CN115429789A - Use of phenolic compounds for treating or preventing viral hepatitis - Google Patents

Abstract

The invention provides application of phenolic compounds in treating or preventing viral hepatitis, in particular to application of equol or pharmaceutically acceptable salts thereof in preparing a medicament for treating or preventing viral hepatitis, preferably the viral hepatitis is hepatitis B. The invention also provides a pharmaceutical composition for the treatment or prevention of viral hepatitis comprising equol, or a pharmaceutically acceptable salt thereof, and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier.

Description

Use of phenolic compounds for treating or preventing viral hepatitis

Technical Field

The invention relates to the technical field of antiviral drugs, in particular to a pharmaceutical composition for treating or preventing viral hepatitis and application thereof.

Background

Human Hepatitis B Virus (HBV) infection is a major public health problem worldwide. After acute hepatitis B virus infection, about 8% of hepatitis B virus still develops into chronic hepatitis B infection, and persistent HBV infection can cause cirrhosis and even liver cancer. The hepatitis B transmission pathway is mainly through vertical transmission and horizontal transmission. Vertical transmission refers to mother-to-baby transmission; horizontal transmission is primarily through the blood.

The treatment of hepatitis b is also a long-term process, and the therapeutic goals are to suppress or eliminate HBV to the maximum extent, to alleviate hepatocyte inflammatory necrosis and liver fibrosis, to delay and arrest disease progression, and to reduce and prevent liver decompensation, cirrhosis, HCC and its complications, thereby improving quality of life and prolonging survival time.

There are many hepatitis b therapeutic drugs on the market today, mainly by antiviral treatment with interferon or nucleoside analogues. In the case of interferon, recombinant DNA leukocyte interferon (IFN-. Alpha.) inhibits the replication of HBV. However, when the interferon is used for treating hepatitis B, strong adverse reactions are often accompanied, including bone marrow suppression, thyroid function influence, depression and the like.

Nucleoside analogues inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, and clinically useful drugs include the following classes: lamivudine and famciclovir, such as acyclovir, adefovir, entecavir, tenofovir, foscarnet and the like, and the medicaments have certain HBV inhibiting effect.

Although the reverse transcriptase inhibitors can effectively reduce the DNA level of HBV and enable patients to control the level of hepatitis B virus, the reverse transcriptase inhibitors have no direct effect on the elimination of HBeAg and HBsAg because the target of action is the process of reverse transcription of RNA into DNA. Therefore, the seroconversion probability of HBeAg and HBsAg in the single-drug treatment of the nucleoside analogue is extremely low, hepatitis B cannot be really cured, and patients need to take the drugs for a long time or even for life.

Although the reverse transcriptase inhibitor can control the level of hepatitis B virus, the problems of drug resistance, huge medical cost, serious side effects of the drug and the like are not small. The key point is that at present, no medicine can completely eliminate viruses to achieve the functional cure of hepatitis B. Therefore, the urgent need in the art is to provide a new drug for treating hepatitis b, which can eliminate HBsAg and achieve a functional cure.

The basic structure of equol (Fluticasone) is pregnane, the molecule is inactive, but has strong anti-inflammatory effect after esterification, and has high affinity with glucocorticoid receptors in human bodies. The mechanism may be through enhancing the stability of mast cells and lysosome membranes, suppressing inflammation caused by immune response, reducing synthesis of prostaglandins and leukotrienes, etc.

Disclosure of Invention

The present invention provides a novel viral hepatitis treatment option by applying equol or a pharmaceutically acceptable salt thereof to the treatment or prevention of viral hepatitis.

In one aspect, the invention provides the use of equol, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of viral hepatitis.

In a preferred embodiment, the pharmaceutically acceptable salt is the hydrochloride, sulfate or propionate salt of equol.

In a preferred embodiment, the viral hepatitis is hepatitis b.

In a preferred embodiment, the medicament is capable of reducing Hepatitis B Virus (HBV) load.

In a preferred embodiment, the medicament further comprises one or more additional therapeutic or prophylactic agents.

In a preferred embodiment, the additional therapeutic or prophylactic agent is selected from at least one of an interferon, a pegylated interferon, or a nucleoside analog.

