Use of radiomitigating compounds for prevention and treatment of acute radiation syndromes

Abstract

Methods and compositions for the prevention and treatment of acute radiation syndromes and radiation illnesses from exposure to toxic radiation including radiation therapy treatments, the methods and compositions comprise Indole derivatives and their administration to a living being, where Indole derivative compositions include a racemic mixture of R-Indole derivative and S-Indole derivative enantiomers, or isolated R-Indole derivative enantiomers, or S-Indole derivative enantiomers. The compositions of the invention are suitable for treating and / or preventing radiation injury, and embodiments may comprise functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof. Indole derivative compositions include compositions having the formulae: (S)-1-(3-Indolyl)-2-(methylamino) ethanol; (S)-α-[(Methylamino)methyl]-1H- Indole-3-methanol, indolo[a]pyrrolo[3,4-c] carbazole integrin composition. The method involves administering an effective amount of an indole composition in a pharmaceutically acceptable form, to provide a fast-acting medical countermeasure with radioprotective and radiomitigative functionalities for treatment or prevention of radiation illnesses.

Description

USE OF RADIOMITIGATING COMPOUNDS FOR PREVENTION AND TREATMENT OF ACUTE RADIATION SYNDROMESBACKGROUND OF THE INVENTION1. Field of the Invention

[0001] The field of the invention relates to prevention and treatment of acute radiation syndromes, and more particularly to methods and compositions for treating and preventing acute radiation syndromes and other radiation illnesses from exposure to toxic radiation, and more particularly relates to compositions and methods comprising radioprotectant compositions of one or more heterocyclic compounds and methods for their production and administration.2. Brief Description of the Related Art

[0002] Radiation typically can affect humans. Some forms of radiation, which arc non-ionizing radiation like of light, radio waves, microwaves, and radar are in common use and generally do not typically damage the tissue of a living being. However, ionizing radiation, such as for example, X- rays, gamma rays, and particle bombardment (neutron beam, electron beam, protons, mesons, and others) is very hannful and typically causes immediate effects on the tissue of living beings, such as humans and other mammals. Exposure to radiation may cause cancer and other illnesses. The risk for cancer correlates with the amount of exposure and even with very low dosage exposure may build and can be cumulative. When living beings, such as humans (or other animals) are exposed to very large doses of ionizing radiation, then radiation sickness may occur. This is referred to as acute radiation sickness or syndrome, where a living being is exposed to a single large dose of radiation (ionizing radiation). Even if exposure does not immediately produce symptoms, delayed medical problems such as cancer and premature aging, can happen over a long period of time, and typically this is referred to a chronic exposure. Radiation sickness can have different levels of severity depending on the type and amount of radiation, as well as the location of the living being where the radiation exposure took place. In has been found that bone marrow and gastrointestinal tract are more sensitive to radiation injury . Radiation exposure can be due to purposeful exposure, such as a medical treatment (e.g., radiation therapy) to attack cancer in a living being, or for a medical test, such as imaging (e.g., an x-ray or other scan) of a living being to assess a potential medical condition. Other radiation exposure is not purposeful and may be due to accidental exposure.

[0003] Radioprotective agents are defined as compounds that are administered before exposure to ionizing radiation to reduce its damaging effects, including radiation-induced lethality. They have applications in radiological terrorism, military scenarios, clinical oncology, space travel, radiation site cleanup.

[0004] To date, there is no effective drug to ameliorate radiation injury' after accidental exposureto ionizing irradiation, or after damage to healthy tissues during therapeutic radiation or radiomimetic agents; nor is there an effective prophylactic drug to prevent or minimize such injuries when administered before the event (for example, to first responders).

[0005] A need exists for radio protective compositions and concomitant treatment protocols that may be administered as a protectant to guard against potential exposure to radiation, and for radio protective compositions that may be used to treat radiation exposure and illness. A further need exists for radio protective compositions that ameliorate radiation injury after accidental exposure to ionizing irradiation, or after damage to healthy tissues during therapeutic radiation or radiomimetic agents; as well as an effective prophylactic drug to prevent or minimize such injuries when administered before the event (for example, to first responders).SUMMARY OF THE INVENTION

[0006] The invention relates to non-toxic tissue-stimulating heterocyclic compounds ("TSHCs" or "TSHC radioprotectant"), which may comprise heterocyclic aromatic compounds, designed to be effective as drugs against radiation damage. Importantly, the anti-radiation compositions of the invention can protect when administered several hours after exposure to radiation, making them extremely suitable for use in accidental exposure to radiation.

[0007] The compositions of the invention, including those referred to as TSHCs are designed to be safe and effective for acute radiation syndrome (ARS) survival benefits. Administration of a TSHC composition before or after exposure to radiation can protect against acute radiation injury and syndromes. According to some embodiments, the TSHC compositions may comprise or contain a heterocyclic aromatic compound that includes a fused bicyclic benzene and pyrrole ring. According to some embodiments, the radioprotectant compositions of the invention, and treatment methods based their administration to a living being, may comprise an Indole derivative compound..

[0008] The invention provides methods and compositions for the prevention and treatment of acute radiation syndromes and radiation illnesses from exposure to toxic radiation. Embodiments of compositions according to the invention encompass non-toxic, tissue-stimulating heterocyclic compounds ("TSHCs"). According to some preferred embodiments the TSHC may include as protective agent, one or more Indole based compounds or derivatives thereof. According to some embodiments, the TSHCs may comprise Indole based compounds or derivatives, provided in the forms of compositions comprising a racemic mixture of an R-Indole compound and an the S-Indole enantiomer thereof; and compositions comprising S-Indole compounds. The compositions of the invention are suitable for treating and / or preventing radiation injury, and according to some preferred embodiments provide compositions comprise functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof, which according to some preferred embodiments the TSHC has the formula (S)-l-(3-Indolyl)-2-(methylamino) ethanol; (S)-a-[(Methylamino )methyl]-lH- Indole-3 -methanol. indolo[a]pyrrolo[3.4-c]carbazole. The TSHC radioprotectant compositions according to the invention preferably include one or more of: (S)-l - (3-Indolyl)-2-(methylamino) ethanol; (S)-a-[(Methylamino)methyl]-lH- Indole-3-methanol; and / or indolo[a]pyrrolo[3,4-c] carbazole, including functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof and integrin for inflammation. The compositions of the invention include an effective amount of an the TSHC, which according to some preferred embodiments comprises an Indole based compound as the active agent. The TSHC, in a pharmaceutically’ acceptable form, is a fast-acting medical countermeasure w ith radioprotective and radiomitigative functionalities for treatment or prevention of Acute Radiation Syndromes (Hematopoietic Syndrome (ARS-H), Cardiovascular / Central Nervous System Syndrome (ARS-C) and Gastrointestinal Syndrome (ARS-G)); acute radiation sickness, radiation injury or myelosuppression. Similarly, the invention may be used in patients undergoing internal or external beam radiation or proton beam therapy, before or after treatment of cancer or other diseases, especially important for pediatric patients. Described are uses to reduce, prevent, or treat cell damage from radiation, where the agent is an Indole Derivative Radioprotectant and exhibits great potency, efficacy and safety.

