CN116139120A - Application of arginine in treating osteoporosis - Google Patents
Application of arginine in treating osteoporosis Download PDFInfo
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- CN116139120A CN116139120A CN202211716165.XA CN202211716165A CN116139120A CN 116139120 A CN116139120 A CN 116139120A CN 202211716165 A CN202211716165 A CN 202211716165A CN 116139120 A CN116139120 A CN 116139120A
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- arginine
- osteoporosis
- arginine hydrochloride
- bone
- treating osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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Abstract
The invention discloses an application of arginine in treating osteoporosis, comprising an application of L-arginine hydrochloride in treating osteoporosis of menopausal women, wherein the administration dosage of L-arginine hydrochloride is 15mg/Kg daily in treating osteoporosis diseases of menopausal women, and the L-arginine hydrochloride is used for preparing a medicament for treating osteoporosis; the preparation method is used for preparing health care products for preventing osteoporosis; the medicine or the health care product is a medicine or a health care product for stimulating secretion of parathyroid hormone and promoting bone synthesis. The L-arginine hydrochloride provided by the invention stimulates PTH secretion through the mediation of CaSR, so that the blood calcium level is increased, the blood phosphorus level is reduced, the synthesis and catabolism of bones are regulated, and the L-arginine hydrochloride can effectively reduce side effects and cost as amino acid necessary for human bodies, and arginine can effectively stimulate the secretion of parathyroid hormone and promote the synthesis of bones.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of arginine in treating osteoporosis.
Background
Osteoporosis (OP) is a metabolic bone disease characterized by reduced bone mass, degraded bone tissue microstructure, increased fragility of bone and increased risk of fracture, and has now become a common and frequent worldwide disease, and is clinically divided mainly into primary OP and secondary OP. Epidemiological investigation shows that OP has become the seventh disease affecting human health, and that it is expected that OP patients in China will reach 2.12 hundred million times in 2050, and mortality, disability rate and occurrence rate of various complications will all rise. The current primary treatment means of OP is drug treatment, and currently, traditional OP-treating drugs mainly comprise bone formation stimulation (such as sodium fluoride, anabolic steroids and growth hormone), anti-resorption agents (such as calcitonin and bisphosphonates) which can effectively prevent further bone loss of patients suffering from osteoporosis, but are unfavorable for preventing and treating osteoporosis for a large number of people due to the high cost, and have limited use in clinical treatment due to possible malignant effects of Hormone Replacement Therapy (HRT) on reproductive tissues.
Teriparatide (teriparatide) is an active fragment (1-34) of human endogenous parathyroid hormone (rhPTH (1-34)), and is the only bone formation promoting medicament for treating osteoporosis in a plurality of countries at present, and various researches show that teriparatide can more effectively and rapidly improve the bone density of OP patients compared with other therapeutic medicaments, has more remarkable treatment effect and is beneficial to improving the life quality of patients, so that the teriparatide gradually becomes a research hot spot for increasing the bone density and preventing osteoporosis fracture. The action mechanism is similar to the physiological function of parathyroid hormone, and can promote the rise of blood calcium level, the decline of blood phosphorus level and fine-tune the synthesis of bone. Exogenous intermittent injection of parathyroid hormone (iPTH, japanese Li Patai) can increase bone mass, increase bone formation, and reduce the occurrence of fracture in high risk individuals. However, teriparatide is used as a macromolecular peptide preparation, and can be used as an antigenic substance to stimulate the immune system, thereby causing congestion and edema of skin mucous membrane tissues, and simultaneously can be combined with plasma protein to cause a foreign protein reaction, thereby causing systemic anaphylactic reaction and limiting the treatment cycle. Therefore, a medicament with high safety, proper price and good treatment effect is clinically required to improve the current situation of osteoporosis treatment.
Amino acids are one of three nutritional substances of human body, and are divided into essential amino acids and non-essential amino acids, so that people need to maintain the nutrition and metabolism balance of the human body through supplementing the essential amino acids. In the current report, PTH secretion is mainly regulated by a calcium sensitive receptor (CaSR), and the experiment shows that arginine can stimulate PTH secretion through the CaSR, regulate calcium phosphate metabolism and promote bone generation, and the mechanism meets the research content requirements of the patent of the invention.
