Methods and compositions for preventing, reducing, or eliminating toxicity caused by acetaminophen (APAP)

Abstract

To provide methods and compositions for preventing, reducing or eradicating toxicity caused by acetaminophen (APAP).SOLUTION: A method comprises administering to a subject in need thereof a compound selected from the group consisting of any combinations of Eudragit S100, Pluronic F68, Nariagenin, Kaempferol, and the like.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 630,489, filed Feb. 14, 2018. The entire disclosure of the above application is incorporated herein by reference. Technical Field The present invention relates to methods and compositions for preventing, reducing or eliminating toxicity caused by acetaminophen (APAP).

Background Art

[0002] Acetaminophen (also known as Panadol), also called paracetamol or N-acetyl-para-aminophenol (APAP), is the most widely used analgesic and antipyretic drug in the market. Every year, numerous cases of drug poisoning or suicide, such as inappropriate use and toxicity of APAP, are reported, and the hepatotoxicity and nephrotoxicity caused by APAP are the main causes of serious diseases and death. Many clinical studies have demonstrated that the hepatotoxicity induced by APAP is preventable, and the immediate administration of the antidote N-acetylcysteine (NAC) for early diagnosis can prevent the occurrence of hepatotoxicity.

[0003] Early detection of acetaminophen overdose is crucial because the best prognosis can be achieved by administering an antidote within 8 hours of poisoning. Early signs of drug poisoning include discomfort, nausea, and vomiting. However, some patients may not show signs of poisoning in the early stages (stage 1), even if their blood acetaminophen levels are at toxic levels and their liver function is clearly abnormal. Signs of hepatotoxicity, such as abdominal pain, persistent vomiting, jaundice, and right upper abdominal pain, usually become apparent 24 to 48 hours after ingestion of a large amount of acetaminophen (stage 2). Serum aminetransferases usually begin to rise with clinical symptoms 16 hours after administration. Stage 3 usually occurs 3 to 4 days after administration, at which point the degree of liver damage and prognosis can be well predicted. Signs of hepatotoxicity progress from mild symptoms with elevated liver function values ​​(AST > 1,000 IU / L) to severe acute fulminant hepatitis with metabolic acidosis, jaundice, hyperglycemia, AST > 1,000 IU / L, abnormal blood clotting, and liver / brain lesions. Stage 4 leads to renal failure with oliguria or, in severe cases, death.

[0004] While some patients with acetaminophen poisoning exhibit only mild liver damage, severe nephrotoxicity is primarily caused by the direct metabolism of APAP in the P-450 (cytochrome P450, CYP) in the renal tubules. Nevertheless, acute renal failure can also arise from hepatorenal syndrome caused by acute liver failure, and partial excretion of Na (FeNa) can be used to distinguish hepatorenal syndrome (FeNa>1) from (FeNa>1). The formula for calculating FeNa is (urinary sodium ÷ urinary creatinine) ÷ (plasma sodium ÷ plasma creatinine) × 100.

[0005] The peak concentration of acetaminophen in the blood is achieved 1-2 hours after oral administration. A significant amount is eliminated by the liver, with over 90% binding to glucuronides and sulfates to form non-toxic metabolites. Less than 5% is eliminated by various CYP enzymes, including CYP2E1, CYP1A2, and CYP3A4, of which CYP2E1 and CYP1A2 are the major enzymes for metabolism. The metabolite produced by these enzymes, N-acetyl-p-benzoquinone imine (NAPQI), is a highly active electrophile. Under normal conditions, NAPQI reacts readily with intracellular glutathione to form a non-toxic mercaptide. In cases of acetaminophen overdose, where glutathione consumption exceeds its synthesis rate and cellular glutathione levels are below 30% of the normal range, NAPQI can bind to larger molecules or nucleic acids, including cysteine, leading to liver damage. Histochemical staining revealed that NAPQI binds to the thiol group of cysteine ​​and forms covalent bonds in the central lobular region before hepatocyte necrosis occurs.