[0009] The invention relates to the field of drug development, methods and compositions against acute radiation injury, protecting and mitigating radiation damage and administration of a TSHC Radioprotectant, a fast-acting medical countermeasure with radioprotective and radiomitigative and tissue functionalities for defense from and treatment of radiation injury or sickness, acute radiation syndrome, or myelosuppression before or after exposure to ionizing radiation. Methods for reducing or preventing the effects of radiation in healthy cells before, during, or after a radiological or nuclear emergency, radiation therapy or a radiodiagnostic procedure are provided. The radiation causing the harmful effects that the Indole Derivative Radioprotectant compositions of the invention are designed to protect, mitigate and / or treat may be from alpha particles, beta particles, neutrons, photons, protons, external beam, sealed or unsealed source exposure, peptide receptor radionuclide therapy, high-energy electromagnetic waves, X-rays, alpha particle, proton therapy, photon therapy, or gamma radiation. The invention provides a method of treating a subject comprising administering as a radioprotectant an Indole Derivative, a functional analog, or derivative thereof. This invention can be used to treat the three forms of acute radiation syndromes, hematopoietic syndromes, (ARS-H), cardiovascular / central nervous system syndrome (ARS-C) and gastrointestinal syndrome (ARS-G). The drug may also be administered to a cancer patient prior to or after receiving external beam radiation therapy, radioimmunotherapy or internal radiation therapy, e.g., peptide receptor radionuclide therapy or targeted alpha therapy. The agent may’ be taken orally in tablet or capsule form and supports recovery’ of all three blood components (red andwhite cells, and platelets), and may even be administered 48 hrs. following exposure to radiation, enabling treatment of injuries to tissue, potentially for broad-spectrum indications. The drug has a direct alphal -adrenomimetic and vasoconstrictive effect and can increase tissue oxygen consumption.

[0010] The active pharmaceutical ingredient or moiety, a TSHC was developed. Protection against radiation damage is expected to occur if this TSHC Radioprotectant is administered either before or after exposure to radiation. The particularly preferred TSHC agent comprises an Indole based compound, is useful as a radioprotectant agent. Such agents find application in minimizing, reducing and / or preventing tissue, organ, bone, and DNA or RNA damage following intentional or accidental radiation exposure, as well as increasing the therapeutic efficacy of radiation therapies by protecting non-target tissue and organs from incidental radiation damage. It is an oral capsule designed to act as a defense against the potential damage of radiation therapy, particularly important for children receiving radiation treatment. Also provided herein are methods of protecting tissue from damage caused by radiation exposure, comprising contacting the tissue, organ, bone, DNA or RNA with a therapeutically effective amount of an Indole Derivative Radioprotectant.

[0011] According to some preferred embodiments, TSHC compositions of the invention comprise a direct alphal -adrenomimetic that increases arterial pressure and reduces pulse rate. As a direct alpha-adrenomimetic, this radioprotectant TSHC causes changes in microcirculation due to the vasoconstriction of pre-capillaries and the simultaneous increase in oxy gen consumption by7cells through the stimulation of tissue respiration. As a mitigator of radiation effects, the TSHC radioprotectant is designed to increase survival in multiple animal models and non-human primates when administered after irradiation. The damage-mitigating properties of this THSC radioprotectant are designed to increase under conditions of non-uniform irradiation.

[0012] In various embodiments, the disclosed methods include administering one or more of the TSHC compounds, including Indole based compounds, derivatives and compositions that include these TSHC compounds. Methods for treatment and / or prevention include administering a TSHC radioprotectant composition, including Indole based compounds, derivatives and compositions that include these derivatives. These compounds and compositions containing them serve as a radioprotectant and treatment for Acute Radiation Syndrome when administered to a subject. The protective mechanism of TSHC radioprotectant is the result of acute hy poxic effects in radiosensitive tissues. As a direct alphal -adrenomimetic, TSHC radioprotectant causes changes in microcirculation due to the vasoconstriction of pre-capillaries and the simultaneous increase in oxygen consumption by7cells through the stimulation of tissue respiration. The respiration of 100% oxy gen during irradiation decreases the radioprotective effects of the TSHC radioprotectant. As a radioprotector, the TSHC radioprotectant, is designed to provide protection against the adverseeffects of radiation illness. Suitable doses of the TSHC radioprotectant, including for example, the Indole based compounds, may be between 150 - 450 milligrams per day. For example, the method may employ administering from about 2.30 milligrams to about 6.90 milligrams per kilogram of body weight, per day to the subject, preferably in three doses every hour after or before exposure to therapeutic or non-therapeutic radiation. Preferably the treatment is by oral administration of the compound or compounds, optionally together for combination therapy, such as to raise the Indole concentration which may be or in combination with another radioprotectant such as an iodine- containing agent.

[0013] Administration of the Indole Derivative Radioprotectant compositions, preferably is done over a duration of time, which may comprise hours or days, administering periodically several times during a day (such as every hour, or other span), until the symptoms or measured quantity of radiation is no longer at a detectible level. According to some implementations, the Indole Derivative Radioprotectant compositions may be given for a period after the patient is asymptomatic or for a period when radiation is no longer detectible.

[0014] According to preferred embodiments, the active pharmaceutical agent is a tissuestimulating heterocyclic compound ("TSHC") , used interchangeably, as TSHC or is " TSHC Radioprotectant" .

[0015] The invention relates to methods and compositions against acute radiation injury for protecting and mitigating radiation damage with a TSHC, and according to preferred embodiments and implementations, with a TSHC comprising an Indole based compound, isomer derivative for an Indole based compound, examples of which TSHC compounds include: (S)-l-(3-Indolyl)-2- (methylamino)ethanol: (S)-a-[(Methylamino)methyl]-lH- Indole-3 -methanol, combination with ab integrin, a fast-acting medical countermeasure with radioprotective and radio mitigative functionalities for treatment of Acute Radiation Syndrome (ARS), also known as acute radiation sickness or related compound thereof, and radioprotection, radio mitigation and radio recovery methods for ionizing radiation energy exposure, radiomimetic exposure, or radio contamination. The intention is to expand access for the public and mitigators to treatment for evolving health needs as pertains to radiation and radio contamination exposure and more specifically Acute Radiation Syndrome.

[0016] Similarly, the invention may be used in patients undergoing internal or external beam radiation or proton beam therapy, before or after treatment of cancer or other diseases, especially important for pediatric patients. Described are uses to reduce, prevent, or treat cell damage from radiation, where the agent is an TSHC radioprotectant and exhibits great potency, efficacy and safety.