Disclosure of Invention
The invention provides application of arginine in treating osteoporosis diseases, so as to solve the problems that the osteoporosis of middle-aged and elderly people and menopausal women is mostly accompanied with basic diseases such as cardiovascular and cerebrovascular systems, diabetes mellitus, respiratory systems and the like, and the selected medicine cannot aggravate the basic diseases.
The invention provides the use of arginine in the treatment of osteoporosis.
Preferably, the arginine is L-arginine hydrochloride.
Preferably, it is used for treating osteoporosis in menopausal women.
Preferably, in the treatment of osteoporosis in menopausal women, L-arginine hydrochloride is administered at a dose of 15mg/Kg per day.
Preferably, the use in any one of the following:
a1, preparing a medicament for treating osteoporosis;
a2, preparing the health care product for preventing osteoporosis.
Preferably, the medicine or the health product is a medicine or a health product for stimulating secretion of parathyroid hormone and promoting bone synthesis.
The invention provides a medicament for treating osteoporosis, wherein the active ingredients of the medicament comprise L-arginine hydrochloride.
Preferably, the L-arginine hydrochloride stimulates PTH secretion through the mediation of CaSR, so that the blood calcium level is increased, the blood phosphorus level is reduced, and the synthesis and catabolism of bones are regulated.
CaSR is involved in the processes of parathyroid hormone secretion, synthesis, and cell proliferation as a whole. As a G protein-coupled receptor, caSR mainly monitors extracellular calcium (Ca 2+ ) To regulate PTH secretion, serum calcium maintenance through classical endocrine feedback loopsIs kept in a narrow physiological range to ensure the steady state of blood calcium. L-arginine hydrochloride is an amino acid medicine, and is mainly mediated by CaSR in human body to stimulate PTH secretion, wherein PTH can promote the rise of blood calcium level and the decline of blood phosphorus level, can finely regulate the synthesis and catabolism of bone, and plays an important role in the differentiation, maturation and apoptosis of osteoblasts and osteoclasts. PTH exerts biological effects by acting on PTHR1 on target cell membranes, mainly through the activation of three signal pathways (1) cAMP/PKA pathway, (2) PLC/PKC pathway and (3) non PLC/PKC pathway, wherein the activation of the non PLC/PKC signal transduction pathway of PTH can obviously raise the expression level of osteoblast cotranscription factor CITED1, and mediate the effect of PTH on osteogenic metabolism. Meanwhile, PTH has a dual effect on bone formation and bone resorption, and continuous large doses of PTH promote bone resorption, intermittent small doses of PTH promote bone formation.
Compared with the prior art, the invention has the beneficial effects that:
arginine plays an important role in ornithine circulation, is an essential basic amino acid for maintaining infant growth and development, and is widely used as a tool medicine in various diseases such as hepatic encephalopathy. The risk of osteoporosis in postmenopausal women increases due to the decrease in bone biomechanical properties caused by low levels of estrogen. The animal model of postmenopausal osteoporosis is interfered by L-arginine hydrochloride to find that the animal model has the function of resisting osteoporosis. The discovery has great influence on the research and treatment of postmenopausal osteoporosis diseases, has clinical practical value, and opens up a new clinical approach for L-arginine hydrochloride.
1. The invention provides a medicament with high safety and good treatment effect to improve the current situation of osteoporosis treatment.
2. The L-arginine hydrochloride can stimulate the release of PTH, form a certain PTH rhythm and has a certain curative effect on osteoporosis.
3. The L-arginine hydrochloride can obviously reduce the loss of bone mass of menopausal women and has certain clinical significance.
