Potassium channel blockers or derivatives thereof for prevention, alleviation and / or treatment of tissue dysfunction caused by toxic damage

Abstract

The present invention provides compositions and methods for preventing, alleviating, or treating subjects having toxic agent-induced injury. The present invention also provides compositions and methods for preventing, alleviating or treating tissue damage caused by exposure to toxic agents or restoring at least a portion of normal tissue function. In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker. In some embodiments, the potassium channel blocker includes 4-aminopyridine, a derivative thereof, or a combination thereof. In some embodiments, the pharmaceutical compositions may be administered with additional therapeutic agents, such as anticonvulsions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 367,934 filed on July 8, 2022, U.S. Provisional Patent Application No. 63 / 380,143 filed on October 19, 2022, and U.S. Provisional Patent Application No. 63 / 490,267 filed on March 15, 2023, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] Pathological changes caused by exposure to toxic insults can result in serious clinical conditions for which there are currently no effective treatments. Therefore, the problems caused by toxic insults represent a significant unmet medical need. Many different tissues can be injured, the effects can be rapid, delayed, or a combination of both, and if left untreated, the tissue may or may not eventually recover.

[0004] Particularly problematic are toxic insults that do not occur in nature and require some kind of industrial process to produce. There are many different types of such toxic insults (e.g., industrial chemicals, chemotherapy agents, war toxins). The most common exposures involve non-biological chemicals that did not exist before the development of the chemical industry. Although the chemical industry dates back thousands of years, large-scale production of chemicals did not develop until the 19th century. The chemical industry emerged with the Industrial Revolution in the late 18th century and began to accelerate in the 19th century when it became possible to produce synthetic dyes from coal tar. The chemical industry began to grow explosively in the first half of the 20th century and has continued to grow at an accelerated rate ever since.

[0005] The fact that the development of the chemical industry is one of the factors that has led to the exposure of people to more and more chemicals that have never existed in evolutionary history is of conceptual importance for understanding the novelty of the present invention. The fact that these chemicals are not part of evolutionary history means that there is no evolutionary selection for biological protection strategies. This is very different from the situation of traumatic injury (such as blunt force or sharp injury) or biological trauma (such as myocardial infarction or other ischemic injuries) or even exposure to toxic chemicals that are produced by natural biological processes or already exist in nature.

[0006] Man has created tens of millions of different chemicals, the vast majority of which have been created in the past few decades. It is estimated that a new substance is isolated or synthesized every few seconds, and in the most recent year 10 million new compounds were synthesized. Man-made chemicals have many purposes, and not all of them are toxic, but a large proportion of them are produced specifically to exploit their toxicity.

[0007] For example, chemicals such as pesticides, avicides, and herbicides are developed specifically to produce toxic effects on various organisms. Therefore, it is not surprising that these chemicals can also be harmful to humans. Other chemicals, such as those involved in industrial processes or developed to achieve chemical reactions or produce different kinds of materials, can accidentally produce toxicity. Other toxic harms such as radiation can be developed for disinfection by killing pathogens, for cancer treatment, or for military purposes and have the ability to intentionally produce toxicity. Exposure to radiation can also accidentally produce toxicity, such as in the case of accidental exposure to radiation.

[0008] Perhaps the most notable chemicals that cause tissue damage are those used to kill cancer cells, which are intentionally applied to millions of people each year. These chemicals are produced specifically to kill mammalian cells. Although the desired goal is to selectively target cancer cells, this selectivity rarely exists, and many normal cells are damaged by most chemotherapeutic agents. This is true even for new drugs that attempt to enhance immune attacks on cancer cells, but they have been found to exhibit unexpected toxicity. Other examples of such chemicals include agents developed for agricultural purposes, such as pesticides and insecticides, or agents developed for military purposes (such as nerve gases and other incapacitating agents).

[0009] An example of a clinically important side effect of exposure to toxic chemicals for a specific class of agents used to treat cancer is chemotherapy-induced peripheral neuropathy (CIPN). It is estimated that 30%-70% of the 650,000 patients who receive chemotherapy each year in the United States experience symptoms of CIPN, which can include numbness and tingling in the hands and feet, burning pain, muscle weakness, and loss of coordination. CIPN is a leading cause of noncompliance, decreased quality of life, and reduced cancer survival. Patients with symptomatic CIPN also have an increased overall cost of care of $20,000 compared to those without symptoms and are also more likely to experience a recurrence of their cancer.

[0010] One of the most intensively studied cancers for CIPN is breast cancer, which was the most common cancer in women worldwide in 2018, accounting for more than a quarter of all cancers. Among the various subtypes of breast cancer, hormone-resistant tumors have the worst prognosis. Surgical removal of the tumor and affected lymph nodes is effective for early-stage disease, but the mainstay of treatment for resistant tumors is neoadjuvant chemotherapy. One of the preferred chemotherapeutic agents for this patient group is the taxanes, the most common of which is paclitaxel (PTX, most commonly used in its ). PTX is an effective agent for the treatment of hormone-resistant metastatic breast cancer. The problem is that PTX often induces CIPN and other toxic side effects to normal tissues (e.g., nephrotoxicity and damage to the central nervous system). Currently, there are no established treatments available for patients with CIPN to prevent the development of CIPN without blocking the effects of the chemotherapeutic agent itself, or to successfully treat CIPN after it has already developed (where treatment may represent treatment that reverses symptoms caused by the injury, prevents or repairs the injury, or any combination of these features). Preclinical studies are investigating a variety of compounds to prevent or treat CIPN by blocking ion channels, targeting inflammatory cytokines, and combating oxidative stress, but results have not been encouraging.

[0011] In addition to peripheral nerves, there are many other tissues that are damaged by the therapies used to treat cancer. For example, chemotherapy agents and radiation can damage the heart, lungs, central nervous system, intestines, hair follicles, skin, immune system, oral cells, reproductive system cells, blood-forming cells commonly found in the bone marrow, and many other tissues.

[0012] There is currently an unmet medical need for any tissue damage caused by exposure to toxic insults (e.g., chemotherapy, radiation, and / or toxic chemicals) for which there are no effective treatments. These toxic insults can cause many different types of damage, and existing treatments are often limited in their application. For example, chelation therapy for exposure to toxic metals (e.g., methylmercury, lead, etc.) is ineffective in treating chemotherapy-induced damage.

[0013] The medical need represented by tissue damage caused by cancer treatments is a critical unmet medical need. In many cases, patients face the difficult choice of accepting the toxic effects that treatment may induce, or allowing the cancer to grow uncontrollably and cause damage to the patient. It often happens that patients are treated with increasing doses of chemotherapeutic agents, radiation, or both until toxicity reaches levels that are no longer tolerated. These are called dose-limiting toxicities because they represent the point at which the aggressiveness of anticancer treatments can no longer be increased because the dose of chemotherapy or radiation required to kill cancer cells causes unacceptable levels of damage to normal tissues and unacceptable physical symptoms. This may require a reduction in the dose of cancer treatment, or cessation of treatment altogether, thus limiting its efficacy. Being able to prevent toxicity caused by chemicals used to treat cancer would offer a huge benefit to cancer care, but the current ability to provide this benefit is insufficient to meet the medical need.

[0014] The medical need represented by tissue damage caused by exposure to toxic chemicals in the environment is another critical unmet medical need. For example, damage can occur when an individual is exposed to individual chemicals used for various industrial purposes, such as manufacturing or agriculture. Other examples of exposure may include contamination of water sources, such as from chemical spills or hydraulic fracturing, or other exposures in the environment. For example, toxic damage produced near burn pits can cause multiple tissue damage. Other examples may include side effects of exposure to chemicals used for therapeutic purposes other than cancer treatment, such as side effects of exposure to fluoroquinolone antibiotics. In these and many other similar types of exposures, individuals may exhibit multiple types of symptoms due to exposure to multiple different types of toxic damage from anthropogenic sources. Being able to prevent, reverse, ameliorate, or otherwise treat the toxicity caused by such toxic damage would provide a huge benefit to medical care, but the current ability to provide such benefits is insufficient to meet the medical needs.

[0015] There are many challenges that interfere with the development of treatments for the effects of exposure to toxic insults. One particularly challenging question is when to initiate treatment. Does it need to be initiated within a short period of time after exposure? If so, this may apply to situations where the time of exposure is known but does not provide an opportunity to treat an injury that is already present. In practice, the goal of treating an existing injury is very important. Another important challenge when treating an injury that has already been identified is whether the treatment will provide symptom relief that is dependent on the continued availability of the medication or whether it will actually provide and promote durable recovery such that the benefit can be maintained after treatment is stopped. All of these goals, namely being able to initiate treatment after injury and / or symptoms are evident, provide symptom relief, and promote durable recovery, are important. However, developing treatments that can provide durable recovery benefits and can be initiated after side effects have emerged is one of the greatest challenges facing the development of treatments for the effects of exposure to toxic agents.

[0016] Another type of toxic damage is exposure to high doses of radiation from various locations on the electromagnetic spectrum, which are strong enough to cause tissue damage. Examples of this damage include heat-producing wavelengths in the infrared range, radiation in the ultraviolet range, and most importantly, radiation toxicity, which represents ionizing radiation, the most common of which are alpha, beta, gamma, delta, and theta wavelengths, which cause damage at the chromosomal and cellular levels.

[0017] The most common source of radiation toxicity is cancer treatment, as radiation is used to treat many different types of cancer. Radiation can be precisely targeted to a specific part of the body or it can be used to irradiate a larger area up to whole body irradiation. Radiation toxicity can also occur in other situations, such as nuclear power plant accidents and military situations, such as the use of weapons that emit toxic levels of radiation.

[0018] As discussed above, damage caused by non-biological chemicals or radiation toxicity can occur in many different tissues and can manifest in a variety of ways. For example, normal cells that may be damaged by chemotherapeutic agents include, but are not limited to, hematopoietic cells in the bone marrow, hair follicles, cells in the mouth, digestive tract, reproductive system, and cells in the heart, kidneys, bladder, salivary glands, auditory system, visual system, lungs, and nervous system. Side effects of treatment with chemotherapeutic agents include, but are not limited to, fatigue, hair loss, easy bruising and bleeding, infections, anemia (low red blood cell count), mouth, tongue and throat problems (e.g., pain when swallowing and ulcers), peripheral neuropathy or other nerve problems (e.g., numbness, tingling and pain), urine and bladder changes and kidney problems, weight changes (e.g., caused by cachexia), skeletal muscle atrophy and / or fibrotic changes, heart muscle damage, chemo brain (may affect attention and concentration), blood vessel damage, fertility problems (effects on reproductive cells), anemia, diarrhea, nausea, vomiting, infections, nervous system changes, (e.g., National Cancer Institute: Chemotherapy Side Effects Chart, cancer.gov / cancertopics / coping / physicaleffects / chemo-side-effects.)

[0019] In addition to the complexities associated with injury to different tissues, the timing of the onset of toxic side effects may also occur over a long time frame. Side effects of exposure to toxic insults are classified as acute toxicity (within days), early delayed toxicity (within weeks), and late delayed toxicity (within months to years). A subset of pathological findings are given as examples of problems arising from exposure to toxic insults. These illustrative findings have been selected to provide non-limiting examples of this general class of problems, and the examples selected are particularly well-studied.

[0020] An example of damage caused by toxic insult is the range of conditions included in the general category of peripheral neuropathy, which includes the subset of CIPN. The broad category of variations that are classified as peripheral neuropathy is identified by presenting symptoms, such as sensory changes in the peripheral nerves, but the underlying causes and mechanisms vary widely. For example, although some common symptoms of peripheral neuropathies occur in many different conditions, there is little or no reason to believe that the underlying cause and pathology are the same even for neuropathies caused by biological diseases, such as diabetic neuropathy, neuropathic pain associated with spinal stenosis, peripheral neuropathy in autoimmune diseases such as Guillain-Barré syndrome, neuropathic pain after spinal cord injury or stroke. The underlying causes and pathologies of neuropathies caused by toxic insults still represent different general categories of diseases that share common symptoms rather than being caused by common mechanisms or being treatable by common approaches.

[0021] The use of peripheral neuropathy as an indicator of a specific pathological process is flawed, particularly for neuropathy syndromes resulting from exposure to toxic insults. Many industrially produced chemicals can cause symptoms such as peripheral neuropathy in exposed individuals, but the presentation of these symptoms has little or no bearing on understanding the etiology, pathophysiology, or treatment of the clinical problem. Therefore, it should be understood that the term peripheral neuropathy is used only to indicate that an individual exhibits symptoms that lead to their inclusion in this broad and multi-member category, but the term is not associated with a specific cause or type of injury. There are many types of insults that can result in the consequences collectively referred to as neuropathy, but this does not mean that these neuropathies are identical in their specific nature, pathogenesis, or treatment.

[0022] Examples of neuropathies include a variety of different disorders, and even when they result from exposure to toxic agents, they extend to damage to other tissues. Toxic insults can cause many different types of damage to the central nervous system, immune system, gut, heart, lungs, and a variety of other tissues. For example, damage to the central nervous system caused by exposure to chemotherapeutic agents, radiation, or industrial toxins can cause myelin damage, neuronal damage, astrocyte activation, promotion of inflammation, and a variety of cognitive and neurological manifestations. The variety of damage caused highlights the challenge of developing effective treatments for this type of problem because there are so many different types of damage that can occur. Analysis of chemotherapeutic agents provides a particularly powerful example of this problem because they can cause multiple types of damage, and these drugs can be used to test the hypothesis that a given treatment strategy will work for multiple types of damage in a variety of tissues.

[0023] Therefore, there is a need in the art for new compositions and methods to prevent, alleviate and / or treat tissue dysfunction caused by toxic insults. The present invention satisfies the need in the art. Summary of the invention

[0024] In one aspect, the present invention provides a method for preventing, ameliorating or treating tissue damage or tissue dysfunction caused by toxic insult in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or its analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative.

[0025] In one aspect, the present invention provides a method of reducing or reversing tissue damage, oxidative damage, scarring, or any combination thereof caused by toxic insult in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt, or derivative thereof.

[0026] In one aspect, the present invention provides a method for restoring, improving or enhancing at least a portion of tissue function reduced by toxic damage in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or its analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative.

[0027] In one aspect, the present invention provides a method for restoring, improving or enhancing myelination reduced or modulated by toxic insult in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

[0028] In one aspect, the present invention provides a method for preventing, ameliorating or treating mitochondrial damage or mitochondrial dysfunction caused by toxic insults in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or its analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative.

[0029] In one aspect, the present invention provides a method for preventing, ameliorating or treating axonal damage or axonal dysfunction caused by toxic insult in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or its analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative.

[0030] In one aspect, the present invention provides a method for preventing, ameliorating or treating at least one gait abnormality caused by a toxic insult in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

[0031] In one aspect, the present invention provides a method of enhancing tissue regeneration, cell survival, or a combination thereof in a subject in need thereof, the subject being exposed to at least one toxic insult, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt, or derivative thereof.

[0032] In various embodiments, at least one potassium channel blocker comprises 4-aminopyridine, a derivative of 4-aminopyridine, or a combination thereof. In some embodiments, the derivative of 4-aminopyridine is a compound having the structure of formula (I):

[0033]

[0034] or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug or pharmaceutically acceptable salt thereof. 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof. 1 , R 2 , R 3 , R 4 and R 5 Optionally substituted.

[0035] In some embodiments, the tissue is kidney tissue, liver tissue, heart tissue, lung tissue, brain tissue, central nervous system tissue, peripheral nervous tissue, gastrointestinal tissue, intestinal tissue, visual system tissue, auditory system tissue, skin tissue, bladder tissue, reproductive system tissue, hematopoietic system tissue, musculoskeletal tissue, or any combination thereof.

[0036] In some embodiments, the tissue function is motor function, sensory function, cognitive function, visual function, auditory function, kidney function, hematopoietic system function, normal skin function, salivary gland function, liver function, gallbladder function, gastrointestinal (GI) function, sexual function, or any combination thereof.

[0037] In some embodiments, tissue damage is kidney tissue damage, liver tissue damage, heart tissue damage, lung tissue damage, brain tissue damage, central nervous system damage, peripheral nerve tissue damage, peripheral neuropathy, nephropathy, chemotherapy-induced peripheral neuropathy (CIPN), radiation-induced peripheral neuropathy (RIPN), chemotherapy-induced nephrotoxicity (CINT), chemotherapy-induced neutropenia, radiation-induced neutropenia, gastrointestinal tissue damage, intestinal tissue damage, visual system tissue damage, auditory system tissue damage, skin tissue damage, bladder tissue damage, reproductive system tissue damage, hematopoietic system tissue damage, or any combination thereof. In some embodiments, chemotherapy-induced peripheral neuropathy (CIPN) is taxane-induced CIPN (P-CIPN), cisplatin-induced CIPN (CisIPN), anticancer agent-induced CIPN, platinum-based antitumor agent-induced CIPN, vinca alkaloid agent-induced CIPN, epothilone agent-induced CIPN, proteasome inhibitor-induced CIPN, immunomodulatory drug-induced CIPN, or any combination thereof.

[0038] Therefore, in one aspect, the present invention provides a method for preventing, ameliorating or treating chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or its analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative.

[0039] In some embodiments, the tissue injury is multiple tissue injury, multiple organ tissue injury, or any combination thereof.

[0040] In some embodiments, the toxic insult is an acute toxic insult, a chronic toxic insult, or any combination thereof.

[0041] In some embodiments, treatment can be initiated at the time of initial injury, during ongoing exposure to the toxic insult, or in delayed treatment of tissue damage that occurs after exposure to the toxic insult has ended.

[0042] In some embodiments, toxic insults include exposure to damaging levels of radiation along the electromagnetic spectrum.

[0043] In some embodiments, the toxic insult is a non-biological substance, a non-naturally occurring compound, a toxin, an agent used to treat cancer, a chemotherapeutic agent, a biological response modifier, radiation, or any combination thereof. In some embodiments, the chemotherapeutic agent comprises a platinum-based anti-tumor agent, a vinca alkaloid agent, an epothilone agent, a taxane agent, a proteasome inhibitor, an immunomodulatory drug, or any combination thereof. In some embodiments, the toxic insult comprises at least one environmental toxicant. In some embodiments, the toxic insult comprises at least one industrially produced compound. In some embodiments, the radiation comprises radiation from radiation cancer treatment, radiation from nuclear power accidents, radiation from nuclear waste exposure, radiation from the use of radioactive materials in military applications, or any combination thereof.

[0044] In some embodiments, the toxic insult comprises at least a first toxic insult and a second toxic insult. In some embodiments, the first toxic insult is a chemotherapeutic agent, radiation, or a combination thereof, and the second toxic insult is a chemotherapeutic agent, radiation, or a combination thereof.

[0045] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject prior to a toxic insult.

[0046] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject at the time of a toxic insult.

[0047] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject following a toxic insult.

[0048] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject more than once. In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject repeatedly for about 1 day to about 100 years.

[0049] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject systemically, topically, or a combination of both.

[0050] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject by intraperitoneal injection, intravenous injection, intramuscular injection, intrathecal injection, subcutaneous injection, sublingual administration, inhalation, oral administration, transdermal administration, administration to the outside of the body in liquid form, application to the outside of the body in ointment form, application to the outside of the body in bandage form, or any combination thereof.

[0051] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject at a dose of about 1 mg / day to about 1,000 mg / day of a potassium channel blocker. In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject at a dose of about 2.5 mg / day to about 40 mg / day of a potassium channel blocker. In some embodiments, a therapeutically effective amount of a pharmaceutical composition is administered to a subject at a dose of about 40 mg / day to about 100 mg / day of a potassium channel blocker.

[0052] In some embodiments, a therapeutically effective amount of a pharmaceutical composition is co-administered with at least one anticonvulsant agent or a combination thereof.

[0053] In some embodiments, at least one anticonvulsant is a barbiturate, a benzodiazepine Bromide, carbamate, carboxamide, fatty acid, fructose or its derivatives, gamma-aminobutyric acid (GABA) or its analogs, hydantoin, oxazolidinedione, propionate, pyrimidinedione, pyrrolidine, succinimide, sulfonamide, triazine, urea, valproamide or any combination thereof.

[0054] In various embodiments, the methods also enhance cell survival, reduce scarring, or any combination thereof.

[0055] In various embodiments, the methods also enhance the repair or regeneration of endogenous stem cells, enhance the repair or regeneration of transplanted stem cells, enhance the repair or regeneration of progenitor cells, promote neurogenesis, enhance cell survival, reduce scar formation, reduce lesion size, reduce oxidative damage, or any combination thereof.

[0056] In one aspect, the present invention also provides a method for identifying a subject responsive to administration of 4-aminopyridine, thereby preventing, ameliorating or treating tissue damage or tissue dysfunction caused by toxic insult in a subject in need thereof.

[0057] In various embodiments, the method includes the steps of: a) administering 1 to 5 therapeutically effective amounts of a pharmaceutical composition comprising 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof to a subject; b) assessing the subject for symptoms of tissue damage or tissue dysfunction caused by toxic damage; and c) identifying the subject as responsive to administration of 4-aminopyridine when the symptoms of tissue damage or tissue dysfunction caused by toxic damage in the subject improve, so as to prevent, alleviate or treat tissue damage or tissue dysfunction caused by toxic damage. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The following detailed description of the preferred embodiments of the present invention will be better understood when read in conjunction with the accompanying drawings. In order to illustrate the present invention, presently preferred embodiments are shown in the accompanying drawings. However, it should be understood that the present invention is not limited to the precise arrangements and means of the embodiments shown in the accompanying drawings.

[0059] Figure 1 (include Figure 1 A to Figure 1 H) Depicts representative results demonstrating that 4-aminopyridine (4-AP) is able to prevent chemotherapy-induced peripheral neuropathy (CIPN) and mitochondrial damage caused by clinically relevant doses of paclitaxel (PTX). 16-week-old C7BL / 6 female mice were given a single dose of 35 mg / kg PTX (ip). Animals were divided into control (saline, ip, n=4) or treatment groups (daily 2 mg / kg 4-AP, ip, n=4). Catwalk scores before treatment were compared with those 21 days after PTX injection. Figure 1 A depicts a representative nerve conduction study showing that latency in the control group increased significantly over the study period. In 4-AP treated mice, the increase in latency was significantly smaller. Figure 1 B depicts a representative nerve conduction study showing that the velocity of the control group decreased significantly during the study period. In 4-AP treated mice, the velocity decrease was significantly less. Figure 1 C depicts representative catwalk analysis demonstrating a significant increase in the swing phase in control mice but no significant changes in the 4-AP treated group (p<0.05; p<0.01; p<0.001). Figure 1 D depicts representative catwalk analysis demonstrating a significant increase in stance phase (indicating gait abnormalities) in control mice but no significant changes in 4-AP treated groups (p<0.05; p<0.01; p<0.001). Figure 1 E depicts representative results showing that 4-AP treatment also reduces PTX-induced mitochondrial damage. Mitochondria were scored as healthy or diseased, and data were analyzed using a contingency chi-square test for overall 4-AP vs. NaCl. Mitochondria were scored from 64 (saline) or 57 (4-AP) randomly selected axons, for a total of 172 (saline) or 177 (4-AP) mitochondria scored. Figure 1 F depicts a representative image of healthy mitochondria. Figure 1 G depicts a representative image of diseased (ie, unhealthy) mitochondria. Figure 1 H depicts representative results showing that mitochondria analyzed in saline-treated animals also displayed a greater proportion of enlarged mitochondria that were generally swollen and unhealthy in appearance (*p<0.05).

[0060] Figure 2(include Figure 2 A to Figure 2 E) Depicted are representative results demonstrating that 4-AP prevents chemotherapy-induced axonal injury. Figure 2 A depicts representative G ratio (axon:myelin area) data, demonstrating that axons in 4-AP treatment were better myelinated than those in controls. Figure 2 B depicts representative circularity data, showing that axons in 4-AP treatments have more regular structures than those in controls. Figure 2 C depicts a representative baseline appearance of the sciatic nerve. Figure 2 D depicts the representative appearance of control axons after 3 weeks of 35 mg / kg PTX treatment. Figure 2 E depicts a representative appearance of 4-AP (2 mg / kg daily) treated axons showing thicker myelin and more regular structure. In this figure, "Control" = PTX + saline.