[0017] The invention pertains to a compound, as described in claim 1, formulated for treating acuteradiation syndrome (ARS) resulting from exposure to ionizing radiation. The compound, administered intravenously at a dose between 10-20 mg / kg before or within 24 hours post-exposure, exhibits efficacy in mitigating the detrimental effects of radiation on biological tissues. Additional!} , repeated daily administration for 3-5 days enhances its therapeutic benefits. The invention encompasses pharmaceutical compositions containing the compound and pharmaceutically acceptable carriers, facilitating its delivery and effectiveness. These compositions, administered to subjects in need, demonstrate promising outcomes in treating ARS. The invention extends to racemic and isolated derivatives of the compound, each tailored for specific therapeutic applications. These derivatives offer versatility and precision in targeting radiation-induced injuries across diverse patient populations. The invention encompasses methods for treating radiation-induced damage, including ARS and associated syndromes. These methods involve administering the compound or its derivatives to mitigate cellular damage, enhance tissue repair, and improve overall patient outcomes. The invention's applicability spans various scenarios, from medical emergencies such as nuclear disasters to routine radiation therapy in cancer patients. The invention addresses practical considerations, such as dosage, administration routes, and treatment regimens, ensuring optimal therapeutic effects while minimizing adverse events. Notably, the invention's efficacy is not limited to humans, extending its benefits to veterinary medicine and potentially other animal populations. The disclosed invention offers a promising avenue for mitigating the adverse effects of radiation exposure, underscoring its significance in both medical emergencies and routine clinical practice. Its broad scope, encompassing compounds, compositions, and methods, positions it as an asset in the field of radioprotection and radiation oncology.DETAILED DESCRIPTION OF THE INVENTION

[0018] The TSHC radioprotectant comprises or contain a heterocyclic aromatic compound that includes a fused bicyclic benzene and pyrrole ring. According to some embodiments, the radioprotectant compositions of the invention, and treatment methods based their administration to a living being, may comprise an Indole based compound that includes one or more Indole based compounds or derivatives. The compositions also include one or more other components, which may comprise excipients and binders for a tablet, pill or capsule form of the composition, or with a liquid or aqueous carrier in an injectable form or intravenous form.

[0019] According to some embodiments, the TSHC radioprotectant composition is provided in the form of a tablet formed with pharmaceutically' acceptable excipients and a dosage amount of an Indole derivative. The injectable form comprises the Indole derivative along with a suitable carrier. According to preferred compositions TSHC radioprotectant compounds, including Indole basedcompounds, may be provided in the forms of compositions comprising a racemic mixture of R- Indole based and S-Indole based enantiomers, and compositions comprising isolated S-Indole based enantiomers. Indole based compounds includes compounds that have the fused ring structure of the bicyclic benzene and pyrrole ring, and according to some preferred THSC radioprotectant compositions include additional branched chains on the pyrrole ring portion of the compound. The TSHC radioprotectant compositions of the invention are suitable for treating and / or preventing radiation injury, and according to some preferred embodiments provide compositions comprise functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof, which according to some preferred embodiments has the formula: (S)-l-(3-Indolyl)-2-(methylamino) ethanol; (S)-a-[(Methylainino)inethyl]-lH- Indole-3 -methanol, indolo[a]pyrrolo[3,4-c]carbazole, and (R)-l-(3-Indolyl)-2-(methylamino) ethanol; (R)-a-[(Methylamino)methyl]-lH- Indole-3 - methanol, indolo[a]pyrrolo[3,4-c]carbazole, and racemic mixtures thereof. Indole compositions also may include a racemic mixture of the S- and R- Indole compound forms. According to some embodiments and implementations, Indole Derivative Radioprotectant compositions according to the invention preferably include one or more of (S)-l-(3-lndolyl)-2-(methylamino) ethanol: (S)-a- [(Methylamino)methyl]-1H- Indole-3 -methanol, indolo[a]pyrrolo[3,4-c]carbazole, and (R)-l-(3- IndolyI)-2-(methylamino) ethanol; (R)-a-[(Methylamino)methyl]-lH- Indole-3 -methanol, indolo[a]pyrrolo[3,4-c]carbazole, and racemic mixtures thereof, which include mixtures of the S- and R- Indole based compound forms. Some preferred embodiments of the TSHC radioprotectant compositions include Indole compositions comprised of a racemic mixture of the S- and R- Indole based compound forms, and according to some embodiments may include functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof. The TSHC radioprotectant compositions of the invention include an effective amount of a TSHC radioprotectant, which may include the Indole based compositions described and disclosed herein.. The TSHC radioprotectant, in a pharmaceutically acceptable form, is a fast-acting medical countermeasure with radioprotective and radiomitigative functionalities for treatment or prevention of Acute Radiation Syndromes (Hematopoietic Syndrome (ARS-H), Cardiovascular / Central Nervous System Syndrome (ARS-C) and Gastrointestinal Syndrome (ARS-G)); acute radiation sickness, radiation injury or myelosuppression. Similarly, the invention may be used in patients undergoing internal or external beam radiation or proton beam therapy, before or after treatment of cancer or other diseases, especially important for pediatric patients. Described are uses to reduce, prevent, or treat cell damage from radiation, where the agent is an Indole Derivative Radioprotectant and exhibits great potency, efficacy and safety.

[0020] According to preferred embodiments and implementations, the tissue-stimulating heterocyclic compounds ("TSHCs" or "TSHC radioprotectant") comprise and Indole based compound of the following:where R is an alky l chain containing OH, NH, and one or more alky groups.

[0021] According to some embodiments the treatment compound of formula (I) may comprise an enantiomer compound with a chiral center, and preferably with the chiral center on the C atom of the alky chain that contains the OH substituent. The TSHC composition according to some embodiments, includes racemic mixtures of the S- and R- form of an enantiomeric treatment compound of formula (I).

[0022] According to some preferred embodiments, the TSHC Indole based compound and method of use for treatment or prevention of radiation syndrome comprises compound (I), where R is an alkyl chain containing OH, NH, and one or more alky groups, the terminal group of the alkyl chain is -CHv

[0023] The TSHC treatment composition and method of use for treatment or prevention of radiation syndrome, according to preferred embodiments and implementations, is:

[0024] The treatment compositions of the invention and methods for treating or preventing radiation syndrome by administering the treatment compositions, include one or more of the above THSC composition forms (as the treatment agent), and suitable carriers such as excipients and / or binders for pill forms of the composition, or aqueous type liquids for delivery through intravenous means.

