Medicinal and edible substance for reducing toxicity of realgar

Abstract

The invention relates to the technical field of traditional Chinese medicines, and provides a medicinal and edible substance for relieving toxicity of realgar. The medicinal and edible dual-purpose substance is composed of realgar and a medicinal and edible dual-purpose component, the medicinal and edible dual-purpose component is selected from at least one of radix angelicae or angelica sinensis, and the medicinal and edible dual-purpose substance reduces the toxicity of realgar. The radix angelicae or the radix angelicae sinensis is respectively compatible with the realgar, so that the arsenic concentration of plasma can be reduced, and the arsenic metabolism can be accelerated, thereby reducing the accumulation of arsenic and metabolites thereof in various organs, effectively relieving the arsenic toxicity and reducing the acute and chronic arsenic poisoning risk. While the toxicity is reduced, the anti-leukemia activity of realgar (standardized arsenic agent) is reserved, the treatment effect is guaranteed, and the synergistic effect of reducing the toxicity without reducing the effect is realized; the medicine is assisted by food, the toxicity is reduced, the effect is enhanced, and a natural and low-cost solution is provided for safety optimization of the arsenic-containing traditional Chinese medicine preparation.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, and in particular relates to a medicinal and edible substance that can reduce the toxicity of realgar. Background Technology

[0002] Realgar's main component is arsenic disulfide, which has been used in traditional Chinese medicine for over two thousand years. It is pungent and warm in nature, and enters the liver and large intestine meridians. Its traditional functions include detoxification, insecticidal activity, dampness-drying and phlegm-resolving, and malaria treatment. Modern research shows that standardized arsenic preparations extracted and purified from realgar have clear clinical value in the treatment of leukemia: compound Huangdai tablets are a first-line treatment for acute promyelocytic leukemia (APL); and it has also shown some exploratory therapeutic potential in refractory cases such as the accelerated / terminal phase of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with myeloid antigen expression. However, natural realgar has a complex composition and unstable arsenic content, posing significant toxicity risks; the clinical application of standardized arsenic preparations is still limited by toxicity issues such as bone marrow suppression and liver and kidney damage caused by arsenic accumulation.

[0003] Currently, there are limited methods for dealing with realgar poisoning: acute poisoning requires emergency treatment and the use of chelating agents, but chelating agents have side effects and are poor at repairing organ damage caused by chronic arsenic poisoning; liposome encapsulation is a costly method for reducing toxicity; and solvent relay methods leave organic solvent residues, making them unsuitable for children, pregnant women, and other vulnerable groups. Therefore, there is an urgent need to develop a dual-purpose food and medicine substance to reduce the arsenic toxicity of realgar without affecting its efficacy in treating leukemia. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention provides a medicinal and edible substance that reduces the toxicity of realgar, and its purpose is to solve the problems mentioned in the background art.

[0005] This invention provides a medicinal and edible substance that reduces the toxicity of realgar. The medicinal and edible substance is composed of realgar and a medicinal and edible component, wherein the medicinal and edible component is selected from at least one of Angelica dahurica or Angelica sinensis. The medicinal and edible substance reduces the toxicity of realgar.

[0006] Furthermore, by mass ratio, realgar:angelica = 1:25-40.

[0007] Furthermore, by mass ratio, realgar:angelica = 1:50-65.

[0008] Furthermore, by mass ratio, Realgar:Angelica:Angelica = 1:25-40:50-65.

[0009] Furthermore, the application of a dual-use substance in the preparation of drugs for treating leukemia, wherein the dual-use substance is used to reduce the arsenic toxicity of realgar without reducing the anti-leukemia activity of realgar.

[0010] Furthermore, the medicinal and edible substance is used to reduce the arsenic toxicity of realgar, specifically by reducing plasma arsenic concentration and accelerating arsenic metabolism to reduce the accumulation of arsenic and its metabolites in organs and alleviate arsenic toxicity.