[0061] Figure 3 (include Figure 3 A to Figure 3 I) depicts representative results demonstrating that 4-AP also provides protection against developing CIPN when animals are repeatedly exposed to PTX. 16-week-old C7BL / 6 female mice were treated with PTX at a dose of 35 mg / kg PTX (ip) every three weeks for four cycles. 4-AP treatment was shown to prevent the peripheral nerve function changes associated with CIPN caused by repeated exposure to paclitaxel (PTX). Mice were treated with PTX (35 mg / kg) once every 3 weeks for 4 cycles. Mice were also treated with saline or 4-AP (0.5 mg / kg / day) from weeks 1 to 12. Signs of PTX-induced CIPN. 4AP treatment significantly reduced mechanical allodynia ( Figure 3 A), and reduce the total number of jumps ( Figure 3 C) (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). 4-AP treatment significantly prevented the deterioration of gait and nerve conduction ( Figure 3 D- Figure 3 I). (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). The animals were divided into a control group (saline, ip) or a treatment group. Figure 1 and Figure 2 The 4-AP 25% dose used in the study (ie, 0.5 mg / kg 4-AP daily, ip) was compared with the results at 3, 6, 9, and 12 weeks after PTX injection. Figure 3A depicts the ability of 4-AP treatment to prevent PTX-induced mechanical hypersensitivity as tested by application of the von Frey filament test, in which sensitivity to smaller filaments reveals increased sensitivity to painful stimuli. Results at weeks 3, 6, 9, and 12 were highly significant. Figure 3 B and Figure 3 C shows the action of lifting the paw in response to cold plate stimulation ( Figure 3 B) and jumping behavior ( Figure 3 C), 4-AP treatment also prevented the opposite symptom of decreased sensitivity to stimulation. Pawlift results showed a significant trend at weeks 6 and 9 and a highly significant trend at week 12. Jumping behavior was highly significant at weeks 6, 9, and 12. Figure 3 D- Figure 3 F depicts the ability of 4-AP to prevent PTX-induced gait abnormalities detected by catwalk analysis, with significant effects at multiple time points. Figure 3 G- Figure 3 I depicts the 4-AP incubation period ( Figure 3 G), amplitude ( Figure 3 H) and speed ( Figure 3 I) The ability to prevent PTX-induced nerve conduction abnormalities in multiple outcomes.

[0062] Figure 4 (include Figure 4 A to Figure 4 G) Demonstrates ultrastructural damage caused by PTX to the peripheral nervous system. The figure depicts representative results showing that 4-AP can prevent chemotherapy-induced axonal damage even after multiple applications of chemotherapy (35 mg / kg every 3 weeks for 4 treatment cycles), and the dose of 4-AP is only Figure 1 and Figure 2 25% of the dose used in the study and administered at 0.5 mg / kg instead of 2 mg / kg. In this figure, "Control" = PTX + saline. 4-AP treatment has been shown to prevent the ultrastructural changes in peripheral nerves associated with CIPN caused by repeated exposure to paclitaxel (PTX). Mice were treated with PTX (35 mg / kg) once every 3 weeks for 4 cycles. From weeks 1 to 12, mice were also treated with saline or 4-AP (0.5 mg / kg / day). PTX induced various deleterious changes in neural ultrastructure, which were significantly reduced by 4-AP treatment. ( Figure 4 A) Overview of parameter studies. Figure 4 B) Examples of structural changes. Figure 4 C- Figure 4 E) Quantification of the effects of PTX and 4-AP on neuronal ultrastructure. Figure 4 F) Example of mitochondrial ultrastructure. Figure 4G) Quantification of the effects of PTX and 4-AP on mitochondria (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Figure 4 A summarizes the ultrastructural analysis of myelination performed. In general, CIPN resulted in less myelinated and less rounded axons. Figure 4 B depicts representative images of changes in myelin-related parameters due to PTX exposure and the benefit of 4-AP treatment. By directly comparing electron micrographs after animals completed 4 cycles of PTX treatment (as described above), it is clear that animals treated with 4-AP (0.5 mg / kg per day) had more rounded and better myelinated axons than controls and were similar in appearance to naive animals (baseline) that did not receive any PTX treatment. Figure 4 C depicts representative G ratio (axon:myelin area) data, demonstrating that 4-AP treated axons maintained better myelination than controls (normal G ratio value is 0.65). Figure 4 D depicts representative circularity data, showing that axons in 4-AP treatments have more regular structures than those in controls. Figure 4 E depicts representative data demonstrating that 4-AP reduces the frequency profile of myelin degeneration. Figure 4 G depicts a representative image of damaged mitochondria. Figure 4 H depicts that treatment with 4-AP prevents mitochondrial degradation as determined by loss of mitochondrial membrane integrity and the presence of vacuoles.

[0063] Figure 5 (include Figure 5 A to Figure 5 I) depicts representative results showing that 4-AP also reverses the effects of repeated PTX treatment on peripheral nerves, where 4-AP treatment was initiated at week 6 after mice received their third PTX exposure. 4-AP treatment has been shown to reverse CIPN-related changes in peripheral nerve function and ultrastructure caused by repeated exposure to paclitaxel (PTX). Mice were treated with PTX (35 mg / kg) once every 3 weeks for 4 cycles. At weeks 6 to 12, mice were also treated with saline or 4-AP (0.5 mg / kg / day). PTX induced symptoms of CIPN. 4AP treatment significantly reduced mechanical allodynia ( Figure 5 A), and reduce the total number of jumps ( Figure 5 B). 4-AP treatment significantly prevented the deterioration of gait and nerve conduction ( Figure 5 C- Figure 5H). (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). 16-week-old C7BL / 6 female mice received four cycles of PTX treatment at a dose of 35 mg / kg PTX (ip). Starting from the 6th week after the onset of CIPN symptoms, the animals were divided into a control group (saline, ip) or a treatment group, and the treatment group was treated with a 4-AP dose (0.5 mg / kg 4-AP, daily, ip). As mentioned above, this dose is Figure 1 and Figure 2 25% of the dose was used. Figure 5 A depicts the effect of 4-AP treatment on PTX-induced mechanical hypersensitivity as tested by application of the von Frey filament test, in which sensitivity to smaller filaments reveals increased sensitivity to painful stimuli. Benefits were observed from week 12 onwards. Figure 5 B shows that 4-AP treatment also reversed the opposite symptom of hyposensitivity to stimulation using analysis of jumping behavior in response to cold plate stimulation ( Figure 5 B) At 9 and 12 weeks, jumping behavior changed significantly. Figure 5 C- Figure 5 E depicts the ability of 4-AP to reverse PTX-induced gait abnormalities detected by catwalk analysis, with significant effects on swing time and regularity index at weeks 9 (first analysis after initiation of 4-AP treatment) and 12, with results for stance time trending toward significance at these same time points. Figure 5 F- Figure 5 H depicts the expression of 4-AP in the presence of multiple rounds of PTX exposure during the incubation period ( Figure 5 F), amplitude ( Figure 5 G) and speed ( Figure 5 H) The ability of PTX to reverse PTX-induced nerve conduction abnormalities was established in multiple results. Figure 5 I depicts the ability of 4-AP to reverse PTX-induced myelin degeneration.

[0064] Figure 6 (include Figure 6 A to Figure 6G) Depicts results demonstrating that 4-AP treatment reversed the effects of repeated PTX exposure on peripheral nerve function, which were retained even after treatment ended. Such persistent changes suggest that the pro-reparative effects of 4-AP treatment are not limited to symptom relief during treatment. 4-AP treatment has been shown to durably reverse CIPN-associated changes in peripheral nerve function and ultrastructure caused by repeated exposure to paclitaxel (PTX). Mice were treated with PTX (35 mg / kg) once every 3 weeks for 4 cycles. At weeks 6 to 12, mice were also treated with saline or 4-AP (0.5 mg / kg / day). After completion of 4-AP treatment, mice were followed for an additional 6 weeks. 4-AP treatment significantly reduced mechanical allodynia ( Figure 6 A), and reduced the total number of jumps ( Figure 6 C). 4-AP treatment significantly prevented the deterioration of gait and nerve conduction ( Figure 6 D- Figure 6 G). (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001) In these experiments, 16-week-old C7BL / 6 female mice were treated with four cycles of PTX at a dose of 35 mg / kg PTX (ip). Figure 5 Animals were treated with 4-AP at the same dose and treatment schedule as in the 4-AP treatment group. 4-AP treatment ended at week 12 after the first exposure to PTX and after 6 weeks of treatment with 4-AP, and the animals were observed for an additional six weeks thereafter (i.e., 6 weeks without 4-AP treatment). Figure 6 A depicts the effect of 4-AP treatment on PTX-induced mechanical hypersensitivity as tested by application of the von Frey filament test, in which sensitivity to smaller filaments reveals increased sensitivity to painful stimuli. Benefits were observed starting at week 12 and were maintained at weeks 15 and 18. Figure 6 B shows the paw lifting response to cold plate stimulation ( Figure 6 B) and jumping behavior ( Figure 6 C), 4-AP treatment also resulted in a durable reversal of the opposing symptom of hyposensitivity to stimulation. Figure 6 D depicts the ability of 4-AP to durably reverse PTX-induced gait abnormalities as determined by the cat-walk regularity index, with benefits observed at week 9 (i.e., 3 weeks after 4-AP treatment) and retained for at least 6 weeks after the end of 4-AP treatment. Figure 6 E depicts the ability of 4-AP to reverse PTX-induced abnormalities in nerve conduction latency after the abnormalities have been established by multiple rounds of PTX exposure. Figure 6 F- Figure 6 G depicts the ability of 4-AP to induce durable pro-repair changes when used to treat established PTX-induced CIPN and tissue damage. The G ratio ( Figure 6 F) and roundness ( Figure 6 G) normalized at the 12-week time point, and these benefits were maintained at the 18-week time point (i.e., 6 weeks after the end of treatment).

[0065] Figure 7 (include Figure 7 A to Figure 7 D) Depicts representative results demonstrating that 4-AP can reverse CIPN induced by clinically relevant doses of cisplatin, a chemotherapeutic agent with a distinct mechanism of action from PTX. Here we demonstrate that 4-AP treatment reverses CIPN-associated changes in peripheral nerve function caused by repeated exposure to cisplatin (CIS). Mice were treated with CIS (2 mg / kg per week for 8 weeks). At weeks 9 to 15, mice were also treated with saline or 4-AP (1 mg / kg / day). CIS induced symptoms of CIPN. 4AP treatment reversed weight loss ( Figure 7 A) Mechanical allodynia ( Figure 7 B) and changes in nerve conduction ( Figure 7 C and Figure 7 D). 16-week-old C7BL / 6 female mice were treated with CIS (2.5 mg / kg, once a week, ip) for eight weeks. Animals were treated with 4-AP (1 mg / kg) starting at week 9 and continued treatment for a total of 6 weeks (n=8). Figure 7 Representative results demonstrating the effect of 4-AP on body weight are depicted in A. As shown, mice treated with 4-AP starting at week 9 after the start of CIS treatment regained normal body weight. Figure 7 B depicts representative results demonstrating the effects of 4-AP on the von Frey filament assay. Analysis of hyperalgesia by von Frey filament assay demonstrated a significant increase in sensitivity in CIS-treated mice, whereas sensitivity was restored to normal levels following 4-AP treatment. The restoration of normal sensitivity was maintained for at least two weeks after the end of treatment, well beyond the 12-16 hour time point when all 4-AP is expected to be cleared from the body, demonstrating a durable recovery of function and indicating a pro-reparative effect of the treatment. Figure 7 C depicts representative results demonstrating the effect of 4-AP on nerve impulse amplitude, which was also restored by 4-AP treatment, and the improvement was again maintained for at least two weeks after the end of treatment with 4-AP. Figure 7 D depicts representative results demonstrating the effects of 4-AP on nerve impulse velocity, which were also restored by 4-AP treatment and the improvements were maintained for at least two weeks after the end of 4-AP treatment, demonstrating durable recovery of function and indicating a pro-reparative effect of the treatment.

[0066] Figure 8 (include Figure 8 A to Figure 8C) shows that 4-AP co-treatment also prevents multiple aspects of histological kidney damage caused by PTX exposure. 16-week-old female C57BL / 6 mice were inoculated with the triple-negative murine breast cancer cell line E0771. When tumors were palpable, mice were injected with paclitaxel and saline, 4-AP (1 mg / kg), both, or saline as a control. All mice were injected with paclitaxel (35 mg / kg) on ​​the first day and injected with 4-AP or saline every day. Mice were sacrificed on day 14 and perfused with 4% paraformaldehyde and harvested. The kidneys were removed, sectioned and stained with hematoxylin and eosin (H&E). Saline treatment ( Figure 8 A) PTX treatment Figure 8 B) and PTX+4-AP treatment ( Figure 8 C) Kidneys ( Figure 8 , from left to right) show that the proximal and distal tubules of kidneys treated with saline and PTX+4-AP are normal. Disappearance of the brush border (dark gray arrows), nuclear shedding (gray arrows), and blebbing of tubular epithelial cells (black arrows) were observed in kidneys treated with PTX, but not in kidneys isolated from animals treated with PTX+4-AP.

[0067] Fig. 9 The ability of 4-AP treatment to prevent PTX-induced increases in the reactive inflammatory response of the brain as detected by increased expression of glial fibrillary acidic protein (GFAP) in the corpus callosum is described. GFAP is increased in astrocytes under conditions associated with injury and inflammation. These experiments were performed in conjunction with Figure 8 The same mice were performed. Female C57BL / 6 mice aged 16 weeks were inoculated with the triple-negative murine breast cancer cell line E0771. When tumors were palpable, mice were injected with paclitaxel and saline, 4-AP, both, or saline as a control. Paclitaxel (35 mg / kg) was injected on the first day, and 4-AP and water were injected every day. The mice were killed on the 14th day and their brains were perfused and harvested. Coronal cryosections were performed on the brains. Mouse brain sections were stained with anti-GFAP antibodies and then stained with fluorescent secondary antibodies and analyzed by immunofluorescence. Images were captured by confocal microscopy and analyzed using Image-J. The data are shown as areas of tissue expressing GFAP and indicate that PTX treatment is associated with increased GFAP expression. The increase in GFAP expression was greatly reduced in mice co-treated with 4-AP.

[0068] Fig.10 (include Fig.10 A and Fig.10 B) Depicts experimental results demonstrating that protection against chemotherapeutic agents is specific to normal (non-transformed) cells and does not extend to cancer cells. Fig.10A depicts representative results showing that co-treatment with 4-AP does not protect E0771 murine breast cancer (BC) cells from 5 days of PTX exposure in vitro, an important result because treating the toxic side effects of cancer treatments while protecting tumor cells would have little clinical value. Fig.10 B shows that similar treatment of A549 lung cancer cells with 4-AP did not protect these cancer cells from the toxic effects of cisplatin. DETAILED DESCRIPTION

[0069] In the following description, chemotherapy-induced peripheral neuropathy (CIPN) is described as a particularly well-studied non-limiting example of tissue damage caused by exposure to various different types of toxic insults. However, even clustering some of these insults as chemotherapeutic agents themselves is an oversimplification, as chemotherapeutic agents can have a wide range of targets and a wide range of molecular structures. Some of these agents, such as taxanes and vinca alkaloids, although industrially produced for the treatment of cancer, are closely related to substances found in nature. In contrast, other agents, such as platinum-containing drugs (e.g., cisplatin and oxaliplatin) are more like industrial chemicals produced because of their toxicity.

[0070] One of the best studied examples of peripheral neuropathy-like syndromes induced by exposure to toxic chemicals is peripheral neuropathy induced by treatment with neoplastic agents, known as chemotherapy-induced peripheral neuropathy (CIPN) (Hershman et al., 2014, J. Clin. Oncol., 32: 1941-1967). CIPN is so frequent that it occurs in 19-85% of individuals treated, with varying frequencies depending on the component of treatment (Fallon et al., 2013, Br. J. Anaesth., 111: 105-111). Factors that modulate the prevalence of CIPN include the use of specific therapeutic agents, with reported prevalence ranging from 19% to more than 85%, with platinum-based drugs (70-100%), taxanes (11-87%), thalidomide and its analogs (20-60%), and ixabepilone (60-65%) having the highest prevalence (Banach et al., 2016, Brain Behav., 7: e00558).

[0071] Chemotherapeutic agents can cause a variety of neuropathies, including, for example, large and small fibers, sensory and / or motor, demyelination and axonal, cranial nerve and autonomic neuropathy (e.g., Cioroiu et al., 2017, Curr. Neurol. Neurosci. Rep., 17: 47). Briefly, CIPN is often described as sensory neuropathy, which may be accompanied by motor and autonomic changes (Seretny et al., 2014, Pain, 155: 2461-2470). In addition, pain sensations, including spontaneous burning pain, tingling or electric pain, and mechanical or thermal allodynia or hyperalgesia, are often present (Bernhardson et al., 2007, J. Pain Symptom Manag., 34: 403-412). In severe cases, CIPN can lead to paresis, complete immobility and severe disability of the patient (Mols et al., 2016, Eur. J. Cancer, 69: 28-38). Overall, sensory disturbances are more common than autonomic symptoms, which often include orthostatic hypotension, constipation, and changes in sexual or urinary function (Mols et al., 2016, Eur. J. Cancer, 69:28-38).

[0072] Some compounds, such as paclitaxel and oxaliplatin, can cause acute neuropathy during or immediately after infusion (Argyriou et al. Clinical pattern and associations of oxaliplatin acute neurotoxicity: A prospective study in 170 patients with colorectal cancer (Cancer. 2013; 119: 438-444)). In contrast, in many other cases, CIPN symptoms may appear weeks or months after chemotherapy is completed. Some patients experience paradoxical worsening and / or aggravation of symptoms after stopping treatment (Starobova H et al., 2017, Front. Mol. Neurosci., 10: 174). Affected individuals may also experience worsening of mild neuropathy or the appearance of new CIPN. The severity of symptoms is generally proportional to the cumulative dose of the drug (Maestri et al., 2005, Tumori, 91: 135-138), but there are other factors that can affect the severity of symptoms, such as age, genetic factors, exposure to other chemicals or radiation, and a range of other factors.

[0073] Recent studies have shown that the prevalence of CIPN is about 68.1% when measured in the first month after chemotherapy, 60.0% in the third month, and as high as 30.0% after the sixth month (Seretny et al., Pain. 2014; 155: 2461-2470). In particular, in the case of platinum-based anticancer agents and taxanes, CIPN may persist for several years after the completion of chemotherapy (Kerckhove et al., Front. Pharmacol. 2017; 8: 86). The damage caused by different chemotherapeutic compounds may vary, and each compound that can cause CIPN has been studied in detail. The following examples provide a non-limiting illustration of the complexity and severity of this problem.

[0074] The effects of chemotherapy on the nervous system vary by drug class, depending on the specific physical and chemical properties of the drug used and its single or cumulative dose (Banach et al., Brain Behav. 2016, 7: e00558). Toxicity may still occur even after a single high-dose treatment or cumulative exposure. The symptoms of peripheral nervous system damage observed vary in intensity and duration. They range from acute, transient heat sensations to permanent changes in peripheral nerves with chronic pain and irreversible nerve damage (Seretny et al., Pain. 2014, 155: 2461-2470). Six major categories of chemotherapeutic agents can cause damage to peripheral sensory, motor and autonomic neurons, leading to the development of CIPN. These include platinum-based antineoplastic drugs (especially oxaliplatin and cisplatin), vinca alkaloids (especially vincristine and vinblastine), epothilones (ixabepilone), taxanes (paclitaxel, docetaxel), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide) (Starobova H et al., Front. Mol. Neurosci. 2017, 10: 17). Among these agents, the most neurotoxic categories are platinum-based drugs, taxanes, ixabepilone, thalidomide and their analogs. Vinca alkaloids show less neurotoxicity but can cause a variety of other toxicities.

[0075] One of the challenges in developing methods to prevent injury caused by chemotherapeutic agents and toxic chemicals in general is that multiple types of disruptions can occur at the cellular level. Examples of a variety of such potential disruptions are provided in the illustrative examples that follow. In general, disruptions in normal cellular function that have been implicated in the pathogenesis of peripheral nervous system injury include microtubule disruption, oxidative stress, mitochondrial damage, altered ion channel activity, myelin damage, DNA damage, immune processes, and neuroinflammation. ( et al., 2019, Int. J. Mol. Sci., 20:1451; ncbi.nlm.nih.gov / pmc / articles / PMC6471666 / ). All of these changes are considered potentially important for CIPN, but there is no indication whether any are critical in terms of pathogenesis or treatment. As discussed elsewhere in this application, these suggestions are of no use in the development of either preventive or post-injury treatments. In short, targeting these changes in a specific manner has not led to the development of effective therapeutics, suggesting that the discovery of such therapeutics is neither simple nor predictable.

[0076] Taxane-induced CIPN provides an example of the complexity of these lesions and how they differ from those caused by traumatic injury. Taxanes cause CIPN in 11%-87% of patients (Banach et al., Brain Behav. 2016;7:e00558.) Taxanes have a variety of different effects on cellular function. Paclitaxel is a good example of the complexity of the lesions caused by taxanes and other types of toxic insults and how they differ from those caused by physical trauma. Some of these are thought to be direct effects, while others may be indirect effects.

[0077] Taxanes are best known for disrupting microtubule function, which is thought to be associated with the development of CIPN (Gornstein et al., Exp. Neurol. 2017, 288: 153-166). Taxanes also cause damage to mitochondria. This can lead to oxidative stress, and the production of reactive oxygen species damages many cellular components, which in turn may lead to impaired axonal transport due to these reasons and the effects of taxanes on microtubules. These changes may have a variety of effects, such as impaired signal transmission, inflammation, and myelin damage. However, among these changes, myelin damage shows the least evidence of a causal relationship with CIPN (Areti et al., Redox Biol. 2014; 2: 289-295; Bulua et al., J. Exp. Med. 2011; 208: 519-533; Griffiths et al., J. Pain. 2015; 16: 981-994; Duggett et al., Pain. 2017; 158: 1499-1508). Other types of damage associated with paclitaxel treatment include mitochondrial damage, including mitochondrial swelling, vacuolization, and loss of mitochondrial structure (Flatters et al., Pain. 2006; 122: 245-257; Xiao et al., Pain. 2012; 153: 704-709).

[0078] Another suspected factor of paclitaxel-induced CIPN is Ca2+ homeostasis (Siau et al., Anesth. Analg. 2006; 102: 1485-1490; Yilmaz et al., Cell Calcium. 2017; 62: 16-28; Kidd et al., J. Biol. Chem. 2002; 277: 6504-6510; Mironov et al., J. Biol. Chem. 2005; 280: 715-721). Paclitaxel can cause mitochondrial Ca2+ release, which seems to be achieved by opening the mitochondrial permeability transition pore and rapid mitochondrial depolarization, and can also cause endoplasmic reticulum Ca2+ release. (Kidd et al., J. Biol. Chem. 2002; 277: 6504-6510; Mironov et al., J. Biol. Chem. 2005; 280: 715-721; Boehmerle et al., Proc. Natl. Acad. Sci. USA. 2006; 103: 18356-18361; Li et al., Pain. 2017; 158: 417-429). Another indicator of the potential contribution of elevated Ca2+ levels to CIPN is the increased expression of CaV3.2 channels in rats treated with paclitaxel, and it was found that inhibition of these specific Ca2+ channels reversed hyperalgesia (Okubo et al., Neuroscience. 2011; 188: 148-156). These results suggest that the increase in Ca2+ is an important factor in the development of paclitaxel-induced CIPN. Since one of the properties of 4-AP is to activate high-voltage-activated Ca2+ channels, leading to Ca2+ release, these studies would disprove the utility of 4-AP.

[0079] The expression and function of various other ion channels in paclitaxel-induced CIPN also changed. Cation channels TRPV1 and TRPA1 play an important role in pain signaling and also play an important role in paclitaxel-induced CIPN (Hara et al., Pain. 2013; 154: 882-889; Materazzi et al., Pflugers Arch. 2012; 463: 561-569), and TRPA1 antagonists can relieve paclitaxel-induced inflammation, cold allodynia and hyperalgesia (Chen et al., Neuroscience. 2011; 193: 440-451). Paclitaxel treatment also leads to an increase in the number of NaV1.7 channels, and blocking this channel can reduce hyperalgesia in rats. (Li et al., J. Neurosci. 2018; 38: 1124-1136; Aromolaran et al., Mol Pain. 2017; 13: 1744806917714693; Gheraldin et al., Neuroscience. 2010; 169: 863-873). In addition, in the paclitaxel-induced CIPN model, it was observed that the expression of K+ channels in DRG was reduced, resulting in the spontaneous activity of pain receptors (Zhang H et al., Anesthesiology. 2014; 120: 1463-1475).

[0080] Another pathogenesis of paclitaxel-induced CIPN is inflammation. Paclitaxel exposure increases the production of pro-inflammatory cytokines (TNF alfa and IL-1beta) and reduces anti-inflammatory cytokines (IL-4 and IL-10), leading to the attraction and activation of immune cells and the development of neuroinflammation. Paclitaxel can also lead to the activation of microglia and astrocytes and an increase in the number of macrophages in DRGs and peripheral nerves. The release of cytokines stimulates the TLR4 receptor in DRG cells, and blocking this receptor reduces pain behavior in mice. IL-10 can also alleviate paclitaxel-induced CIPN. Inhibition of macrophages and microglia can also prevent the development of mechanical hyperalgesia and epidermal nerve fiber loss (Krukowski et al., J. Neurosci. 2016; 36: 11074-11083; Zhang et al., J. Pain. 2012; 13: 293-303; Ruiz-Medina et al., Eur. J. Pain. 2013; 17: 75-85; Zhang et al., J. Pain. 2016; 17: 775-786; Liu et al., Mol. Pain. 2010; 6: 76; Li et al., J. Pain. 2014; 15: 712-725). Another potential factor in paclitaxel-induced CIPN is the activation of astrocytes and the production of inflammatory cytokines, which can be effectively treated with minocycline (Zhang et al., J Pain. 2012 Mar; 13 (3): 293-303).