[0025] According to a preferred implementation and embodiment, the method comprising administering an effective amount of the TSHC radioprotectant in a suitable biocarrier for administration to a living being, preferably a mammal, such as a human. According to on implementation the TSHC radioprotectant is provided as the S- enantiomer, or a racemic mixture of the S- and R- enantiomers of the indole compound. One preferred implementation of the TSHC radioprotectant is in the form of a TSHC radioprotectant composition comprising a) a compound selected from the group consisting of:and, and b) a biocompatible carrier in a fonn suitable for mammalian administration.

[0026] For reference, indole compositions are show n below comprising an S- enantiomer fonn:and an R- enantiomer form:

[0027] According to some alternate embodiments, the indole compounds may be provided in the form of functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R of an indole compound together with a biocompatible agent for administration to living beings, and more particularly to mammalian beings. The invention is designed to provide protective compositions that ameliorate radiation injury after accidental exposure to ionizing irradiation, or after damage to healthy tissues during therapeutic radiation or radio-mimetic agents, and are effective as prophylactic drugs to prevent or minimize radiation injuries when administered before a radiation exposing event. In the simplest form, the invention comprises a radioprotectant composition including an indole having the formula:and including functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof. The radio protectant composition preferably further comprises a biocompatible carrier in a form suitable for mammalian administration. The invention further comprises concomitant treatment protocols using tlie radioprotecti e compositions of the invention to prevent or treat radiation syndrome in a mammalian being. Preferred compositions comprise the S- enantiomer form of the indole composition, and other preferred compositions comprise a racemic mixture of the S- and R- enantiomers of the indole composition, and / or the functional analogs, and / or derivatives thereof.

[0028] The TSHC radioprotectant is a direct al -adrenomimetic that increases arterial pressure and reduces pulse rate. The protective mechanism of the TSHC radioprotectant is the result of acute hypoxic effects in radiosensitive tissues. As a direct al -adrenomimetic, TSHC radioprotectant causes changes in microcirculation due to the vasoconstriction of pre-capillaries and the simultaneous increase in oxygen consumption by cells through the stimulation of tissue respiration. The respiration of 100% oxygen during irradiation decreases the radioprotective effects of the TSHC radioprotectant.

[0029] As a radioprotector, the TSHC radioprotectant , may be administered to provide protection against exposure to radiation. Suitable doses of the TSHC radioprotectant may be between 150 - 450 milligrams per day. For example, the treatment and preventative methods may employ administering from about 2.30 milligrams to about 6.90 milligrams per kilogram of body weight, per day to the subject, preferably in three doses every hour after or before exposure to therapeutic or non-therapeutic radiation.

[0030] The TSHC radioprotectant is designed to stimulate oxygen consumption by bone marrow cells under conditions of oxygen deficiency. This effect, mediated through the al -adrenergic receptor, is believed to contribute to the high radioprotective efficacy of Indole Derivative Radioprotectant. By inducing acute tissue hypoxia, the TSHC radioprotectant enhances the radioresistance of radiosensitive tissues.

[0031] The mechanism of action of indole in radiation countermeasures is believed to involve scavenging free radicals and enhancing DNA repair, thereby inhibiting oxidation and protecting cells.

[0032] Additionally, gut microbiota-derived metabolites like indole 3 -propionic acid (IPA) have been found to protect against radiation toxicity by activating enteric PXR / ACBP signaling and retaining intestinal protein profiles in radiation-challenged hosts. These findings suggest that indole-based compounds play a crucial role in mitigating the harmful effects of ionizing radiation by enhancing cellular protection mechanisms and reducing tissue damage.

[0033] According to some preferred embodiments and implementations, where the TSHC radioprotectant comprises an Indole based compound, the indole S -isomer refers to a specific enantiomer (mirror image isomer) of an indole compound, where the stereochemistry at the chiral center is designated as the S configuration based on the Cahn-Ingold-Prelog priority rules. It contains only one specific spatial arrangement of atoms.- An indole S-isomer is a single cnantiomcrically pure form, while a racemic isomer is a 1 : 1 mixture of both enantiomers.- Enantiomers like the indole S-isomer can exhibit different biological activities and pharmacological properties in chiral environments like the human body.- Racemic mixtures are optically inactive (do not rotate plane-polarized light), whereas each pure enantiomer rotates light in opposite directions.- Racemic mixtures can sometimes have different physical properties (melting point, solubility) compared to the individual enantiomers.- Pharmaceuticals may be marketed as the single enantiomer (e.g. indole S-isomer) or as the racemic mixture, depending on factors like potency, and safety considerations.Stereochemistry:- An indole S-isomer is a single enantiomer, meaning it has a specific three-dimensional arrangement of atoms around the chiral center(s) with an S configuration.- A racemic isomer (or racemate) is an equimolar mixture of both the R and S enantiomers of the indole compound.Molecular composition:- An indole S-isomer is a single stereochemically pure form containing only one enantiomer.- A racemic isomer consists of equal amounts of both enantiomers in the same molecule.Optical activity:- An indole S-isomer rotates plane-polarized light in one direction (either clockwise or counterclockwise) due to its chiral nature.- A racemic isomer is optically inactive as the equal amounts of opposite enantiomers cancel out each other's optical rotation.

[0034] Crystallization behavior:- Indole S-isomers can crystallize as enantiomerically pure solids.- Racemic isomers can crystallize in different ways, such as a conglomerate (mechanical mixture of enantiomeric cry stals), a racemic compound (ordered 1:1 ratio in the crystal lattice), or a pseudoracemate (solid solution).

[0035] The TSHC radioprotectant compounds and compositions provide potent radioprotective properties which is believed to be through its ability to induce acute tissue hypoxia and stimulate cellular antioxidant defenses. For an increase in the efficacy the inventor expects that the radioprotective properties are further enhanced when used in combination with other radioprotective agents.

[0036] TSHC radioprotectant Indole based compounds. In further embodiments, methods and compositions are provided for radioprotection by administering pharmaceutical compositions comprising an Indole based compound and additional therapeutic compounds. The use of the invention makes it possible to provide anti-radiation efficacy using a low, safe dose. The Indole based compounds, (S)-l -(3 -Indolyl)-2-(m ethylamino) ethanol; (S)-a-[(Methylamino)methyl]-lH- IndoIe-3 -methanol, also known as the ‘Radioprotectanf ’, a fast-acting medical countermeasure with radioprotective and radiomitigative functionalities for treatment of Acute Radiation Syndrome (ARS), also known as acute radiation sickness. Isomer derivatives, demonstrate efficacy and safety for treatment and protection from Acute Radiation Syndrome or isomer derivative but not limited to- for Indole, (S)-l-(3-Indolyl)-2-(methylamino)ethanol; (S)-a-[(Methylamino)methyl ]- 1 H- Indole-3 -methanol, also referred to as a TSHC radioprotectant with radioprotective and radiomitigative functionalities for treatment of Acute Radiation Syndrome (ARS). also known as acute radiation sickness. Other isomer derivatives are l-(lH-indol-3-yl), 2-(methylamino) ethanol, l-(lH-indol-3-yl)-2-(methylamino)ethanol and functional analog, or Indole derivative isomers.

