BACKGROUND

Field

The present disclosure relates to compounds and/or materials for use in mitigating toxicity of an aflatoxin. More particularly, the compounds and/or materials can be used for mitigating toxicity of the Aflatoxin B1 in order to mitigate liver injury caused by the aflatoxin.

Description of Related Art

Previously, it has been known that aflatoxins are poisonous carcinogens and mutagens that are generated by some molds that are commonly found in decaying vegetation or soil. The aflatoxins are often found to be contaminants in various staple commodities, which results in exposure to animals, such as humans and agricultural animals. Unfortunately, animals that consume the aflatoxin can pass it to the human in eggs, milk products, or meat products. As a result, humans, especially children, can suffer the adverse effects of aflatoxin exposure.

Some aflatoxins are mycotoxins, which are secondary metabolites of several fungi produced in particular conditions of humidity, temperature and pH. Among mycotoxins, Aflatoxin B1, produced byAspergillusspecies are of special concern. These fungi infect food crops, such as maize and tree nuts, leading to a global exposure of about 4.5 billion people a year to Aflatoxin B1 through diet. The International Agency for Research on Cancer (IARC) has classified “naturally occurring mixture of Aflatoxin B1” as a Group 1 human carcinogen, and in this group Aflatoxin B1 is the most toxic agent. Aflatoxin B1 exposures leads to acute effects, including rapid death, and chronic outcomes such as hepatocarcinoma and stunned growth in children. It has also been demonstrated that even low toxin levels in the diet can cause to multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus along with effecting immune, reproductive, and digestive systems.

Overall the putative mechanism of action of Aflatoxin B1 in the body is complex and involves multiple transformation steps and hosts of Phase I (Cyp450) and Phase II (UDP-GT and GST) metabolic enzymes, proteins and nucleic acids in the liver (hepatocyte cells) before Aflatoxin B1 is biotransformed into its toxic metabolite Aflatoxin B1-exo-8,9-epoxide (AFBO). The AFBO interacts with DNA to form AFB-DNA adducts causing DNA breakages. The CYP1A2 is the principal metabolizer of Aflatoxin B1 at low concentrations while the reverse is true for CYP3A4. The accumulation of Aflatoxin B1 and AFBO also depletes the glutathione (GSH) due to the formation of high amounts of epoxides and other reactive oxygen species (ROS). These synergistic toxic events induces G:C to T:A transversions at certain sites in DNA and promotes tumorigenesis and ultimately hepatocellular carcinoma (HCC).

Currently, there are no known countermeasures that can selectively block or reduce Aflatoxin B1 toxicity after exposure, and the available options are only limited to relieve the resulting symptoms for individuals exposed to Aflatoxin B1. For example, atropine is used to treat Aflatoxin B1 poisoning that accompanies with emesis or abdominal pain. Among potential prophylactic agents, Oltripraz, an antischistosomal agent, has attracted most interest in recent years, but due to undesirable side effects and therapeutic costs it has limited long-term daily use.

This lack of effective countermeasures against Aflatoxin B1 toxicity is also of significant relevance to military. There is considerable evidence that Iraq weaponized Aflatoxin B1 in the 1980s. Though the resulting effects of using Aflatoxin B1 would be too slow to have a tactical advantage on the battlefield, it could still be used as a biological weapon to spread fear and panic in the general public and to contaminate food supplies to cause economic damage. Further the effects of inhaled Aflatoxin B1 from weapons and its co-exposure with other bioweapon toxins such as ricin, botulinum and enterotoxins, are not known. Hence, the demand for effective Aflatoxin B1 countermeasures is unmet which limits both the military biodefense security and pose grave danger to public health. Examples of treatments of Aflatoxin B1 toxicity include U.S. No. 2009/0249551 and U.S. No. 2003/0191137, which are incorporated herein by specific reference.

Thus, there is a need for a compounds and composition that can be used for mitigating effects of an aflatoxin-induced liver toxicity or injury.

SUMMARY

In some embodiments, a method for providing a therapy to a subject that has been exposed to an aflatoxin (e.g., Aflatoxin B1) can include: administering a compound having a structure of Formula 1 to the subject after exposure to the aflatoxin:



wherein: R1, R2, R3, R4, R5and/or R6are each individually a chemical moiety and n is 1, 2, 3, 4, or 5. In some aspects, R1includes a C1-C12alkyl, secondary C1-C12alkylamine or tertiary C1-C12alkylamine, any substituted or unsubstituted; R2includes a C1-C12alkyl or cycloalkyl, any substituted or unsubstituted; R3includes a hydroxyl, halogen, cyano, or C1-C12alkylhydroxyl, substituted or unsubstituted; R4includes a hydrogen, hydroxy, halogen, cyano, phosphate, sulfate, C1-C12alkyl, substituted or unsubstituted; R5includes a C4-C6cycloalkyl or C4-C6heterocycloalkyl, any substituted or unsubstituted; and R6includes hydrogen or C1-C12alkyl, substituted or unsubstituted. In some aspects, the compound has a structure of Amprenavir or a derivative thereof, prodrug thereof, salt thereof, or stereoisomer thereof, or having any chirality at any chiral center, or tautomer, polymorph, solvate, or combination thereof. In some embodiments, the compound is an Amprenavir prodrug that has a structure of Amprenavir Phosphate:

In some embodiments, the Amprenavir is provided in a therapeutically effective amount to mitigate liver injury in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit onset of liver injury in the subject prior to detecting liver injury. I

In some embodiments, the subject is exposed to Aflatoxin B1. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit transformation of the Aflatoxin B1 to Aflatoxin B1-exo-8,9-epoxide (AFBO) in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit AFBO interacting with DNA in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit G:C to T:A transversions in DNA in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit tumorigenesis in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit formation of hepatocellular carcinoma in the subject.

In some embodiments, the Amprenavir is provided in a therapeutically effective amount as a prophylactic prior to detecting liver injury in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount after detecting liver injury in the subject to inhibit development of liver injury symptoms. In some aspects, the Amprenavir is provided in a therapeutically effective amount to reduce symptoms of liver injury in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to inhibit Aflatoxin B1 and/or AFBO from depleting glutathione in the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount to improve liver function of the subject after a liver injury from exposure to Aflatoxin B1.

In some embodiments, the Amprenavir is provided in a therapeutically effective amount of 120 mg to 2,800 mg per day. In some aspects, the Amprenavir is provided in a therapeutically effective amount of 0.1 mg/kg to 100 mg/kg of the subject. In some aspects, the Amprenavir is provided in a therapeutically effective amount at least once daily.

The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.