In a preferred embodiment, the nucleoside analogue is selected from entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide.

In a preferred embodiment, the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

In a preferred embodiment, the medicament is formulated for oral administration, preferably in the form of a tablet or capsule.

In another aspect, the invention provides a pharmaceutical composition for the treatment or prevention of viral hepatitis comprising a therapeutically effective amount of equol, or a pharmaceutically acceptable salt thereof, and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier.

The technical scheme of the invention has the following beneficial effects:

1. the equol or the pharmaceutically acceptable salt thereof is applied to treating or preventing viral hepatitis, so that a novel viral hepatitis treatment option is provided.

2. The equol or the pharmaceutically acceptable salt thereof has excellent clinical safety and pharmacokinetic property, and has better druggability.

3. Equol, or a pharmaceutically acceptable salt thereof, is capable of eliminating hepatitis b virus from various aspects, optionally in combination with one or more additional therapeutic or prophylactic agents, with the potential for synergy.

Description of the drawings:

FIG. 1: different concentrations of equol, 0.1nM of entecavir, 20 mu M equol and 0.1nM of entecavir are combined to act together to inhibit the load of Hepatitis B Virus (HBV).

FIG. 2 is a schematic diagram: different concentrations of equol, 0.1nM of entecavir, 20 μ M equol and 0.1nM of entecavir act together to inhibit HBsAg.

FIG. 3: the inhibition effect on HBeAg is achieved by the combined action of equol with different concentrations, 0.1nM entecavir, 20 mu M equol and 0.1nM entecavir.

FIG. 4: and (3) detecting the cytotoxicity of the equol.

Detailed Description

The inventor of the invention unexpectedly finds HD025 (namely equol) with the effect of treating hepatitis B, and further proves that the HD025 can effectively reduce Hepatitis B Virus (HBV) through the verification of biological experiments.

In one aspect, the invention provides the use of equol, a derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of viral hepatitis.

In a preferred embodiment, the derivative of equol comprises deuterated equol. To those skilled in the art, deuterated compounds do not change the original properties of the compound, but can slow metabolic processes, thereby extending half-life. Can more effectively play the role of the medicine.

In a preferred embodiment, the pharmaceutically acceptable salt is the hydrochloride, sulfate, propionate, etc. of equol. In a preferred embodiment, the viral hepatitis is hepatitis b. In a preferred embodiment, the medicament is capable of reducing Hepatitis B Virus (HBV) load, HBsAg and/or HBeAg levels.

The basic structure of equol (Fluticasone) is pregnane, and the molecule is inactive, but has strong anti-inflammatory effect after esterification and high affinity with glucocorticoid receptors in human bodies. The mechanism may be through enhancing the stability of mast cells and lysosome membranes, suppressing inflammation caused by immune response, reducing synthesis of prostaglandins and leukotrienes, etc.

Viral hepatitis

The etiological typing of viral hepatitis is currently recognized by five hepatitis viruses, namely hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus and hepatitis E virus, which are respectively written as HAV, HBV, HCV, HDV and HEV, and the rest are RNA viruses except the hepatitis B virus which is a DNA virus.

Hepatitis b is an infectious disease mainly caused by hepatitis b virus, and is a liver disease. Clinically, anorexia, nausea, epigastric discomfort, liver pain, and asthenia are the main manifestations. Some patients may have jaundice fever and hepatomegaly with impaired liver function. Some patients can become chronic, even develop cirrhosis of the liver, and a few can develop liver cancer.

The etiological agent of hepatitis b is hepatitis b virus, abbreviated as HBV, and hepatitis b virus is DNA virus. The genome is double-stranded, circular, incompletely closed DNA. The outermost layer of the virus is the outer membrane or coat membrane of the virus, the inner layer is the core part, and the nucleoprotein is the core antigen (HBcAg) and cannot be detected in the serum. Serum from HBsAg positive patients was observed under electron microscope to have 3 kinds of particles, circular and filamentous particles with a diameter of 22nm, and a smaller number of particles with a diameter of 42 nm. The spherical particles of (a), also known as Dane's particles, are intact HBV particles.