[0037] The radioprotectant is a small molecule radioprotective agent in tablet or capsule form, based on a compound of the general formula or pharmaceutically acceptable salts thereof, and excipients.

[0038] The compounds according to the invention may be used in any pharmaceutical composition formulated so as to facilitate administration thereof. The inventive compositions may comprise all commonly used pharmaceutically acceptable excipients such as carriers) or diluent(s).

[0039] The TSHC radioprotectant, including for example, the Indole based compounds, may be administered intravenously at a dose between 10-20 mg / kg, either before or within 24 hours afterradiation exposure. This administration is repeated daily for 3-5 days to effectively treat acute radiation syndrome (ARS).

[0040] The TSHC radioprotectant compounds may be combined with a pharmaceutically acceptable carrier, ensures stability and efficacy during administration.

[0041] According to some embodiments, the TSHC radioprotectant compound may comprise Indole based compounds of a racemic mixture of R-Indole and / or S-Indole derivatives, with isolated R-Indole and S-Indole derivatives being substantial!}’ free of each other, enabling targeted administration and enhanced therapeutic effects.

[0042] According to some embodiments the method involves the administration of aa Racemic mixture of R- and S- Indole derivatives, or an S-Indole compound or its analog or derivative, as specified in the claim, effectively reduces, inhibits, or treats damage resulting from exposure to various forms of ionizing radiation, including ARS. The TSHC radioprotectant compounds may be administered at specific dosages depending on body weight and timing relative to radiation exposure, ensuring optimal therapeutic effects while minimizing adverse reactions, and may be administered before, during, or after radiation exposure effectively prevents or reduces adverse effects associated with radiation exposure, promoting tissue protection and recovery. The TSHC radioprotectant compounds may be administered either alone or in combination with other agents, to reduce apoptosis in hematopoietic stem cells and / or progenitor cells, mitigating the effects of radiation exposure and promoting recovery. The TSHC radioprotectant compounds may be administered to effectively protect tissues from radiation-induced damage and mitigates various side effects associated with radiation exposure, ensuring improved patient outcomes and quality of life. The TSHC radioprotectant compounds may be administered before or after radiation therapy to enhance the therapeutic window, minimizing adverse effects and improving treatment efficacy without interfering with tumor control.

[0043] The inventive compositions may be administered via the oral, enteral, parenteral (intravenous, intramuscular or subcutaneous, intraperitoneal), transcutaneous (or transdermal or percutaneous), cutaneous or mucosal (especially transmucosal-buccal, nasal, ophthalmic, otologic, vaginal, rectal) routes, or via the intragastric, intracardiac, intraperitoneal, intrapulmonaiy or intratracheal routes. The inventive compositions may be in dry form, dry form to be reconstituted at the time of use (powder, lyophilizate, etc.), solid form (in particular cachet, powder, capsule, pill, granule, suppository’, tablet, and more precisely fast-release tablet, gastro-resistant tablet or extended-release tablet), paste form (particularly gel, ointment, cream or pessary), liquid form (particularly sy rup; injectable, infusible or oral solution; or eye drops), aerosol form (spray, vapor or gas), patch form, injectable form (in aqueous, non-aqueous or isotonic solution). Furthermore, the inventive compositions may be packaged for administration in the form of a single dose(monodose) or a multiple dose (multidose)

[0044] Compared with the prior art, the invention has the advantages that: in the application of an Indole to the preparation of the medicaments for treating acute radiation sickness, the usage range is expanded, and new medicaments are provided for the treatment of the acute radiation sickness simultaneously; and results of pharmacodynamic experiments indicate that TSHC radioprotectant, including the Indole based compounds, has a positive effect on treatment of acute radiation sickness.

[0045] This agent has antioxidant properties is comprised of a TSHC, and in preferred embodiments an Indole, a blocking agent of the initiation of free-radical processes. The claimed agent reduces the expression of maximal leukopenia above two-fold, normalizes the intensity of free-radical oxidation in blood plasma and liver tissue and results in increasing the activity of antioxidant systems. The invention is designed for use in the treatment of acute radiation disease.

[0046] Radioprotection, radiomitigation and radiorecovery is especially important for subjects exposed to or who may be affected by ionizing radiation, radiomimetic exposure and ionizing radiation contamination. The method in the form of strategically timed preemptive and postirradiation radioprotection. Radiomitigation and radiorecovery formulations are comprised of an anti-incorporation, antioxidant, decorporation, multi-mechanistic, pro-survival, and pro- hematopoietic for protection or treatment of Acute Radiation Syndromes (ARSs) including the three types or main presentations of ARS, namely, hematopoietic, gastrointestinal, and cardiovascular ARS.

[0047] The invention provides radioprotection to a subject prior to, during, just after or well-after exposure to ionizing radiation energy — alpha, beta, neutron, gamma, proton, photon, positron, sealed or unsealed source, X-ray or external beam — for long or short periods of time, and use of the compound to protect healthy tissue / organs of subjects to reduce the injuries caused by ionizing radiation and particularly exposure to or contamination by radioactive elements or compormds such as radioiodine, radiostrontium, radiophosphorus, radiocobalt, radiocadmium, radiopolonium, radioradium, radioplutonium, radiocesium, radiouranium and transuranics, radioamericium, radiocerium, radioindium, radiogallium, radiofluorine, radiocopper, radiotechnetium, radiolutetium, radioactinium, radiobismuth, and the like. A radiomimetic protective method for mucosal or kidney exposure and overcoming collateral effects of the radioprotectant is also described.Reaction to Ionizing Radiation Exposure

[0048] Indole derivative radioprotectant compositions can be applied as an emergency radioprotective drug to prevent ARS given rise to from exposure to high dose rates of ionizing radiation (>lGy / hour) and to reduce the risk of mortality from exposure at doses that cause severeand extremely severe forms of acute radiation illnesses. The major cause of this syndrome is depletion of immature parenchymal stem cells in specific tissues. Clinical manifestations are skin bums, nausea, vomiting, confusion, fever and chills. ARS can result in pneumonia and give rise to cancer (Centers for Disease Control 2016, 2017). ARS may be caused by exposure to a high dose of ionizing radiation over a brief period of time, where unintended or unexpected radiation is encountered. The acute signs and symptoms affect the hematologic, gastrointestinal, skin and central nervous systems.