[0006] Patients with liver disease, alcohol dependence, or those taking drugs that may induce P450 activity, such as carbamazepine, ethanol, isoniazid, phenobarbital (or other barbiturates), phenytoin, sulfinpyrazone, sulfonylurea, rifampine, and primidone, are in a group susceptible to developing severe hepatotoxicity caused by APAP, and may easily die if they develop complications such as adult respiratory distress syndrome, cerebral edema, uncontrolled bleeding, infection, or multiple organ failure syndrome (MODS). Taking alcohol as an example, it is primarily eliminated by CYP2E1 in the liver, and the mechanism of APAP poisoning can be divided into three stages: In the first stage, alcohol competes for APAP and CYP2E1 receptors in the liver, and the concentration of NAPQI decreases during this stage; in the second stage, alcohol extends the half-life of CYP2E1 from 7 hours to 37 hours, which increases the level of CYP2E1 in the liver, and the concentration of NAPQ1 gradually increases during this stage; and in the third stage, during alcohol withdrawal, a large amount of CYP2E1 is found in the liver, eliminating acetaminophen, resulting in a significant increase in toxic metabolites of acetaminophen and causing liver damage. Recent studies have shown that diallyl sulfide can effectively prevent hepatotoxicity caused by acetaminophen in mice, and have further demonstrated that diallyl sulfide can inhibit the activity of CYP2E1. The protective mechanism of diallyl sulfide against acetaminophen-induced hepatotoxicity is presumed to be by inhibiting the production of the intermediate NAPQI from acetaminophen. Previous studies have suggested that it can suppress the consumption of reduced glutathione in hepatocytes, oxidative activation, mitochondrial dysfunction, and DNA damage caused by NAPQI, thereby minimizing acetaminophen-induced liver damage. For example, ginseng, adenosine, and its derivatives adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate can prevent acetaminophen-induced liver damage through this protective mechanism. [Overview of the project] [Problems that the invention aims to solve]

[0007] The toxicity of APAP needs to be addressed, and effective analgesic approaches and low-toxicity or non-toxic APAP formulations need to be provided. [Means for solving the problem]

[0008] Embodiments are shown below to illustrate the present invention. However, it should be understood that the present invention is not limited to the preferred embodiments shown. [Brief explanation of the drawing]

[0009] [Figure 1] Histological examination results are shown: (Figure 1A) Normal kidney structure from the normal control group; (Figure 1B) Stained kidney section from the acetaminophen 1 g / kg group. Severe necrosis, congestion, and extravasation of red blood cells were observed; (Figure 1C) Stained kidney section from the acetaminophen 1 g / kg and NAC groups. Mild to moderate degeneration was observed; (Figure 1D) Stained kidney section from the acetaminophen 1 g / kg and test compound groups consisting of Eudragit S100, sucralose, and luteolin. The kidney structure was similar to that of the normal control group. Hematoxylin and eosin. Magnification 200x. [Modes for carrying out the invention]

[0010] Outline of the invention In one aspect, the present invention provides a method for preventing, reducing, mitigating, or eliminating toxicity caused by acetaminophen (APAP) or its derivatives, the method comprising: Eudragit S100, Pluronic F68, Naringenin, Kaempferol, Mannitol, Sucralose, Luteolin, Menthol, Polyethylene glycol sorbitan monolaurate (Tween 20), Microcrystalline cellulose, Brij 35, Saccharin, Cremofol RH40, Crospovidone, Sodium starch glycolate, Eudragit S100, Croscarmellose sodium, Low-substituted hydroxypropyl cellulose, Pregelatinized starch, Dextrate NF hydrate, Citric acid, Cremofol EL, Aerosil 200, Myrj 52, Sorbic acid, Lemon oil, Hydroxypropyl cellulose, Sorbitol, Acesulfame potassium, Hydroxypropyl methylcellulose, Lactose monohydrate, Maltodextrin, Brij 58, Brij 76, Tween The treatment involves administering a compound selected from the group consisting of PEG-80, Tween 40, PEG-400, PEG-4000, PEG-8000, Span 60, sodium benzoate, hydroxyethyl methylcellulose, methylcellulose, Span 80, sodium cyclamate, glyceryl behenate, oxide red, glycerin monostearate, copovidone K28, starch acetate, magnesium stearate, sodium lauryl sulfate, providedon K30, PEG-2000, and any combination thereof, to a subject in need in an amount effective to prevent, reduce, or eliminate the toxicity caused by APAP.

