CN113230253A - Antiviral composition and application thereof in preparation of medicine for preventing and/or treating herpes virus - Google Patents
Antiviral composition and application thereof in preparation of medicine for preventing and/or treating herpes virus Download PDFInfo
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- CN113230253A CN113230253A CN202110497951.4A CN202110497951A CN113230253A CN 113230253 A CN113230253 A CN 113230253A CN 202110497951 A CN202110497951 A CN 202110497951A CN 113230253 A CN113230253 A CN 113230253A
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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Abstract
The invention belongs to the technical field of medicines, and discloses an anti-herpesvirus composition which adopts houttuynin, berberine and andrographolide as active substances. The anti-herpes virus composition provided by the invention has an inhibition effect on herpes simplex virus, and particularly has high activity and low toxicity for inhibiting herpes simplex virus type 1. In addition, the composition comprises the anti-herpes virus composition and acyclovir, and the combined use can obviously reduce the occurrence of acyclovir drug-resistant strains, can be used for solving the problem that acyclovir drug-resistant strains are easy to generate drug resistance and toxicity, is particularly suitable for developing the research on acyclovir combined use of people with low immune function, provides reference for developing a clinical antiviral drug mechanism, and has good clinical application and popularization values.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an antiviral composition and application thereof in preparing a medicament for preventing and/or treating herpes viruses.
Background
Herpes Simplex Virus (HSV) mainly comprises herpes virus type 1 (HSV-1) and herpes virus type 2 (HSV-2), can cause various diseases after infecting a human body, and is easy to relapse. HSV-1 primarily infects the skin and mucous membranes of the mouth, eyes, lips, and central nervous system, causing cutaneous herpes simplex, herpes labialis, severe corneal infections, and central nervous system inflammation (encephalitis), and HSV-1-induced encephalitis can be life threatening if not treated in time. HSV-2 is commonly associated with external genital infections and neonatal infections, which can cause genital herpes, pregnant women infected with HSV-2 are liable to abortion or cause congenital malformation and mental retardation of the fetus, and newborns infected with HSV-2 through the birth canal have high fever, dyspnea and central nervous system pathological changes and even die.
Acyclovir (ACV) is the first choice for clinical use and the most widely used anti-herpes virus drug, and the mechanism of action is based on the "competitive inhibition" effect on deoxynucleoside triphosphates, thereby affecting replication of the viral genome. In order to exert antiviral effect, the dosage in clinical use is high, the treatment medicament is single, the drug resistance problem is serious, adverse reactions are more in the use process, and the drug resistance problem is more serious especially for patients with low immunity. Therefore, the drug resistance problem and adverse reaction of acyclovir become problems to be solved urgently.
The action of traditional herbs in vitro and in vivo against herpes simplex virus type 2 and acyclovir resistant herpes simplex virus type 1 is disclosed in Nie's plus-sense translation, foreign medicine (TCM booklet, 1997): 12 traditional herbal extracts have therapeutic effect on herpes simplex virus type 1 (HSV-1) infection of mouse skin. 4 of the 12 herbs, Geum japonicum (whole plant), Rhus chinensis Mill (insect fistula), Eugenia caryophyllata (flower bud) and Terminalia chebula (fruit), have antiviral effects against HSV-1 and Phosphoryloylhexanoic acid (PAA) resistant strains of thymidine kinase deficiency (TK) and wild HSV-1 strains in vitro. When Acyclovir (ACV) was used in combination with herbal extracts, the herbal extracts enhanced the biosynthesis of ACV alone in a model of HSV-1 infected mouse skin, with effects very similar to PAA. The antiviral effect of the herbal extract on mice infected with wild type HSV-2 strain was stronger than that of 2.5mg/kg ACV. The research results are that: the conventional use of each herbal extract can be used as both prophylactic and therapeutic agents for patients infected with HSV-2 and ACV-resistant strains of HSV-1.
Therefore, the combination of the Chinese herbal medicine extract and acyclovir is probably a good way for solving the problem of drug resistance of acyclovir at present. Related reports that houttuynin, berberine and andrographolide are combined to treat herpes simplex virus are not available. In view of this, the present application is specifically made.
Disclosure of Invention
The primary object of the present invention is to provide an anti-herpesvirus composition.
The invention also aims to provide application of the anti-herpesvirus composition in preparing a medicament for preventing and/or treating herpesvirus.
In order to achieve the purpose, the invention provides the following technical scheme:
an anti-herpesvirus composition comprises houttuynin, berberine and andrographolide as effective components.
As a preferable technical scheme, the mol ratio of the houttuynine sodium bisulfite, the berberine and the andrographolide is 1: (0.2-0.5): (0.3-0.7).