[0081] Another drug that destroys microtubules and causes a variety of toxic reactions (including CIPN) is vincristine, a member of the vinca alkaloid family. Part of the mechanism by which vincristine induces axonal neuropathy is by destroying the microtubule axonal transport system. Vincristine binds to tubulin and prevents it from polymerizing into microtubules. Due to this activity, vincristine inhibits axonal transport. Vincristine also causes other types of axonal cytoskeletal changes (Cioroiu et al., Curr. Neurol. Neurosci. Rep. 2017; 17: 47). Vincristine induces distal axonal degeneration, and vincristine-induced peripheral neuropathy is associated with pain (Boyette-Davis et al., Pain Manag. 2018; 8: 363-375). Symptoms of distal numbness and tingling usually begin to appear about 4-5 weeks after treatment. Vincristine-induced neuropathy often involves motor and sensory fibers, with a particular tendency to affect small fiber patterns and autonomic nerve fibers (Topp et al., J. Comp. Neurol. 2000; 424:563-576).

[0082] Platinum-based chemotherapeutics are also known to cause a variety of side effects, including CIPN. Acute and chronic neurotoxicity following platinum-based chemotherapy is a major challenge and leads to prolonged infusion times, dose reductions, treatment delays, and even cessation of treatment (Storey et al., Ann. Oncol. 2010; 21: 1657-1661). In addition to peripheral neuropathy, cisplatin can also induce ototoxicity, myelotoxicity, and nephrotoxicity.

[0083] Cisplatin is one of the most widely prescribed chemotherapy drugs, accounting for nearly 50% of all tumor chemotherapy. Cisplatin is used to treat a variety of childhood and adult malignancies, such as ovarian cancer, testicular cancer, bladder cancer, head cancer, neck cancer, breast cancer and lung cancer. (Galanski et al., Curr. Med. Chem. 2005; 12: 2075-2094). Cisplatin has a variety of toxic side effects, and about 40 side effects have been reported so far (Qi et al., Chem. Res. Toxicol. 2019; 32: 1469-1486). Due to the extensive supportive medical care of cancer patients treated with cisplatin, the use of high-dose treatment has become more common, and includes some problems, such as acute kidney injury, gastrointestinal problems including persistent diarrhea, neurological disorders and hearing loss. Many side effects of cisplatin lead to a reduction or cessation of treatment, or have a significant impact on the patient's quality of life, leading to higher levels of negative states, such as depression and anxiety. (Crona et al., Oncologist. 2017; 22: 609-619; Grunberg et al., Cancer Chemother. Pharmacol. 1989; 25: 62-64; Van der Hoop et al., Cancer. 1990; 66: 1697-1702; Perse Cisplatin Mouse Models: Treatment, Toxicity and Translatability Biomedicines. 2021 October; 9(10): 1406). One of the toxic effects of cisplatin treatment is cisplatin-induced peripheral neuropathy (CisIPN), which occurs in a time- and dose-dependent manner. The development of CisIPN appears to be unrelated to pretreatment, age, sex, tumor type, and co-treatment with other chemotherapeutic agents (Park et al., Cancer J. Clin. 2013; 63: 419-437; Schmoll et al., J. Clin. Oncol. 2003; 21: 4083-4091).

[0084] In addition, oxaliplatin treatment can also lead to oxaliplatin-induced CIPN. Oxaliplatin-induced CIPN can manifest as acute or chronic, and its risk factors include the cumulative dose of oxaliplatin, infusion time, low body weight, younger age, body surface area>2,0 and several genetic variants (including variants of voltage-gated sodium channel genes SCN4A, SCN9A and SCN10A) (Velasco et al., J. Neurol. Neurosurg. Psychiatry. 2014; 85: 392-398; Alejandro et al., Am. J. Clin. Oncol. 2013; 36: 331-337; Palugulla et al., Asian Pac. J. Cancer Prev. 2017; 18: 3157-3165).

[0085] The anti-tumor mechanisms of platinum-based chemotherapy may be related to CIPN and other toxicities caused by exposure to these compounds. These mechanisms include the following factors: factors that bind to DNA and form DNA-platinum adducts, resulting in inhibition of DNA replication and RNA (ribonucleic acid) transcription; activation of apoptotic pathways by following DNA adducts; disruption of mitochondrial function, followed by disruption of respiratory chain function and increased production of reactive oxygen species (ROS); inhibition of mitochondrial DNA replication and transcription, resulting in altered mitochondrial function and activation of apoptosis; activation of the immune system (macrophages, T cells, and monocytes), followed by release of proinflammatory cytokines and activation of apoptosis; effects on calcium signaling pathways and protein kinase family function, which can also lead to apoptosis (Dasari et al., Eur. J. Pharmacol. 2014; 740: 364-378; Tesniere et al., Oncogene. 2010; 29: 482-491; Canta et al., Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN) Toxics. 2015; 3: 198-223; Ray et al., J. Biomol. Struct. Dyn. 2018 doi: 10.1080 / 07391102.2018.1531059; Riddell Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions. Met. Ions Life Sci. 2018 doi: 10.1515 / 9783110470734-007; McKeage et al., Br. J. Cancer. 2001; 85: 1219-1225; Sharawy et al., Exp. Toxicol. Pathol. 2015; 67: 315-322; Kober et al., Mol. Pain. 2018; 14: 1-16; Jaggi et al., Toxicology. 2012; 291: 1-9; Viatchenko-Karpinski et al., Mol. Pain. 2018; 14: 1-11). Although accumulation of platinum adducts in dorsal root ganglion and trigeminal ganglion neurons has been proposed to be particularly important for CIPN induced by platinum-containing drugs, the breadth of other disruptive effects on cellular function and the ability to inhibit other processes provide some intriguing indications that other processes may also need to be considered.

[0086] Another class of anticancer agents known to cause CIPN and other types of normal tissue damage is the protease inhibitors, of which bortezomib and carfilzomib are the most intensively studied. Peripheral neuropathy occurs in about one-third of patients treated with these drugs and can persist for weeks, months, or even years after drug withdrawal. Patients treated with bortezomib develop chronic, distal, and symmetrical sensory peripheral neuropathy, often with a neuropathic pain syndrome, and may develop inflammation, myelin damage, and other problems. (Saifee et al., J. Peripher. Nerv. Syst. 2010; 15: 366-368; Peng et al., Support. Care Cancer. 2015; 23: 2813-2824; Farquhar-Smith et al., Curr. Opin. Support. Palliat. Care. 2011; 5: 1-7).

[0087] Thus, it is clear that even in cases where CIPN is limited, there are multiple types of injury that need to be addressed in the context of injury due to toxic insults. Identifying therapeutics that can address these multiple types of injury is a daunting scientific challenge, and there is little indication of how to successfully accomplish this goal. The goal of addressing multiple types of injury contrasts with the more standard goal of attempting to treat each type of injury separately, such as attempting to identify a therapy that targets mitochondrial health and a separate therapy that targets repair of myelin damage (as a non-limiting example).

[0088] Radiation-induced peripheral neuropathy (RIPN) is also a problem in cancer patients. RIPN is typically a chronic disorder that is progressive and often irreversible, and usually occurs several years after radiation therapy. Compared with CIPN, RIPN is rare, but has increased with the improvement of long-term cancer survival rates. Over the past few decades, technical advances in RT regimens have reduced its incidence, but once it occurs, it can greatly impair the patient's quality of life. (Delanian et al., Radiation-induced neuropathy in cancer survivors, 2012, 105(3): 273-282). The pathophysiological mechanism of RIPN is still unclear. Neural compression caused by indirect large-area radiation-induced fibrosis is thought to play a central role, but other potential factors include axonal damage and demyelination and vascular damage caused by ischemia after capillary network failure. In general, RIPN is associated with delayed local damage to mature neural tissue. Delayed effects enhance damage to irradiated tissues and can include direct axonal injury and demyelination, extensive fibrosis in and around nerve trunks, and ischemia induced by damage to the capillary network supplying the nerves (compensated by neovascularization) (Delanian et al., Radiation-induced neuropathy in cancer survivors, 2012, 105(3):273-282).

[0089] RIPN is thought to be due in part to initial microvascular damage, followed by radiation-induced fibrosis (RIF) combined with specific nerve damage. RIF itself is a complex process with multiple components, including fibroblast proliferation, extracellular matrix deposition, amplification by cytokines such as TGFβ1 and CTGF, as well as inflammation, oxidative stress, capillary network damage, and changes in fibroblast function. (Delanian et al., Radiother Oncol. 2004; 73: 119-131; Denham et al., Radiother Oncol. 2002; 63: 129-145). Transient electrophysiological and biochemical changes may also occur in the acute phase after irradiation, accompanied by changes in vascular permeability of the irradiated nerves (Pradat et al., Rev Neurol (Paris). 1994; 150: 664-677).

[0090] Because radiation therapy is often applied in a localized fashion, much attention has been paid to relatively localized types of nerve injury. For example, cranial nerve injury following radiation therapy for both intracranial and extracranial tumors has been described. Radiation can also result in optic neuropathy, hypoglossal nerve palsy, facial palsy, and / or trigeminal neuropathy. When the upper extremities are irradiated, treated individuals may develop chronic brachial plexopathy with an onset ranging from months to decades after treatment at an average incidence of 1.8–2.9% per year, whereas early manifestations of RIBP are much rarer. With irradiation of the lower extremities, compression by radiation-induced fibrosis can result in nerve trunk injury.

[0091] The challenge in treating RIPN is that many issues are often delayed, which in itself can lead to diagnostic problems because the effects of previous radiation therapy are not taken into account (Delanian et al., Radiation-induced neuropathy in cancer survivors, 2012, 105(3):273-282). Treatment of RIPN is usually symptomatic, and curative strategies are lacking. Symptomatic treatment includes non-opioid analgesics, benzodiazepines, Class, tricyclic antidepressants, antiepileptic drugs and membrane stabilizing drugs (such as carbamazepine). Surgery is useless, but physical therapy may be useful. Although the pathogenesis of RIPN initially involves vascular mechanisms, fibrosis and atrophy are the main targets of therapeutic intervention. Because the combined pentoxifylline and tocopherol (PE) have synergistic clinical and biological properties, they can significantly reduce radiation-induced fibrosis (Delanian et al., J Clin Oncol. 2003; 21: 2545-2550; Hamama et al., Radiother Oncol. 2012; 105: 305-312).

[0092] Clodronate is a bisphosphonate that inhibits osteoclastic bone destruction and has anti-inflammatory effects and appears to inhibit macrophage myelin nerve destruction in rats (Delanian et al., Semin Radiat Oncol. 2007; 17: 99-107). Recently, clodronate was combined with pentoxifylline tocopherol (PENTOCLO) to cure 54 patients with refractory radiation-induced osteonecrosis in an average of 9 months (Delanian et al., Int J Radiat Oncol Biol Phys. 2011; 80: 832-839).

[0093] Nervous system injury is only one type of injury that can result from exposure to toxic agents such as chemotherapy, radiation, or industrial chemicals. Although injury to the nervous system has been particularly well studied due to its important medical consequences, it is also critical to identify therapeutic strategies that can be used to ameliorate injury to other tissues, including but not limited to the kidneys, lungs, immune system, digestive system, endocrine system, and other tissues specified herein and in the literature and known to those skilled in the art.

[0094] For example, it is well known that treating cancer with chemotherapeutic agents can cause damage to the central nervous system and is associated with neural and cognitive changes. This phenomenon is commonly referred to as "chemo-brain", and has been observed in a variety of different types of cancers and a variety of different types of chemotherapeutic agents. Changes in cognitive function can be observed during treatment, and damage to the central nervous system can occur rapidly and last for a long time. Central nervous system damage may involve a variety of cell types, including oligodendrocytes, neurons, microglial endothelial cells and astrocytes that produce myelin. Astrocytes, as the main supporting cells of the brain, seem to be particularly sensitive to this damage, and react by raising one of its main cytoskeletal proteins, known as glial fibrillary acidic protein (GFAP). This increase is considered to be a sign that astrocytes are activated in response to damage.

[0095] Another important and well-studied example of tissue damage caused by exposure to toxic damage from chemotherapeutic agents is chemotherapy-induced nephrotoxicity (CINT). Damage may occur acutely and may last for a long time (Santos et al., World J Clin Oncol. 2020, 24; 11 (4): 190-204; ncbi.nlm.nih.gov / pmc / articles / PMC7186234 / ; Rosner et al., N Engl J Med. 2017; 376: 1770-1781; Perazella et al., Clin JAm Soc Nephrol. 2012; 7: 1713-1721). CINT can be caused by a variety of anticancer treatments. As a non-limiting example, alkylating agents can cause acute kidney injury (AKI), hemorrhagic cystitis, inflammatory lesions, syndrome of inappropriate antidiuretic hormone secretion (SIADH); and damage to proximal and distal tubular structures through the action of metabolites and increased cellular oxidative stress. Antimetabolites can cause AKI, decreased glomerular filtration rate (GFR), interstitial edema, and renal tubular acidosis. Antimicrotubule agents can cause SIADH, while antineoplastic antibiotics can cause nephrotic syndrome, focal segmental glomerulosclerosis, thrombotic microangiopathy (TMA), AKI, and hemolytic uremic syndrome. Platinum agents can cause AKI, anemia, hypomagnesemia, and proximal tubular dysfunction (Rabah et al., Saudi J Biol Sci. 2010; 17: 105-114; Carron et al., Hemodial Int. 2014; 18: 846-847; Shavit et al., Kidney Int. 2014; 85: 213; Cordonnier et al., Nephrologie. 1985; 6: 19-26; Giroux et al., Am J Kidney Dis. 1985; 6: 28-39; Bitran et al., Cancer. 1982; 49: 1784-1788; Crona et al., Oncologist. 2017; 22: 609-619; Raj et al., J Clin Oncol. 2006; 24: 3095-3100).

[0096] For CIPN, the cause of CINT is still unclear, making the development of preventive or therapeutic strategies particularly challenging. (Santos et al., World J Clin Oncol. 2020 Apr 24; 11(4): 190-204; ncbi.nlm.nih.gov / pmc / articles / PMC7186234 / ). As with other types of toxicity caused by exposure to chemotherapeutic agents, a variety of renal dysfunctions have been reported and included in the general category of CINT (Santos et al., Nephrotoxicity in cancer treatment: An overview World J Clin Oncol. 2020 Apr 24; 11(4): 190-204; ncbi.nlm.nih.gov / pmc / articles / PMC7186234 / ). For example, treatment may address AKI due to toxic acute tubular necrosis, TMA, and crystalline nephropathy; proteinuria / nephrotic syndrome due to TMA and glomerulopathy; tubulopathy due to electrolyte and acid-base imbalances; and chronic kidney disease (CKD) due to glomerulopathy or interstitial nephritis.

[0097] There may also be intrinsic renal damage associated with the patient's pre-existing risk factors, which are primarily related to older age, hypertension, diabetes, congestive heart failure, cirrhosis, liver failure, hyperbilirubinemia, and hypoalbuminemia. There are also kidney-related risk factors such as kidney disease, previous renal damage, nephrotic syndrome, and water electrolyte disturbances caused by vomiting, diarrhea, and use of diuretics. (Perazella MA, Izzedine H. New drug toxicities in the onco-nephrology world. Kidney Int. 2015; 87: 909-917).

[0098] A particularly dangerous side effect of chemotherapy treatment can be the effect of these agents on the hematopoietic system. Chemotherapy-induced hematopoietic toxicity is a multifactorial challenge that affects the treatment of cancer patients. Among these problems, neutropenia (i.e., a decrease in the number of neutrophils) is particularly dangerous because it can increase the risk of infection. However, neutropenia is only one of several hematopoietic toxicities, others include thrombocytopenia and anemia (pubmed.ncbi.nlm.nih.gov / 12166034 / ). Bleeding secondary to thrombocytopenia is the main risk of chemotherapy-induced thrombocytopenia. The frequency of cancer-related anemia depends on the type, stage, and duration of the disease. Chemotherapy-induced anemia is affected by the type of agent used, the drug administration regimen, and the intensity of treatment. Fatigue is the most common symptom of anemia, and 80%-100% of patients undergoing chemotherapy experience this symptom. Although fatigue is a major factor affecting patients' quality of life, fatigue is often not treated systematically and actively.

[0099] Despite extensive research into the side effects of chemotherapeutic treatment, few drugs have been shown to partially prevent or reverse this damage, or to treat the symptoms it causes. Therefore, while existing research has identified potential mechanisms that warrant consideration, translation of these ideas has not been successful, and therefore previous findings cannot be used as predictors of medically useful outcomes.

[0100] This general problem is illustrated by research into developing treatments for CIPN and other types of nervous system damage. In this context, not only is there extensive research on the effects of cancer treatments on the peripheral and central nervous systems. CIPN also benefits from the ability to define outcome measures that can be determined noninvasively, and quantitative information can often be obtained through the use of patient questionnaires. Given the high prevalence of CIPN in cancer patients, the improving management of multiple cancer types, and the increasing number of cancer survivors, the discovery of new and effective strategies to prevent and / or treat CIPN and its long-term consequences is seen as a priority. The proportion of cancer patients who experience neuropathic pain at some point during their survival ranges from 40% to 70%. However, there is a need for improved treatment of CIPN, and a recent systematic review suggests that there is insufficient evidence to confirm the efficacy of central nervous system (CNS) medications for CIPN. There are currently no known preventive measures, and for many patients, pain control requires the use of opioids.

[0101] This problem is general and even more specific to single agents, as demonstrated in a recent review of cisplatin-induced toxicity ( Cisplatin Mouse Models: Treatment, Toxicity and Translatability Biomedicines. 2021 Oct; 9(10): 1406), the authors concluded: "There are currently no effective therapies to prevent these side effects; current treatment strategies are symptomatic and have limited efficacy." Therefore, although it is widely believed that preventing CIPN is a highly desirable goal and multiple efforts have been made to find agents that can do this, they have not been successful (e.g., Hershman et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 2014; 32: 1941-1967; Hou et al. Treatment of chemotherapy-induced peripheral neuropathy: systematic review and recommendations. Pa in Physician. 2018; 21: 571-592). Although some compounds initially showed promise, none of them is currently used or recommended. As pointed out in a recent review on the topic (Z et al., Mechanisms of Chemotherapy-Induced Peripheral Neuropathy Int J Mol Sci. 2019 Mar;20(6):1451), "Clinical practice guidelines issued by the American Society of Clinical Oncology (ASCO) do not recommend the use of any agent to prevent CIPN. In the ASCO guidelines, a moderate recommendation is given for duloxetine for the treatment of established CIPN. There is also a weak recommendation for a topical gel containing baclofen, amitriptyline, and ketamine."

[0102] Looking at this question in more detail, the Cochrane Interventions Review and the American Society of Clinical Oncology (ASCO) Panel Review recommend against the use of a wide range of interventions that have been tried in the field, that have been suggested by laboratory findings, or that have been extrapolated from findings in other fields. Treatments recommended in this review include acupuncture, cryotherapy, exercise therapy, or ganglioside monosialoside (GM-1), retinoic acid, amifostine, amitriptyline, calcium magnesium infusion (Ca / Mg), calcium magnesium plus fodipir, cannabinoids, carbamazepine, L-carnosine, diethyl dithiocarbamate (DDTC), gabapentin, pregabalin, glutamate, glutathione, goshajinkigan (GJG), metformin minocycline, N-acetylcysteine, nimodipine, omega-3 fatty acids, ORG 2766, oxcarbazepine, recombinant human leukemia inhibitory factor, venlafaxine, vitamin B or vitamin E) in CIPN. In addition, there is high-quality evidence that acetyl-L-carnitine causes worsening of neurotoxic neuropathy, and therefore its use is strongly advised against. For example, despite positive findings in preclinical studies, alpha-lipoic acid, OPERA, curcumin, and Neuronorm have not shown any benefit in randomized controlled trials. Similarly, despite positive pilot studies, large-scale phase III trials have not demonstrated significant neuroprotective effects of vitamin E and glutathione supplementation. Patients who were administered diethyldithiocarbamate (DDTC) and had a lower cumulative dose of cisplatin were also more likely to withdraw from treatment due to CisPN-related adverse events. Similarly, in a smaller cohort study, ORG 2766, a hexapeptide analog of ACTH, increased the incidence of CIPN. Caution is recommended when using nutritional products and supplements whose efficacy has not yet been proven. Therefore, previous studies have failed to successfully predict treatment outcomes.

[0103] In addition, glutamine was associated with a reduction in the incidence and severity of paresthesias, nerve conduction disturbances, and interference with daily function in two randomized standard-care controlled trials and one smaller nonrandomized standard-care controlled trial. Amifostine showed clinically meaningful benefits in preventing sensory and auditory CIPN but was associated with worsening nausea and vomiting and is therefore unlikely to be used clinically. There is also some evidence that duloxetine can reduce patient discomfort by modifying symptoms, but even so, the mean benefit was only a reduction in pain of 0.72 points on a 0–10 scale.

[0104] In a November 2016 review of this issue by Majithia et al. (New Practical Approaches to Chemotherapy-Induced Neuropathic Pain: Prevention, Assessment, and Treatment.cancernetwork.com / view / new-practical-approaches-chemotherapy-induced-neuropathic-pain-prevention-assessment-and-treatment), the authors also noted that one of the problems with identifying treatments for CIPN is that one must be cautious in extrapolating trials from patients with other neuropathic pain syndromes, as other syndromes sometimes respond to drugs that CIPN does not. Prevention and treatment of established CIP N have generally been unsuccessful. Although anticonvulsants such as gabapentinoids and lamotrigine have been used to treat other neuropathic pain conditions, they have not been shown to be effective in patients with CIP N and do not change symptom severity more than placebo. The complexity revealed by analyses of CIPN has been a topic of particular interest because of the prevalence of CIP N and its contribution to the reduction or cessation of anticancer therapy. Nonetheless, the multiple other cellular and tissue targets affected by anticancer therapies are equally problematic and complex.

[0105] The novelty of the present invention is highlighted by the fact that none of the potential therapies previously used to ameliorate damage caused by chemotherapy and radiation are potassium channel blockers. This is true for CIPN as well as other tissue injuries.

[0106] Another example of the toxic effects of cancer treatments and the need to alleviate such toxicity involves various kidney injuries. Renal injury (including AKI and advanced renal injury) is a common and serious complication of cancer and / or its treatment. AKI may be the most common form of renal dysfunction in cancer patients and can produce a variety of negative consequences. AKI may also disrupt the bioavailability and / or safety profile of many oncology drugs, possibly leading to suboptimal treatment, or increasing the risk of drug-induced toxicity. Preventing renal injury is widely recognized as a means to improve oncological outcomes and prevent unnecessary dose reductions or interruptions of potentially life-prolonging tumor treatments. Compared with patients without kidney disease, cancer patients who develop AKI on the basis of CKD also have an increased mortality rate.

[0107] Cytotoxic chemotherapy, targeted drugs and immune checkpoint inhibitors are usually nephrotoxic. Among cytotoxic chemotherapeutics, cisplatin (CDDP), mitomycin-C (MM-C), gemcitabine, methotrexate (MTX), ifosfamide and pemetrexed are most commonly associated with the development of AKI. Paclitaxel may also cause kidney damage. Cisplatin-induced nephrotoxicity has been studied particularly thoroughly and appears to be multifactorial (Yao et al. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007, 334: 115-124). Cisplatin can cause a large amount of oxidative stress damage and tubular cell apoptosis (Volarevic et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019; 26: 25). It can also lead to mitochondrial dysfunction, reduced ATPase activity, impaired solute transport and changes in cation balance. As a result of these changes, sodium and water reabsorption decreases and salt and water excretion increases, often leading to polyuria. Although most patients experience improvement in renal function, some develop irreversible renal impairment.

[0108] Prevention of chemotherapy-induced renal injury is limited. Overhydration and forced diuresis (ultimately with mannitol) may reduce the incidence of AKI in patients receiving cisplatin. Intravenous (iv) magnesium supplementation (8-20 mEq) may also limit renal injury, although it is unclear whether this is better than adequate oral rehydration with diuresis. (Yamamoto et al. Hydration with 15 mEq magnesium is effective at reducing the risk for cisplatin-induced nephrotoxicity in patients receiving cisplatin (≥50 mg / m2) combination chemotherapy. Anticancer Res. 2016;36:1873-1877; Saito et al. Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity. Support Care Cancer 2017;25:481-487).

[0109] The only FDA-approved drug for the prevention of cumulative nephrotoxicity is the ROS scavenger amifostine. However, side effects, cost, and concerns about reduced antitumor effects limit the use of amifostine in clinical practice. A variety of natural compounds and drugs (e.g., allopurinol and statins) have been proposed to prevent cisplatin and other cytotoxic-associated nephrotoxicity, but the level of evidence for all of these drugs appears to be low (Heidari-Soreshjani et al. Phytotherapy of nephrotoxicity-induced by cancer drugs: an updated review. J Nephropathol 2017;6:254-263; Volarevic et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019;26:25). In the case of gemcitabine, ifosfamide, and pemetrexed, no measures to prevent AKI caused by these agents have been established to date, except for general interventions for the prevention of AKI in non-oncology patients.

[0110] Questions remain about the pathogenesis of chemotherapy-related thrombotic microangiopathy (TMA), another aspect of kidney injury resulting from cancer therapy. In some cases, microvascular thrombosis is the key event, but it is unclear whether this is due to direct endothelial toxicity or immune-mediated effects on other targets. TMA is also considered a common cause of late-onset AKI in patients who undergo high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA after HSCT is not well understood, but renal endothelial cell injury is thought to play a key role (Wanchoo et al. Acute kidney injury in hematopoietic stem cell transplantation. Curr Opin Crit Care 2019;25:531-538).