[0011] In one embodiment, the present invention provides a method for preventing, reducing, or eliminating toxicity caused by acetaminophen (APAP) or its derivatives, the method comprising administering a compound selected from the group consisting of Eudragit S100, Pluronic F68, Naringenin, Kaempferol, Mannitol, Sucralose, Luteolin, and any combination thereof, to a subject in need of such a compound in an amount effective to prevent, reduce, or eliminate toxicity caused by APAP.

[0012] In some embodiments, the compound comprises a first compound selected from the group consisting of Eudragit S100, Pluronic F68, Naringenin, Kaempferol, and any combination thereof. In some embodiments, the compound comprises a second compound selected from the group consisting of mannitol, sucralose, luteolin, and any combination thereof.

[0013] In one embodiment, the present invention provides a method for preventing, reducing, or eliminating toxicity caused by acetaminophen (APAP) or its derivatives, the method comprising administering a first compound selected from the group consisting of Eudragit S100, Pluronic F68, Naringenin, Kaempferol and any combination thereof, to a subject in need of it in an amount effective to prevent, reduce, or eliminate toxicity caused by APAP.

[0014] In some embodiments, the toxicity is nephrotoxicity and / or hepatotoxicity.

[0015] In some embodiments, the first compound encompasses a combination of Eudragit S100, Pluronic F68, and Naringenin.

[0016] In some embodiments, the method of the present invention further comprises administering to a subject a second compound selected from the group consisting of mannitol, sucralose, luteolin, and any combination thereof.

[0017] In some embodiments, the first and second compounds administered to the subject are as follows: (i) A combination of Eudragit S100 and sucralose; (ii) A combination of Pluronic F68 and sucralose; (iii) A combination of Eudragit S100 and mannitol; (iv) Pluronic F68 and mannitol combination; (v) A combination of Eudragit S100, sucralose, and luteolin; (vi) combinations of kaempferol, mannitol and sucralose; and (v) A combination of naringenin, mannitol, and sucralose; This is a combination selected from a group consisting of [the specified elements].

[0018] Also provided is the use of the compounds described herein (the first compound and / or the second compound and / or any combination thereof) for the manufacture of agents (e.g., antidotes) for preventing, reducing, or eradicating the toxicity caused by acetaminophen (APAP) or its derivatives (e.g., as acetaminophen toxicity inhibitors or protectors). Further provided are compositions for preventing, reducing, or eradicating the toxicity caused by acetaminophen (APAP) or its derivatives, comprising the compounds described herein (the first compound and / or the second compound and / or any combination thereof). In particular, the first compound is used in combination with the second compound as necessary, as described herein.

[0019] In another aspect, the present invention provides a method for preventing, reducing or eliminating toxicity caused by acetaminophen (APAP) or its derivatives, the method comprising administering a compound (the first compound and / or the second compound and / or any combination thereof) to a subject in need of it in an amount effective to prevent, reduce or eliminate toxicity caused by APAP.

[0020] In some embodiments, the first compound comprises a second compound selected from the group consisting of Eudragit S100, Pluronic F68, Naringenin, Kaempferol, and any combination thereof. In some embodiments, the compound comprises a second compound selected from the group consisting of mannitol, sucralose, luteolin, and any combination thereof.