Drawings
FIG. 1 is a graph showing the detection of PTH in serum before and after tail vein injection of L-arginine hydrochloride in rats;
FIG. 2 is a graph of bone microstructure of proximal femur of rats tested in each experimental group of the present invention for Micro-CT detection;
FIG. 3 is a statistical chart of the bone volume fraction BV/TV (%) of rats in each experimental group according to the present invention;
FIG. 4 is a statistical plot of trabecular bone thickness Tb.Th (mm) for rats of each experimental group of the present invention;
FIG. 5 is a statistical chart of the number of trabeculae Tb.N (1/mm) of rats in each experimental group according to the invention;
FIG. 6 is a statistical plot of the trabecular separation of rat bone for each experimental group of the present invention, tb.Sp (mm);
FIG. 7 is a graph of structure model index SMI for each experimental group in accordance with the present invention;
FIG. 8 shows bone density BMD (g/cm) of each experimental group according to the present invention 3 ) Is a statistical graph of detection values;
FIG. 9 is a graph of HE staining and Pinus massoniana staining of pathological sections of bone tissue of rats in each experimental group according to the present invention;
FIG. 10 is a graph showing the change in blood calcium index of an osteoporosis model mouse according to the present invention;
FIG. 11 is a graph showing the change of blood phosphorus index of an osteoporosis model mouse according to the present invention;
FIG. 12 is a graph showing changes in urinary calcium index in an osteoporosis model mouse of the present invention;
FIG. 13 is a graph showing changes in urine phosphorus index in an osteoporosis model mouse of the present invention;
FIG. 14 is a graph showing the change in index of bone alkaline phosphatase in an osteoporosis model mouse according to the present invention;
FIG. 15 is a graph showing changes in parathyroid hormone index in model mice with osteoporosis in accordance with the present invention;
FIG. 16 is a graph showing changes in blood alkaline phosphatase index in an osteoporosis model mouse of the present invention;
FIG. 17 shows active vitamin D in an osteoporosis model mouse of the invention 3 An index change map;
FIG. 18 is a chart of the parathyroid pathology HE staining of the osteoporosis groups of the invention;
FIG. 19 is a graph showing the variation of injection of 450mg/Kg arginine PTH over time at 16 weeks according to the present invention;
FIG. 20 is a graph showing the variation of arginine PTH injected at 16 weeks of the present invention with time of 1800 mg/Kg.
Detailed Description
The invention is further illustrated below in connection with specific examples, but is not limited in any way.
Patients with osteoporosis mainly take middle-aged and elderly people, so that most patients often have basic diseases such as cardiovascular and cerebrovascular systems, diabetes mellitus and respiratory systems, and the basic diseases can not be aggravated by selected medicines. Therefore, the technical scheme of the invention is that the arginine is used for treating osteoporosis diseases in order to solve the problems in the prior art.
PTH secretion is mainly regulated by calcium sensitive receptors (CaSR), and it has been found in experiments that arginine may stimulate PTH secretion through CaSR, regulate calcium phosphate metabolism, and promote bone formation.
Examples
According to the influence of L-arginine hydrochloride on the secretion of rat parathyroid hormone and the animal experimental result of treating osteoporosis of menopausal women, the invention can adopt L-arginine hydrochloride for slow intravenous infusion when treating osteoporosis diseases.
The results of the study supporting this experiment are as follows:
the experimental grouping is as follows: 50 SPF-class female SD rats (8-10 weeks old, 200-270 g) were randomly divided into SHAM-operated SHAM group, ovariectomized OVX group, treatment group (small dose group L-Arg450mg/Kg+OVX, large dose group L-Arg1800 mg/Kg+OVX).
SHAM group is: the white adipose tissue near the ovaries was excised, and the wound was sutured and sterilized after the operation.
OVX group is: rats were fasted for 12h, anesthetized with intraperitoneal injection of tribromoethanol (350 mg/kgi.p.), and after sterilization, separated from both sides of the dorsal spine of the rats and bilateral ovaries were excised.
The treatment group is: the week of surgery was week 0, 3d antibiotics were continuously intramuscular injected, and small and large dose groups were intraperitoneally injected with L-arginine hydrochloride daily for 16 weeks starting at week 1 after OVX.
The result shows that: compared with the sham operation group, the thickness and the bone quantity of the cortical bone of the OVX group are obviously reduced, and the trabecular microstructure of the bone is obviously damaged. Small doses of arginine (450 mg/Kg) significantly improved bone microstructural damage and improved cortical thickness and bone mass. Compared to OVX groups, the arginine treated rats had significantly increased tb.n, BV/TV, tb.th and BMD. As shown in figures 1-8, the bone tissue is sliced and dyed again to show the change of the bone microstructure, the bone tissue structure of the prosthetic operation group is complete, the bones are small Liang Cu and uniform, the arrangement is orderly, and the bone tissue is staggered to form a net shape. The bone trabeculae of the OVX group are obviously reduced, the arrangement is sparse and the fracture appears partially, and compared with the OVX group, the large-dose group and the small-dose group are improved, the bone trabeculae are relatively complete, but the fracture gap is slightly larger. The bone tissue mainly contains type I collagen, so that normal bone blue is mostly, the sham operation group is basically normal, red myofibers of the OVX group are obviously increased, the myofibers of the small-dose group and the large-dose group are obviously reduced compared with the OVX group, and the small-dose group is more obviously prone to the sham operation group, as shown in figure 9.