[0049] A high radiation dose can result in death. Radiation injury to nuclear reactor personnel and emergency- workers exposed during the early stage of an accident can occur due to external y- and P-radiation from radioactive material released into environment, y- and -radiation, i.e., deposited on clothes, body and mucous membrane, and internal irradiation through inhalation of radioactive substances. Epidemiological studies on populations exposed to radiation, such as radiotherapy patients, showed a significant increase of cancer risk at doses above 100 mSv. More recently, some epidemiological studies in individuals exposed to medical exposures during childhood (pediatric CT) suggested that cancer risk may- increase even at lower doses (between 50-100 mSv). Prenatal exposure to ionizing radiation may induce brain damage in fetuses following an acute dose exceeding 100 mSv between weeks 8-15 of pregnancy and 200 mSv between yveeks 16-25 of pregnancy .Radioprotection by Modulation of NF-kB pathway

[0050] Nuclear factor (NF)-KB is a transcription factor that plays significant role in immunity, cellular survival and inhibition of apoptosis, through the induction of genetic networks. Depending on the stimulus and the cell type, the members of NF-KB related family (RelA, c-Rel, RelB. p50, and p52), forms different combinations of homo and hetero-dimers. The activated complexes (Es) translocate into the nucleus and bind to the lObp KB site of promoter region of target genes in stimulus specific manner. In response to radiation, NF-KB is knoyvn to reduce cell death by promoting the expression of antiapoptotic proteins and activation of cellular antioxidant defense system.

[0051] Constitutive activation of NF-KB associated genes in tumor cells are known to enhance radiation resistance, whereas deletion in mice results in hypersensitivity to IR induced GI damage. NF-KB is also known to regulate the production of a wide variety of cytokines and chemokines, which contribute to enhancing cell proliferation and tissue regeneration in various organs, such as the GI crypts stem cells and bone marrow following exposure to IR (Singh V, Gupta D, Arora R. "NF-kB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures." Discoveries (Craiova). 2015 Mar 31 ;3(1):3535. doi: 10.15190 / d.2015.27. PMID: 32309561; PMCID: PMC7159829).

[0052] NF-KB is a protein complex that controls transcription of DNA, cytokine production, and cell survival in general: for some agents under development as ARS -countering medicinals, NF-KB seems to play a significant role in radioprotection or in radiomitigation. The protective role of NF- kB plays out three waj s and is mediated via transcriptional activation of multiple genes coding for: (1) anti-apoptotic proteins inhibiting apoptotic pathways; (2) grow th factors and cytokines which induce cell proliferation and are responsible for survival of hematopoietic progenitors and other stem cells; and (3) potent reactive oxygen species-scavenging antioxidant proteins, such as manganese superoxide dismutase (MnSOD, also known as superoxide dismutase 2 (SOD-2)). There are several Toll-like receptor (TLR) agonists such as CBLB502, CBLB612, CBLB613, and a-1- antitrypsin, which bind with different TLRs leading to NF-KB signaling and radioprotection. Recombinant human interleukine-12 (rhuIL-12, HemaMax / NMIL12-l) is also known to modulate NF-KB activation. Unlike the above-mentioned agents, BIO 300 (nanosuspension) / Genistein is a promising radiation countermeasure which has been shown to inhibit NF-KB activation.Inflammation is a protective response of the host to infections and tissue damages, characterized by a series of reactions, including vasodilation and recruitment of immune cells and plasma proteins to the site of infection or tissue injury. Normally, inflammation is beneficial to the host and can be resolved in a timely manner; however, deregulated inflammatory responses can cause excessive or long-lasting tissue damages, contributing to the development of acute or chronic inflammatory diseases. NF-KB is a central mediator of pro -inflammatory gene induction and functions in both innate and adaptive immune cells. One know n function of NF-KB is the regulation of inflammatory responses. Also, in addition to mediating induction of various proinflammatory genes in innate immune cells, NF-KB regulates the activation, differentiation and effector function of inflammatory T cells. Recent and updated evidence suggests that NF-KB also has a role in regulating the activation of inflammasomes. Unsurprisingly , deregulated NF-KB activation is an indication of chronic inflammatory diseases. The mechanism of hematopoiesis stimulation is associated with an activation of tissue transglutaminase and new G-protein-coupling al-adrenergic receptors. (Feng JF, Gray CD, Im MJ: Alpha IB-adrenoceptor interacts with multiple sites of transglutaminase II: characteristics of the interaction in binding and activation. Biochemistry 1999, 38(7):2224-2232; Zhang J, Tucholski J, Lesort M, Jope RS, Johnson GV: Novel bimodal effects of the G-protein tissue transglutaminase on adrenoreceptor signaling. Biochem J 1999, 343: 541-549; and Park H, Park ES, Lee HS, Yun HY, Kwon NS, Baek KJ: Distinct characteristic of Galpha(h) (transglutaminase II) by compartment: GTPase and transglutaminase activities. Biochem Biophys Res Commun 2001, 284: 496-500) that are able to activate nuclear factor (NF)-kappa (Chen ZJ, Minneman KP: Recent progress in alphal -adrenergic receptor research. Acta Pharmacol Sin 2005, 26: 1281-1287; and Kumar S, Mehta K: Tissue transglutaminase constitutively activates HIF-lapromoter and nuclear factor-KB via a non-canonical pathway. PLoS One 2012, 7: e49321. doi: 10.1371 / joumal.pone.0049321). This is associated with a subsequent increase in gene expression of pro-inflammatory cytokines, including IL-1, tumor growth factor, IL-6, and IL-12, which promote cell proliferation of myeloid hematopoiesis. larmonenko SP, Rampan II, Karochkin BB, Berezhnova LI, Ovakimov VG: [Oxygen tension kinetics in critical organs under the effects of mexamine in comparison with its radiation-protective effect], Radiobiologiia 1970, 10(5):700-705.

[0053] The mitigatory effect of Indole based compositions is expected to result in a rise in the condition of partial shielding of the body. Radiation mitigatory effect of serotonin has been reported to be detected in vitro. As noted, the sympathetic nervous system is actively involved in the regulation of the mobilization and migration of hematopoietic cells. Catecholamines also are considered to enhance the stress-associated increase in the secretion of pro-inflammatory cytokines interleukin (IL)-l and IL-6, which contribute to the mobilization of myeloid hematopoiesis. This is associated with a subsequent increase in gene expression of pro-inflammatory cytokines, including IL-1, tumor growth factor. IL-6, and IL- 12, which promote cell proliferation of myeloid hematopoiesis.

[0054] The role of the TSHC radioprotectant administration is primarily therapeutic. The radioprotector is designed to take effect in 5 minutes reaching the maximum action in 10-15 minutes. The duration of the protective effect is designed to last for an hour or more. The TSHC radioprotectant tablets will be administered orally on a continuous 1-hr dosing regimen for 3 hours at a dose of 0.45g per hour (3 x 0.15g tablets) with or without food. ARS is divided into three ty pes: bone marrow, gastrointestinal, and neurovascular syndrome, with bone marrow syndrome occurring at 0.7 to lOGy, and neurovascular syndrome occurring at doses that exceed 50Gy. The cells that are most affected are those that are rapidly dividing.