[0021] The use of the compounds described herein (the first compound and / or the second compound and / or any combination thereof) for producing an agent (e.g., an antidote) for preventing, reducing or eradicating acetaminophen (APAP)- or its derivative-induced nephrotoxicity (e.g., as an acetaminophen toxicity preventive agent or inhibitor) is also provided. Further provided is a composition for preventing, reducing or eradicating acetaminophen (APAP)-induced nephrotoxicity, which comprises the compounds described herein (the first compound and / or the second compound and / or any combination thereof).

[0022] In a further aspect, the present invention provides a method of administering APAP for treating a condition treatable by APAP in combination with one or more of the antidote compounds described herein. Also provided is a combination of APAP in combination with one or more of the antidote compounds described herein.

[0023] Details of one or more embodiments of the present invention are set forth in the following description. Other features or advantages of the present invention will become apparent from the following detailed description of some embodiments and the appended claims.

[0024] Detailed Description of the Invention 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 belongs.

[0025] As used herein, the articles “a” and “an” mean one or more (i.e., at least one) for the grammatical purpose of the article. By way of example, “an element” means one element or more than one element.

[0026] The terms "comprise" or "comprising" are generally used to mean "include / including," which means to permit the presence of one or more features, components, or constituent elements. The terms "comprise" or "comprising" encompass the terms "consists" or "consisting of."

[0027] As used herein, the terms “about” or “approximately” mean a degree of acceptable deviation as understood by those skilled in the art, which may vary to some extent depending on the context in which they are used. Generally, “about” or “approximately” can mean a number that is within a range of ±10% of the cited value.

[0028] This invention discloses that one or more of the compounds described herein have the effect of preventing, reducing, or eradicating toxicity caused by acetaminophen (APAP). Accordingly, this invention provides the use of one or more of the compounds described herein for the production of agents (e.g., acetaminophen toxicity inhibitors or inhibitors) for preventing, reducing, or eradicating toxicity caused by APAP. This invention also provides a method for preventing, reducing, or eradicating toxicity caused by APAP by administering an effective amount of one or more of the compounds described herein to a subject in need. This invention further provides a composition comprising one or more of the compounds described herein for use in preventing, reducing, or eradicating toxicity caused by APAP.

[0029] As used herein, the term "acetaminophen (APAP)" is intended to encompass chemical derivatives of the acetaminophen structure having equivalent pharmaceutical effects.

[0030] As used herein, the toxicity caused by APAP may include nephrotoxicity and / or hepatotoxicity. Nephrotoxicity and hepatotoxicity may include both functional toxicity and histological changes in the kidneys and liver. Liver damage includes injury, damage or loss of hepatocytes or tissues, resulting in abnormal liver function or liver protein content. In some embodiments, the liver injury described herein is acute liver injury, meaning liver injury that develops relatively rapidly, for example, within a period of less than 12 weeks, particularly less than 6 weeks, from the onset of symptoms. In some embodiments, patients with acute liver injury do not have a background of chronic liver disease. Liver function can be determined by many routine assays, such as alanine aminotransferase (ALT) or aspartate transaminase (AST) analysis for liver function. Renal damage includes injury, damage or loss of renal cells or tissues, resulting in abnormal renal function. Such renal injury can be identified, for example, by a decrease in glomerular filtration rate, a decrease in urine output, an increase in serum creatinine, or an increase in serum cystatin C. In some embodiments, the renal injury described herein is acute renal injury, which may mean, for example, a sudden or rapid decline in renal filtering function within 14 days, preferably within 7 days, more preferably within 72 hours, and even more preferably within 48 hours. Renal function can be determined by a number of routine assays, such as creatinine or blood urea nitrogen (BUN) measurements.