[0011] Furthermore, the arsenic and its metabolites include trivalent inorganic arsenic, pentavalent inorganic arsenic, monomethylarsenic, and dimethylarsenic.

[0012] Furthermore, the organs include the heart, liver, spleen, testes, kidneys, lungs, or brain.

[0013] Furthermore, the dosage form of the drug includes powder, granules, capsules, or tablets.

[0014] Realgar: It is pungent, warm and toxic, and enters the liver and large intestine meridians. It has the functions of detoxifying and killing parasites, drying dampness and eliminating phlegm, and treating malaria. It is mainly used to treat carbuncles, boils, snake and insect bites, abdominal pain due to intestinal parasites, epilepsy, malaria, scabies and eczema.

[0015] Angelica dahurica: It is pungent and warm, and enters the lung, stomach and large intestine meridians. It has the functions of relieving exterior syndromes and dispelling cold, dispelling wind and relieving pain, clearing nasal passages, drying dampness and stopping leukorrhea, reducing swelling and draining pus. It is mainly used to treat colds due to wind and cold, headaches and toothaches, nasal congestion and runny nose, nasal congestion and sinusitis, excessive leukorrhea, carbuncles and boils.

[0016] Angelica sinensis: sweet, pungent and warm, enters the liver, heart and spleen meridians. It has the functions of nourishing blood and promoting blood circulation, regulating menstruation and relieving pain, moistening the intestines and promoting bowel movement. It is mainly used to treat blood deficiency and chlorosis, dizziness and palpitations, irregular menstruation, amenorrhea and dysmenorrhea, abdominal pain due to deficiency and cold, rheumatic pain, and constipation due to intestinal dryness.

[0017] The present invention has the following technical effects: (1) Angelica dahurica or Angelica sinensis can be combined with realgar to reduce plasma arsenic concentration and accelerate arsenic metabolism, thereby reducing the accumulation of arsenic and its metabolites in various organs, effectively alleviating arsenic toxicity and reducing the risk of acute and chronic arsenic poisoning.

[0018] (2) While reducing toxicity, the anti-leukemia activity of realgar (standardized arsenic preparation) is retained to ensure the therapeutic effect and achieve a synergistic effect of reducing toxicity without reducing efficacy; food helps medicine, reducing toxicity and increasing efficacy, providing a natural and low-cost solution for the safety optimization of arsenic-containing Chinese medicine preparations. Attached Figure Description

[0019] Exemplary embodiments of the present invention can be more fully understood by referring to the following figures: Figure 1 This figure shows the accumulation of trivalent and pentavalent inorganic arsenic in various organs of rats in the realgar-only group and the realgar-Angelica-combined group of Example 1 of this invention. * indicates P < 0.5, ** indicates P < 0.01, *** indicates P < 0.001, and **** indicates P < 0.0001.

[0020] Figure 2 The figures show the accumulation of monomethylarsenic and dimethylarsenic in various organs of rats in the realgar-only group and the realgar-Angelica-combined group of Example 1 of this invention. * indicates P < 0.5, ** indicates P < 0.01, *** indicates P < 0.001, and **** indicates P < 0.0001.

[0021] Figure 3 These are the metabolic curves of arsenic in different valence states in the realgar-only group and the realgar-Angelica-combined group of Example 1 of the present invention.

[0022] Figure 4 This figure shows the accumulation of trivalent and pentavalent inorganic arsenic in various organs of rats in the realgar-only group and the realgar-in-Angelica combination group of Example 2 of this invention. * indicates P < 0.5, ** indicates P < 0.01, *** indicates P < 0.001, and **** indicates P < 0.0001.

[0023] Figure 5 The figures show the accumulation of monomethylarsenic and dimethylarsenic in various organs of rats in the realgar-only group and the realgar-in-Angelica combination group of Example 2 of this invention. *** indicates P < 0.001, **** indicates P < 0.0001.