[0055] An TSHC radioprotectant has been developed as a mandatory standard agent for prevention of the acute radiation injuries. TSHC radioprotectant compositions, being a radioprotective drug of emergency action, is designed to prevent the acute radiation damage at exposures to a high dose rate of ionizing radiation (>1 Gy / hour) and particularly to reduce the risk of mortality from emergency exposures at the doses that cause severe and extremely severe forms of acute radiation illness. According to the dose reduction factor, the expected radiation protective effect of the radioprotector for humans is up to 1.5. In terms of the dose reduction factor (DRF), the anticipated anti -radiation effect of the protector for humans is 1.5.

[0056] This TSHC radioprotectant is classed as a radioprotectant acting through a cell receptor mechanism. It belongs to a group biogenic amine. Pharmacological properties of the agent are as a direct al -adrenergic agonist. Pharmacological and anti-radiation action is like other a-adrcnoccptor blocking drugs such as tropaphen, prazosin, terazosin and promazine. This is designed to induceacute hypoxia in radiosensitive tissues affecting microcirculation by contraction of pre-capillary smooth muscles with simultaneous enhancement of oxygen intake by cells as a result of the direct a (l)-adrenergic effect. The oral TSHC radioprotectant dose of 0.45g is designed to produce in humans a typical adrenergic effect, which is expected to increase blood pressure (BP) over 90 minutes; and expected to increase BP (e.g., by about 15-22%) within proximity to dosing (e.g., about 15-55 minutes following dosing). The effect is expected to come about initially by way of a diastolic pressure rise conditioned by strengthening of peripheral resistance to circulation during vasoconstriction at the pre-capillary level and a coronary’ rate reduction to 50-60 bcats / min without episodic arrhythmia. A minor hypertension effect (diastolic BP rise to 90 mmHg) is usually well- tolerated. The TSHC radioprotectant compositions are designed not to significantly affect renal, hepatic and hemopoietic functions. In contrast to the sulfur-containing radioprotectant Amifostine, the Indole Derivative Radioprotectant does not cause biliary complications.

[0057] TSHC radioprotectant does not cross the blood-brain barrier; it also is expected not to weaken or decrease human performance assessed by changes in neuromotor functioning (ability to perform strenuous work, affect endurance, cause static and dynamic tremor or sensorimotor reaction). The radioprotector is expected to not lower tolerance to temperature loads up to 40°C during moderate physical activity and activities during flight (aviation) including longitudinal and latitudinal G-forces, hypoxic hypoxia, vibration and vestibular loads.

[0058] The radioprotective activity of the TSHC radioprotectant is considered by the inventor to be associated with a partial neutralization of the radiobiological oxygen effect’ phenomenon (further radiation-induced damage because of the increase in cellular oxygen pressure). Indole Derivative Radioprotectant as a direct alphal -adrenomimetic is expected to have a vasoconstrictive effect and can increase tissue oxygen consumption. This is expected to promote the development of circulatory and tissue hypoxia, e.g., in the hematopoietic tissues. The radioprotective efficacy on hematopoiesis is initially expected to be a result of the protection of hematopoietic stem cells in the bone marrow and spleen. This enables rapid post-radiation recovery of the blood The inventor considers the Indole Derivative Radioprotectant (Indole derivative) to provide protection of hematopoietic stem cells in the bone marrow and spleen The inventor also considers that the TSHC radioprotectant may also reduce radiation injury to the salivary glands.This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Radiation is defined as energy emission or energy transmission via some type of medium, either as waves or as subatomic particles. Betaleukin, recombinant human IL-ip may be an effective agent for earty emergency radiation therapy. It potentiates the radioprotective action of TSHC radioprotectant. There have been studies or reports about the role of pharmacologically induced disturbances of the local blood flow inhemopoietic tissues in the implementation of radiation protective action for many derivatives of serotonin at different doses and methods of application. The same effect has been reported with animal radiation exposure in an atmosphere of increased oxygen pressure.

Claims

CLAIMSWhat is claimed is:

1. A composition for treatment and prevention of radiation syndrome comprising: an indole-based compound having the formula (I):where R is an alkyl chain containing OH, NH, and one or more alky' groups.

2. The composition of claim 1. wherein the compound of formula (I) comprises an enantiomer compound with a chiral center, and wherein the chiral center is on the C atom of the alky drain that contains the OH substituent.

3. The composition of any one of claims 1 or 2, wherein the formula (I) is a racemic mixture of the S- and R- forms of an enantiomeric compound of formula (I).

4. The composition of any one of claims 1 to 2, wherein R is an alkyl chain containing OH, NH, and one or more alky groups, and wherein the terminal group of the alkyl chain is -CFL5. The composition of any one of claims 1 to 2. wherein R = COH-CH2-NH-CH3:

6. The composition of claim 5, wherein formula (I) is:

7. The composition of claim 5, wherein formula (I) is:

8. The composition of claim 1. wherein formula (I) comprises the R- enantiomer.

9. The composition of claim 1, wherein formula (I) comprises the S- enantiomer.

10. The composition of claim 1, wherein formula (I) comprises a racemic mixture of tire R- enantiomer of formula (I) and the S- enantiomer of formula (I).

11. A composition for treatment and prevention of radiation syndrome comprising: an indole-based compound having the formula: indolo[a]pyrrolo[3.4-c] carbazole.

12. The composition of any one of claims 1 or 2, including one or more carriers, excipients and / or binders for pill forms of tire composition, and / or one or more aqueous type liquids for delivery of the composition through intravenous means.

13. A compound having the structure:and derivatives thereof,and / or(ii), and derivatives thereof, for use in treating acute radiation syndrome in a subject who has received a dose of ionizing radiation.

14. A radioprotectant composition comprising a) an indole compound selected from the group consisting of:and(HI). and b) a biocompatible carrier in a form suitable for mammalian administration.

15. The radioprotectant composition of claim 14, wherein the indole compound comprises the compounds (I) and functional analogs, derivatives, racemic mixtures and / or chiral forms, or (I) and (II) in a racemic mixture and functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof.

16. A radioprotectant composition comprising: a) an indole compound selected from the group consisting of:(i) one or more of:(S)-l-(3-Indolyl)-2-(methylamino) ethanol,(S)-a-[(Methylamino)methyl]-lH- Indole-3-methanol. indolo[a]pyrrolo[3,4-c] carbazole, and functional analogs, derivatives, racemic mixtures and / or chiral forms thereof; or(ii) one or more of the compounds of (i), and an enantiomer thereof, selected from the group consisting of:(R)- 1 -(3 -Indolyl)-2 -(methylamino) ethanol,(R)-a-[(Methylamino)methyl] - 1H- Indole-3 -methanol. indolo[a]pyrrolo[3,4-c] carbazole, and functional analogs, derivatives, racemic mixhires and / or chiral forms thereof.