The markers for hepatitis b were detected as follows: (1) HBsAg and anti-HBs: HBsAg positive indicates that HBV is currently in the stage of infection, and anti-HBs positive for immunoprotective antibodies indicates that immunity to HBV has developed. The diagnosis basis of the chronic HBsAg carrier is that the chronic HBsAg carrier has no clinical symptoms and physical signs, the liver function is normal, and the HBsAg is continuously positive for more than 6 months. (2) HBeAg and anti-HBe: HBeAg positive is an index of HBV active replication and strong infectivity, and the change of the detected serum from HBeAg positive to anti-HBe positive indicates that the disease has remission and weakened infectivity. (3) HBcAg vs anti-HBc: HBcAg positive indicates that complete HBV particle direct reaction exists, and HBV active replication is less clinically used due to the complex detection method. anti-HBc is a marker of HBV infection, and anti-HBc IgM positive indicates that the virus is replicated in vivo at an early stage of infection. HBsAg, HBeAg and anti-HBc are all positive in chronic mild hepatitis B and HBsAg carriers, and have high infectivity index and are difficult to convert from negative to positive.

In a preferred embodiment, the medicament further comprises one or more additional therapeutic or prophylactic agents. In a preferred embodiment, the additional therapeutic or prophylactic agent is selected from an interferon or a nucleoside analogue. In a preferred embodiment, the nucleoside analogue is selected from entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide.

Additional therapeutic or prophylactic agents

In some embodiments, the additional therapeutic or prophylactic agent is selected from one or more of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, for example, one selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide or at least two selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.

Entecavir (Entecavir) is chemically known as 2-amino-1, 9-dihydro-9- [ (1s, 3r,4 s) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentane ] -6H-purin-6-one.

US patent US5206244 discloses entecavir and its use for the treatment of hepatitis b virus; a novel synthesis of entecavir is disclosed in WO 9809964; WO0164421 discloses low dose entecavir solid formulations.

Entecavir is a highly potent antiviral agent developed in the 90's 20 th century by schrobo, usa and has a strong anti-HBV effect. It can be phosphorylated to active triphosphate, which has a half-life in cells of 15h. Entecavir triphosphate inhibits all three activities of the viral polymerase (reverse transcriptase) by competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase: (1) the initiation of HBV polymerase; (2) formation of a reverse transcribed minus strand of the pregenomic mRNA; (3) synthesis of HBV DNA plus strand.

Tenofovir disoproxil fumarate (the name of England: (TDF); (R) - [ [2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phosphonic acid diisopropoxycarbonylmethyl ester fumarate) is an ester precursor of Tenofovir, belongs to a novel nucleotide reverse transcriptase inhibitor, and has the activity of inhibiting HBV viruses.

TDF is another novel open-ring nucleoside phosphonate successfully developed by Gilidard company in the United states following Adefovir dipivoxil, is first marketed in the United states in 10 months in 2001, and is currently marketed in countries such as Europe, australia, and Canada.

TDF can inhibit viral polymerase in vivo by competitively binding to the native deoxyribose substrate and stop the synthesis of DNA strands by insertion into DNA. The main action mechanism is that the tenofovir is hydrolyzed into tenofovir after being taken orally, the tenofovir is phosphorylated by cell kinase to generate a metabolite tenofovir diphosphate with pharmacological activity, the tenofovir diphosphate competes with 5 '-deoxyadenosine triphosphate to participate in the synthesis of virus DNA, and after entering the virus DNA, the DNA is prevented from being prolonged due to the lack of 3' -OH groups, so that the replication of the virus is blocked. Clinical application shows that TDF has obvious anti-HBV curative effect and less toxic side effect, so that TDF has great clinical application prospect.

Tenofovir Alafenamide (Tenofovir Alafenamide), a prodrug of the new Nucleoside Reverse Transcriptase Inhibitor (NRTI) Tenofovir (Tenofovir) developed by Gilidard scientific, USA. Compared with the prior generation of similar anti-hepatitis B medicine tenofovir disoproxil TDF, the antiviral activity of tenofovir alafenamide is 10 times, the stability in blood plasma is 200 times, and the half-life period is improved by 225 times. Compared with TDF, tenofovir alafenamide requires only one-tenth of the dose of TDF administered to achieve the same antiviral efficacy as TDF. Therefore, the tenofovir alafenamide is used for preventing or/and treating Hepatitis B Virus (HBV) infection and has better curative effect, higher safety and lower drug resistance.

