.

Experimental example:

among patients who received antiretroviral therapy (ART) for a long time in hospitals, 30 patients with poor immune reconstitution and abnormal lipid metabolism such as hyperlipidemia due to ART administration were selected, and preliminary experimental observation was carried out and approved by ethical committee.

30 persons are combined into a group, and the group is divided into 3 groups at random, wherein each group comprises 10 persons, and the group is respectively a treatment group (combination treatment group) taking total ginsenoside combined with Rg1, a treatment group (treatment group) taking total ginsenoside and an observation group. Combination treatment group and treatment double-blind group.

Grouping standard: under the premise of ensuring good compliance, people who are infected with HIV for 18-60 years are treated with antiretroviral therapy (ART) for more than 3 years, and HIV-RNA cannot be detected, CD4+ T lymphocytes cannot rise or rise less than 100/ul, and CD4+ T lymphocytes are lower than 350/ul. Voluntarily attend the study, sign an informed consent, and follow-up.

Exclusion criteria: those with severe opportunistic infections not controlled before group entry (pneumocystis pneumonia, meningitis, esophageal candida infection, lymphoma, toxoplasma encephalopathy, tuberculosis, etc.); patients within 1 month prior to enrollment or who are participating in other drug clinical trials;

those who received immunomodulatory therapy within 1 month prior to group entry;

WBC < 2 × 109/L, N < 1.0 × 109/L, Hb < 90g/L, PLT < 75 × 109/L, and hepatic and renal insufficiency (AST, ALT, T-BIL are greater than or equal to 2 times of the upper limit of the reference value or creatinine detection value is greater than or equal to 2 times of the upper limit of the reference value);

patients with pancreatitis, active gastric ulcer;

clinically significant active respiratory, digestive, circulatory, blood, neuroendocrine, and genitourinary diseases;

patients suffering from autoimmune diseases;

tumor patients in need of chemotherapy;

pregnant or lactating women and women of child-bearing age who do not employ safe contraceptive measures, and male patients who cannot employ a reasonable contraceptive method during the test period;

those with allergic constitution;

there are intellectual or language barriers that do not allow a full understanding of the test content or a good cooperation of the patients.

Exit criteria: each subject may be withdrawn from the study at any stage of the study for any reason (specific or non-specific) without discrimination. The treatment of the patient will not be limited and the investigator will treat the patient using conventional treatment.

At the discretion of the investigator or sponsor, subjects should be withdrawn from the trial if:

violation of the scheme: violation of the main content of the protocol, especially when it concerns the safety of the subject; the compliance is poor: study medication or follow-up visits cannot be taken according to the protocol;

serious adverse events, complications and special physiological changes occur, and the test is not suitable to be continued;

pregnancy;

automatically withdrawing;

drugs influencing the effectiveness and safety evaluation of the test are used in combination in the test process; loss of visit: the contact can not be realized according to the conventional contact way;

breaking the blind or uncovering the blind in an emergency.

The drug scheme is as follows: the total ginsenoside capsule and Rg1 capsule treatment group (combination treatment group): the dosage is 2 times daily, 1 capsule (containing total ginsenoside 150mg, Rg150mg) is orally administered for 12 weeks.

The total ginsenoside capsule treatment group (treatment group) comprises: the dosage is 2 times daily, 1 capsule (containing total ginsenoside 150mg) is orally administered each time, and the total administration time is 12 weeks.

Observation group: follow-up examination was performed according to the combination treatment group and treatment without taking the drug.

Evaluating the safety and the curative effect of the medicine:

(1) the patient reports spontaneously or the physician directly or by non-induced means asks the patient for the number of adverse events; and recording quality of life indices including appetite, sleep and physical strength, and sexual life.