17. The radioprotectant compound according to any one of claims 13-16, wherein the compound is administered intravenously.

18. The radioprotectant compound according to any one of claims 13-16, wherein the dose is between 10-20 mg / kg.

19. The radioprotectant compound according to any one of claims 13-16, wherein the compound is administered before or within 24 hours after radiation exposure.

20. The radioprotectant compound according to any one of claims 13-16, wherein the administration is repeated daily for 3-5 days.

21. A pharmaceutical composition comprising the compound according to claim 13 and a pharmaceutically acceptable carrier.

22. A method of treating acute radiation syndrome comprising administering to a subject in need thereof an effective amount of the compound according to claim 13.

23. The treatment composition of claim 1, wherein the compound comprises Racemic Indole derivative comprising a mixture of R-Indole derivative and / or the S-Indole derivative.

24. The treatment composition of claim 6. wherein the Isolated S-Indole derivative is substantially free of R-Indole derivative.

25. The treatment composition of claim 7. wherein the Isolated R-Indole derivative is substantially free of S-Indole derivative.

26. A method for reducing, inhibiting, or treating damage from exposure to ionizing radiation caused by a nuclear attack or disaster, external beam radiation therapy or irradiation, proton therapy, peptide receptor radionuclide therapy, brachytherapy, or astronauts exposed to cosmic radiation, and in particular. Acute Radiation Syndrome, comprising administering to the subject an effective amount of an Indole derivative radioprotectant compound according to claim 1. an analog or derivative thereof, to protect or treat tissue, organs, bone, deoxyribonucleic acid (DNA), and / or ribonucleic acid (RNA) from radiation damage.

27. The method of claim 26, wherein the subject is a mammal.

28. A method for treating Acute Radiation Syndrome comprising administration of a tissuestimulating heterocyclic radioprotectant compound ("TSHC radioprotectant").

29. The method according to claim 28, wherein the means for treating or preventing radiation injury comprises an Indole based compound, a functional analog, derivative, or chiral form thereof which has the formula: (S)-l-(3-Indolyl)-2-(methylamino)ethanol; (S)-a-[(Methylamino)methyl]-lH- Indole-3 -methanol, indolo[a]pyrrolo[3,4-c]carbazole or a functional analog or derivative in a pharmaceutically acceptable form, and administering the TSHC radioprotectant as a fast-acting medical countermeasure with radioprotective and radiomitigative functionalities for treatment or prevention of Acute Radiation Syndromes (hematopoietic syndrome (ARS-H). cardiovascular / central nervous system syndrome (ARS-C) and gastrointestinal syndrome (ARS- G)); acute radiation sickness, and / or radiation injury or myelosuppression.

30. The method of claim 29, wherein the TSHC radioprotectant is provided in the form of a pharmaceutically acceptable composition and is administered to a subject.

31. The method of claim 29. wherein administering the TSHC radioprotectant to the subject comprises administering a pharmaceutically acceptable composition comprising the TSHC radioprotectant to the subject.

32. The method of claim 31, which is employed as a method of protecting persons exposed to a radioactive substance or ionizing radiation, comprising contacting tissue of the persomrel with the therapeutically effective amount of the agent that protects and overcomes Acute Radiation Syndrome.

33. The method of treating radiation exposure by administration of the composition of any one of claims 1 or 2 at a concentration of 450mg (3 x 150mg). before, during, or after radiation therapy.

34. The method according to claim 31, wherein administration comprises 2.3 mg to 6.90 mg of the TSHC radioprotectant per kilogram depending upon the subject's body weight.

35. The method according to claim 32, comprising administering 150 - 450 milligrams per day of the composition of any one of claims 1 or 2 to a subject.

36. The compound of any one of claims 1 or 2, administered intravenously at a dose between 10- 20 mg / kg, either before or within 24 hours after radiation exposure. This administration is repeated daily for 3-5 days to effectively treat acute radiation syndrome (ARS).

37. A pharmaceutical composition comprising the compound described in any one of claims 1 or 2, combined with a pharmaceutically acceptable carrier, ensures stability and efficacy during administration.

38. A method of treating ARS comprising administering the compound described in any one of claims 1 to 2, to individuals in need of treatment, effectively mitigating the effects of radiation exposure and promoting recovery.

39. A racemic mixture of R-Indole and / or S-Indole derivatives according to the compound of any one of claims 1 to 2, with isolated R-Indole and S-Indole derivatives being substantially free of each other, enabling targeted administration and enhanced therapeutic effects.

40. A method comprising the administration of a Racemic and S-Indole compound or its analog or derivative, as specified in any one of claims 1 or 2, effectively reduces, inhibits, or treats damage resulting from exposure to various forms of ionizing radiation, including ARS.

41. A method comprising administering the compound of any one of claims 1 or 2 at specific dosages depending on body weight and timing relative to radiation exposure, ensuring optimal therapeutic effects while minimizing adverse reactions.

42. A method comprising administering the active agent comprising an TSHC radioprotectant compound, before, during, or after radiation exposure to effectively prevent or reduce adverse effects associated with radiation exposure, and to promote tissue protection and recovery.

43. A method of administering the compound of any one of claims 1 or 2, either alone or in combination with other agents, to reduce apoptosis in hematopoietic stem cells and / or progenitor cells, mitigating the effects of radiation exposure and promoting recover .

44. A method of administering the compound of any one of claims 1 to 2 that effectively protects tissues from radiation-induced damage and mitigates various side effects associated with radiation exposure, ensuring improved patient outcomes and quality of life.

45. A method of administering the compound of any one of claims 1 to 2 before or after radiation therapy enhances the therapeutic window, minimizing adverse effects and improving treatment efficacy without interfering with tumor control.

46. A protective composition that ameliorates radiation injury after accidental exposure to ionizing irradiation, or after damage to healthy tissues during therapeutic radiation or radio-mimetic agents, and is effective as a prophylactic drug to prevent or minimize radiation injuries when administered before a radiation exposing event, comprising: a composition including an indole having the formula:and including functional analogs, derivatives, racemic mixtures and / or chiral forms, S and / or R thereof.

47. The protective composition of claim 46, further comprising a biocompatible carrier in a form suitable for mammalian administration.

48. A composition for treatment and prevention of radiation syndrome comprising: an indole-based compound of one or more of the following:(i) (R)-l-(3-Indolyl)-2-(methylamino) ethanol;(ii) (R)-a-[(Methylamino)methyl]-lH- Indole-3 -methanol; and / or(iii) indolo[a]pyrrolo[3,4-c] carbazole; and functional analogs, derivatives, racemic mixtures and / or chiral forms thereof.

Images