As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective at a dose and for a period of time required to achieve a desired therapeutic result. A therapeutically effective amount of a therapeutic agent for hepatitis b will depend on the nature of the disorder or condition and on the particular agent, and can be determined by standard clinical techniques known to those skilled in the art.

The therapeutic result may be, for example, alleviation of symptoms, prolongation of survival, increased mobility, and the like. The therapeutic result need not be a "cure". The therapeutic outcome may also be prophylactic.

In a preferred embodiment, the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

In a preferred embodiment, the medicament is formulated for oral administration, preferably in the form of a tablet or capsule

Route of administration

The medicaments or pharmaceutical compositions of the present disclosure are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, a medicament or pharmaceutical composition disclosed herein is administered by intravenous injection. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. One advantage of the disclosed medicaments or pharmaceutical compositions is that they are orally bioavailable and can be administered orally.

Pharmaceutical composition

In certain embodiments, the equol drug, the derivative thereof, or the pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be formulated with conventional carriers and excipients, which will be selected in accordance with common practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and, when used for delivery by non-oral administration, are generally isotonic. All formulations will optionally contain Excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, but is typically about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but typically from about 3 to 4.

The formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing co., easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product as necessary.

Formulations of the invention suitable for oral administration may be presented as: discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: the active ingredient in a free-flowing form such as a powder or granules is compressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide sustained or controlled release of the active ingredient therefrom.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions of the present disclosure may also be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable carriers and solvents that may be employed include water, ringer's solution, isotonic sodium chloride solution and hypertonic sodium chloride solution.

Additional objects, advantages and novel features of the present invention will become apparent to one of ordinary skill in the art upon examination of the following examples.

Examples

Example 1 evaluation of in vitro anti-HBV Activity of test Compound Equol (HD 025) Using HepG2-NTCP cells

The compound preparation method comprises the following steps:

in the case of preparation of 20mM concentration, volume (. Mu.l) = sample mass (. Mu.l). Times.purity ÷ molecular weight ÷ 20X 10 of DMSO as solvent ⁶

Control compounds include ETV (batch No.: P1214012;99.0% purity) available from Shanghai Tantake Technology, inc. Batch number: ET25747-14-P1;99.5% pure), available from Shanghai drug Mingkude New drug development, inc. The mother liquors of the above control compounds were all at 20mM and stored at-20 ℃.

Table 1: primary reagents and cellular viruses

Experimental protocol

Plating cells and compound treatment

HepG2-NTCP planking

On day 0, hepG2-NTCP cells were seeded into 48-well cell plates (7.5X 104 cells/well).

Infectious virus and compound treatment

On day 2, cells were pretreated with the compound for 2 hours before the addition of D-type HBV to infect HepG2-NTCP cells (compound was added at the same time as infection). The tested compound is provided with 3 single drug concentrations and 1 combined drug concentration, the three single drug concentrations of the equol and the deuterated equol are respectively 1, 10 and 20 mu M, and the combined drug concentration is 20 mu M of equol plus ETV0.1nM; control compound was ETV, wells containing DMSO alone without compound were set up and ETV single drug concentration 0.1nm,2 duplicate wells tested. The compound concentrations are shown in Table 2.

The culture medium containing the compound was changed once on day 3, day 5 and day 7. On day 9, cell supernatants were collected for detection of HBV DNA (qPCR), HBeAg and HBsAg (ELISA). After collecting the cell supernatant, cellTiter-Glo was added to test the cell viability, and the specific procedure of the experiment is shown in Table 3.

Table 2: concentration of the Compound

Table 3: experimental procedure

Sample detection

1) qPCR method for detecting HBV DNA content in cell culture supernatant

DNA was extracted from the cell culture supernatant according to QIAamp 96DNA Blood Kit instructions. The sample volume was 120. Mu.l, and the DNA elution volume was 120. Mu.l of supernatant. qPCR detects the HBV DNA content.