(2) And (3) laboratory detection: HIV-RNA, CD4+ T lymphocytes, CD8+ T lymphocytes, will be administered before and after treatment as planned; blood routine (RBC, Hb, WBC, absolute neutrophil count, absolute lymphocyte count, PLT), urine routine (RBC, WBC, urine glucose), blood biochemical (ALT, AST, TBIL, CHO, TG, LDH, amylase, fasting glucose, BUN, Cr) index measurements, and chest X-ray, electrocardiogram, abdominal B-ultrasound examinations were performed. After 12 weeks of administration, the primary therapeutic effect was as follows:

side effects: the combination of the total ginsenoside capsule and Rg1 capsule (combined treatment group) has symptoms of asthenia in 1 person. After the ginseng total saponin capsule treatment group (treatment group) takes the medicine, 1 person has symptoms of dryness-heat, nosebleed and angina inflammation, and 3 persons have occasional symptoms of dizziness and giddiness; observation group: no side reaction occurs;

and (3) related indexes are as follows: 1. the increase of CD4+ T lymphocytes of the ginsenoside capsule and Rg1 capsule treatment group (combination treatment group) is 8 people, and the maximum increase amplitude is 64.9%. Cholesterol (CHOL) CHOL was reduced by 8 persons. Triglyceride (TG) reduction 9 persons, low density lipoprotein (LDL-C) reduction 7 persons, and high density lipoprotein (HDL-C) increase 6 persons. The appetite improves 6 people, the sleep improves 5 people, the energy improves 8 people, the physical strength improves 7 people, and the sexual life satisfaction improves 5 people.

2. The increase of CD4+ T lymphocytes of the capsule treatment group (treatment group) of the total ginsenoside has 3 (4) persons, and the maximum increase amplitude is 49.3%. Cholesterol (CHOL) CHOL decreased 5 people. Triglyceride (TG) reduction 4 people, low density lipoprotein (LDL-C) reduction 3 people, and high density lipoprotein (HDL-C) increase 2 people. The appetite improves 6 people, the sleep improves 5 people, the energy improves 6 people, the physical strength improves 6 people, and the sexual life satisfaction improves 2 people.

3. There were 0 persons observed to have an increase in the group of CD4+ T lymphocytes. Cholesterol (CHOL) CHOL decreased 1 person. Triglyceride (TG) reduction 0 person, low density lipoprotein (LDL-C) reduction 0 person, and high density lipoprotein (HDL-C) increase 0 person. The appetite is improved by 1 person, the sleep is improved by 0 person, the energy is improved by 1 person, the physical strength is improved by 0 person, and the sexual life satisfaction is improved by 0 person.

The experiments can prove that: the compound preparation provided by the invention can improve and regulate human immunity, reduce the occurrence of diseases, reduce hyperlipidemia and reduce cardiovascular diseases, can be developed as an auxiliary medicine for AIDS, and can also be used for health care and disease prevention of common people and treatment and immunoregulation of hyperlipidemia people.

The new compound preparation is formed by 150mg of total ginsenoside and 50mg of ginsenoside Rg1 extracted from panax notoginseng, the Rg1 in the total ginsenoside is low, the bottleneck of anti-inflammation, immunoregulation and hypolipidemia is solved, the Rg1 has better anti-inflammation and hypolipidemia curative effects in numerous researches and observations, the total ginsenoside and Rg1 are used as a new formula method in clinic, a preliminary experiment is carried out in patients with poor immune reconstitution of AIDS and dyslipidemia to obtain the clinical initial curative effect, during the extraction of the Rg1, the ginsenoside Rg1 accounts for only 1.1 percent, and the notoginsenoside Rg1 accounts for 3.18-5.16 percent, the formula greatly improves the utilization rate of panax notoginseng, and expands and promotes the development of the panax notoginseng industry.

Multiple studies have observed that activation of the innate and adaptive immune systems persists in chronic HIV-infected patients receiving chronic cART therapy. The activation of the innate immune system is manifested in:

1. activation of innate immune cells, including an increased proportion of activated macrophages, dendritic-like cells.

2. Innate immune cells activate to further express and release a variety of cytokines and chemokines, including Tumor Necrosis Factor (TNF), interleukin-1 (IL-1), IL-6, IL-8, IL-10, IL-15, inducible protein-10 [ IP-10(CXCL-10) ], interferons, and other inflammatory factors, and these factors are observed to be continuously elevated in virally-fully-controlled chronic HIV infectors (HIVcontroller), and even in HIV Elite controllers (HIV Elite controllers).