The results show that the L-arginine hydrochloride can improve the bone microstructure parameters and the bone microstructure changes of the bone trabecula of the ovariectomized rat.
As shown in fig. 10-17, the experimental group conditions and interventions were the same as above, and after 16 weeks of OVX model establishment and treatment, serum was taken from each group to detect the change of biochemical index related to bone transformation. The detection shows that the bone resorption markers BALP (P < 0.001) and plasma ALP activity (P < 0.01) of the OVX group are significantly increased compared with the Sham group. However, large doses of arginine (1800 mg/Kg/d) had a more pronounced lowering effect on BALP (P < 0.01) compared to the OVX group; small doses of arginine (450 mg/Kg/d) significantly reduced the activity of ALP (P < 0.05). For each group of blood calcium, blood phosphorus, urine calcium and urine phosphorus were measured, and compared with the sham operation group, the blood calcium and blood phosphorus of the OVX group were reduced, which showed a certain degree of hypocalcemia and hypophosis, and after arginine treatment at different doses, there was a rebound (blood calcium, sham operation group vsOVX (< 0.001) and L-Arg450mg/KgvsOVX group #P < 0.05), and there was no statistical difference between blood phosphorus groups. Urine calcium urine phosphorus showed increased discharge in the OVX group compared to the sham group and decreased after treatment with different doses of arginine, but the differences in the measured values were statistically significant and not dose dependent.
Effect of L-arginine hydrochloride on parathyroid glands and body
As shown in FIGS. 18-20, the pathological HE staining was performed by isolating the parathyroid glands from each group, and no significant differences were observed in the parathyroid gland size, cell morphology, and tissue proliferation from each group. At 16 weeks post OVX surgery, OVX group PTH was elevated compared to sham surgery group due to estrogen reduction and BALP elevation, but there was no statistical difference. After 16 weeks of continuous intraperitoneal injection of arginine, the acute elevation of arginine stimulated PTH was still present, manifested by a significant elevation at 5min of injection, with a substantial decrease to normal levels within 30min, and the size dose group did not have an elevation of PTH basal value due to continuous 16 weeks of injection. The L-arginine hydrochloride has no obvious side effect on parathyroid glands and even organisms in the long-term treatment of osteoporosis.
In the treatment of osteoporosis of women in menopause, the administration dosage of the L-arginine hydrochloride is 15mg/Kg per day, and the L-arginine hydrochloride can be infused intravenously.
Many possible variations and modifications of the disclosed technology can be made by anyone skilled in the art without departing from the scope of the technology, or the technology can be modified to be equivalent. Therefore, any simple modification, equivalent variation and modification of the above embodiments according to the technical substance of the present invention shall still fall within the scope of the technical solution of the present invention.
Claims (8)
1. Use of arginine in the treatment of osteoporosis.
2. The use according to claim 1, wherein the arginine is L-arginine hydrochloride.
3. The use according to claim 1 for the treatment of osteoporosis in menopausal women.
4. Use according to claim 3, characterized in that in the treatment of osteoporosis in women in menopause, L-arginine hydrochloride is administered in a dose of 15mg/Kg per day.
5. The use according to any of claims 1-4, characterized by the use in any of the following:
a1, preparing a medicament for treating osteoporosis;
a2, preparing the health care product for preventing osteoporosis.
6. The use according to claim 5, wherein the medicament or the health product is a medicament or a health product for stimulating secretion of parathyroid hormone and promoting bone synthesis.
7. A medicament for treating osteoporosis, wherein the active ingredient of the medicament comprises L-arginine hydrochloride.
8. The medicament for treating osteoporosis according to claim 7, wherein said L-arginine hydrochloride stimulates PTH secretion, increases blood calcium level, decreases blood phosphorus level, and regulates bone synthesis and catabolism through CaSR mediation.
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| CN101838254A (en) * | 2009-01-13 | 2010-09-22 | 李毅林 | L-arginine derivative epimedium herb flavone combination and preparation method thereof |
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| US20040254238A1 (en) * | 2003-04-07 | 2004-12-16 | Osteoscreen | Bone growth stimulation with NO/statin and other NO modulating combinations |
| KR20090029946A (en) * | 2007-09-19 | 2009-03-24 | 계명대학교 산학협력단 | A food composition with arginin for preventing and treating osteoporosis |
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