[0024] Figure 6 These are the metabolic curves of arsenic in different valence states in the realgar-only group and the realgar-in-Angelica combination group of Example 2 of the present invention. Detailed Implementation

[0025] To make the technical problems to be solved, the technical solutions, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0027] This invention provides a medicinal and edible substance that reduces the toxicity of realgar. The medicinal and edible substance is composed of realgar and medicinal and edible components. The medicinal and edible components are selected from at least one of Angelica dahurica or Angelica sinensis. The medicinal and edible substance reduces the toxicity of realgar.

[0028] In some embodiments, the ratio of realgar to angelica is 1:25-40 by mass.

[0029] In some embodiments, the ratio of realgar to angelica is 1:50-65 by mass.

[0030] In some embodiments, the ratio of realgar to angelica to angelica sinensis is 1:25-40:50-65 by mass.

[0031] In some embodiments, the use of a dual-use substance in the preparation of a drug for treating leukemia involves reducing the arsenic toxicity of realgar without reducing its anti-leukemia activity.

[0032] In some embodiments, the dual-use substance is used to reduce the arsenic toxicity of realgar, specifically by reducing plasma arsenic concentration and accelerating arsenic metabolism to reduce the accumulation of arsenic and its metabolites in organs and alleviate arsenic toxicity.

[0033] In some embodiments, arsenic and its metabolites include trivalent inorganic arsenic, pentavalent inorganic arsenic, monomethylarsenic, and dimethylarsenic.

[0034] In some embodiments, the organ includes the heart, liver, spleen, testis, kidney, lung, or brain.

[0035] In some embodiments, the dosage form of the drug includes powder, granules, capsules, or tablets.

[0036] Example 1: (1) Experimental animals: male SD rats.

[0037] (2) Experimental groups: Realgar alone group and Realgar combined with Angelica dahurica group, with 6 rats in each group.

[0038] (3) Experimental drug administration: Rats were housed in individual cages. After 5 days of acclimatization, the group with realgar and angelica was given angelica decoction by gavage alone for 6 days (calculated as the equivalent dose for rats according to the human dose in the pharmacopoeia) once a day. On the 7th day, the group with realgar alone was given realgar by gavage, and the group with realgar and angelica was given a single dose of a mixture of angelica and realgar (by mass ratio, realgar: angelica = 1:30) by gavage.

[0039] (4) Experimental sampling: At 0.25, 0.5, 1, 2, 4, 8, 16, 32, and 48 hours after the last administration, approximately 0.2-0.5 ml of blood was collected from the animal's orbital cavity and placed into a heparinized 1.5 ml polyethylene tube. The tube was centrifuged at 12000 rpm for 10 minutes at 4°C and stored at -80°C. For HPLC-ICP-MS analysis, eight replicates (corresponding to eight rats) were measured at each time point. The plasma concentration at each time point was evaluated using the equation in the standard curve of each batch of samples, and the average concentration was used to establish the pharmacokinetic time curve. After blood collection from the rat's orbital cavity, the rat was anesthetized by intraperitoneal injection of sodium pentobarbital. The brain, heart, lungs, liver, spleen, kidneys, and testes were collected. The tissues were cleaned with pre-cooled 0.9% physiological saline to remove residual blood. After drying the filter paper, the tissues were weighed, and then 0.5 g of tissue was cut and placed in a cryovial and stored at -80°C. The content of different forms of arsenic metabolites in each organ was assessed using equations from the standard curves run for each batch of samples, and the content of arsenic in various valence states was calculated.