[0031] An increase in the level of a toxicity indicator or condition may be used as an indicator of the induction or occurrence of toxicity (toxic condition) compared to its control (or normal) level. As used herein, “normal level” or “control level” means a value that is within the acceptable range of values ​​that a person skilled in the art and / or a medical professional, such as a physician, would expect to be a healthy individual or a population with similar physical characteristics and medical history. A “reduced” level of a toxicity indicator or condition may be used as an indicator of the reduction or elimination of toxicity compared to that of the corresponding toxic condition. In particular, if the level of a toxicity indicator or condition decreases to or further than the normal or control level, the toxicity may be considered “eradicated.”

[0032] Toxicity, such as nephrotoxicity and / or hepatotoxicity, as used herein may be caused by an overdose of APAP. An overdose may refer to the administration of a dose exceeding the useful or standard dose, which is the effective dose approved by a drug regulatory authority such as the Food and Drug Administration, or prescribed by a physician for the treatment or prevention of a disease condition or the relief of symptoms of a disease. For example, paracetamol tablets are the current APAP drug approved on the market for oral administration, and in human adults, its standard dose is 500 mg to 1 g of paracetamol, taken as needed, every 4 to 6 hours, up to 4 times a day. An overdose of APAP means, for example, an overdose of 5%, 10%, 20%, 30%, 50%, 75%, 100%, or more than the useful or standard dose of APAP.

[0033] As used herein, the term “to treat” refers to therapeutic means for a disease or symptoms or conditions of a disease, including, but not limited to, applying or administering one or more active agents to a subject suffering from the disease, symptoms or conditions of the disease, or an exacerbation of the disease. The objective of therapeutic means is to treat, cure, reduce, alleviate, modify, improve, or influence the disease, symptoms or conditions of the disease, the impairment caused by the disease, or an exacerbation of the disease.

[0034] As used herein, the terms “individual” or “subject” include human or non-human animals, particularly mammals, such as companion animals (dogs, cats, etc.), livestock (cattle, sheep, pigs, horses, etc.), or laboratory animals (rats, mice, guinea pigs, etc.).

[0035] As used herein, the term “effective dose” refers to the amount of the active ingredient that achieves the desired biological efficacy or therapeutic effect in the subject being treated, for example, to prevent or reduce toxicity in the liver or kidneys of a subject receiving an overdose of APAP.

[0036] For transport and ingestion, an effective amount of the active ingredient according to the present invention can be formulated with a pharmaceutically acceptable carrier to form a suitable pharmaceutical composition. Depending on the route of administration, the pharmaceutical composition of the present invention preferably contains about 0.1% to about 100% by weight of the active ingredient, based on the total weight of the composition. As used herein, the term “pharmaceutically acceptable” means that the carrier is compatible with the active ingredient of the composition (and does not affect the effect of the active ingredient), and preferably the carrier can stabilize the active ingredient and is safe for the subject being treated. The carrier may be a diluent, vehicle, excipient, or medium for the active ingredient. The compositions of the present invention can provide an immediate, sustained, or delayed release effect of the active ingredient after administration to a patient. According to the present invention, the forms of the compositions may be tablets, pills, powders, lozenges, packets, troches, elixirs, suspensions, lotions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injections, and packaged powders.

[0037] The compositions of the present invention can be delivered orally, parenterally (such as intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermally, as suppositories, and intranasally, via physiologically acceptable routes. For parenteral administration, it is preferable to use the compositions in the form of a sterile aqueous solution that may contain sufficient salts or other substances, such as glucose, to make the solution isotonic with respect to blood. The preparation of suitable parenteral compositions under sterile conditions can be achieved using standard pharmacological techniques well known to those skilled in the art, and requires no additional creative effort.

[0038] The present invention also provides a method of administering APAP to treat a condition treatable by APAP (e.g., pain), characterized in that APAP is administered simultaneously or sequentially in combination with one or more detoxification compounds described herein. In certain embodiments, APAP can be administered in an overdose with reduced or no toxicity compared to the administration of the same dose of APAP alone without one or more detoxification compounds described herein. For example, APAP may be administered to an adult in doses of 4 g or more per day, for example, 5 g or more, 6 g or more per day, 7 g or more per day, 8 g or more per day, 9 g or more per day, or 10 g or more per day.