[0111] Some of the most extensive efforts to find ways to prevent damage caused by exposure to toxic insults have focused on the problem of CIPN. There are many reasons for the focus on this topic, including the large number of people affected by the problem, its importance as a dose-limiting toxicity that can reduce the ability to effectively treat cancer, and the ability to study the evolution of CIPN in a relatively straightforward manner. The only other toxicity that has attracted similar attention is chemotherapy-induced damage to the hematopoietic system. However, attempts to develop treatments to overcome the effects of chemotherapy on the hematopoietic system have been more successful than in the case of CIPN. The classification of CIPN as a peripheral neuropathy has naturally led to interest in determining whether any approaches that have shown promise in treating peripheral nerve damage might help prevent or treat CIPN. Unfortunately, efforts in this direction have thus far been unsuccessful.

[0112] The central approach of this invention is to use potassium channel blockers (preferably 4-AP) to prevent and / or treat CIPN, but the problem of CIPN is not taken into account. In fact, a detailed examination of the results of the 4-AP studies reveals a wealth of evidence to suggest that 4-AP should not be used, even for the narrow purpose of preventing or treating CIPN. There are many reasons to suggest that 4-AP is unlikely to be useful in preventing or treating CIPN or other peripheral neuropathies, let alone preventing other types of damage caused by exposure to toxic insults.

[0113] One of the early suggestions that 4-AP may be useful in pain management was reported in studies of individuals with chronic spinal cord injury. In these studies, 4-AP was reported to reduce neuropathic pain in some individuals (Hansebout et al., 4-Aminopyridine in chronic spinal co rd injury: a controlled, double-blind, crossover study in eight patient s J Neurotrauma 1993; 10(1): 1-18). Although several further studies were conducted on 4-AP and emphasized its importance in reducing chronic pain in patients with spinal cord injury, these studies did not develop into a treatment. In contrast, a Phase III study of the effects of 4-AP in individuals with chronic spinal cord injury failed to reveal a significant benefit.

[0114] As another example of disproving the hypothesis that 4-AP may be useful for treating CIPN, it was reported in 1988 that 4-AP can alter peripheral nerve conduction properties three months after chronic exposure to large amounts of pyridoxine (vitamin B6), a natural compound occasionally used to induce changes in peripheral nerve function (Bowe et al., 1988, Exp. Neurol., 100:448-458). An examination of the details of these studies revealed that they were conducted on nerves studied in an ex vivo recording chamber at room temperature and exposed to 4-AP concentrations (1 mM) three orders of magnitude higher than the maximum serum concentration considered clinically relevant. Furthermore, these studies only revealed changes in nerve sensitivity to 4-AP after 3 months of pyridoxine treatment, and pain was not analyzed, nor were inferences about the understanding or treatment of sensory neuropathy included in the paper.

[0115] Another study showed that 4-AP was able to promote recovery from acute traumatic peripheral nerve crush injuries that were precisely located so that they could be treated with local application of a 4-AP sustained-release formulation or systemically (Tseng et al. 4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. EMBO Mol Med (2016) 8: 1409-1420). This injury is qualitatively different from diffuse injuries associated with systemic exposure to chemotherapeutic agents or other toxic insults. Studies on the use of 4-AP to promote recovery from localized peripheral nerve crush injuries also reported that treatment with 4-AP promoted recovery of specific parameters or thermal hyperalgesia, but not mechanical allodynia. In contrast, in the case of the present invention, 4-AP provided benefits for mechanical allodynia, thermal hyperalgesia, and thermal hypoalgesia in paclitaxel-induced CIPN, an unusual and unexpected result due to the opposite direction of symptomatic changes in response to temperature. Therefore, the above-mentioned different results further demonstrate the lack of predictability of the current results compared with previous results.

[0116] It has also been suggested that electrical stimulation may provide benefits for patients with CIPN (Smith et al., Pilot trial of a patient-specific cutaneous electrostimulation device (MC 5-A )for chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage, 2010, 40:883-891). Despite earlier suggestions that electrical stimulation may help treat CIPN, a recent randomized, placebo-controlled, double-blind study showed "no differences between active treatment and placebo groups in terms of pain, numbness / tingling, symptom frequency, or impact on activities of daily living." (Tonezzer et al. Effects of transcutaneous electrical nerve stimulation on chemotherapy-induced periph eral neuropathy symptoms (CIPN): a preliminary case-control study. J Phys Ther Sci. 2017 Apr;29(4):685-692; ncbi.nlm.nih.gov / pmc / articles / PMC5430273 / ). These results suggest that transcutaneous electrical nerve stimulation applied in a frequency-varying pattern does not improve symptoms of CIPN during chemotherapy.

[0117] As another relevant example, there was no difference in pain scores between patients with Guillain-Barré Syndrome treated with 4-AP and those with Guillain-Barré Syndrome who received placebo (p = .92), as assessed by the McGill Pain Rating Questionnaire and a visual analog scale (Use of 4-Aminopyridine in Peripheral Neuropathy (2003) U.S. Patent 6,503,931). There were no clinically significant changes in nerve conduction velocity either. (Meythaler et al. Phase IIB Randomized Trial on the Use of 4-Aminopyridine in Guillain-Barré Syndrome. Arch Rehabil Res Clin Transl. 2021 Jun;3(2):100123). Therefore, these studies suggest that 4-AP has no utility in the treatment of pain, even for the type of neuropathy that may occur in patients with Guillain-Barré Syndrome.

[0118] This study reveals a previously unknown and unexpected approach to preventing and / or treating damage caused by toxic insults using the potassium channel blocker 4-AP. This study investigated repeated administration of clinically relevant doses of 4-AP to individuals exposed to toxic insults. This treatment can be initiated before, during, or after the toxic insult. This treatment approach also had the unexpected effect of preventing damage and promoting durable repair at the functional and structural levels. This treatment approach also had the unexpected effect of rescuing mitochondrial damage induced by chemotherapy. Therefore, this study provides additional new discoveries for the new use of 4-AP in addressing unmet medical needs. This study showed unexpected benefits that could not be predicted by previous observations. This study also demonstrates a new finding that 4-AP treatment can be used to treat the adverse effects of adverse exposures to toxic insults, which can include, for example, chemotherapy, radiation, and environmental toxicants.

[0119] In addition, the present invention provides new treatment methods for any exposure to toxic substances. For example, the present invention provides treatments for tissue damage caused by chemotherapy and / or radiation therapy for cancer. The present invention provides treatments for exposure to artificially produced toxicants, such as treatments for CIPN induced by paclitaxel (PTX) or CIPN induced by cisplatin, although the chemical structures and biological activities of these two toxic compounds are different. The present invention also provides treatments for chemotherapy-induced nephrotoxicity, chemotherapy-induced mitochondrial damage, and chemotherapy-induced central nervous system effects.

[0120] With respect to the effects of chemotherapy, this study first focused on CIPN as a specific example of the general problem. Although the mechanisms of injury involved in CIPN are largely unknown, they are thought to differ greatly from traumatic injury in terms of both the mechanism of injury and the potential breadth of damage caused. In the case of CIPN induced by paclitaxel, a microtubule-stabilizing drug, this activity was not clearly related to any effects of traumatic injury. Another difference is that the pathological changes that occur after trauma follow a defined sequence that includes local events such as local cell death, immune infiltration, local scarring, and other well-defined pathological changes. In contrast, exposure to chemotherapy, radiation, or environmental toxins does not typically induce such rapid pathological changes and also induces different pathological consequences that may take longer to develop. Therefore, the novelty of using 4-AP to treat toxic insults lies in the cause of the injury (i.e., the toxic insult) and the unexpected ability of 4-AP to be used to treat such injuries.

[0121] Thus, the present invention is based in part on the unexpected finding that 4-AP is effective in treating tissue damage caused by toxic insults. Thus, the present invention relates in part to compositions and methods for treating subjects exposed to toxic insults (e.g., toxic compounds or toxic levels of radiation). The method may comprise administering to the subject a pharmaceutical composition comprising a potassium channel blocker, preferably 4-AP, a derivative thereof, or a combination thereof. In some embodiments, the damage caused by the toxic insult may be multi-site and / or multi-organ. In some embodiments, the method may comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4-AP, a derivative thereof, or a combination thereof. In some embodiments, the pharmaceutical composition may be formulated to provide sustained release of 4-AP, a 4-AP derivative, or a combination thereof. In certain embodiments, 4-AP or a derivative thereof may be represented by a structure according to formula (I)

[0122]

[0123] or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof. 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl, or any combination thereof; and wherein R 1 , R 2 , R 3 , R 4 and R 5 Optionally substituted. In some embodiments, the derivative of 4-AP includes 3,4-diaminopyridine, 3-hydroxy-4-AP, or a combination thereof.

[0124] In some embodiments, 4-AP can be replaced by a different potassium channel blocker. It is known that 4-AP can bind to a variety of potassium channels, and other potassium channel blockers such as 4-AP derivatives and tetraethylammonium can produce similar effects in experimental situations, and the 4-AP derivative 3,4-diaminopyridine can also produce similar effects in certain clinical situations. Therefore, in the present invention, it is expected that other potassium channel blockers are also effective for the purpose of using 4-AP in the experimental examples of the present invention.

[0125] In some embodiments, the pharmaceutical composition can be administered to a subject by injection, intraperitoneal injection, intravenous injection, intramuscular injection, intrathecal injection, subcutaneous injection, sublingual administration, inhalation, oral administration, transdermal administration, implantation, insertion of a device into the subject, or any combination thereof.

[0126] In some embodiments, the pharmaceutical composition can be administered in combination with an additional therapeutic agent to provide protection against the ability of at least one potassium channel blocker to cause convulsions in rare individuals when serum levels exceed a defined threshold. For example, the pharmaceutical composition can be administered with an anticonvulsant. The anticonvulsant can be selected from lamotrigine, gabapentin, valproic acid, topiramate, famotidine, phenobarbital, phenytoin, diphenylhydantoin, mephenytoin, ethotoin, mefenamic acid, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine Phenacetamide, acetazolamide, progabit, clonazepam, sodium valproate, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, sodium valproate, clobazam, sultimethoxazole, phenytoin, diphenylhexamine and L-5-hydroxytryptophan, or any combination thereof.

[0127] The pharmaceutical composition may be administered at different times depending on the therapeutic goal. To prevent the effects of toxic insults, prophylactic treatment may be administered, starting before exposure or within the first week after exposure or before symptoms of injury become apparent. To slow or reverse the progression of injury or overcome symptoms of injury, treatment may be administered at any time when injury begins to manifest, as determined, for example, by the development of clinically relevant symptoms.

[0128] If the goal is to prevent the manifestation of damage, the pharmaceutical composition can be repeatedly administered throughout the period of exposure to the toxic insult. In some cases, particularly when treatment is used to relieve symptoms, treatment can be continued as long as the symptoms persist.

[0129] A dosage of about 5 mg / day to about 100 mg / day of 4-AP, a 4-AP derivative, or a combination thereof may be administered to a subject in need of treatment. In certain embodiments, a dosage of about 5 mg / day to about 40 mg / day or about 40 mg / day to about 100 mg / day of 4-AP, a 4-AP derivative, or a combination thereof may be administered to a subject. In some embodiments, the dosage of 4-AP or its derivatives may be increased or decreased from these levels depending on the effective therapeutic dosage range for each particular agent.

[0130] It will also be apparent to those skilled in the art that the amount and frequency of administration of a potassium channel blocker or pharmaceutical composition thereof will depend on many factors, including but not limited to the properties of the potassium channel blocker, the type and severity of the subject's disease or condition, the subject's condition, the subject's age, the subject's sex, the subject's overall health, and other factors, although appropriate dosages can be determined through clinical trials. Therefore, the present invention should not be construed as limited to any particular dosage regimen, and the precise dosage and composition administered to any subject will be determined by the attending physician in consideration of all other factors for the subject.

[0131] In some embodiments, the methods described herein can be used to treat injuries caused by toxic insults in subjects. For example, the methods described herein can be used to treat the effects of exposure to chemotherapy and / or radiotherapy in individuals undergoing cancer treatment. In some embodiments, the methods described herein can be used to treat the effects of exposure to industrial chemicals or toxic radiation from nuclear power plant leaks, or the effects caused by the release of toxic radiation in military scenarios. In other embodiments, the methods described herein can be used to treat the effects of environmental toxicant exposure, such as those associated with air pollution, water pollution, exposure to chemicals released in burn pits, exposure to agricultural chemicals, and other environmental exposures well known to those skilled in the art.

[0132] In some embodiments, the damage may be most evident in one system of the body, such as chemotherapy-induced peripheral neuropathy (CIPN). In other embodiments, the damage may be manifested in more than one tissue, including, for example, the peripheral nervous system, central nervous system, visual system, auditory system, hematopoietic system, gastrointestinal system, bladder, heart, skeletal muscle, hair follicles, skin, vasculature, salivary glands, or a combination of any of these tissues.

[0133] In some embodiments, toxic damage can be an industrial chemical used for any of a variety of purposes, such as for agriculture and manufacturing processes, and its exposure can cause damage to any of a variety of tissues, including, for example, the peripheral nervous system, central nervous system, visual system, auditory system, hematopoietic system, gastrointestinal system, bladder, heart, skeletal muscle, hair follicles, skin, vascular system, salivary glands, or any combination of these tissues. In the context of the present invention, special attention is paid to medicaments that are intentionally produced by industrial processes and have the ability to cause tissue damage. It does not matter whether the toxic agent that causes tissue damage is intentionally toxic or accidentally toxic. Importantly, the agent (whether in the form of chemical structure or electromagnetic radiation) can cause tissue damage and / or tissue dysfunction.

[0134] In some embodiments, the methods described herein can restore at least a portion of the motor function or / and sensory function lost by the subject, enhance the repair and regeneration of nerve cells, such as promoting nerve cell generation, enhancing cell survival, reducing scarring, or a combination thereof, compared to untreated subjects. In other embodiments, the methods described herein can restore at least a portion of the function of damaged tissue, enhance repair and regeneration, increase cell survival, reduce scarring, reduce other aspects of tissue damage, or a combination thereof, compared to untreated subjects. In further embodiments, the methods described herein can restore at least a portion of the function of damaged tissue, enhance repair and regeneration, enhance cell survival, reduce scarring, or a combination thereof, compared to untreated subjects.

[0135] In some embodiments, the methods disclosed herein can be used to prevent or treat muscle atrophy. In some embodiments, muscle atrophy may be caused by exposure to chemotherapy, other toxic chemicals, toxic radiation.

[0136] In some embodiments, the methods disclosed herein can be used to prevent, ameliorate, reverse or otherwise treat tissue dysfunction caused by exposure to artificially generated toxic insults. In some embodiments, tissue dysfunction can occur in cells in, for example, the hematopoietic system, hair follicles, oral cavity, digestive tract, reproductive system, and cells in the heart, kidney, bladder, salivary glands, auditory system, visual system, lung, nervous system, or any combination thereof.

[0137] In some embodiments, the methods disclosed herein can be used to identify individuals who will benefit from treatment with a potassium channel blocker (e.g., 4-AP, a derivative of 4-AP, or any combination thereof). For example, in some embodiments, the present invention relates to a method for identifying a subject who is responsive to administration of 4-AP to prevent, alleviate, or treat tissue damage or tissue dysfunction caused by toxic damage in a subject in need thereof, the method comprising the following steps: a) administering to the subject 1 to 5 therapeutically effective amounts of a pharmaceutical composition comprising 4-AP, a derivative of 4-AP, or a combination thereof; b) assessing the subject for symptoms of tissue damage or tissue dysfunction caused by toxic damage; and c) identifying the subject as responsive to administration of 4-AP to prevent, alleviate, or treat tissue damage or tissue dysfunction caused by toxic damage when the symptoms of tissue damage or tissue dysfunction caused by toxic damage in the subject improve.

[0138] In some embodiments, individuals exhibiting dysfunction in one or more tissues after exposure to artificially generated toxic insults can be treated with the methods disclosed herein for one to ten days to determine whether treatment improves tissue function. Thus, in some embodiments, the methods disclosed herein can be used to provide personalized therapeutic targeting.

[0139] In some embodiments, individuals who are exposed to toxic insults and have one or more changes in tissue function caused by exposure to toxic insults are treated with a potassium channel blocker (e.g., 4-AP, a derivative of 4-AP, or a combination thereof) 1 to 5 times to predictively identify individuals in whom treatment should be continued for a longer period of time. In some embodiments, if the individual shows improvement in tissue function, the long-term methods disclosed herein are applied. In some embodiments, individuals with injuries caused by toxic insults and symptoms in the areas of gait, pain, or nerve conduction velocity are treated with 4-AP or its derivatives 1 to 5 times, and symptoms are measured between 1-8 hours after the start of treatment (i.e., within two half-lives of 4-AP in serum). For example, in some embodiments, individuals with CIPN or RIPN who have symptoms in terms of gait, pain, or nerve conduction velocity are treated with 4-AP or its derivatives 1 to 5 times, and symptoms are measured between 1-8 hours after the start of treatment (i.e., within two half-lives of 4-AP in serum).

[0140] Additional advantages will be set forth in part in the description below, will be apparent from the description, or may be learned through practice of the aspects described below. The advantages described below will be realized and achieved by means of the elements and combinations specifically identified in the appended claims. It should be understood that the above general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0141] definition

[0142] 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 the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described.

[0143] As used herein, each of the following terms has the meaning associated with it in this section.

[0144] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0145] As used herein, "about" when referring to a measurable value such as an amount, duration, etc., is intended to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the stated value as such variations are applicable to performing the disclosed methods.

[0146] Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein. In one embodiment, the term also refers to stereoisomers and / or optical isomers (including racemic mixtures) or enantiomerically enriched mixtures of the disclosed compounds.

[0147] The term "analog" as used herein refers to a compound or molecule made from a parent compound or molecule by one or more chemical reactions. Thus, an analog may be a structure having a structure similar to that of a small molecule therapeutic described herein, or may be based on a scaffold of a small molecule therapeutic described herein, but differing therefrom in certain components or structural compositions, which may have similar or opposite effects on metabolism. An analog or derivative may also be a small molecule that has a structure different from that of a reference molecule but retains the basic properties of the reference molecule. Relative to a reference molecule, an analog or derivative may change its interaction with certain other molecules. Analogs or derivative molecules may also include salts, adducts, tautomers, isomers or other variants of a reference molecule.

[0148] The term "derivative" refers to a small molecule that is structurally different from a reference molecule but retains the essential properties of the reference molecule. A derivative may alter its interactions with certain other molecules relative to the reference molecule. A derivative molecule may also include salts, adducts, tautomers, isomers, or other variants of a reference molecule.

[0149] The term "tautomer" refers to constitutional isomers of organic compounds that are readily interconvertible by a chemical process (tautomerization).

[0150] The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0151] The term "prodrug" refers to a compound that is structurally different from a reference molecule but is chemically modified by a specific cellular process and is ultimately modified to retain the essential properties of the reference molecule or to become the reference molecule. The term "prodrug form" and its derivatives as used herein refer to a drug that has been chemically modified to add and / or remove one or more substituents so that after the prodrug form is introduced into a subject, the modification can be reversed by naturally occurring processes to regenerate the drug. Examples of prodrugs include, but are not limited to, esters, optionally substituted esters, branched esters, optionally substituted branched esters, carbonates, optionally substituted carbonates, carbamates, optionally substituted carbamates, thioesters, optionally substituted thioesters, branched thioesters, optionally substituted branched thioesters, thiocarbonates, optionally substituted thiocarbonates, sulfinylthiocarbonates, optionally substituted sulfinylthiocarbonates, 2-hydroxypropionates, optionally substituted 2-hydroxypropionates, S-thiocarbonates, optionally substituted S-thiocarbonates, dithiocarbonates, optionally substituted dithiocarbonates, thioesters carbamate, optionally substituted thiocarbamate, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid ester, D-amino acid ester, oxymethoxyamino ester, N-substituted L-amino acid ester, N,N-disubstituted L-amino acid ester, N-substituted D-amino acid ester, N,N-disubstituted D-amino acid ester, sulfinyl, optionally substituted sulfinyl, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, imidate, optionally substituted imidate, hydrazine, optionally substituted hydrazine, oxime, optionally substituted oxime, imidazolyl, optionally substituted imidazolyl, imidazolyl, optionally substituted imidazolyl, acetal, optionally substituted acetal, hemiacetal, optionally substituted hemiacetal, carboimidate ester, optionally substituted carboimidate ester, thiocarboimidate ester, optionally substituted thiocarboimidate ester, carboimidate An amine, an optionally substituted carboimidyl, a carbamate, an optionally substituted carbamate, a carbamate, an optionally substituted carbamate, a thioacetal, an optionally substituted thioacetal, an S-acyl-2-thioethyl, an optionally substituted S-acyl-2-thioethyl, an (acyloxybenzyl) ether, an (acyloxybenzyl) ester, a PEG ester, a PEG carbonate, a bis(acyloxybenzyl) ester, an optionally substituted bis(acyloxybenzyl) ester, an (acyloxybenzyl) ester, an optionally substituted (acyloxybenzyl) ester, or a BAB ester, acetate, formate and benzoate derivative of an alcohol functional group in the compound.Methods for constructing compounds as prodrugs can be found in Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs are converted to active metabolites by hydrolytic enzymes, hydrolysis of amides, lactams, peptides, carboxylates, epoxides, or cleavage of inorganic acid esters.

[0152] As used herein, the term "alkyl" by itself or as part of another substituent means, unless otherwise indicated, a group having the specified number of carbon atoms (i.e., C 1-6 The term "alkyl" refers to a saturated hydrocarbon radical of one to six carbon atoms) and includes a straight or branched chain of a straight, branched or cyclic substituent. Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, such as homologues and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl. Unless otherwise indicated, the term "alkyl" also means alkyl derivatives including those defined in more detail below, such as "heteroalkyl", "haloalkyl" and "homoalkyl".

[0153] The term "substituted alkyl" as used herein refers to an alkyl group as defined above substituted by one, two or three substituents selected from halogen, -OH, alkoxy, -NH2, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1-C4)alkyl, -C(=O)NH2, -SO2NH2, -C(=NH)NH2 or -NO2, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2 or -C(=O)OH, more preferably selected from halogen, alkoxy or -OH. Examples of substituted alkyl groups include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.

[0154] As used herein, the term "alkylene" by itself or as part of another molecule refers to a divalent group derived from an alkane, such as (-CH2-) n By way of example only, such groups include, but are not limited to, groups having 24 or fewer carbon atoms, such as the structures -CH2CH2- and -CH2CH2CH2CH2-. Unless otherwise indicated, the term "alkylene" is also intended to include those groups described below as "heteroalkylene".

[0155] As used herein, the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense and refer to an alkyl group attached to the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.

[0156] Unless otherwise indicated, the term "alkoxy" as used herein, alone or in combination with other terms, refers to an alkyl group having the specified number of carbon atoms as defined above, which is attached to the rest of the molecule via an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred are (C1-C3) alkoxy, particularly ethoxy and methoxy.

[0157]

[0043] As used herein, unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0158] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic non-aromatic group in which each atom (i.e., backbone atom) forming the ring is a carbon atom. In one embodiment, the cycloalkyl is saturated or partially unsaturated. In another embodiment, the cycloalkyl is fused to an aromatic ring. The cycloalkyl includes groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl include, but are not limited to, the following parts:

[0159]

[0160] Monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl includes but is not limited to tetrahydronaphthyl, indanyl and tetrahydropentalenyl. Polycyclic cycloalkyl includes adamantane and norbornane. The term "cycloalkyl" includes "unsaturated non-aromatic carbocyclic group" or "non-aromatic unsaturated carbocyclic group", both of which refer to non-aromatic carbocyclic rings as defined herein, which contain at least one carbon-carbon double bond or one carbon-carbon triple bond.

[0161] Unless otherwise indicated, the term "heteroalkyl" as used herein, by itself or in combination with another term, means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom may be located at any position of the heteroalkyl, including between the remainder of the heteroalkyl and the fragment to which it is attached, and attached to the most distal carbon atom in the heteroalkyl. Examples include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3 and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0162] Unless otherwise indicated, the term "heterocycle" or "heterocyclyl" or "heterocyclic" as used herein, alone or as part of another substituent, refers to an unsubstituted or substituted, stable monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from N, O or S, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized. Unless otherwise indicated, the heterocyclic ring system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocycle may be aromatic or non-aromatic in nature. Examples of 3-membered heterocycloalkyls include, but are not limited to, aziridine. Examples of 4-membered heterocycloalkyls include, but are not limited to, azetidine and beta-lactams. Examples of 5-membered heterocycloalkyls include, but are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidine, morpholine and piperazine. Other non-limiting examples of heterocycloalkyls are:

[0163]

[0164] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophene, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepene, and hexamethylene oxide.

[0165] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings and having aromatic character, ie, having (4n+2) delocalized p (pi) electrons, where n is an integer.

[0166] Unless otherwise indicated, the term "aryl" as used herein, alone or in combination with other terms, refers to a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), wherein the rings may be linked together in a pendant manner, such as biphenyl, or may be fused, such as naphthalene. Examples of aryl include phenyl, anthracenyl and naphthyl. Phenyl and naphthyl are preferred, and phenyl is most preferred.