The houttuynin is an antibacterial component of volatile oil of Houttuynia cordata (Houttuynia cordia-ta Thunb) of Saururaceae. Berberine is an alkaloid extracted from plants such as coptis chinensis and phellodendron amurense, has remarkable antibacterial, anti-inflammatory and antioxidant effects and small toxic and side effects, and is clinically used for treating bacillary dysentery and gastroenteritis. Andrographolide (Andrographolide) is the main effective component of herba Andrographitis, and can be used for treating various inflammatory diseases, including rheumarthritis, pharyngolaryngitis, diarrhea, bacterial and viral infection, etc.
The invention adopts the effective components extracted from the three Chinese herbal medicines to jointly act on inhibiting the herpes virus, has high inhibiting activity and safe components. Therefore, the invention claims the application of the antiviral composition in the preparation of the medicine for preventing and/or treating herpes virus.
The application of the compound in preparing the medicament for preventing and/or treating the herpes simplex virus is a preferable technical scheme.
In a preferred embodiment, the herpes simplex virus is herpes simplex virus 1. When the target is herpes simplex virus type 1, the antiviral composition has a better effect.
The invention also protects the application of the antiviral composition in preparing the medicine for reducing the drug resistance of the alprenovir.
As a preferred technical scheme, the antiviral composition can reduce the using amount of the alprenovir in the treatment of herpes simplex virus.
The invention also provides a herpes simplex virus composition, which adopts the alprenovir and the antiviral composition as the effective components in the claim 1.
As a preferred technical scheme, the mole ratio of the alprenovir to the antiviral composition is 1: (0.3 to 1).
The invention uses Chinese herbal medicine to extract active substances and combines acyclovir, expands the application of the Chinese herbal medicine, has the effects of inhibiting the activity of herpes simplex virus and reducing the drug resistance problem of acyclovir, and can be used for preparing the drugs for preventing and/or treating herpes simplex virus.
The term "prophylaxis and/or treatment" as used herein means either the sole prophylaxis or the sole treatment of herpes simplex virus or the simultaneous prophylaxis and treatment of herpes simplex virus.
The specific type of the herpes simplex virus is not limited in the invention, and all virus strains belonging to the herpes simplex virus are within the protection scope of the invention.
In some preferred embodiments, the medicament further comprises a pharmaceutically acceptable excipient.
The pharmaceutically acceptable auxiliary materials added in the medicine provided by the invention can play roles in forming, serving as a carrier or improving the stability, and also has important functions of solubilization, dissolution assistance or sustained and controlled release and the like.
The pharmaceutical excipients referred to in the present invention refer to additives such as pharmaceutically acceptable carriers, excipients, diluents, colorants, plasticizers, etc. in solid, liquid or other forms, which are conventionally used in the art. Such as magnesium carbonate, magnesium stearate, calcium phosphate, diatomaceous earth, microcrystalline cellulose, hydroxymethyl cellulose and salts, talc, lactose, glucose, mannitol, sucrose, pectin, dextrin, starch, gelatin, cellulosic materials, and the like. The dosage form of the medicament can be, but is not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions or oral emulsions.
Compared with the prior art, the invention has the beneficial effects that:
the anti-herpes virus composition provided by the invention has a good effect on inhibiting herpes simplex viruses, and particularly has a remarkable effect on inhibiting HSV-1 viruses. The anti-herpes virus composition can be used together with acyclovir, can obviously reduce the problem of acyclovir resistance, and is suitable for solving the problem that acyclovir is easy to generate drug resistance and toxicity.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. 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.
Example 1
Houttuynin, berberine and andrographolide, wherein the molar ratio is 1: 0.2: 0.7, mixing.
Example 2
Houttuynin, berberine and andrographolide, wherein the molar ratio is 1: 0.5: 0.3, mixing.
Example 3
Houttuynin, berberine and andrographolide, wherein the molar ratio is 1: 0.3: 0.5, mixing.
Example 4
Houttuynin, berberine and andrographolide, wherein the molar ratio is 1: 0.4: 0.4 mixing was performed.
Example 5
Houttuynin, berberine and andrographolide, wherein the molar ratio is 1: 0.3: 0.7, mixing.
Comparative example 1
Houttuynin
Comparative example 2
Berberine
Comparative example 3
Andrographolide
Comparative example 4
Houttuynin and berberine in a molar ratio of 1: 0.3, mixing.
Comparative example 5
Mixing houttuynin and andrographolide at a molar ratio of 1: 0.7.
Comparative example 6
Berberine and andrographolide, wherein the molar ratio is 0.3: 0.7, mixing.
The test results of the above examples and comparative examples of the present invention are as follows (the test methods used are conventional methods unless otherwise specified; and the materials, reagents, etc. used are commercially available reagents and materials unless otherwise specified): cytotoxicity test of samples: each of the samples of examples and comparative examples was dissolved in serum-free and double-antibody-free medium to perform serial 10-fold gradient dilution, and each dilution was added to Vero cells forming substantially a monolayer on each 96-well plate at 0.1mL per well and 3 wells per dilution. And non-dosed liquid cells were set as normal controls. Placing at 37 ℃ and 5% CO2Incubate for 1 week in incubator, observe CPE daily: i.e., diffuse cell rounding, swelling, lysis. Calculating half Toxic Concentration (TC) according to Reed-Muench method50) And a very large non-Toxic Concentration (TC)0). The test results are shown in table 1 below.