[0039] The present invention further provides combinations of APAP and one or more detoxification compounds as described herein. In certain embodiments, the combination includes amounts of APAP higher than the usual single dose (e.g., 500 mg for adults), such as 600 mg or more, 700 mg or more, 800 mg or more, 900 mg or more, or 1,000 mg or more.

[0040] The present invention will be further illustrated by the following embodiments, which are provided for demonstrative purposes rather than limitation. [Examples]

[0041] 1. Materials and Methods 1.1 Animals Male Sprague Dolly rats (weighing 220-300g) were obtained from Dr. Gonzalez at the American Country Health Research Institute (USA), and introduced with three male and four female mice, which reproduced spontaneously. All experiments were conducted in accordance with the National Institutes of Health animal guidelines. All mice were housed in rooms with air / humidity control and a 12-hour light / dark cycle, and had free access to food and water throughout the experiments.

[0042] 1.2 APAP-induced toxicity in animal models In a single-dose study investigating the detoxification effect of APAP-metabolizing enzyme inhibition on APAP-induced nephrotoxicity, rats were randomly divided into three treatment groups: (1) Normal control group (NC, n=5): Normal SD rats were orally administered saline at a dose of 1 mL / kg four times daily; (2) APAP control group (APAP, n=5): Normal SD rats were orally administered a single dose of APAP in saline at a dose of 1 g / kg (1,000 mg / kg); (3) (4) Positive control group (NAC, n=5): Normal SD rats were orally administered APAP and N-acetylcysteine ​​(NAC) in saline at doses of 1 g / kg and 140 mg / kg as single oral doses; (5) Various selected antidote test groups (each group, n=5): Normal SD rats were administered APAP in saline at a dose of 1,000 mg / kg, and various antidotes as single oral doses of 200 mg or less per 60 kg of body weight. Furthermore, in accordance with the US FDA guidance "Assessment of the maximum safe starting dose in initial clinical trials for therapies in healthy adult volunteers," the HED (human equivalent dose) for a 60 kg adult can be calculated as follows: HED = animal dose (1,000 mg / kg in rats) x human body weight (60 kg) / 6.2 = 9.677 g (approximately 10 g).

[0043] 1.3 Blood sampling At the end of the procedure, the animals were sacrificed under diethyl ether anesthesia. Blood was collected from the mouse hearts into heparin tubes and the plasma was separated by centrifugation at 13,000 xg at 4°C for 5 minutes. Aliquots of the plasma were transferred to Eppendorf tubes and stored at -80°C until analysis.

[0044] 1.4 Serum biochemical investigation of renal function Serum creatinine and BUN levels were measured at 340 nm and 510 nm, respectively, using commercially available kits (BEN) (Biochemical Enterprise, Milano, Italy) CR280 and BK151, on an automated biochemical analyzer (ChemWell, Palm City, FL).

[0045] 1.5 Measurement of liver AST and ALT Plasma enzyme activity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) was measured at 37°C using a Synchron LXi 725 (Beckman Instruments, Palo Alto, CA, USA) equipped with a kit provided by the manufacturer.

[0046] 1.6 Histological examination The kidney tissue was fixed in 10% neutral formalin for 48–72 hours. The tissue was then trimmed and prepared for standard histopathological examination. The tissue was embedded in paraffin wax, and sections 4–5 mm thick were cut. All tissue sections were stained with hematoxylin and eosin (H&E) and then examined under a light microscope (Olympus BX51, Tokyo, Japan). Rat renal lesions were evaluated according to Zhang et al. (2008) and classified into five categories using a 0–5 scale: where 0 = normal tissue structure; 1 = degeneration of tubular epithelial cells, no significant necrosis / apoptosis; 2–5: <25%, <50%, <75%, and ≥75% tubules show necrosis / apoptosis of tubular epithelial cells, respectively, accompanied by other concomitant changes.