[0167] As used herein, the term "aryl-(C1-C4)alkyl" refers to a functional group in which an alkylene chain of 1 to 3 carbons is attached to an aryl group, for example -CH2CH2-phenyl. Preferred are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C4)alkyl" refers to an aryl-(C1-C4)alkyl functional group in which the aryl group is substituted. Preferred are substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C4)alkyl" refers to a functional group in which an alkylene chain of one to three carbons is attached to a heteroaryl group, for example -CH2CH2-pyridyl. Preferred are heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C4)alkyl" refers to a heteroaryl-(C1-C4)alkyl functional group in which the heteroaryl group is substituted. Preferred are substituted heteroaryl-(CH2)-.

[0168] Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furanyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0169] Examples of polycyclic heterocycles include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl (particularly 1- and 5-isoquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuranyl (particularly 3-, 4-, 5-, 6- and 7-benzofuranyl), 2,3-dihydrobenzofuranyl, 1,2-benzisoxazolyl, benzothiophenyl (especially 3-, 4-, 5-, 6- and 7-benzothiophenyl), benzoxazolyl, benzothiazolyl (especially 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (especially 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl and quinolyl.

[0170] The foregoing list of heterocyclyl and heteroaryl moieties is representative only and is not intended to be limiting.

[0171] The term "aminoaryl" as used herein refers to an aryl moiety containing an amino moiety. Such amino moieties may include, but are not limited to, primary amines, secondary amines, tertiary amines, masked amines, or protected amines. Such tertiary amines, masked amines, or protected amines may be converted to primary amine or secondary amine moieties. Additionally, the amine moiety may include an amine-like moiety having chemical properties similar to the amine moiety, including, but not limited to, chemical reactivity.

[0172] The term "substituted" as used herein refers to an atom or a group of atoms that has replaced hydrogen as a substituent attached to another group. For aryl, aryl-(C1-C4) alkyl and heterocyclyl, the term "substituted" when applied to the rings of these groups refers to any degree of substitution, i.e., mono-, di-, tri-, tetra- or penta-substitution, as long as such substitution is permitted. Substituents are independently selected, and substitution can be carried out at any chemically accessible position. In one embodiment, the number of substituents varies between one and four. In another embodiment, the number of substituents varies between one and three. In another embodiment, the number of substituents varies between one and two. In yet another embodiment, substituents are independently selected from C1-C4, ... 1-6 Alkyl, -OH, C 1-6 In yet another embodiment, the substituents are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo, acetylamino or nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with a straight chain being preferred.

[0173] As used herein, the term "optionally substituted" means that the group mentioned may be substituted or unsubstituted. In one embodiment, the group mentioned is optionally substituted with zero substituents, i.e., the group mentioned is unsubstituted. In another embodiment, the group mentioned is optionally substituted with one or more additional groups, which are individually and independently selected from the groups described herein.

[0174] In one embodiment, the substituents are independently selected from oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including linear, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted benzene. alkyl], -C(=O)N[H or alkyl]2, -OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -N[substituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]2 or -C(NH2)[substituted or unsubstituted alkyl]2. In another embodiment, for example, the optional substituents are selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, or -C(=O)OH. In yet another embodiment, the substituents are independently selected from C 1-6 Alkyl, -OH, C 1-6 In yet another embodiment, the substituents are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo, acetylamino or nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain may be branched, linear or cyclic.

[0175] The term "abnormal" when used in the context of organisms, tissues, cells, or parts thereof, refers to those organisms, tissues, cells, or parts thereof that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or part thereof that exhibits the "normal" (expected) corresponding characteristic. A characteristic that is normal or expected for one cell or tissue type may be abnormal for a different cell or tissue type.

[0176] A disease is when the health of an animal is compromised by a process initiated by an organism. Such biological processes can be pathogens, such as viruses and bacteria, for example. They can also be genetic diseases or autoimmune diseases caused by the immune system attacking our own cells.

[0177] The term "disorder" generally refers to any disorder of normal mental or physical function. For example, the disorder of normal health that is the subject of the present invention is not a disease, as defined in the above description. The present invention is primarily directed to the disruption of normal health and tissue function caused by exposure to artificially generated toxic insults. Non-limiting examples of such toxic insults include anticancer agents, industrial chemicals, radiation, and other disruptors of normal cell and tissue function. There is no single word to describe this disruption. As with all disorders, there are biological consequences. However, in the case of disruption caused by exposure to artificially generated toxic insults, biological changes occur immediately after the initial exposure to the toxic insult.

[0178] The term "cancer" or "tumor" as used herein includes, but is not limited to, benign and malignant cancers of the oral cavity (e.g., mouth, tongue, throat, etc.), digestive system (e.g., esophagus, stomach, small intestine, colon, rectum, liver, bile duct, gall bladder, pancreas, etc.), respiratory system (e.g., larynx, lung, bronchi, etc.), bones, joints, skin (e.g., basal cell, squamous cell, melanoma, etc.), breast, reproductive system (e.g., uterus, ovary, prostate, testicles, etc.), urinary system (e.g., bladder, kidney, ureter, etc.), eyes, nervous system (e.g., brain, etc.), endocrine system (e.g., thyroid, etc.), and hematopoietic system (e.g., lymphoma, myeloma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, etc.).

[0179] The terms "patient", "subject", "individual" and the like are used interchangeably herein and refer to any animal or its cells suitable for the methods described herein, whether in vitro or in situ. In certain non-limiting embodiments, the patient, subject or individual is a human.

[0180] As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of tissue function or response of a subject compared to the level of tissue function or response of the subject in the absence of a treatment or compound, and / or compared to the level of tissue function or response of an otherwise identical but untreated subject. The term encompasses perturbing and / or influencing a natural signal or response, thereby mediating a beneficial therapeutic response in a subject (preferably a human).

[0181] A disease or condition is "relieved" if the signs or symptoms of the disease or condition are less severe, the patient experiences such signs or symptoms less frequently, or both.

[0182] As used herein, the term "treating" a disease or condition refers to reducing the frequency or severity of at least one sign or symptom of the disease or condition experienced by a subject.

[0183] The term "treating" refers to administering a therapeutically effective amount of a therapeutic agent (eg, 4-AP) to a subject known or suspected of being exposed to an artificial toxic insult.

[0184] The term "treatment" refers to the medical management of a patient with the intention of curing, improving, stabilizing, or preventing a pathological condition or illness. The term includes active treatment, i.e., treatment specifically directed to improving a pathological condition or illness. In general, it may include targeted treatments intended to eliminate the causes of the associated pathological condition or disorder (i.e., toxic damage). In contrast, treatment as defined in the present application also includes preventive treatments, i.e., treatments intended to minimize or partially or completely inhibit the development of damage that may be caused by exposure to toxic damage. This treatment can be used to supplement another specific therapy for the lasting improvement of an associated disease, pathological condition, or illness.

[0185] As used herein, "treatment of disruption of normal health and tissue function caused by exposure to anthropogenic toxic insults" refers to reducing the severity and / or frequency of signs or symptoms of disruption of normal health and tissue function experienced by a subject. Such treatment may include preventing the disruption, stabilizing the disruption to slow or prevent gradual deterioration, reversing the disruption, and / or partially or completely restoring normal tissue structure and / or function. Treatment may also include controlling the symptoms of tissue disruption to reduce its severity, preventing, stabilizing or reversing dysfunction, and / or partially or completely restoring normal tissue structure and / or function.

[0186] "Treatment for prognostic purposes" refers to the use of the methods of the present invention to identify individuals who may benefit from continued treatment. Such treatment for prognostic purposes generally employs short-term treatment, such as (but not limited to) one to five days of treatment and analysis of any symptoms of tissue dysfunction caused by exposure to one or more toxic insults. In this way, people who are likely to respond to treatment can be identified as early as possible, so that further attention can be paid to those individuals who are most likely to benefit from treatment of the present invention.

[0187] As used herein, the term "treatment" or "treatment regimen" refers to activities taken to alleviate or change the normal health and tissue function disorders caused by exposure to artificial toxic insults, for example, the use of pharmacology, surgery, diet and / or other techniques, aimed at reducing or eliminating at least one sign or symptom of such disorders. In general, a treatment regimen may include one or more drugs or surgeries at prescribed doses. In the context of the present invention, a treatment regimen may include treatment with 4-AP, its derivatives or different potassium channel blockers or a combination of these agents. Such treatment regimens may include other drugs such as anticonvulsants to prevent the side effects that may occur with 4-AP doses in individuals who are susceptible to epilepsy (such epilepsy is not caused by the doses usually used to treat these drugs). Treatment is generally beneficial and can reduce or eliminate at least one sign or symptom of normal health and tissue function disorders. In the broader use of the term "treatment", some situations of therapeutic effects will produce undesirable effects or side effects, such as anti-cancer treatment. The effect of treatment will also be affected by the physiological state of the subject, such as age, sex, genetics, weight, other disease conditions, etc.

[0188] A "therapeutic" treatment is one administered to a subject exhibiting signs of a pathology with the goal of alleviating or eliminating those signs.

[0189] The term "nephropathy" refers to a broad category of conditions in which renal function is impaired in some way. As with nephropathy, the term nephropathy is broadly used to describe the symptomatic consequences of various aspects of renal dysfunction, but the cause of such dysfunction cannot be inferred. For example, such tissue dysfunction may occur due to exposure to a variety of artificially generated toxic insults, and its cause may be different from that of nephropathy induced by biological causes such as nephropathy or ischemia-reperfusion injury to a variety of different tissues (such as may occur in myocardial infarction). Nephropathy caused by exposure to artificially generated toxic insults represents another class of unmet medical needs addressed by the present invention.

[0190] An example of damage caused by toxic insults is the range of conditions included in the general category of peripheral neuropathy. Peripheral neuropathy is a general description of a large class of changes that are identified by presenting symptoms, such as sensory changes in peripheral nerves, but whose underlying causes and mechanisms vary widely. Therefore, the term neuropathy describes the symptoms, but includes a variety of different individual disruptions of normal tissue function. Therefore, although some common symptoms of peripheral neuropathy occur in many different situations, there is little or no reason to believe that even for neuropathy caused by biological diseases, such as diabetic neuropathy, neuropathic pain associated with spinal stenosis, peripheral neuropathy in autoimmune diseases such as Guillain-Barré syndrome, neuropathic pain after spinal cord injury or stroke, the underlying cause and pathology are the same. The underlying causes and pathologies of neuropathy caused by toxic insults still represent different large classes of diseases that share common symptoms rather than being caused by common mechanisms or being treatable by common methods. There are flaws in using peripheral neuropathy as an indicator of a specific pathological process, especially for neuropathy syndromes caused by exposure to toxic insults. Many industrially produced chemicals can cause symptoms such as peripheral neuropathy in exposed individuals, but the presentation of these symptoms has little or no bearing on understanding the etiology, pathophysiology, or treatment of the clinical problem. Therefore, it should be understood that the term "peripheral neuropathy" is used only to indicate that a person exhibits symptoms that lead to their inclusion in this broad and multi-member category, but the term is not associated with a specific cause or type of injury. There are many types of damage that can result in the consequences collectively referred to as neuropathies, but this does not mean that these neuropathies are identical in their specific nature, pathogenesis, or treatment.

[0191] Another example of damage associated with chemotherapy or radiation therapy is damage to the central nervous system. This type of damage occurs with treatment of a variety of different types of cancer, whether or not the treatment targets the central nervous system. For example, patients being treated for breast cancer frequently experience cognitive changes associated with the various anticancer treatments and just as frequently show signs of neurological changes as shown on magnetic resonance imaging studies. As with other types of toxic responses observed with cancer treatment, toxic responses in the brain lack treatment strategies.

[0192] Similar issues as described in the two paragraphs above apply to all disruptions of normal tissue function, regardless of the tissue in which they occur, meaning that applying a specific category name to a dysfunction generally does not reveal anything about cause or treatment. As non-limiting examples, dysfunctions of the visual system, auditory system, olfactory system, respiratory system, gastrointestinal system, genitourinary system, musculoskeletal system, peripheral nervous system, central nervous system, musculoskeletal system, and other parts of the body can be caused in many different ways, and saying that a specific type of dysfunction exists in a specific tissue generally does not reveal information about cause or treatment.

[0193] Thus, the observation that tissue dysfunction caused by exposure to artificially generated toxic insults may have features that overlap with tissue dysfunction caused by other means means that, as a general principle, the use of similar terminology to place outcomes in a certain functional category has no bearing on the cause, pathological basis, or treatment of tissue dysfunction.

[0194] An "effective amount" or "pharmaceutically effective amount" of a compound refers to an amount of the compound sufficient to provide a beneficial effect to a subject to which the compound is administered. An "effective amount" of a delivery vehicle refers to an amount sufficient to effectively bind or deliver a compound. As used herein, the phrase "therapeutically effective amount" refers to an amount sufficient or effective to prevent or treat (delay or prevent onset, prevent progression, inhibit, reduce or reverse) normal health and tissue function disorders (including alleviation of symptoms of such disorders) caused by exposure to artificial toxic damage.

[0195] "Therapeutically effective amount" refers to an amount that provides a therapeutic effect for a given condition and administration regimen. Specifically, a "therapeutically effective amount" refers to an amount that can effectively prevent, alleviate or improve the symptoms of normal health and / or tissue dysfunction caused by exposure to man-made toxic damage, or prolong the survival of the subject (which can be a human or non-human animal) receiving treatment. The determination of a therapeutically effective amount is within the capabilities of those skilled in the art. "Therapeutically effective amount" refers to an amount of a therapeutic agent that will have a lasting beneficial effect on the health and well-being of the subject for normal health and tissue dysfunction caused by exposure to man-made toxic damage, and the effect can be curative. Beneficial effects on the health and well-being of the subject may include, but are not limited to: (1) curing the condition; (2) slowing the progression of the condition; (3) causing the condition to degenerate; (4) alleviating symptoms caused by exposure to toxic damage. Beneficial effects on the health and well-being of the subject may also include preventive outcomes, including but not limited to: (1) preventing or delaying damage to at least one tissue affected by the toxic insult; (2) maintaining the damage at a regressed level once the extent of damage has been achieved by a therapeutically effective amount of the substance; (3) preventing or delaying the recurrence of damage after a course of treatment; or (4) reducing the likelihood of tissue damage following a toxic insult, or (5) alleviating any partial symptoms caused by exposure to the toxic insult.

[0196] The term "pharmacological composition", "therapeutic composition", "therapeutic formulation" or "pharmaceutically acceptable formulation" may refer to, but is in no way limited to, a composition or formulation that allows for effective distribution of the medicament provided by the present invention, in a form suitable for administration to the physical location most suitable for its desired activity, such as systemic administration. The term "pharmaceutical composition" as used herein refers to a mixture of at least one compound of the present invention with other chemical components and entities (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). Pharmaceutical compositions facilitate administration of compounds to an organism. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous, topical, intraperitoneal, intramuscular, oral, aerosol, parenteral, ocular, pulmonary and topical administration. Non-limiting examples of agents suitable for formulation with, for example, the compounds provided herein include: cinnamoyl, PEG, phospholipids or lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (e.g., Pluronic P85), which can enhance drug entry into various tissues, such as the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13, 16-26); biodegradable polymers, such as poly (DL-lactide-co-glycolide) microspheres for sustained release delivery after implantation (Emerich, DF et al., 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; loaded nanoparticles, such as nanoparticles made of polybutylcyanoacrylate, which can deliver drugs across the blood-brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999); and oil-based delivery systems (Kirtane et al. 2022, Sci. Adv. 8, eabm8478).

[0197] The term "pharmaceutically acceptable" or "pharmacologically acceptable" may refer to, but is in no way limited to, molecular entities and compositions that do not produce side effects, allergies or other adverse reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio, and in compliance with the guidelines of agencies such as the Food and Drug Administration.

[0198] The term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt that can (directly or indirectly) provide a compound as described herein after being administered to a subject. Such salts are preferably acid addition salts formed with physiologically acceptable organic or inorganic acids. Examples of acid addition salts include inorganic acid addition salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, and organic acid addition salts, such as acetates, trifluoroacetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, and p-toluenesulfonates. Examples of base addition salts include inorganic salts, such as sodium salts, potassium salts, calcium salts, and ammonium salts, and organic base salts, such as ethylenediamine, ethanolamine, N,N-dialkylethanolamines, triethanolamines, and basic amino acid salts. However, it should be understood that non-pharmaceutically acceptable salts also belong to the scope of the present invention, because they can be used to prepare pharmaceutically acceptable salts. The procedure for salt formation is conventional in the art.

[0199] The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, for carrying or transporting the useful compounds of the present invention in or to a subject so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable", i.e., compatible with the other ingredients in the formulation (including the useful compounds of the present invention) and harmless to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like that are compatible with the activity of the compounds useful in the present invention and are physiologically acceptable to the subject. Supplementary effective compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may also include pharmaceutically acceptable salts of compounds useful in the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present invention are known in the art.

[0200] "Pharmaceutically acceptable excipients" refer to excipients commonly used to prepare generally safe, non-toxic and desirable pharmaceutical compositions, including excipients acceptable for veterinary and human pharmaceutical use. Such excipients may be solid, liquid, semisolid or, in the case of aerosol compositions, gas.

[0201] According to the invention, the term "solvate" is understood to mean any form of the active compound of the invention in which the compound is bound to another molecule (usually a polar solvent) by non-covalent bonds, especially including hydrates and alcoholates.

[0202] As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical disruption of a subject's tissue and administration of the pharmaceutical composition through the tissue breach. Thus, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection of the composition, application of the composition through a surgical incision, application of the composition through a tissue-penetrating non-surgical wound, and the like. Specifically, parenteral administration is contemplated, including, but not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intradermal, intrasternal injection, intratumoral, intravenous, intracerebroventricular, and renal dialysis infusion techniques.

[0203] Range: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be interpreted as a rigid limitation on the scope of the invention. Therefore, the description of a range should be considered to have explicitly disclosed all possible sub-ranges and individual numerical values ​​within the range. For example, a description of a range such as from 1 to 6 should be considered to have explicitly disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies to any width range.

[0204] Specific implementation plan

[0205] The present invention is based in part on the unexpected result that 4-aminopyridine is effective in treating tissue damage caused by toxic insults. Therefore, the present invention relates in part to compositions and methods for treating subjects exposed to toxic insults (e.g., toxic compounds or toxic levels of radiation). The method may include administering to the subject a pharmaceutical composition comprising a potassium channel blocker. In some embodiments, the damage caused by the toxic insult may be multi-site and / or multi-organ. In some embodiments, the method may include administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4-aminopyridine, a derivative thereof, or a combination thereof. In some embodiments, the pharmaceutical composition may be formulated to provide sustained release of 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof. In certain embodiments, 4-aminopyridine or a derivative thereof may be represented by a structure according to formula (I):

[0206]

[0207] or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof. 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl, or any combination thereof; and wherein R 1 , R 2 , R 3 , R 4 and R 5 Optionally substituted. In some embodiments, the derivative of 4-aminopyridine includes 3,4-diaminopyridine, 3-hydroxy-4-aminopyridine, or a combination thereof.

[0208] In some embodiments, the methods described herein can be used to treat damage caused by toxic damage in a subject. For example, the methods described herein can be used to treat the effects of exposure to chemotherapy or other chemical cancer treatments and / or radiation therapy in individuals receiving cancer treatment. In some embodiments, the methods described herein can be used to treat the effects of exposure to industrial chemicals, chemicals produced by chemical reactions from different chemicals (e.g., as may occur in burn pits), or toxic radiation leaked from nuclear power plants or toxic radiation produced due to the release of toxic radiation in military scenarios.

[0209] In some embodiments, the damage may be most evident in one system of the body, such as chemotherapy-induced peripheral neuropathy. In other embodiments, the damage may be manifested in more than one tissue, including, for example, the peripheral nervous system, central nervous system, visual system, auditory system, hematopoietic system, gastrointestinal system, bladder, genitourinary system, heart, skeletal muscle, hair follicles, skin, vasculature, salivary glands, or a combination of any of these tissues.

[0210] In some embodiments, the methods described herein can restore at least a portion of the motor function or / and sensory function lost by the subject, enhance the repair and regeneration of nerve cells, such as promoting nerve cell generation, enhancing cell survival, reducing scarring, or a combination thereof, compared to untreated subjects. In other embodiments, the methods described herein can restore at least a portion of the function of damaged tissue, enhance repair and regeneration, increase cell survival, reduce scarring, reduce other aspects of tissue damage, or a combination thereof, compared to untreated subjects. In further embodiments, the methods described herein can restore at least a portion of the function of damaged tissue, enhance repair and regeneration, enhance cell survival, reduce scarring, or a combination thereof, compared to untreated subjects.

[0211] In some embodiments, the methods disclosed herein can be used to prevent or treat muscle atrophy. In some embodiments, muscle atrophy may be caused by treatment with chemotherapy, other toxic chemicals, or toxic radiation.

[0212] In other embodiments, the methods disclosed herein can be used to prevent or treat dysfunction of the peripheral nervous system, central nervous system, visual system, auditory system, hematopoietic system, gastrointestinal system, bladder, urogenital system, heart, skeletal muscle, hair follicles, skin, vasculature, salivary glands, or any combination thereof. In some embodiments, tissue dysfunction is attributable to chemotherapy treatment, or exposure to other toxic chemicals or toxic radiation.

[0213] Compounds and compositions

[0214] In one aspect, the present invention provides compounds that are effective in preventing, alleviating and / or treating tissue damage caused by toxic insults, tissue dysfunction caused by toxic insults, mitochondrial dysfunction caused by toxic insults, muscle atrophy caused by toxic insults, neuropathy caused by toxic insults, or other types of dysfunctions in any other aspect of the body, or any combination thereof. As non-limiting examples, such dysfunctions may include dysfunctions of the visual system, auditory system, olfactory system, respiratory system, gastrointestinal system, genitourinary system, musculoskeletal system, peripheral nervous system, central nervous system, musculoskeletal system, and other parts of the body that may be caused by many different means, and specific types of dysfunctions are said to be present in specific tissues.

[0215] In one aspect, the present invention provides compounds that effectively reduce or reverse tissue damage caused by toxic damage, oxidative damage caused by toxic damage, and / or scar formation caused by toxic damage. In one aspect, the present invention provides compounds that can effectively restore, improve and / or enhance at least a portion of tissue function caused by toxic damage, myelination caused by toxic damage, tissue regeneration caused by toxic damage, cell survival caused by toxic damage, cell generation caused by toxic damage, repair or regeneration of endogenous stem cells or precursor cells caused by toxic damage, repair or regeneration of transplanted stem cells or precursor cells caused by toxic damage, repair or regeneration of stem cells or progenitor cells caused by toxic damage, or any combination thereof. In one aspect, the present invention provides compounds that effectively reduce the size of lesions caused by toxic damage, or any combination thereof. In one aspect, the present invention provides compounds that can effectively inhibit at least one ion channel affected by 4-AP or its derivatives.

[0216] Thus, in some embodiments, the compound is a potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof having the structure of formula (I):

[0217]

[0218] or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

[0219] In various embodiments, R 1 R is hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl, amino, aminoalkyl, aminoaryl, aminoalkyl-aryl, aminoheteroaryl, aminoalkyl-heteroaryl, amide, aminoalkenyl, aminoalkynyl, aminoacetate, acyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, alkoxy, carboxyl, carboxylate, ester, =O, -NO2, -CN, sulfoxide, sulfonyl, alkylsulfonyl, secondary amide, tertiary amide, amino acid, or any combination thereof. In some embodiments, R 1 Optionally substituted. For example, in some embodiments, R 1 is hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof.

[0220] In various embodiments, R 2R is hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl, amino, aminoalkyl, aminoaryl, aminoalkyl-aryl, aminoheteroaryl, aminoalkyl-heteroaryl, amide, aminoalkenyl, aminoalkynyl, aminoacetate, acyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, alkoxy, carboxyl, carboxylate, ester, =O, -NO2, -CN, sulfoxide, sulfonyl, alkylsulfonyl, secondary amide, tertiary amide, amino acid, or any combination thereof. In some embodiments, R 2 Optionally substituted. For example, in some embodiments, R 2 is hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof.

[0221] In various embodiments, R 3 R is hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl, amino, aminoalkyl, aminoaryl, aminoalkyl-aryl, aminoheteroaryl, aminoalkyl-heteroaryl, amide, aminoalkenyl, aminoalkynyl, aminoacetate, acyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, alkoxy, carboxyl, carboxylate, ester, =O, -NO2, -CN, sulfoxide, sulfonyl, alkylsulfonyl, secondary amide, tertiary amide, amino acid, or any combination thereof. In some embodiments, R 3 Optionally substituted. For example, in some embodiments, R 3 is hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof.

[0222] In various embodiments, R 4 R is hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl, amino, aminoalkyl, aminoaryl, aminoalkyl-aryl, aminoheteroaryl, aminoalkyl-heteroaryl, amide, aminoalkenyl, aminoalkynyl, aminoacetate, acyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, alkoxy, carboxyl, carboxylate, ester, =O, -NO2, -CN, sulfoxide, sulfonyl, alkylsulfonyl, secondary amide, tertiary amide, amino acid, or any combination thereof. In some embodiments, R 4 Optionally substituted. For example, in some embodiments, R 4 is hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof.