[0040] (5) Determination of different forms of arsenic by HPLC-ICP-MS: Extractable arsenic metabolites were determined by HPLC-ICP-MS. To determine multiple arsenic metabolites in selected tissue and plasma samples, 100 μL of homogenized tissue solution (0.5 g tissue: 1 ml physiological saline) or plasma sample was added to 300 μL of formaldehyde: acetonitrile solution (7:3), vortexed thoroughly, and centrifuged at 12000 rpm for 10 min at 4 °C to precipitate proteins. 200 μL of the supernatant was dried under nitrogen at 60 °C, and then reconstituted with 400 μL of mobile phase (sodium hexanesulfonate + citric acid aqueous solution, pH=4.3). After centrifugation at 12000 rpm for 5 min, 200 μL of the supernatant was filtered through an aqueous filter membrane (0.22 μm) and injected into the HPLC-LCP-MS system.

[0041] The accumulation of different forms of arsenic and its metabolites in different organs of rats in each group are as follows: Figure 1 and Figure 2 As shown, the results indicated that compared to the realgar alone group, the accumulation of trivalent inorganic arsenic (AsIII) in the heart, liver, spleen, and testes of rats was significantly reduced in the realgar combined with angelica group; and compared to the realgar alone group, the accumulation of pentavalent inorganic arsenic (AsV) in the heart, liver, spleen, testes, kidneys, lungs, and brain of rats was significantly reduced in the realgar combined with angelica group. Figure 1 Compared to the realgar alone group, the accumulation of monomethylarsenic (DMA) in the heart, liver, spleen, testes, kidneys, lungs, and brain of rats was significantly reduced in the realgar combined with angelica group; compared to the realgar alone group, the accumulation of dimethylarsenic (MMA) in the heart, liver, spleen, testes, kidneys, and lungs of rats was significantly reduced in the realgar combined with angelica group. Figure 2 ).

[0042] Metabolic curves of arsenic in different valence states in rats of each group are shown below. Figure 3 As shown, the results indicate that compared with the realgar alone group, the realgar combined with angelica can optimize the arsenic metabolism process and reduce toxicity. Specifically, it reduces the exposure of highly toxic arsenic valence state (AsⅢ), accelerates the metabolism of intermediate state (AsV, MMA), and promotes the formation of low-toxicity end products (DMA), thereby optimizing the arsenic metabolism process and reducing toxicity.

[0043] Example 2: (1) Experimental animals: male SD rats.

[0044] (2) Experimental groups: Realgar alone group and Realgar combined with Angelica sinensis group, with 6 rats in each group.

[0045] (3) Experimental drug administration: Rats were housed in individual cages. After 5 days of acclimatization, the group with realgar and angelica was given angelica decoction by gavage alone for 6 days (calculated according to the human dosage in the pharmacopoeia to the rat equivalent dose) once a day. On the 7th day, the group with realgar alone was given realgar by gavage, and the group with realgar and angelica was given a mixture of angelica and realgar (by mass ratio, realgar: angelica = 1:50) by gavage.

[0046] (4) Experimental sampling: At 0.25, 0.5, 1, 2, 4, 8, 16, 32, and 48 hours after the last administration, approximately 0.2-0.5 ml of blood was collected from the animal's orbital cavity and placed into a heparinized 1.5 ml polyethylene tube. The tube was centrifuged at 12000 rpm for 10 minutes at 4°C and stored at -80°C. For HPLC-ICP-MS analysis, eight replicates (corresponding to eight rats) were measured at each time point. The plasma concentration at each time point was evaluated using the equation in the standard curve of each batch of samples, and the average concentration was used to establish the pharmacokinetic time curve. After blood collection from the rat's orbital cavity, the rat was anesthetized by intraperitoneal injection of sodium pentobarbital. The brain, heart, lungs, liver, spleen, kidneys, and testes were collected. The tissues were cleaned with pre-cooled 0.9% physiological saline to remove residual blood. After drying the filter paper, the tissues were weighed, and then 0.5 g of tissue was cut and placed in a cryovial and stored at -80°C. The content of different forms of arsenic metabolites in each organ was assessed using equations from the standard curves run for each batch of samples, and the content of arsenic in various valence states was calculated.