[0047] 1.7 Statistical analysis All data were expressed as mean ± standard deviation (SD), and significance was determined by calculating the results using ANOVA. The calculation was performed using the Statistical Package of the Social Science program (version 13, SPSS Inc.), followed by post-hoc tests to examine the minimum significant difference for multiple comparisons, confirming that the significant differences between groups and the mean differences between groups were statistically significant. p < 0.05.

[0048] 2. Results At the end of the experiment, the body weight, liver weight, and relative kidney weight of the experimental animals were measured. There were no statistically significant differences compared to the control animals.

[0049] Toxicity, including nephrotoxicity and hepatotoxicity, was successfully induced by oral administration of APAP at a single dose of 1,000 mg / kg once daily. In the toxic control group, serum BUN (87.8±6.6 mg / dL) and creatinine (1.13±0.17 mg / dL) were significantly increased (p < 0.005) compared to the normal control group (18.7±2.5 and 0.29±0.04 mg / dL, respectively), indicating renal impairment in the toxic control group; and plasma AST levels (591.0±59.2 IU / L) and plasma ALT levels (382.3±32.1 IU / L) were significantly increased compared to the normal control group (190.0±27.2 IU / L and 49.9±4.7 IU / L, respectively), indicating hepatic impairment in the toxic control group. To assess the detoxification effects against APAP-induced toxicity, a first group of compounds, including Eudragit S100, Pluronic F68, naringenin, and kaempferol, and a second group of compounds, including mannitol, sucralose, and luteolin, were tested. The results are shown in Table 1.

[0050] Table 1 shows that the tested compounds are effective as antidotes against the toxicity (nephrotoxicity and hepatotoxicity) caused by APAP. [Table 1]

[0051] As shown in Table 1, the tested compounds, including those from Group 1 (Eudragit S100, Pluronic F68, Naringenin, Kaempferol) and Group 2 (Mannitol, Sucralose, Luteolin), are effective in reducing or eliminating the toxicity (nephrotoxicity and hepatotoxicity) caused by APAP. In particular, the combination of Naringenin, Pluronic F68, and Eudragit S100 exhibits excellent detoxification activity. Furthermore, combining one of the Group 1 compounds with one or more of the Group 2 compounds shows superior (synergistic) detoxification activity compared to the Group 1 or Group 2 compounds alone.

[0052] Furthermore, as shown in the histological examination results in Figure 1, severe renal lesions such as necrosis, congestion, and extravasation of red blood cells were observed in the APAP overdose group (Figure 1B). In contrast, such renal lesions were reduced to mild to moderate levels in the NAC group (Figure 1C), and significantly reduced to near-normal control levels in the group administered the test compound of the present invention (Figure 1D).

[0053] Based on the above, the compounds described herein can be used as antidotes to prevent, reduce, or eliminate the toxicity (nephrotoxicity and hepatotoxicity) caused by APAP. These compounds belong to the category of pharmaceutically acceptable excipients or natural plant phenol compounds, all of which have been deemed safe through animal studies. Accordingly, the present invention provides methods and compositions for preventing, reducing, or eliminating the toxicity caused by acetaminophen (APAP) using one or more such antidotes. The present invention also provides methods for administering APAP to treat APAP-treatable conditions, in combination with one or more such antidotes, which result in reduced or eliminated toxicity compared to administration of APAP alone. Combinations of APAP and one or more such antidotes are also provided.

Claims

1. A pharmaceutical composition for preventing, reducing, or eliminating nephrotoxicity caused by acetaminophen (APAP), (i) A pharmaceutical composition comprising an effective amount of mannitol, or a combination of mannitol and one or more compounds selected from the group consisting of Eudragit® S100, Pluronic® F68, Kaempferol, and sucralose.