[0223] In various embodiments, R 5R is hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl, amino, aminoalkyl, aminoaryl, aminoalkyl-aryl, aminoheteroaryl, aminoalkyl-heteroaryl, amide, aminoalkenyl, aminoalkynyl, aminoacetate, acyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, alkoxy, carboxyl, carboxylate, ester, =O, -NO2, -CN, sulfoxide, sulfonyl, alkylsulfonyl, secondary amide, tertiary amide, amino acid, or any combination thereof. In some embodiments, R 5 Optionally substituted. For example, in some embodiments, R 5 is hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof.

[0224] For example, in one embodiment, the compound represented by formula (I) is selected from 4-AP or its analogs, racemates, tautomers, isomers, enantiomers, diastereomers, prodrugs, pharmaceutically acceptable salts or derivatives, 3,4-diaminopyridine or its analogs, racemates, tautomers, isomers, enantiomers, diastereomers, prodrugs, pharmaceutically acceptable salts or derivatives, 3-hydroxy-4-aminopyridine or its analogs, racemates, tautomers, isomers, enantiomers, diastereomers, prodrugs, pharmaceutically acceptable salts or derivatives, N-(4-pyridyl)-tert-butylcarbamate or its analogs, racemates, tautomers, isomers , enantiomers, diastereomers, prodrugs, pharmaceutically acceptable salts or derivatives, N-(4-pyridyl)ethylcarbamate or an analog thereof, racemate, tautomer, isomer, enantiomer, diastereomer, prodrugs, pharmaceutically acceptable salts or derivatives, N-(4-pyridyl)methylcarbamate or an analog thereof, racemate, tautomer, isomer, enantiomer, diastereomer, prodrugs, pharmaceutically acceptable salts or derivatives, N-(4-pyridyl)isopropylcarbamate or an analog thereof, racemate, tautomer, isomer, enantiomer, diastereomer, prodrugs, pharmaceutically acceptable salts or derivatives, or any combination thereof.

[0225] The compounds described herein may form salts with acids or bases, and such salts are also included in the present invention. The term "salt" includes addition salts of either the free acid or the free base of a compound of the present invention.

[0226] In one aspect, the present invention relates in part to a composition comprising one or more compounds of the present invention. In some embodiments, the composition comprises one or more compounds having a structure of formula (I) or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof. In some embodiments, the composition is a pharmaceutical composition. Therefore, in one aspect, the present invention provides a composition that effectively prevents, alleviates and / or treats tissue damage caused by toxic damage, tissue dysfunction caused by toxic damage, mitochondrial dysfunction caused by toxic damage, muscle atrophy caused by toxic damage, neuropathy caused by toxic damage, or any combination thereof.

[0227] In one aspect, the present invention provides a composition that can effectively reduce or reverse tissue damage or dysfunction caused by toxic damage, oxidative damage caused by toxic damage, and / or scar formation caused by toxic damage. In one aspect, the present invention provides a composition that can effectively restore, improve and / or enhance at least a portion of tissue function caused by toxic damage, myelination caused by toxic damage, tissue regeneration caused by toxic damage, cell survival caused by toxic damage, neuron generation caused by toxic damage, repair or regeneration of endogenous stem cells or precursor cells caused by toxic damage, repair or regeneration of transplanted stem cells or precursor cells caused by toxic damage, repair or regeneration of stem cells or progenitor cells caused by toxic damage, or other types of dysfunction in any other aspect of the body, or any combination thereof. As a non-limiting example, such dysfunction may include dysfunction of the visual system, auditory system, olfactory system, respiratory system, gastrointestinal system, urogenital system, musculoskeletal system, peripheral nervous system, central nervous system, musculoskeletal system and / or other parts of the body. Tissue dysfunction may be caused by a variety of different ways. In addition, saying that there is a particular type of dysfunction in any particular tissue does not distinguish between different types of injuries that may lead to similar symptomatic results, as in the case of peripheral neuropathy. In one aspect, the present invention also provides a composition that is effective in reducing the size of lesions caused by toxic insults.

[0228] In some embodiments, the toxic damage is an acute toxic damage, a chronic toxic damage, or a combination thereof. Examples of such toxic damage include, but are not limited to, non-biological substances such as chemotherapeutic drugs, toxic non-biological substances of natural origin (e.g., arsenic, lead, mercury), non-naturally occurring compounds, toxins, environmental toxicants, agents used to treat cancer (e.g., chemotherapeutic agents), biological response modifiers, toxic industrial chemicals (e.g., chemicals used in manufacturing or agricultural environments), radiation (e.g., cancer treatment, industrial accidents, or military exposures), toxic radiation from natural sources (e.g., harmful heat generated by exposure to fire, extreme weather conditions, and / or ultraviolet radiation associated with sunlight sufficient to cause tissue damage), or any combination thereof.

[0229] In various embodiments, the toxic damage is an anticancer agent. The anticancer agent may be any anticancer agent known in the art. In certain embodiments, the anticancer agent may effectively treat one or more of pancreatic cancer, esophageal cancer, rectal cancer, colon cancer, prostate cancer, kidney cancer, liver cancer, breast cancer, ovarian cancer, and gastric cancer. Examples of anticancer agents include, but are not limited to, chemotherapeutic agents, antiproliferative agents, antitumor agents, checkpoint inhibitors, and anti-angiogenic agents. For example, in one embodiment, the anticancer agent is gemcitabine, doxorubicin, 5-FU, a tyrosine kinase inhibitor, sorafenib, trametinib, rapamycin, fulvestrant, ezalutamide, or paclitaxel.

[0230] Examples of chemotherapeutic agents include, but are not limited to, cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramustine sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alpha-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylsulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bissulfonamide, carboxyplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin, clomethasone, daunorubicin oxide, cyclohexanedione, cyclophosphamide, dianhydrogalactitol, fluorodopan, heptasone, hycanthone, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazine dione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, troxidomycin, tetraplatin, thiotepa, trimethoprim, thiophene, thiophene carboxylate, thiophene sulfonate ... ethylene melamine, uracil nitrogen mustard, and Yoshi-864), antimitotic agents (e.g., isocolchicine, halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoctonia, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mithramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine, and taxotere), biologics (e.g., interferon α, BCG, G-CSF, GM-CSF, and leukopenia), cytokine-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives and morpholino oxadoxantrone), topoisomerase II inhibitors (e.g., mitoxantrone, aminafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene hydrochloride, daunorubicin, deoxydoxorubicin, menogaline, N,N-dibenzyldaunorubicin, anthracene, rubidazone, VM-26 and VP-16) and synthetics (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diammine dichloroplatinum, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, glimepiride and porfimer sodium) or any combination thereof.

[0231] Antiproliferative agents are compounds that reduce cell proliferation. Examples of antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, ondansetron, or any combination thereof.

[0232] Examples of anti-tumor agents include, but are not limited to, cytotoxic / antitumor agents and anti-angiogenic agents. Cytotoxic / antitumor agents are defined as agents that attack and kill cancer cells. Some cytotoxic / antitumor agents are alkylating agents that can alkylate the genetic material in tumor cells, such as cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, beluastine, uracil nitrogen mustard, chlorothiazide and dacarbazine. Other cytotoxic / antitumor agents are antimetabolites of tumor cells, such as cytarabine, fluorouracil, methotrexate, mercaptopurine, thiopurine and procarbazine. Other cytotoxic / antitumor agents are antibiotics, such as adriamycin, bleomycin, actinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C and daunorubicin. These compounds have many commercially available liposomal preparations. Other cytotoxic / antitumor agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Other cytotoxic / antineoplastic agents include paclitaxel and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0233] Anti-angiogenic agents are well known to those skilled in the art. Examples of anti-angiogenic agents include, but are not limited to, anti-VEGF antibodies (including humanized and chimeric antibodies), anti-VEGF aptamers, antisense oligonucleotides, angiostatin, endostatin, interferon, interleukin 1 (including α and β), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases-1 and -2. (TIMP-1 and -2), small molecules, including topoisomerases such as razoxane, topoisomerase II inhibitors with anti-angiogenic activity, or any combination thereof.

[0234] Examples of other anticancer agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; aclonine; adolesin; aldesleukin; hexamethylmelamine; ambomycin; ametanequinone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; tricline; azacitidine; azetepa; azotomycin; bacitracin; azithromy ... Masatastat; benzodepa; bicalutamide; bisantrene hydrochloride; binefide dimesylate; bierexin; bleomycin sulfate; brequinar sodium; bropiridamine; busulfan; actinomycin; carlotestosterone; caramamide; carbetimer; carboplatin; carmustine; carrubicin hydrochloride; carzeresin; cedifenol; chlorambucil; siromycin; cisplatin; cladribine; clenadol mesylate; cyclophosphamide; cytarabine glycosides; dacarbazine; actinomycin; daunorubicin hydrochloride; decitabine; desoplatin; dezaguanine; dezaguanine mesylate; diazinon; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; droloxifene propionate; doxorubicin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enprostatate; epiprodil; epirubicin hydrochloride; erbulazole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide glycosides; etoposide phosphate; etoposide; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flucitabine; fosquilla; fostramoxine sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; interleukin II (including recombinant interleukin II or rIL2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-I a; interferon γ-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; lirozole hydrochloride; lometrexol sodium; lomustine; lorthroline hydrochloride; masoprodol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogali; mercaptopurine; methotrexate; methotrexate sodium; metoline; metodepa; miltedimide; mitokacin; mitolomine; mitogillin; mitomycin; mitomycin; mitosperm; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogaramycin; ormaplatin ; oxicilib; paclitaxel; pegaspargase; pelimycin; pentamustine; pelimycin sulfate; perfosfamide; piperobroman; piperosulfan; pyroxantrone hydrochloride; plicamycin; plometane; porfimer sodium; porfimer; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazolidinone; ribonucleoside; rosiglitazone; safenol; safenol hydrochloride; semustine; cimetrazine; sparfomide sodium; sparmycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptozocin; streptozotocin; sulfochlorophenylurea; talisomycin;Tecogalan sodium; tegafur; tiloxantrone hydrochloride; temoporfin; teniposide; troxitone; testolactone; thiamidine; thioguanine; thiotepa; thiazofurine; tirapazamine; toremifene citrate; triptolon acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tibutazole hydrochloride; uracil mustard; uracipa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate sulfate); vorozole; zeniplatin; nestatin; doxycycline hydrochloride. Other anticancer drugs include, but are not limited to: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosine; adolesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; aminomustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarek; anti-dorsal morphogenetic protein-1; anti-androgen, prostate cancer; anti-estrogen; anti-angiogenic factor; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis modulators; apurinic acid; ara-CDP-DL -PTBA; arginine deaminase; asuraline; atamestane; atramustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; baranol; batimastat; BCR / ABL antagonists; benzochloranil; benzoylstaurosporine; β-lactam derivatives; β-aloethamine; beta-clarithromycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridine spermine; bistamide; bitrastatin A; bisezolesine; buflufenate; bropirimine; budotentan; buthionine sulfoximine; calcipotriol; calphostin C C); camptothecin derivatives; canarypox IL-2; capecitabine; carboxyamide aminotriazole; carboxyamide triazole; CaRest M3; CARN 700; cartilage-derived inhibitors; kazeresin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colimycin A; colimycin B; combretastatin A4; combretastatin analogs;conagenin; crambescidin 816; crisnatol; candidin 8; candidin A derivative; curacin A; cyclopentanthrone; cycloplatin; cypemycin; cytarabine alkylphosphoester; cytolytic factor; cytostatic; daximab; decitabine; deslorelin; dexamethasone; desfosfamide; dexrazoxane; dexverapamil; diazinon; disfosfamide B; dioxy; diethyldespermine; dihydro-5-azacytidine; 9-dihydropaclitaxel; dioxin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; icomustine; edelfosine; edrecolomab; eflornithine; elemene; imiflunomide; epirubicin; eprelide; estramustine analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide ; filgrastim; finasteride; flavopiridol; flustatin; flusterone; fludarabine; fludaunomycin hydrochloride; fufenimex; formestane; fostramexine; fostramustine; teixafillin gadolinium; gallium nitrate; galoxalic acid; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; heptasulfane; herigelin; hexamethylenebisacetamide; hyperforin; ibandronic acid; idarubicin; idoxifene; idramanone; imofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenzylguanidine; iodoxorubicin; 4-isopropanol; iroprax; irsogladine; isofenzodazole; isohomochondroitin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lenamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon-alpha; leuprolide + estrogen + progesterone; leuprolide; levamisole; lialorazole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lobuclidin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lutetamine; lutetamine; lutetamine; lysozyme; lytic peptide; maytansine; mannostatin A; marimastat; masoprofen; maspine; matrixlysin inhibitor; matrix metalloproteinase inhibitor; menogali; mebarone; mitrelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; miristostim; mismatched double-stranded RNA; mitoguanidine; dibromodulanol; mitomycin analogs; mitonadamide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotin; morasporastin; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall sk; mopidarol;Multiple drug resistance gene inhibitors; multiple tumor suppressor 1-based therapies; mustard anticancer agents; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nargastatin; naloxone + pentazocine; napalm; natropine; nargastatin; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; olacin; oral cytokine inducers; ormaplatin; oxateron; oxaliplatin; oxamycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamide; palmitoyl rhizoxin; pamidronate; panaxytriol; panomiphene; parahydroxybenzoic acid; palilipin; pegaspargase; pidecine; pentosan polysulfate sodium ; Pentostatin; Pentozole; Paflon; Perfosfamide; Perillyl alcohol; Phenazine; Phenylacetate; Phosphatase inhibitors; Pilcibanib; Pilocarpine hydrochloride; Pirarubicin; Pirtrexine; Placenta A; Placenta B; Plasminogen activator inhibitors; Platinum complex; Platinum compound; Platinum triamine complex; Porfimer sodium; Porphinomycin; Prednisone; Propyl diacridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxalyl hemoglobin polyoxyethylene conjugates; Raf antagonists; Raltitrexed; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylated Raltiliptin; Rhenium etidronate Re 186; rhizoctonia; ribozyme; RII retinoic acid amide; rosiglitazone; roxitoin; romurtide; roquimes; lubiquinone B1; ruboxyl; safenol; santopin; SarCNU; inositol A; sargramostim; Sdi 1 analog; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; single-chain antigen binding protein; sizofuran; sobuzosine; sodium borate; sodium phenylacetate; solvelol; growth factor binding protein; sonermin; sparsophos acid); spongiocin D; spiromustine; splenopentin; spongostatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stepiramide; stromelysin inhibitor; sulfinositol; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic aminodextran; tamustine; tamoxifen methyl iodide; tauromustine; tazarotene; tecogalan sodium; tegafur;Telluropyran; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazolamine; thalidomide; thiocoraline; thrombopoietin; thrombopoietin analog; thymalfasin; thymopoietin receptor agonist; thymosin; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topersentine; toremifene; totipotent stem cell factor; translation inhibitor; retinoic acid; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; toretide; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B; vector system, erythrocyte gene therapy; verarezo; veramine; verdins; verteporfin; vinorelbine; vincristine; vitaxin; vorozole; zanotron; zeniplatin; zilascorb; and zinostatin stimalamer, or any combination thereof. ;

[0235] In some embodiments, the anticancer agent may be in the form of a prodrug of the anticancer agent.In certain embodiments, the anticancer agent may be chemically modified with an alkyl or acyl group or a certain form of lipid.

[0236] For example, in some embodiments, the toxic insult is a platinum-based antineoplastic agent, a vinca alkaloid agent, an epothilone agent, a taxane agent, a proteasome inhibitor, an immunomodulatory drug, a taxane, cisplatin, radiation cancer treatment, exposure to harmful levels along the electromagnetic spectrum, nuclear accidents and nuclear war, environmental toxicants, or any combination thereof.

[0237] In one embodiment, the toxic lesion is a hydrophobic agent. In one embodiment, the toxic lesion is a hydrophilic agent. Examples of such toxic lesions include, but are not limited to, one or more drugs, antibiotics, small molecules, anticancer agents, chemotherapeutic agents, immunomodulators, gene silencing agents, medical imaging agents, therapeutic moieties, poorly soluble drugs, anticancer drugs, antibiotics, analgesics, anticonvulsants; antidiabetic agents, antifungal agents, antitumor agents, antiparkinsonian agents, antirheumatic agents, biological response modifiers, cardiovascular agents, contrast agents, diagnostic agents, gastrointestinal agents, ophthalmic agents, osteoporosis agents, psychotherapeutic agents, parasympathomimetic agents, parasympatholytic agents, respiratory agents, sedatives, hypnotic agents, skin and mucosal agents, smoking cessation agents, sympatholytic agents, urinary tract agents, uterine relaxants, vaginal agents, vasodilators, antihypertensive agents, hyperthyroid agents, antihyperthyroid agents, antiasthmatic agents, and vertigo agents, or any combination thereof.

[0238] In some embodiments, the toxic agent can be an industrial chemical. Toxic industrial chemicals are present in a wide variety of environments, including manufacturing, agricultural uses, packaging, food additives, and many other situations. The rate at which new chemicals are created every day and the importance of developing treatments for toxicities from a variety of different chemical structures emphasizes the importance of developing therapeutic strategies to ameliorate these toxicities. 4-AP is unexpectedly effective in preventing toxicity from paclitaxel and cisplatin (their chemical structures are very different, and from a chemical perspective, cisplatin is more similar to industrial chemicals than to industrially produced preparations and chemical derivatives found in nature, taxanes), and is able to prevent toxicity to the peripheral nervous system, central nervous system, kidneys, and mitochondria, indicating that 4-AP is likely to be useful in a variety of situations defined in the experimental embodiments provided herein.

[0239] In some embodiments, the composition further comprises one or more therapeutic agents. In some embodiments, the therapeutic agent is any potassium channel blocker known in the art. Examples of such potassium channel blockers include, but are not limited to, brombenzylamine, chlorpheniramine, Dalfampridine , Dofetilide, E-4031, Ebastine, Gliclazide , Ibutilide, Nifekalant, Semalide, Sotalol, Sulfonylurea , tedisamil or any combination thereof.

[0240] In some embodiments, the composition further comprises one or more anticonvulsants. Examples of such anticonvulsants include, but are not limited to, barbiturates, benzodiazepines, Bromide, carbamate, carboxamide, fatty acid, fructose or its derivatives, gamma-aminobutyric acid (GABA) or its analogs, hydantoin, oxazolidinedione, propionate, pyrimidinedione, pyrrolidine, succinimide, sulfonamide, triazine, urea, valproamide or any combination thereof.

[0241] combination

[0242] In one embodiment, the compositions of the present invention comprise a combination of agents described herein. In certain embodiments, the compositions comprising a combination of agents described herein have an additive effect, wherein the overall effect of the combination is approximately equal to the sum of the effects of each individual agent. In other embodiments, the compositions comprising a combination of agents described herein have a synergistic effect, wherein the overall effect of the combination is greater than the sum of the effects of each individual agent.

[0243] Compositions comprising a combination of multiple agents include individual agents in any suitable ratio. For example, in one embodiment, the composition includes two separate agents in a ratio of 1:1. However, the combination is not limited to any particular ratio. Instead, any ratio shown to be effective is contemplated.

[0244] How to use

[0245] In one aspect, the present invention provides a method for effectively preventing, alleviating and / or treating tissue damage caused by toxic damage, tissue dysfunction caused by toxic damage, mitochondrial dysfunction caused by toxic damage, muscle atrophy caused by toxic damage, neuropathy caused by toxic damage, renal disease caused by toxic damage, or any combination thereof.

[0246] In one aspect, the invention provides methods of reducing or reversing tissue damage caused by toxic insult, oxidative damage caused by toxic insult, and / or scarring caused by toxic insult.

[0247] In some embodiments, tissue damage is multiple tissue damage, multiple organ tissue damage, or any combination thereof. In some embodiments, tissue damage is kidney tissue damage, liver tissue damage, heart tissue damage, lung tissue damage, brain tissue damage, central nervous system damage, peripheral nerve tissue damage, peripheral neuropathy, nephropathy, chemotherapy-induced peripheral neuropathy (CIPN), radiation-induced peripheral neuropathy (RIPN), chemotherapy-induced nephrotoxicity (CINT), neutropenia, gastrointestinal tissue damage, intestinal tissue damage, visual system tissue damage, auditory system tissue damage, skin tissue damage, bladder tissue damage, reproductive system tissue damage, hematopoietic system tissue damage, or any combination thereof. For example, in some embodiments, CIPN is CIPN caused by taxane treatment (P-CIPN), CIPN caused by cisplatin treatment (CisIPN), or any combination thereof.

[0248] In some embodiments, the tissue dysfunction is a motor dysfunction, a sensory dysfunction, a cognitive dysfunction, a visual dysfunction, an auditory dysfunction, a renal dysfunction, a hematopoietic system dysfunction, normal skin function, a salivary gland dysfunction, a liver dysfunction, a gallbladder dysfunction, a gastrointestinal (GI) dysfunction, a sexual dysfunction, or any combination thereof.

[0249] In one aspect, the present invention provides a method for restoring, improving and / or enhancing at least a portion of tissue function affected by toxic damage, myelination affected by toxic damage, tissue regeneration affected by toxic damage, cell survival affected by toxic damage, neuronal cell generation affected by toxic damage, repair or regeneration of endogenous stem cells affected by toxic damage, repair or regeneration of transplanted stem cells affected by toxic damage, repair or regeneration of progenitor cells affected by toxic damage, or any combination thereof.

[0250] In some embodiments, the tissue function is motor function, sensory function, cognitive function, visual function, auditory function, kidney function, hematopoietic system function, normal skin function, salivary gland function, liver function, gallbladder function, gastrointestinal (GI) function, sexual function, or any combination thereof. In some embodiments, the tissue is kidney tissue, liver tissue, heart tissue, lung tissue, brain tissue, central nervous system tissue, peripheral nervous tissue, gastrointestinal tissue, intestinal tissue, visual system tissue, auditory system tissue, skin tissue, bladder tissue, reproductive system tissue, hematopoietic system tissue, musculoskeletal tissue, or any combination thereof.

[0251] In one aspect, the invention provides a method of reducing the size of a lesion resulting from a toxic insult.

[0252] In one aspect, the invention provides methods of inhibiting at least one potassium channel blocker to treat tissue damage resulting from exposure to one or more toxic insults.

[0253] In some embodiments, the method comprises administering to the subject an effective amount of a composition comprising at least one compound (eg, at least one compound of Formula (I)) or a composition of the invention.

[0254] In one aspect, the invention provides a method comprising administering to a subject at least one compound of the invention or a composition thereof, wherein the subject is exposed to and / or affected by at least one toxic insult. The invention also provides a method comprising administering to a subject at least one compound of the invention or a composition thereof, wherein the subject suffers from cancer.

[0255] In some aspects, the present invention provides a method of administering an effective amount of any compound or pharmaceutical composition disclosed herein to a subject. Therefore, in some aspects, the present invention also provides a method comprising administering an effective amount of any compound or pharmaceutical composition disclosed herein to a subject, wherein the subject is exposed to and / or affected by at least one toxic insult. In some aspects, the present invention also provides a method comprising administering an effective amount of any compound or pharmaceutical composition disclosed herein to a subject, wherein the subject suffers from cancer.

[0256] In various embodiments, the toxic insult is any toxic insult described herein. For example, in some embodiments, the toxic insult is a platinum-based antineoplastic agent, a vinca alkaloid agent, an epothilone agent, a taxane agent, a proteasome inhibitor, and an immunomodulatory drug, a taxane, cisplatin, radiation cancer therapy, exposure to damaging levels of radiation along the electromagnetic spectrum, nuclear accidents and nuclear war, environmental toxins, or any combination thereof.

[0257] In some embodiments, treatment can be initiated at the time of initial injury, during ongoing exposure to the toxic insult, or in delayed treatment of tissue damage that occurs after exposure to the toxic insult has ended.

[0258] The compositions of the present invention may be administered to a patient or subject in need thereof systemically, topically, or a combination of both.

[0259] The compositions of the present invention can be applied to patients or subjects in need in a variety of ways, including by inhalation, such as aerosol inhalation, injection, ingestion, oral administration, transdermal administration, blood transfusion, implantation, sublingual administration or transplantation. The compositions described herein can be administered to patients subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, intrathecally, intravenously (iv) or intraperitoneally. In one embodiment, the composition is systemically administered to the subject. In one embodiment, the composition of the present invention is administered to the patient by intravenous injection. In one embodiment, the composition is topically administered to the subject. In one embodiment, the composition of the present invention is topically administered to the patient. Any mode of administration can be a single application or multiple applications of the composition of the present invention. Administration can be directed to a single site or more than one site of the individual to be treated. Multiple administrations can be performed substantially simultaneously or separately in time.

[0260] Subjects contemplated for administration of the pharmaceutical compositions of the present invention include, but are not limited to, humans and other primates, mammals including, but not limited to, non-human mammals such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs.

[0261] The pharmaceutical composition of the present invention can be administered in a manner suitable for the disease to be treated (or prevented). Although appropriate dosage can be determined by clinical trials, the amount and frequency of administration will be determined by factors such as the condition of the subject and the type and severity of the subject's disease.