TABLE 1
II, in-vitro anti-herpes virus efficacy test: the large non-toxic sample solution of each example and comparative example was serially diluted 2-fold into 10 dilutions in the maintenance medium. After the Vero cells were grown to a substantially monolayer on each 96-well plate, 10TCID was seeded into each well500.1mL of a virus solution [ herpes virus type 1 (HSV-1) SM44 strain or herpes virus type 2 (HSV-2) Sav strain, provided by the Wuhan virus institute of Chinese academy of sciences. Adsorbing at 37 deg.C for 1 hr, discarding supernatant, adding the above 2 times diluted medicinal liquid, 0.1mL per well, and 3 wells per dilution. And setting uninfected cells and cells infected by the liquid medicine as negative and positive controls. Then placing at 37 ℃ and 5% CO2Incubate for 1 week in an incubator and observe CPE daily. Calculating the half effective concentration (IC) according to Reed-Muench method50) And statistics of therapeutic index (TC)50/IC50) The test results are shown in table 2 below:
TABLE 2
Thirdly, drug resistance test of combined application with acyclovir: adopting a plaque inhibition test method, specifically, adding 0.1mI HSV l culture supernatant into a BHK cell monolayer, adsorbing at 37 ℃ for 1h, removing virus, adding an equal amount of mixed solution of RPMI1640 maintenance solution containing 1% fetal calf serum and 1% methyl cellosolve, adding acyclovir, acyclovir and the mixed group of the samples of the example 5 with different concentrations (the mass ratio is 1:1) respectively, and performing a test at C02The culture was carried out at 37 ℃ in an incubator. After 72h observation, l 0% formaldehyde was fixed for 10min, 1% crystal violet staining 3And (3) rinsing with clear water and drying in the air for 0min, counting the number of the plaques by referring to a method of Nitta, and calculating the plaque inhibition rate. The plaque inhibition rate (average number of plaques in control group-average number of plaques in experimental group)/average number of plaques in control group × 100%. The half Inhibitory Concentration (IC) of the drug is obtained by plotting the drug concentration on the abscissa and the plaque inhibition rate on the ordinate50). Respectively adding acyclovir or a mixed group of 2 mu g/ml into BHK cells infected with HSV-1 strains, culturing for 72h, repeatedly freezing and recovering to destroy the cells, releasing viruses, centrifuging, taking supernate containing the viruses, inoculating the supernate into the BHK cells, and adding the acyclovir or the mixed group of 2 mu g/ml for culturing. The virus sensitivity to acyclovir or the mixed group was determined in serial 9 passages at 3, 6 and 9 passages, respectively, and the results are shown in table 3 below:
TABLE 3
The test results show that: 1. the antiviral composition disclosed by the invention has a good inhibition effect on the herpes virus, the anti-herpes virus effect of the composition is remarkably superior to that of a single component or a combination of partial components, the therapeutic index is high, and the safety is good; especially for the HSV-1 strain;
2. the antiviral composition disclosed by the invention can be combined with acyclovir for application, so that the dosage of the acyclovir is reduced, and the drug resistance generated after multiple times of administration is obviously reduced.
Claims (10)
1. An anti-herpesvirus composition is characterized by adopting houttuynin, berberine and andrographolide as effective components.
2. The anti-herpesvirus composition of claim 1, wherein the molar ratio of houttuynin, berberine and andrographolide is 1: (0.2-0.5): (0.3-0.7).
3. Use of the anti-herpesvirus composition according to claim 1 in the manufacture of a medicament for the prophylaxis and/or treatment of herpesvirus.
4. The use according to claim 3, for the preparation of a medicament for the prophylaxis and/or treatment of herpes simplex virus.
5. The use according to claim 4, wherein the herpes simplex virus is herpes simplex virus type 1.
6. Use of an anti-herpesvirus composition as described in claim 1 in the manufacture of a medicament for reducing resistance to alprenovir.
7. The use according to claim 6, wherein the anti-herpesvirus composition is for reducing the amount of alprenovir used in herpes simplex virus therapy.
8. A herpes simplex virus composition comprising alprenovir and the anti-herpes virus composition of claim 1 as active ingredients.
9. The herpes simplex virus composition of claim 8, wherein the weight ratio of the alprenovir to the antiviral composition is 1: 1.
10. The herpes simplex virus composition of claim 8, wherein the medicament further comprises a pharmaceutically acceptable excipient.
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| CN102178974A (en) * | 2010-01-15 | 2011-09-14 | 东华大学 | Bacterial cellulose-based antibacterial dry film for acute trauma and preparation method and application |
| US20110218241A1 (en) * | 2010-03-06 | 2011-09-08 | Cacao Bio-Technologies, Llc | Antiviral epicatechins, epicatechin oligomers, or thiolated epicatechins from theobroma cacao for treatment of genital warts |
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