2. The pharmaceutical composition according to claim 1, wherein the composition is used as an antidote, an acetaminophen toxicity inhibitor, or an inhibitor.

3. The pharmaceutical composition contains the following effective amounts: (iii) A combination of Eudragit® S100 and mannitol; (iv) A combination of Pluronic® F68 and mannitol; (vi) A combination of kaempferol, mannitol and sucralose; or (vii) combination of mannitol and sucralose; A pharmaceutical composition according to claim 1 or 2, comprising:

4. The pharmaceutical composition contains naringenin, luteolin, menthol, polyethylene glycol sorbitan monolaurate, microcrystalline cellulose, Brij® 35, saccharin, Cremofor RH40, crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, Dextrate NF hydrate, citric acid, Cremofor® EL, Aerosil® 200, Myrj® 52, sorbic acid, lemon oil, hydroxypropyl cellulose, sorbitol, acesulfame potassium, hydroxypropyl methylcellulose, lactose monohydrate, maltodextrin, Brij® 58, Brij® 76, Tween® 80, Tween® 40, polyethylene glycol (PEG 400), PEG 4000, PEG 8000, and Span®. The pharmaceutical composition according to claim 1 or 2, further comprising an additional compound selected from the group consisting of 60, sodium benzoate, hydroxyethyl methylcellulose, methylcellulose, Span® 80, sodium cyclamate, glyceryl behenate, oxide red, glycerin monostearate, copovidone K28, starch acetate, magnesium stearate, sodium lauryl sulfate, providedon K30, and PEG 2000.

5. The pharmaceutical composition according to claim 1 or 2, wherein nephrotoxicity is defined as damage to the kidneys.

6. The pharmaceutical composition according to claim 1 or 2, wherein the nephrotoxicity is acute kidney injury.

7. The use of a compound for the manufacture of a drug for preventing, reducing, or eliminating nephrotoxicity caused by acetaminophen (APAP), wherein the compound is (i) Mannitol, or a combination of mannitol and one or more compounds selected from the group consisting of Eudragit® S100, Pluronic® F68, Kaempferol, and sucralose.

8. The use according to claim 7, wherein the compound is used as an antidote, an anti-acetaminophen toxicity agent, or an inhibitor.

9. The compounds are as follows: (iii) A combination of Eudragit® S100 and mannitol; (iv) A combination of Pluronic® F68 and mannitol; (vi) combinations of kaempferol, mannitol and sucralose; and (vii) combination of mannitol and sucralose; The use according to claim 7 or 8, which is a combination selected from the group consisting of the following.

10. The compound is naringenin, luteolin, menthol, polyethylene glycol sorbitan monolaurate, microcrystalline cellulose, Brij 35, saccharin, Cremofor® RH40, crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, Dextrate NF hydrate, citric acid, Cremofor® EL, Aerosil® 200, Myrj® 52, sorbic acid, lemon oil, hydroxypropyl cellulose, sorbitol, acesulfame potassium, hydroxypropyl methylcellulose, lactose monohydrate, maltodextrin, Brij® 58, Brij® 76, Tween® 80, Tween® 40, polyethylene glycol (PEG) 400, PEG 4000, PEG 8000, Span® The use according to claim 7 or 8, in combination with an additional compound selected from the group consisting of 60, sodium benzoate, hydroxyethyl methylcellulose, methylcellulose, Span 80, sodium cyclamate, glyceryl behenate, oxide red, glycerin monostearate, copovidone K28, starch acetate, magnesium stearate, sodium lauryl sulfate, providedon K30, and PEG 2000.

11. The use according to claim 7 or 8, wherein nephrotoxicity is defined as damage to the kidneys.

12. The use according to claim 7 or 8, wherein the nephrotoxicity is acute kidney injury.

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