[0047] (5) Determination of different forms of arsenic by HPLC-ICP-MS: Extractable arsenic metabolites were determined by HPLC-ICP-MS. To determine multiple arsenic metabolites in selected tissue and plasma samples, 100 μL of homogenized tissue solution (0.5 g tissue: 1 ml physiological saline) or plasma sample was added to 300 μL of formaldehyde: acetonitrile solution (7:3), vortexed thoroughly, and centrifuged at 12000 rpm for 10 min at 4 °C to precipitate proteins. 200 μL of the supernatant was dried under nitrogen at 60 °C, and then reconstituted with 400 μL of mobile phase (sodium hexanesulfonate + citric acid aqueous solution, pH=4.3). After centrifugation at 12000 rpm for 5 min, 200 μL of the supernatant was filtered through an aqueous filter membrane (0.22 μm) and injected into the HPLC-LCP-MS system.

[0048] The accumulation of different forms of arsenic and its metabolites in different organs of rats in each group are as follows: Figure 4 and Figure 5 As shown, the results indicated that compared to the realgar alone group, the accumulation of trivalent inorganic arsenic (AsIII) in the heart, liver, spleen, and testes of rats was significantly reduced in the realgar combined with angelica group; compared to the realgar alone group, the accumulation of pentavalent inorganic arsenic (AsV) in the heart, liver, spleen, testes, kidneys, lungs, and brain of rats was significantly reduced in the realgar combined with angelica group. Figure 4 Compared to the realgar alone group, the accumulation of monomethylarsenic (DMA) in the heart, spleen, testes, kidneys, and lungs of rats was significantly reduced in the realgar combined with angelica group; compared to the realgar alone group, the accumulation of dimethylarsenic (MMA) in the heart, liver, spleen, testes, kidneys, lungs, and brain of rats was significantly reduced in the realgar combined with angelica group. Figure 5 ).

[0049] Metabolic curves of arsenic in different valence states in rats of each group are shown below. Figure 6 As shown, the results indicate that compared with the realgar alone group, the realgar combined with angelica group can optimize the arsenic metabolism process and reduce toxicity. Specifically, it reduces the exposure of highly toxic arsenic valence state (AsⅢ), accelerates the metabolism of intermediate state (AsV, MMA), and promotes the formation of low-toxicity end products (DMA), thereby optimizing the arsenic metabolism process and reducing toxicity.

[0050] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A nutraceutical substance for alleviating the toxicity of realgar, characterized in that: The medicinal and edible material is composed of realgar and medicinal and edible components, the medicinal and edible components are at least one selected from the group consisting of Baiji and Danggui, and the medicinal and edible material reduces the toxicity of realgar. ​ 2. The dietetic substance of claim 1, wherein: The mass ratio of realgar to Baiji is 1:25-40.

3. The dietetic substance of claim 1, wherein: ###0001### The mass ratio of realgar to Danggui is 1:50-65.

4. The dietetic substance of claim 1, wherein: The mass ratio of realgar to Baiji to Danggui is 1:25-40:50-65.

5. The use of the food and drug dual-purpose substance according to any one of claims 1-4 in the preparation of a drug for treating leukemia, characterized in that: The medicinal and edible material is used for reducing the arsenic toxicity of realgar, but does not reduce the anti-leukemia activity of realgar.

6. Use according to claim 5, wherein: The medicinal and edible material is used for reducing the arsenic toxicity of realgar, specifically, the medicinal and edible material reduces the accumulation of arsenic and its metabolites in organs by reducing the plasma arsenic concentration and accelerating the arsenic metabolism, and alleviates the arsenic toxicity.

7. Use according to claim 6, wherein: The arsenic and its metabolites include trivalent inorganic arsenic, pentavalent inorganic arsenic, monomethylated arsenic and dimethylated arsenic.

8. Use according to claim 7, wherein: The organs include heart, liver, spleen, testis, kidney, lung or brain.

9. Use according to claim 8, wherein: The dosage form of the medicine includes powder, granules, capsules or tablets.

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