[0262] When a "therapeutic amount" is indicated, the precise amount of the composition of the present invention to be administered can be determined by a physician taking into account individual differences in age, weight, disease type, disease extent and condition of the patient (subject).

[0263] Preparation / pharmaceutical composition

[0264] The present invention also encompasses the use of pharmaceutical compositions comprising the compounds of the present invention or compositions thereof. Such pharmaceutical compositions may comprise at least one compound of the present invention suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the present invention and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The compounds of the present invention may be present in the form of physiologically acceptable salts, for example in pharmaceutical compositions in combination with physiologically acceptable cations or anions as known in the art.

[0265] The use of therapeutic agents according to the present invention can be continuous or intermittent, depending on, for example, the physiological condition of the recipient, whether the purpose of use is therapeutic or preventive and other factors known to skilled practitioners. The use of medicament of the present invention can be substantially continuous in the preselected time period, or can be a series of interval dosages. Local and systemic administration have been considered. The amount of application will vary according to various factors, including but not limited to selected compositions, specific diseases, experimenter's body weight, physical condition and age and to achieve prevention or treatment. These factors can be easily determined by clinicians using animal models or other test systems well known in the art.

[0266] In therapeutic methods, administration of the compositions of the present invention can be achieved in a variety of different ways using methods known in the art. In one embodiment, the methods of the present invention include systemic administration to a subject, including, for example, enteral or parenteral administration. In certain embodiments, the methods include intradermal delivery of the composition. In another embodiment, the methods include intravenous delivery of the composition. In some embodiments, the methods include intramuscular delivery of the composition. In one embodiment, the methods include subcutaneous delivery of the composition. In one embodiment, the methods include inhalation of the composition. In one embodiment, the methods include intranasal delivery of the composition.

[0267] Depending on the intended mode of administration, the pharmaceutical composition can be in the form of, for example, a solid, semisolid, liquid, solution, suspension (e.g., incorporated into microparticles, liposomes, etc.), emulsion, gel, etc., preferably a unit dosage form suitable for single administration of precise dosage. As described above, the pharmaceutical composition can include an effective amount of a potassium channel blocker such as a 4-aminopyridine compound, a derivative thereof, or a combination thereof, and a pharmaceutically acceptable carrier, and further, other carriers, adjuvants, diluents, thickeners, buffers, preservatives, surfactants, etc. The pharmaceutical composition can also include one or more additional active ingredients, such as other medicaments, medicaments, antimicrobial agents, anti-inflammatory agents, anesthetics, anticonvulsants, etc.

[0268] Where appropriate, the formulations may conveniently be presented in discrete unit dosage form and may be prepared by any method well known in the art of pharmacy. Such methods may include the step of combining the therapeutic agent with a liquid carrier, a solid matrix, a semi-solid carrier, a finely divided solid carrier, or a combination thereof, and then, if necessary, introducing or shaping the product into a desired delivery system.

[0269] Therefore, the treatment and prevention methods of the present invention encompass the use of a pharmaceutical composition comprising at least one compound of the present invention to practice the method of the present invention. The pharmaceutical composition that can be used to implement the present invention can be used to deliver a dosage of 0.001ng / kg / day to 100mg / kg / day. For example, in some embodiments, the pharmaceutical composition that can be used to implement the present invention can be used to deliver a dosage between 0.005mg / kg / day and 5mg / kg / day. In one embodiment, the present invention includes the use of a certain dose so that the concentration of the compound of the present invention in mammalian serum is 10nM to 10μM.

[0270] Typically, in the method of the present invention, the dosage range that can be applied to a mammal (preferably a human) is 0.01 μg to about 50 mg per kilogram of mammal body weight, and the precise dosage applied will vary according to a variety of factors, including but not limited to the type of mammal and the type of disease state treated, the age of the mammal and the route of administration, and the specific agent used. Preferably, the dosage of the compound will vary between about 0.1 μg to about 10 mg per kilogram of mammal body weight. More preferably, the dosage will vary between about 1 μg to about 5 mg per kilogram of mammal body weight. For example, in some embodiments, the dosage will vary between about 0.005 mg to about 5 mg per kilogram of mammal body weight.

[0271] The relative amounts of active ingredient, pharmaceutically acceptable carrier and any other ingredients in the pharmaceutical composition of the present invention will vary depending on the identity, size and condition of the subject being treated and further on the route of administration of the composition. For example, the composition may contain between 0.1% and 100% (w / w) active ingredient.

[0272] The pharmaceutical composition may contain about 0.01% to about 99% of a potassium channel blocker (e.g., 4-aminopyridine or a derivative or analog thereof), and a carrier and / or excipient. For example, the amount of potassium channel blocker (e.g., 4-aminopyridine, a derivative thereof, or a combination thereof) may be about 0.1% or greater, about 1% or greater, about 2% or greater, about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 50% or greater, about 75% or greater, or about 90% or greater by weight of the pharmaceutical composition.

[0273] In some embodiments, the pharmaceutical composition is defined by its ability to achieve a serum therapeutically effective concentration of 4-aminopyridine or a derivative thereof. In some embodiments, such concentrations range from about 10 nM to about 1 μM 4-aminopyridine, or higher if combined with an anticonvulsant. The desired serum concentration of a 4-aminopyridine derivative is defined by the ability of such an agent to produce the desired therapeutic benefit without causing unacceptable side effects.

[0274] The pharmaceutical compositions described herein use a potassium channel blocker (e.g., 4-aminopyridine, a derivative thereof, or a combination thereof) in a "therapeutically effective amount." In some embodiments, the pharmaceutical composition can be formulated so that when administered, it delivers a therapeutically effective amount of a potassium channel blocker (e.g., 4-aminopyridine, a derivative thereof, or a combination thereof) of 2.5 mg or more. For example, the pharmaceutical composition, upon administration, can deliver 3 mg or more, 4 mg or more, 5 mg or more, 6 mg or more, 7 mg or more, 7.5 mg or more, 8 mg or more, 9 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more, 55 mg or more, 60 mg or more, 65 mg or more, 70 mg or more, 75 mg or more, 80 mg or more, 85 mg or more, 90 mg or more, or 95 mg or more of a potassium channel blocker (e.g., 4-aminopyridine, a derivative thereof, or a combination thereof).

[0275] The composition can be administered to the mammal several times a day, or can be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every few months or even once a year or more. The frequency of administration will be apparent to the skilled artisan and will depend on many factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, and whether the administration is for the treatment of a disorder or for the identification of an individual for whom a full course of treatment would be beneficial, etc.

[0276] In another aspect of the invention, the methods disclosed herein can be used to identify individuals who will benefit from treatment with potassium channel blockers (e.g., 4-AP, derivatives of 4-AP, or any combination thereof). In some embodiments, individuals exhibiting dysfunction in one or more tissues after exposure to artificially generated toxic insults can be treated with the methods disclosed herein for one to ten days to determine whether treatment can improve tissue function. Therefore, in some embodiments, the methods disclosed herein can be used to provide personalized therapeutic targeting.

[0277] When preparing the therapeutic agents of the present invention for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical preparation or unit dosage form. The total active ingredient in such preparations accounts for 0.1 to 99.9% of the weight of the preparation. A "pharmaceutically acceptable" carrier, diluent or excipient is a carrier, diluent, excipient and / or salt that is compatible with the other ingredients of the preparation and harmless to its recipient. The active ingredient administered may be in the form of a powder or granules; it may be in the form of a solution, suspension or emulsion.

[0278] Pharmaceutical formulations containing the therapeutic agents of the invention can be prepared by methods known in the art using well-known and readily available ingredients. The therapeutic agents of the invention can also be formulated into solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.

[0279] The pharmaceutical preparations of the therapeutic agents of the present invention may also be in the form of aqueous or nonaqueous solutions or dispersions, or in the form of emulsions or suspensions.

[0280] Therefore, the therapeutic agent can be formulated for parenteral administration (e.g., by injection, such as push injection or continuous infusion), and can be present in an ampoule, a prefilled syringe, a small volume infusion container, or a multi-dose container with a preservative in a unit dose form. The preparation of the pharmaceutical composition suitable for parenteral administration comprises an active ingredient and a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such preparations can be prepared, packaged, or sold in a form suitable for push injection or continuous administration. Injection preparations can be prepared, packaged, or sold in a unit dose form, such as an ampoule or a multi-dose container containing a preservative. Preparations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable slow release or biodegradable preparations. Such preparations may also include one or more additional ingredients, including but not limited to suspending agents, stabilizers, or dispersants. In one embodiment of formulations for parenteral administration, the active ingredient is provided in dry (ie, powder or granules) form for reconstitution with a suitable vehicle (eg, sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0281] It should be understood that the unit content of one or more active ingredients contained in a single aerosol dose of each dosage form does not itself need to constitute an effective amount for treating a specific indication or disease, because the necessary effective amount can be achieved by administering multiple dosage units. In addition, an effective amount can be achieved using a dose (single or in a series of administrations) that is smaller than that in the dosage form.

[0282] The pharmaceutical preparation of the present invention may include as optional ingredients a pharmaceutically acceptable carrier, diluent, solubilizer or emulsifier and salts of types well known in the art. Specific non-limiting examples of carriers and / or diluents that can be used for the pharmaceutical preparation of the present invention include water and physiologically acceptable buffered saline solutions, such as phosphate buffered saline solutions of pH 7.0-8.0.

[0283] The compounds of the present invention can be formulated and administered by any means that allows the active ingredients to contact the site of action of the agent in the organism to treat various disease states. They can be used in combination with drugs in any conventional manner, either as a single therapeutic active ingredient or as a combination of therapeutic active ingredients. They can be administered alone, but are usually administered with a pharmaceutical carrier selected according to the selected route of administration and standard pharmaceutical practice.

[0284] In general, water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. The solution for parenteral administration comprises active ingredient, suitable stabilizer and (if necessary) buffer substance. Antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, whether used alone or in combination, are suitable stabilizers. Citric acid and its salts and disodium ethylenediaminetetraacetate (EDTA) are also used. In addition, parenteral injections can contain preservatives, such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in the standard reference Remington's Pharmaceutical Sciences in this area.

[0285] In addition, the pharmaceutical method of standard can be adopted to control the duration of the effect. These are well known in the art, include controlled release formulations, and can include suitable macromolecules, such as polymers, polyesters, polyamino acids, polyethylene, pyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethyl cellulose or protamine sulfate. The concentration of macromolecules and the method of incorporation can be adjusted to control release. In addition, agents can be incorporated into polymer material particles, such as polyesters, polyamino acids, hydrogels, polylactic acid or ethylene vinyl acetate copolymers. Except being incorporated, these agents can also be used for capturing compounds in microcapsules.

[0286] Thus, the pharmaceutical compositions of the present invention can be delivered to various sites in the mammalian body by various routes to achieve specific effects (see, e.g., Rosenfeld et al., 1991; Rosenfeld et al., 1991a; Jaffe et al., supra; Berkner, supra). One skilled in the art will recognize that, although more than one route of administration may be employed, a particular route may provide a more direct and more effective response than another route. Local or systemic delivery may be achieved by administration, including application or instillation of the formulation into a body cavity, inhalation or insufflation of an aerosol, or by parenteral introduction, including intramuscular, intravenous, intraperitoneal, subcutaneous, intradermal, and topical administration.

[0287] The active ingredients of the present invention can be provided in unit dosage form, wherein each dosage unit (e.g., a teaspoon, tablet, solution, or suppository) contains a predetermined amount of the composition alone or in appropriate combination with other active agents. The term "unit dosage form" as used herein refers to physically discrete units suitable as unit doses for human and mammalian subjects, each unit containing a predetermined amount of the composition of the present invention alone or in combination with other active agents, the calculated amount of which is sufficient to produce the desired effect, and when appropriate, combined with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications of the unit dosage form of the present invention depend on the specific effect to be achieved and the specific pharmacodynamics associated with the pharmaceutical composition in a specific host.

[0288] In one embodiment, the composition of the present invention is formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of the present invention or a conjugate and a pharmaceutically acceptable carrier. Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions, such as phosphates and organic acid salts. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0289] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. For example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using a surfactant, suitable fluidity can be maintained. Microbial action can be prevented by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, isotonic agents, such as sugar, sodium chloride or polyols such as mannitol and sorbitol, will preferably be included in the composition. Extended absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not just DMSO.

[0290] The present invention also provides pharmaceutical compositions comprising one or more compositions described herein. The preparations can be mixed with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for administration to a subject. The pharmaceutical compositions can be sterilized and mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring substances and / or aromatic substances, etc., when necessary. They can also be combined with other active agents (e.g., analgesics or anticonvulsants) if necessary.

[0291] As used herein, "additional ingredients" include, but are not limited to, one or more of the following: excipients; surfactants; dispersants; inert diluents; granulating agents and disintegrants; binders; lubricants; colorants; preservatives; physiologically degradable compositions, such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersants or wetting agents; emulsifiers, demulcents; buffers; salts; thickeners; fillers; emulsifiers; antioxidants; antibiotics; antifungal agents; stabilizers; and pharmaceutically acceptable polymers or hydrophobic materials. Other "additional ingredients" that may be included in the pharmaceutical compositions of the present invention are known in the art and are described, for example, in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

[0292] The compositions of the present invention may contain about 0.005% to 2.0% preservatives based on the total weight of the composition. Preservatives are used to prevent spoilage under exposure to environmental pollutants. Examples of preservatives useful according to the present invention include, but are not limited to, preservatives selected from benzyl alcohol, sorbic acid, parabens, imidazolidinyl urea, or any combination thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0293] In one embodiment, the composition comprises an antioxidant and a chelating agent that inhibits the degradation of one or more components of the composition. For some compounds, preferred antioxidants are BHT, BHA, alpha-tocopherol and ascorbic acid, preferably ranging from about 0.01% by weight to 0.3% by weight of the total weight of the composition, and more preferably BHT is 0.03% by weight to 0.1% by weight. Preferably, the chelating agent is present in an amount of 0.01% by weight to 0.5% by weight of the total weight of the composition. Particularly preferred chelating agents include ethylenediaminetetrachloride (e.g., disodium ethylenediaminetetraacetate) and citric acid, and their weight range is about 0.01% by weight to 0.20% by weight of the total weight of the composition, more preferably 0.02% by weight to 0.10% by weight. Chelating agents are used to chelate metal ions that may be harmful to the shelf life of the preparation in the chelating composition. Although BHT and disodium edetate are particularly preferred antioxidants and chelating agents for some compounds respectively, other suitable equivalent antioxidants and chelating agents can therefore be substituted, as known to those skilled in the art.

[0294] Pharmaceutical compositions useful in the methods of the invention may be prepared, packaged or sold in formulations suitable for ocular, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intravenous, intracerebroventricular, intradermal, intramuscular or other routes of administration. Other contemplated formulations include projected nanoparticles, liposomal formulations, resealed erythrocytes containing the active ingredient, and immunogenicity-based formulations.

[0295] The pharmaceutical compositions of the present invention can be prepared, packaged or sold in bulk as a single unit dose or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient administered to a subject or a convenient portion of such a dose, such as one-half or one-third of such a dose.

[0296] The preparation of the pharmaceutical composition described herein can be prepared by any method known or hereafter developed in the field of pharmacology. In general, such preparation methods include the steps of mixing the active ingredient with a carrier or one or more other auxiliary ingredients, and then, if necessary or desired, shaping or packaging the product into the desired single or multiple dosage units.

[0297] In exemplary embodiments, a pharmaceutical composition includes a pharmaceutically acceptable excipient (eg, a pharmaceutically acceptable carrier) and an exemplary compound described herein.

[0298] In certain exemplary embodiments, the pharmaceutical composition comprises, or is in the form of, a pharmaceutically acceptable salt, as generally described below.

[0299] Exemplary compounds can be administered in the form of prodrugs. Prodrugs can include covalently bound carriers that release active parent drugs when administered to mammalian subjects. Prodrugs can be prepared by modifying functional groups present in the compound by conventional manipulations or by cleavage into the parent compound in vivo. Prodrugs include, for example, compounds in which a hydroxyl group is bound to any group that, when administered to a subject, cleaves to form free hydroxyls.

[0300] Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, it will be appreciated by those skilled in the art that such compositions are generally suitable for administration to various animals. It is well known that pharmaceutical compositions suitable for administration to humans are modified so that the compositions are suitable for administration to various animals, and ordinary skilled veterinary pharmacologists can design and perform such modifications only by ordinary (if any) experiments. It is contemplated that subjects to whom the pharmaceutical compositions of the present invention are administered include, but are not limited to, humans and other primates, mammals, including commercially relevant mammals, such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs.

[0301] Conventional techniques can be used to prepare controlled-release or sustained-release preparations of the pharmaceutical compositions of the present invention.

[0302] Pharmaceutical compositions can be prepared, packaged or sold in the form of sterile injectable aqueous or oily suspensions or solutions. Such suspensions or solutions can be prepared according to known techniques and, in addition to the active ingredient, may also contain additional ingredients, such as dispersants, wetting agents or suspending agents as described herein. Such sterile injection preparations can be prepared using nontoxic parenteral acceptable diluents or solvents (e.g., water or 1,3-butylene glycol). Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic monoglycerides or diglycerides. Other useful parenteral administration preparations include preparations containing microcrystalline forms, liposome preparations, or active ingredients as components of biodegradable polymer systems. Compositions for sustained release or implantation may include pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts.

[0303] The preparation of the pharmaceutical composition suitable for parenteral administration comprises active ingredient and pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such preparations can be prepared, packaged or sold in a form suitable for push injection or continuous administration. Injection preparations can be prepared, packaged or sold in unit dose form, such as ampoules or multi-dose containers containing preservatives. Preparations for parenteral administration include but are not limited to suspensions, solutions, emulsions, pastes and implantable sustained release or biodegradable preparations in oily or aqueous vehicles. Such preparations may also include one or more additional ingredients, including but not limited to suspending agents, stabilizers or dispersants. In one embodiment of the preparation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granule) form so that it can be reconstructed with a suitable vehicle (e.g., sterile pyrogen-free water) before parenteral administration of the reconstructed composition.

[0304] Transdermal preparations can also be made into creams, ointments, salves, sprays, gels, lotions, emulsions and transdermal patches. Such compositions can contain one or more chemical penetration enhancers, membrane permeation agents, membrane transport agents, emollients, surfactants, stabilizers and combinations thereof.

[0305] Pharmaceutical compositions can be prepared, packaged or sold in the form of sterile injectable aqueous or oily suspensions or solutions. Such suspensions or solutions can be prepared according to known techniques and, in addition to the active ingredient, may also contain additional ingredients, such as dispersants, wetting agents or suspending agents as described herein. Such sterile injection preparations can be prepared using nontoxic parenteral acceptable diluents or solvents (e.g., water or 1,3-butylene glycol). Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic monoglycerides or diglycerides. Other useful parenteral administration preparations include preparations containing microcrystalline forms, liposome preparations, or active ingredients as components of biodegradable polymer systems. Compositions for sustained release or implantation may include pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts.

[0306] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, etc., the compositions described herein and optional pharmaceutical adjuvants in an excipient (e.g., water, saline dextrose, glycerol, ethanol, etc.) to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc., for example, sodium acetate, sorbitol monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. The actual methods for preparing such dosage forms are known or apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences mentioned above.

[0307] Conventional methods can be used to prepare liquid suspensions to achieve suspension of HMW-HA or other compositions of the present invention in aqueous or oily vehicles. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethanol, vegetable oils (such as peanut oil, olive oil, sesame oil or coconut oil), fractionated vegetable oils and mineral oils (such as liquid paraffin). Liquid suspensions may also include one or more other ingredients, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, mitigating agents, preservatives, buffers, salts, flavoring agents, coloring agents and sweeteners. Oily suspensions may also include thickening agents. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, gum arabic and cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose. Known dispersants or wetting agents include but are not limited to naturally occurring phosphatides (such as lecithin), condensation products of alkylene oxide and fatty acids, condensation products with long-chain aliphatic alcohols, condensation products with partial esters derived from fatty acids and hexitol, or condensation products with partial esters derived from fatty acids and hexitol anhydrides (for example, respectively polyoxyethylene stearate, 17ethyleneoxyhexadecyl alcohol, polyoxyethylene sorbitol monooleate and polyoxyethylene sorbitol monooleate). Known emulsifiers include but are not limited to lecithin and gum arabic. Known preservatives include but are not limited to methyl, ethyl or n-propyl p-hydroxybenzoate, ascorbic acid and sorbic acid.

[0308] The powder and granule preparations of the pharmaceutical formulations of the present invention can be prepared using known methods. Such preparations can be directly administered to a subject, for example, to form tablets, fill capsules, or to prepare aqueous or oily suspensions or solutions by adding aqueous or oily vehicles thereto. Each of these preparations may also include one or more dispersants or wetting agents, suspending agents, and preservatives. Other excipients, such as fillers, sweeteners, flavoring agents, or coloring agents, may also be included in these preparations.

[0309] Dry powder formulations ("DPF") with larger particle sizes have better flow properties, such as less aggregation, easier aerosolization, and potentially lower phagocytosis. Dry powder aerosols for inhalation therapy are typically formulated with mean diameters primarily in the range of less than 5 microns, although the preferred range for aerodynamic diameters is between 1 and 10 microns. Large "carrier" particles (without drug) are co-delivered with the therapeutic aerosol, helping to achieve efficient aerosolization as well as other possible benefits.

[0310] The pharmaceutical composition of the present invention can also be prepared, packaged or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oil phase can be a vegetable oil (such as olive oil or peanut oil); a mineral oil (such as liquid paraffin); or a combination of these. Such compositions may also include one or more emulsifiers, such as naturally occurring gums such as gum arabic or tragacanth, naturally occurring phospholipids such as soybean lecithin or lecithin phospholipids, esters or partial esters derived from a combination of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients, such as sweeteners or flavorings.

[0311] Methods for impregnating or coating materials with chemical compositions are known in the art and include, but are not limited to, methods for depositing or bonding the chemical composition onto a surface, methods for incorporating the chemical composition into the structure of the material during its synthesis (i.e., for example, using physiologically degradable materials), and methods for absorbing aqueous or oily solutions or suspensions into an absorbent material, with or without subsequent drying.

[0312] The administration regimen can affect the composition of the effective amount. The therapeutic preparation can be administered to the subject before or after the diagnosis of the disease. In addition, several separate doses and staggered doses can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. In addition, the dose of the therapeutic preparation can be proportionally increased or decreased according to the urgency of the treatment or prevention situation.

[0313] The compositions of the present invention can be administered to a subject (preferably a mammal, more preferably a human) at a dosage and time period that is effective in preventing or treating a disease using known procedures. The effective amount of the therapeutic compound required to achieve the therapeutic effect can vary according to factors such as the following: the activity of the specific compound used; the time of administration; the excretion rate of the compound; the duration of treatment; other drugs, compounds or materials used in combination with the compound; the state, age, sex, weight, condition, general health and past medical history of the disease or condition of the subject being treated; and similar factors well known in the medical field. The dosage regimen can be adjusted to provide the best therapeutic response. For example, several separate doses can be administered daily or the dosage can be reduced in proportion to the urgency of the treatment situation. A non-limiting example of the effective dose range of the therapeutic compound of the present invention is about 1 to 5,000 mg / kg body weight / day. One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of the therapeutic compound without too much experimentation.

[0314] The compound can be applied to the subject at a frequency of several times a day, or can be applied at a lower frequency, such as once a day, once a week, once every two weeks, once a month, or applied at an even lower frequency, such as once every few months or even once a year or longer. It should be understood that, in non-limiting examples, the amount of the compound administered daily can be applied every day, every other day, every 2 days, every 3 days, every 4 days or every 5 days. For example, for application every other day, a dosage of 5 mg can be applied every day starting on Monday, then a dosage of 5 mg is applied every day on Wednesday, a dosage of 5 mg is applied every day on Friday, and the like. The frequency of administration will be apparent to the technician, and depends on many factors, such as but not limited to the type and severity of the disease being treated, the type and age of the animal, etc.

[0315] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.

[0316] A physician with ordinary skills in the art, such as a physician or veterinarian, can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the invention used in the pharmaceutical composition at a level lower than the desired level to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0317] In certain embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the therapeutic compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical vehicle. The dosage unit form of the present invention is dictated by and directly dependent on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of preparing / formulating such therapeutic compounds for treating the disease in the subject.

[0318] In one embodiment, the compositions of the invention are administered to a subject in doses from one to five times per day or more.

[0319] In another embodiment, the composition of the invention is administered to a subject at a dosage range including, but not limited to, once a day, once every two days, once every three days to once a week, and once every two weeks. In another embodiment, the composition of the invention is administered to a subject at a dosage range of a sustained release formulation, including, but not limited to, once every two days, once every three days to once a week, and once every two weeks, depending on the precise sustained release formulation used, in order to maintain serum concentrations of the therapeutic agent that are therapeutically effective without inducing unacceptable side effects.

[0320] It will be apparent to those skilled in the art that the frequency of administration of the various combination compositions of the present invention will vary from subject to subject, depending on many factors, including but not limited to age, the disease or condition to be treated, sex, overall health and other factors. Therefore, the present invention should not be construed as limited to any particular dosage regimen, and the precise dosage and composition administered to any subject will be determined by the attending physician in consideration of all other factors of the subject.