3. Acute inflammatory response protein levels are elevated and include serum amyloid A, C-reactive protein and the like.

4. Increased levels of factors associated with the coagulation cascade, including D-dimers, tissue factor, etc.

5. Activation of inflammatory fibrosis reactions, including matrix metalloproteinase activation, collagen deposition, and the like.

6. The pathogenic recognition system is activated, and the level of inflammatory factors such as lipopolysaccharide binding protein, soluble CD14 and the like is increased.

Meanwhile, the research finds that the activation of the acquired immune system exists in chronic HIV infected people and is represented as follows: (1) increased levels of T cell activation; (2) acceleration of T cell switching and apoptosis; (3) decreased thymic T cell output, etc.

In addition, in the study of professor Litai, Beijing collaborated with Hospital infectious medicine, it was thought that: the mechanisms that lead to an incomplete immune reconstitution in chronic HIV-infected patients include:

1. persistent immune activation in chronically infected persons: persistent existence of virus repository, damage of lymphatic tissue, ectopic flora and other reasons result in persistent existence of immune activation, and the immune persistent activation can promote the persistence of virus repository, damage mucosal barrier, influence the distribution of CD4+ T cells in lymphatic tissue and blood, influence the proliferation and apoptosis of lymphocytes and the like; 2. impaired thymus function, decreased thymus output; 3. alterations in lymphoid tissue architecture, lymph nodes and GALT focal fibrosis; 4. HIV persists and is expressed continuously, directly destroying CD4+ T cells. Among the factors and mechanisms related to the incomplete immune reconstitution, decreased thymus output, damaged lymphoid tissues and the like are related to overlong infection time of patients before treatment and larger age of patients, and no effective intervention measures are available at present. While the abnormal immune activation and immune reconstruction have poor interaction and vicious cycle, and a plurality of known intervention means exist for inhibiting the immune activation, so that the research on the immune activation and the inhibition on the immune activation become the central importance for researching the insufficient immune reconstruction. According to the mechanism that the immune activation exists continuously and the lymphatic tissue structure changes fibrosis, the panax notoginseng saponins Rd and RG1 which are main anti-inflammatory components are researched by Panax Notoginseng Saponins (PNS) and five monomer saponins, so that the panax notoginseng saponins RG1 have the inhibition effect on four inflammatory factors of iNOS, TNF-alpha, IL-6 and IL-1 beta, and RG1 has the anti-inflammatory effect by inhibiting NF-kappa B and MAPK pathways.

Rg1 has inhibitory effects on mouse ear swelling caused by xylene, mouse abdominal cavity capillary permeability increase caused by acetic acid, rat foot swelling caused by carrageenan, etc., and shows certain anti-inflammatory activity, but the action mechanism is not further discussed. Many studies have shown that Rg1 inhibits the expression of inducible nos (inos), and thus inhibition of inflammatory response may be a mechanism by which cerebral ischemic tissue is protected; rg1 can remarkably inhibit rat foot swelling caused by carrageenan, reduce MDA content in rat foot caused inflammation, and increase SOD activity. Meanwhile, Rg1 inhibits the generation of NO in RAW264.7 cells induced by LPS, and the antioxidant effect and the inhibition effect on the generation of NO are probably mechanisms for playing an anti-inflammatory effect.