As shown in table 4, qPCR reaction mixtures were prepared.

TABLE 4.QPCR reaction Components Table

PCR reaction solution Components	1 volume required for the reaction system
		FastStart Universal Probe Master(2×)	5μl
Forward primer (10. Mu.M)	0.4μl
		Reverse primer (10. Mu.M)	0.4μl
Probe (10 μ M)	0.2μl
		AE	2μl

The qPCR reaction mixture was added to 384 well reaction plates and 2. Mu.l of sample or standard was added to the corresponding wells, each in a total volume of 10. Mu.l. And (3) PCR reaction: 10 minutes at 95 ℃;95 ℃,15 seconds, 60 ℃,1 minute, 40 cycles.

2) ELISA method for detecting content of HBsAg and HBeAg in cell culture supernatant

The method refers to the kit specification, and the method is briefly described as follows: respectively taking 50 mu l of standard substance, adding the sample and the reference substance into a detection plate, then adding 50 mu l of enzyme conjugate into each hole, incubating for 60 minutes at 37 ℃, washing the plate by using washing liquid, then sucking to dry, then adding 50 mu l of premixed luminescent substrate, incubating for 10 minutes at room temperature in a dark place, and finally measuring the luminescence value by using an enzyme-linked immunosorbent assay.

3) Cell viability assay

After the supernatant was collected, the medium and CellTiter-Glo were mixed in equal volumes, 50. Mu.l of each well was added to the cell plate, and the plate was shaken at room temperature in the dark for 10 minutes to measure the luminescence value.

4) Data computation

HBV DNA inhibition (%) = (1-HBV DNA copy number of sample of compound group/HBV DNA copy number of DMSO group) × 100

HBsAg inhibition rate (%) = (1-HBsAg value of sample/DMSO control HBsAg value) × 100

HBeAg inhibition (%) = (1-HBeAg value of sample/DMSO control HBeAg value) × 100

Cytotoxicity% =100- [ (sample luminescence value-medium control luminescence value)/(DMSO control luminescence value-medium control luminescence value) ] × 100%

Data analysis

As shown in fig. 1-3, the equol drug group has slight inhibitory effect on both HBsAg and HBeAg, and has more obvious inhibitory effect on HBV DNA, wherein 20 μ M of equol has the best inhibitory effect on HBV, and the inhibitory rate on HBV DNA can reach 40%, and the equol and ETV act together to significantly improve the inhibitory effect on HBV DNA, showing the possibility of drug combination.

As shown in fig. 4, equol is almost non-cytotoxic, providing reliable safety for potential clinical use.

The invention provides a novel compound capable of inhibiting HBV and provides a novel scheme for treating hepatitis B.

While the invention has been described with reference to specific embodiments, those skilled in the art will recognize that changes or modifications can be made to the described embodiments without departing from the spirit and scope of the invention, which is defined by the appended claims.

Claims (10)

1. Use of equol, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of viral hepatitis.

2. The use of claim 1, wherein the pharmaceutically acceptable salt is the hydrochloride, sulfate, propionate salt of equol.

3. The use of any one of claims 1-2, wherein the viral hepatitis is hepatitis b.

4. The use of claim 3, wherein the medicament is for reducing Hepatitis B Virus (HBV) load, HBsAg and/or HBeAg levels.

5. The use of any one of claims 1-4, wherein the medicament further comprises one or more additional therapeutic or prophylactic agents, wherein the additional therapeutic or prophylactic agents are selected from the group consisting of interferons, pegylated interferons.

6. The use of claim 5, wherein the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.

7. The use of any one of claims 1-6, wherein the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

8. The use of claim 7, wherein the medicament is formulated for oral administration, preferably in the form of a tablet or capsule.

9. A pharmaceutical composition for the treatment or prevention of viral hepatitis comprising a therapeutically effective amount of equol, or a pharmaceutically acceptable salt thereof, and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier, wherein the additional therapeutic or prophylactic agent is selected from at least one of an interferon, a pegylated interferon, or a nucleoside analogue, preferably the nucleoside analogue is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.

10. The use of claim 1, wherein the equol is deuterated equol.

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