There are studies: 3 doses of Rgl which are high, medium and low have obvious inhibition effect on the mouse ear swelling degree caused by dimethylbenzene; it is also found that high-dose Rgl shows a certain inhibition effect on subacute inflammatory granulation tissue proliferation; rgl can obviously inhibit excessive apoptosis of chondrocytes and generation and development of knee osteoarthritis, and the mechanism of Rgl mainly eliminates free radicals generated in the cell metabolic process, reduces the effect of cell lipid peroxide generation, and creates a favorable environment for preventing cell aging and repairing cells. Finally, it can be concluded that: the ginsenoside has antiinflammatory and antioxidant effects by scavenging free radicals and inhibiting peroxidation injury. The thermal cracking product of Rg1 can increase the levels of Tumor Necrosis Factor (TNF) -alpha, Interferon (IFN) -gamma and Interleukin (IL) -2 in the serum of H22 tumor-bearing mice, and promote the apoptosis and necrosis of tumor cells; rg1 can significantly reduce ROS induced by LPS, Rg1 can reduce the levels of alanine aminotransferase and aspartate aminotransferase, enhance the antioxidant activity of SOD and reduce the content of MDA, and further prove the anti-inflammatory effect of ginsenoside Rg 1. 2. Effects on inflammatory factors and inflammatory signaling pathways: NF-kB activation, which subsequently promotes the transcription of a plurality of inflammation-related genes (including IL-1 beta, IL-6 and TNF-alpha) into inflammation-related mRNA, and provides a basis for the translation of the inflammation factors; ② activation of the enzyme hemilactasin by various stimuli (i.e., pathogen-associated molecular patterns and damage-associated molecular patterns), which in turn activates the cysteine protease caspase-1 and promotes the maturation of pro-inflammatory cytokines. The long-term inflammatory state is detrimental to health, and long-term macrophages in the tissue activate abnormal expression of inflammatory factors such as TNF- α, IL-6, IL-1 β, NO and prostaglandin E2, stimulating inflammatory signaling pathways, ultimately leading to chronic low grade inflammation.

There are many related studies aiming at the enhancement of immunity by the total saponins of panax ginseng, and the general summary is as follows: ginsenoside Rb1 can reduce the percentage of IL-17+ T cells, increase the content of Treg cells and Th2 cells, reduce the content of R97-116 antibodies (IgG1 and IgG2a), and obviously reduce the severe myasthenia symptom of rats; the derivative of ginsenoside Rh2 can promote the secretion of TNF-gamma and the proliferation of lymphocytes, and the function of macrophages can be obviously enhanced after the derivative is subjected to sulfation modification; ginsenoside Rg1 can reduce IL-8, TGF-beta, IL-4, and TNF-alpha levels in the serum of rats with type III prostatitis, thereby reducing immunoreaction of rats, promoting autophagy of Raw264.7 macrophage induced by serum deprivation, playing the role of anti-apoptosis protection, activating T cells, maintaining balance of Th1/Th2, and improving immune function of patients with systemic lupus erythematosus. The research results have important significance on improvement and innovation of various human immune disease treatment methods.

In addition, the study finds that after ginsenoside Rhl [20, 40 and 80 mg/(kg. d) ] acts on mice with low immune function, the spleen and thymus index, the M phi phagocytic function and the T lymphocyte proliferation effect of the mice in each dose group are obviously improved. The influence of each ginsenoside component on the proliferation function of spleen lymphocytes and the phagocytic function of neutral red by macrophages is respectively determined by adopting an MTT method and a neutral red test of Panweihua and the like. The results show that the ginsenoside components eluted by ethanol with different concentrations have different degrees of promotion effects on the mouse spleen lymphocyte proliferation function and the macrophage neutral red phagocytosis function in the test range, wherein the promotion effect of the ginsenoside components eluted by 70% ethanol is strongest, and the fact that the saponin components obtained by eluting the total ginsenoside with 70% ethanol have good immunopotentiator effect is suggested. The effect of the ginsenoside Rg3 on Dc relates to the expression regulation of a plurality of genes, and the genes control and influence the Dc function, differentiation and maturation, thereby providing clues for further searching for drug targets. Rg1 can improve lipid metabolism by modulating the β -oxidation pathway; rg1 inhibits the adipocyte differentiation and lipid accumulation of epididymis WAT by regulating the expression of related genes; generally, Rg1 can inhibit cell differentiation, promote lipid catabolism, inhibit lipid metabolism of 3T3-L1 cells, especially under 40 μ M Rg1, and can promote AMP K activity, enhance lipid catabolism, inhibit ACC activity, and reduce in vivo and in vitro lipid synthesis enzymes by Rg1 administration.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical preparation for improving immunity is characterized by comprising the following raw materials: total ginsenoside and monomer extract Rg1 of Notoginseng radix.

2. The pharmaceutical preparation for improving immunity according to claim 1, wherein the mass ratio of the total ginsenoside to the panax notoginseng monomer extract Rg1 is 3: 1.

3. The pharmaceutical preparation for improving immunity according to claim 1, further comprising pharmaceutically acceptable excipients, and is prepared into pharmaceutically acceptable dosage forms.