[0321] The range of the compound of the present invention for administration can be from about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 3050 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all integer or partial increments therebetween.

[0322] In some embodiments, the dosage of the compounds of the invention is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds of the invention used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of a second compound as described herein (i.e., a drug used to treat the same or another disease as treated by the composition of the invention) is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0323] In one embodiment, the invention relates to a packaged pharmaceutical composition comprising a container containing a therapeutically effective amount of a compound or conjugate of the invention, alone or in combination with a second agent; and instructions for using the compound or conjugate to treat, prevent or alleviate one or more disease symptoms in a subject.

[0324] The term "container" includes any receptacle for holding a pharmaceutical composition. For example, in one embodiment, the container is a package containing a pharmaceutical composition. In other embodiments, the container is not a package containing a pharmaceutical composition, i.e., the container is a receptacle, such as a box or a vial containing a packaged pharmaceutical composition or an unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. In addition, packaging technology is well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be included in the package containing the pharmaceutical composition, so that the instructions form an enhanced functional relationship with the packaged product. However, it should be understood that the instructions may include information related to the ability of the compound to perform its intended function, such as, treating or preventing a disease in a subject, or delivering imaging or diagnostic agents to the subject.

[0325] Routes of administration of any composition of the present invention include oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivanal), nasal, and rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0326] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, slurries, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

[0327] In some instances, the composition can be a bead, a film or other shape, as understood by those of ordinary skill in the art. The size of each individual bead, film or other shape is the size suitable for implantation or other forms of administration, as understood by those of ordinary skill in the art. In addition, the size of each individual bead, film or other shape can be substantially consistent, or there can be a distribution of different sizes of each shape. Optionally, the bead can be implanted, ingested or placed in the body in some way so that the medicament is locally or systemically administered in a sustained-release manner.

[0328] It will be appreciated that the compositions of the present invention may be administered to a subject alone or in combination with another pharmaceutical agent.

[0329] In certain embodiments, administration of a composition of the invention may be performed via a single administration, or boosted via multiple administrations.

[0330] In one embodiment, the invention includes a method comprising administering a combination of compounds described herein. In certain embodiments, the combination has an additive effect, wherein the overall effect of administering the combination is approximately equal to the sum of the effects of administering each compound. In other embodiments, the combination has a synergistic effect, wherein the overall effect of administering the combination is greater than the sum of the effects of administering each compound.

[0331] Optionally, the composition may include a formulation suitable for delivering treatment in the form of a sustained release formulation that can release the therapeutic substance over a period of time lasting from hours to weeks. Such sustained release formulations may consist of an osmotic pump, fibrin glue, a biocompatible polymer or hydrogel, or other therapeutic means in the form of a formulation capable of sustained release. The compound may be encapsulated in a polymer or hydrogel so that the agent is slowly released in vivo into at least a portion of the damaged tissue by toxic damage. Optionally, the compound may be dispersed throughout the polymer or hydrogel in such a manner that it results in a slow, sustained release when the polymer or hydrogel degrades in vivo. In some examples, the composition may include biodegradable, biocompatible polymers such as polyglycolide or polyglycolic acid (PGA), polylactide or polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D / L-lactic acid and polyglycolic acid (PDLLA-co-PGA), poly-L-lactic acid-co-glycolic acid (PLGA), PDLLA with bioactive glass, PLGA with bioactive glass, poly-L-lactic acid and β-tricalcium phosphate (PLLA-TCP), poly-L-lactic acid and hydroxyapatite (PLLAHA), polydioxanone (PDS), polyethylene glycol (PEG), poly(8-caprolactone) (PCL), polycaprolactone (PCL) and alginate, polyhydroxybutyrate (PHB), polycarbonate (PC), N-vinyl pyrrolidone copolymers, polyorthoesters, chitosan, poly(2-hydroxyethyl methacrylate) (PHEMA), hyaluronic acid, and hydrogels.

[0332] The methods described herein are by no means exhaustive, and further methods suitable for particular applications will be apparent to the skilled artisan. In addition, the effective amount of the composition can be further estimated by analogy with compounds known to exert the desired effect.

[0333] Experimental Examples

[0334] The present invention is further described in detail with reference to the following experimental examples. These examples are provided for illustrative purposes only and, unless otherwise indicated, are not intended to be limiting. Therefore, the present invention should never be construed as being limited to the following examples, but should be construed as covering any and all variations that become apparent due to the teachings provided herein.

[0335] Without further description, it is believed that one of ordinary skill in the art can use the preceding description and the following illustrative examples to implement and utilize the present invention and practice the claimed methods. Therefore, the following working examples particularly point out preferred embodiments of the present invention and should not be construed as limiting the remainder of the present disclosure in any way.

[0336] Example 1: 4-aminopyridine for treating tissue dysfunction caused by toxic damage

[0337] This example demonstrates in vivo studies of properties associated with various toxic insults. More specifically, preliminary studies were conducted in the specific case of CIPN induced by PTX exposure. Figure 1 (include Figure 1 A to Figure 1 H) Depicts representative results demonstrating that 4-aminopyridine (4-AP) provides protection against the development of chemotherapy-induced peripheral neuropathy (CIPN) and mitochondrial damage caused by clinically relevant doses of PTX. A single dose of 35 mg / kg PTX (ip) was administered to 16-week-old C7BL / 6 female mice. Animals were divided into a control group (saline, ip, n=4) or a treatment group (2 mg / kg 4-AP, ip daily, n=4). Catwalk scores before treatment were compared with those 21 days after PTX injection.

[0338] Figure 1 A depicts a representative nerve conduction study showing that latency in the control group increased significantly over the study period. In 4-AP treated mice, the increase in latency was significantly smaller. Figure 1 B depicts a representative nerve conduction study showing that the velocity of the control group decreased significantly during the study period. In 4-AP treated mice, the velocity decrease was significantly less. Figure 1 C depicts representative catwalk analysis demonstrating a significant increase in the swing phase in control mice but no significant changes in the 4-AP treated group (p<0.05; p<0.01; p<0.001). Figure 1 D depicts representative catwalk analysis demonstrating a significant increase in stance phase (indicating gait abnormalities) in control mice but no significant changes in 4-AP treated groups (p<0.05; p<0.01; p<0.001).

[0339] To be consistent with clinical treatment, mice received 35 mg / kg of PTX (equivalent to approximately 110 mg / m 2 Results of this pilot study (n=4) showed that animals tolerated this dose and that this concentration was sufficient to induce clinically significant CIPN symptoms ( Figure 1 ). Next, mice from different cohorts were treated with 35 mg / kg PTX for one cycle (three weeks), which also resulted in CIPN.

[0340] The study also included a 4-AP treatment group (n=4) with daily doses of 2 mg / kg 4-AP administered intraperitoneally (as per most previous studies by MN and colleagues). The 4-AP group was found to have significantly reduced CIPN symptoms compared to control mice that were injected intraperitoneally with an equal amount of saline. The study used a low dose of 4-AP that is equivalent to approximately 40% of the body surface area of ​​mice treated with a dose of 20 mg / day for multiple sclerosis and is less than the equivalent dose examined in patients with chronic spinal cord injury.

[0341] In these studies, 4-AP treatment was found to improve CIPN-related motor functional changes (as measured by catwalk analysis) and electrophysiological parameters caused by PTX treatment and to reduce PTX-induced changes in mitochondrial size and health. TM (Noldus Information Technology, Wageningen, The Netherlands) methods. Electrophysiological data related to nerve conduction studies were also recorded, and both latency and velocity were improved in animals treated with 4-AP.

[0342] We also demonstrate that concurrent 4-AP treatment prevents PTX-induced changes in peripheral nerve function associated with CIPN. Sciatic nerve samples were collected and embedded in resin, sectioned, and imaged by transmission electron microscopy. Images were analyzed to calculate markers of peripheral neuropathy, namely: axon count, fiber size, myelination (G ratio), and circumferential irregularity ( Figure 2 ). Mitochondria were evaluated to assess chemotherapy-induced damage and the results showed that 4-AP improved myelination. Figure 2 (include Figure 2 A to Figure 2 E) Depicted are representative results demonstrating that 4-AP prevents chemotherapy-induced axonal injury. Figure 2 A depicts representative G ratio (axon:myelin area) data, demonstrating that axons in 4-AP treatment were better myelinated than those in controls. Figure 2 B depicts representative circularity data, showing that axons in 4-AP treatments have more regular structures than those in controls. Figure 2 C depicts a representative baseline appearance of the sciatic nerve. Figure 2 D depicts the representative appearance of control axons after 3 weeks of 35 mg / kg PTX treatment. Figure 2 E depicts a representative appearance of 4-AP (2 mg / kg daily) treated axons showing thicker myelin sheaths and more regular structure.

[0343] Example 2

[0344] The second study, which used a longer PTX administration schedule, further demonstrated the ability of 4-AP to prevent CIPN when administered concurrently.

[0345] All animals received four ip injections of PTX at 35 mg / kg every three weeks (equivalent to approximately 110 mg / m 2 A subgroup of animals also received 4-AP (1 mg / kg daily) starting at the same time as the initial PTX treatment and continuing throughout the treatment. Functional outcome responses, including von Frey monofilament testing, cold plate thermal sensitivity, cat walk, and TM Gait analysis and nerve conduction testing. All animals developed functionally demonstrable peripheral neuropathy at six weeks.

[0346] In these experiments, it was observed that simultaneous treatment with 4-AP prevented the development of PTX-induced CIPN. 4-AP treatment prevented PTX-induced changes in multiple motor function and electrophysiological parameters. Analysis of responses to thermal changes using cold plate analysis showed that 4-AP prevented the development of CIPN-like changes, regardless of whether these changes indicated hyperalgesia or hypoalgesia. Analysis of mechanical allodynia using the von Frey filament test revealed increased sensitivity, as indicated by responses to smaller forces. This change was evident at three weeks, worsened at six weeks, and remained stable for the next six weeks. In contrast, the response of mice treated with PTX+4-AP did not change from baseline, and the difference from the PTX alone treatment group was statistically significant at all time points. The sensitivity of mice to cold, determined by the number of times the mice attempted to jump out of the cold plate stimulus, showed a significant increase six weeks after the start of treatment, and this sensitivity was maintained throughout the remaining six weeks of analysis. In contrast, this parameter did not change in mice treated with PTX+4-AP compared to baseline. At weeks 6, 9, and 12, the difference between the two treatment groups was highly statistically significant. Other responses to cold showed a loss of sensitivity in PTX-treated mice, as determined by the number of times the mice lifted their paws off the cold plate or licked their hind paws. For these results, concurrent treatment with 4-AP prevented the development of these changes, with the differences between the PTX group and the PTX+4-AP group being statistically significant.

[0347] Treatment with CIPN in these experiments also resulted in a decrease in the amplitude and velocity of nerve impulse conduction, changes that became evident 6 weeks after the start of PTX treatment and persisted for the next 6 weeks. For both parameters, concurrent treatment with 4-AP prevented the development of these changes, with statistically significant differences between the PTX group and the PTX+4-AP group.

[0348] Example 3: 4-AP treatment prevents PTX-induced CIPN caused by repeated PTX exposure, even at very low water levels. The same is true for the flat 4-AP application.

[0349] It is critical to understand whether 4AP treatment can also prevent PTX-induced peripheral neuropathy when treatment with PTX is repeated. This is the situation that will occur clinically, where cancer patients are not treated with a single dose of paclitaxel but instead experience repeated exposures. There is no prior indication whether 4AP can help prevent the effects of this unusual type of injury, which has elements of both repetitive injury due to repeated exposure to paclitaxel and chronic injury due to accumulation of injury. Therefore, in this setting, 4-AP needs to overcome existing injury and prevent further injury to ameliorate chemotherapy-induced changes.

[0350] To determine whether 4-AP can also prevent CIPN when animals are repeatedly exposed to PTX, 16-week-old C7BL / 6 female mice were treated with four cycles of PTX at a dose of 35 mg / kg PTX (ip). The animals were divided into a control group (saline, ip) or a treatment group, and the treatment group was treated with 25% of the 4AP dose used in Examples 1 and 2 (i.e., 0.5 mg / kg 4-AP per day, ip). The catwalk score before treatment was compared with the score 21 days after PTX injection.

[0351] The analysis showed that 4-AP treatment improved PTX-induced mechanical hypersensitivity as detected by applying the von Frey filament test, in which sensitivity to smaller filaments indicates increased sensitivity to painful stimuli. Results at weeks 3, 6, 9, and 12 were highly significant. 4-AP treatment also prevented the development of the opposite symptom of hyposensitivity to stimulation using analysis of pawlift and jumping behavior in response to cold plate stimulation. Pawlift results showed a significant trend at weeks 6 and 9 and a highly significant trend at week 12. Jumping behavior was highly significant at weeks 6, 9, and 12 ( Figure 3 A- Figure 3 C).

[0352] 4-AP treatment also improved PTX-induced gait abnormalities detected by catwalk analysis, with significant effects at multiple time points ( Figure 3 D- Figure 3 F).

[0353] 4-AP treatment also improved PTX-induced nerve conduction abnormalities in multiple outcomes including latency ( Figure 3 G), amplitude ( Figure 3 H) and speed ( Figure 3 I).

[0354] Example 4: 4-AP treatment prevents PTX-induced changes in peripheral nerve structure caused by repeated exposure to PTX, This was true even when applied at very low levels of 4-AP.

[0355] It is critical to understand whether 4AP treatment can also prevent PTX-induced peripheral neuropathy when treatment with PTX is repeated. This is what will happen clinically, where cancer patients are not treated with a single dose of paclitaxel but experience repeated exposures. There is no prior indication whether 4AP can help prevent the effects of this unusual type of injury, which has elements of both repetitive injury due to repeated exposure to paclitaxel and chronic injury due to cumulative damage.

[0356] It will also be important to determine whether this treatment can prevent the structural damage associated with the development of CIPN. The ability of 4-AP treatment to prevent damage caused by anticancer drugs is unclear, as anticancer drugs have many different effects on cells. It is known that chemotherapy causes a lot of structural damage, but based on current information, it is impossible to predict whether 4AP will help prevent such damage.

[0357] To determine whether 4-AP can prevent chemotherapy-induced structural damage when multiple chemotherapy is applied, ultrastructural analysis was performed on tissues of mice treated with 35 mg / kg PTX every 3 weeks for 4 treatment cycles. The dose of 4-AP used was lower, only 25% of the dose used in Examples 1 and 2, and the administration dose was 0.5 mg / kg per day instead of 2 mg / kg per day.

[0358] Ultrastructural analysis of myelination revealed multiple benefits of 4-AP treatment ( Figure 4 Analysis of the G ratio (axon:myelin area) data showed that axons in 4-AP treated mice were better myelinated than those in the control group (PTX+saline) ( Figure 4 C). Circularity analysis showed that the axons in the 4-AP treated group had more regular structures than those in the control group ( Figure 4 D) The frequency profile of myelin degeneration was also reduced in the 4-AP treated group.

[0359] These experiments also showed that 4AP treatment improved mitochondrial health as determined by mitochondrial structure, even in the setting of repeated exposure to chemotherapy.

[0360] Example 5: 4-AP treatment reverses PTX-induced CIPN, even after established peripheral neuropathy This is valid for both functional and histological analyses.

[0361] Another important question to consider is whether delaying 4AP therapy after CIPN is diagnosed can overcome CIPN. This scenario is associated with ongoing chemotherapy treatment and is of high clinical relevance, as peripheral neuropathy may limit the dose of cancer therapy. When this occurs, patients may delay necessary treatment due to the impact of CIPN on their quality of life.

[0362] There is no indication of what role 4AP might play in this setting, as treatment can cause repetitive injury, where damage begins with the first treatment and continues to increase with subsequent treatments. Previous studies of the use of 4AP in established syndromes such as multiple sclerosis and spinal cord injury have shown limited efficacy in this regard. As discussed elsewhere, the efficacy of 4AP in reducing pain-related symptoms appears to be limited at best and, more likely, ineffective.

[0363] To investigate this question, 16-week-old C7BL / 6 female mice were treated with four cycles of PTX at a dose of 35 mg / kg PTX (ip). The animals were divided into control groups (saline, ip) or treatment groups treated with 4AP at a dose of Figure 1 and 2 25% of the dose used in (i.e. 0.5 mg / kg 4-AP per day, ip, treatment was started 6 weeks after the first PTX treatment, when CIPN-related changes were already evident).

[0364] These experiments showed that 4-AP treatment also reversed the effects of repeated PTX treatment on peripheral nerves, with 4-AP treatment starting at week 6 when mice received their third PTX exposure. For example, the effects of 4-AP treatment on PTX-induced mechanical hypersensitivity were tested by applying the von Frey filament test (sensitivity to smaller filaments indicates increased sensitivity to painful stimuli), and the benefits of 4-AP treatment were observed starting at week 12 ( Figure 5 A). 4-AP treatment also reversed symptoms of hypersensitivity to heat stimuli using analysis of jumping behavior in response to cold plate stimulation ( Figure 5 B) At 9 and 12 weeks, jumping behavior changed significantly.

[0365] 4-AP treatment also reversed the ability of PTX-induced gait abnormalities detected by catwalk analysis, with significant effects on swing time and regularity index at weeks 9 (the first analysis after initiation of 4-AP treatment) and 12, and stance time results trending toward significance at these same time points ( Figure 5 C- Figure 5 E).

[0366] 4-AP treatment was also shown to be effective in the latent period ( Figure 5 F), amplitude ( Figure 5 G) and speed ( Figure 5 H) The ability of PTX to reverse PTX-induced nerve conduction abnormalities was established in multiple results.

[0367] 4-AP treatment also reversed PTX-induced myelin structural abnormalities indicative of myelin degeneration ( Figure 5I). This result reveals an unexpected ability of CIPN to promote tissue repair after establishment.

[0368] Example 6: 4-AP treatment can durably reverse PTX-induced peripheral neuropathy even after it has already occurred CIPN, and the benefit persisted after cessation of treatment.

[0369] An important issue in treating damage induced by exposure to toxic agents is the need for treatments that can reverse damage that has already occurred. Many people are not diagnosed with damage until after the injury. Furthermore, in the specific case of peripheral neuropathy induced by exposure to chemotherapeutic agents, the neuropathy may manifest after cessation of treatment. Furthermore, it may be necessary to delay the initiation of neuropathy treatment until cancer treatment is completed.

[0370] Regarding the use of 4-AP to treat injuries, there is currently no prior information that allows prediction of outcome in established injuries. In fact, predictions based on years of research in chronic injuries would not lead to such a benefit. This is because in syndromes such as multiple sclerosis, chronic spinal cord injury, spinocerebellar ataxia, and other established conditions, 4AP has been shown to relieve symptoms, but when treatment is stopped, the benefits of 4AP treatment disappear.

[0371] Therefore, it is unpredictable whether treatment of CIPN with 4AP will promote recovery after treatment has ended. This lack of predictability is exacerbated by the fact that chemotherapy itself is a repetitive injury with an established chronic component that is exacerbated with each further treatment. This is a very different situation from previous analyses of the effects of 4-AP treatment. Nonetheless, previous studies of established injuries predicted that durable recovery would not occur when treatment with 4-AP was initiated weeks or more after the initial injury. Therefore, in addition to the lack of data indicating whether 4-AP provides any benefit in the treatment of CIPN, there is also no ability to predict whether any benefit that is experienced will persist after treatment has ceased, a situation that requires tissue repair to occur while treating established injuries.

[0372] To investigate this question, 16-week-old C7BL / 6 female mice were treated with four cycles of PTX at a dose of 35 mg / kg PTX (ip). All animals had functional peripheral neuropathy by week six. Figure 5 Animals were treated with 4-AP at the same dose and treatment schedule as in the 4-AP treatment group. 4-AP treatment ended at week 12 after the first exposure to PTX and after 6 weeks of treatment with 4-AP, and the animals were observed for an additional six weeks thereafter (i.e., 6 weeks without 4-AP treatment).

[0373] These experiments revealed an unexpected result: 4-AP treatment reversed the effects of repeated rounds of PTX exposure on peripheral nerve function, and this effect was retained after the end of treatment. Compared with the estimated elimination rate of 4-AP of >99.9% within 24 hours (clearance through the kidney), the benefits were still present 6 weeks after treatment. Such persistent changes suggest that the pro-repair effects of 4-AP treatment are not limited to symptom relief during treatment.

[0374] The results of these experiments suggest that 4-AP treatment can restore normal function after several weeks of PTX treatment, regardless of whether the symptom is hyperalgesia or hypoalgesia, which is the most promising result in terms of meeting clinical needs. Figure 6 A depicts the effect of 4-AP treatment on PTX-induced mechanical hypersensitivity as tested by application of the von Frey filament test, in which sensitivity to smaller filaments reveals increased sensitivity to painful stimuli. Benefits were observed starting at week 12 and were maintained at weeks 15 and 18. Figure 6 B shows the paw lifting response to cold plate stimulation ( Figure 6 B) and jumping behavior ( Figure 6 C), 4-AP treatment also resulted in a durable reversal of the opposing symptom of hyposensitivity to stimulation.

[0375] Figure 6 D depicts the ability of 4-AP to durably reverse PTX-induced gait abnormalities as determined by the cat-walk regularity index, with benefits observed at week 9 (i.e., 3 weeks after 4-AP treatment) and retained for at least 6 weeks after the end of 4-AP treatment. Figure 6 E depicts the ability of 4-AP to reverse PTX-induced abnormalities in nerve conduction latency after the abnormalities have been established by multiple rounds of PTX exposure.

[0376] Figure 6 F- Figure 6 G depicts the ability of 4-AP to induce durable pro-repair changes when used to treat established PTX-induced CIPN and tissue damage. The G ratio ( Figure 6 F) and roundness ( Figure 6 G) normalized at the 12-week time point, and these benefits were maintained at the 18-week time point (i.e., 6 weeks after the end of treatment).

[0377] Example 7: 4-AP treatment reverses cisplatin-induced CIPN

[0378] To determine whether the benefit provided by 4-AP treatment experiments was conducted against another toxic agent with a different mechanism of action than paclitaxel. In these experiments, the toxic agent studied was cisplatin. In contrast to the microtubule stabilizing activity of the taxanes (including paclitaxel), the platinum-containing compound cisplatin is thought to kill rapidly dividing cells by causing DNA crosslinking. The structures of paclitaxel and cisplatin are also very different. The difference in the mechanism of action of cisplatin and paclitaxel is highlighted by the fact that paclitaxel is often used to treat cancers that are resistant to cisplatin. Therefore, this example describes in vivo studies related to the nature of various toxic insults.

[0379] In these experiments, 16-week-old C7BL / 6 female mice were treated with CIS (2.5 mg / kg, once a week, ip) for eight weeks. The animals were then treated with 4-AP (1 mg / kg per day) for the next six weeks (n=4).

[0380] These experiments showed that mice treated with 4-AP beginning at week 9 after initiation of CIS treatment regained normal body weight. CIS-treated mice expressed CIPNs, and 4-AP was as effective in reversing CIS-induced CIPNs as it was in reversing PTX-induced CIPNs. Analysis of hyperalgesia by von Frey filament analysis showed that sensitivity was significantly increased in CIS-treated mice, whereas sensitivity returned to normal levels following 4-AP treatment. The restoration of normal sensitivity was durable and maintained for at least two weeks after the end of treatment, well beyond the 12-16 hour time point when all 4-AP would be expected to be cleared from the body, demonstrating a durable recovery of function and indicating a pro-reparative effect of the treatment. Figure 7 C depicts representative results demonstrating the effect of 4-AP on nerve impulse amplitude, which was also restored by 4-AP treatment, and the improvement was again maintained for at least two weeks after the end of treatment with 4-AP. Figure 7 D depicts representative results demonstrating the effects of 4-AP on nerve impulse velocity, which were also restored by 4-AP treatment and the improvements were maintained for at least two weeks after the end of 4-AP treatment (in contrast to the expected elimination of >99.9% of 4-AP within 24 hours (through renal clearance)), thus demonstrating a durable recovery of function and indicating a pro-repair effect of treatment. This result can only be explained by 4-AP-induced changes in the repair of injured tissue.

[0381] Example 8: 4-AP treatment prevents chemotherapy-induced renal injury

[0382] Another tissue that is often damaged by treatment with chemotherapeutic agents is the kidney, so protecting the kidney from this renal toxicity is critical. The focus on the kidneys combined with the fact that exposure to toxic insults such as chemotherapeutic agents is very different from the types of injuries that occur with traumatic injury and other previously studied uses of 4-AP, so it is not possible to predict whether the benefits of 4-AP in the context of the present invention would also include the kidneys.

[0383] To examine the effects on the kidneys, a histological study of the tissue was performed. Mice received PTX on day 0 of the experiment, and half of the mice were also injected with 4-AP at this time and daily thereafter at a dose of 2 mg / kg. Mice that did not receive 4-AP were injected with saline to control for any stress induced by the daily injections. The experimental group also included mice that did not receive PTX treatment and only received daily injections of saline. The mice were sacrificed after 1 week. The mice were perfused with 4% paraformaldehyde, and the kidneys were then sectioned and stained with hematoxylin and eosin (H&E).

[0384] H&E staining of saline-treated, PTX-treated, and PTX+4-AP-treated kidneys showed that the proximal and distal tubules of saline- and PTX+4-AP-treated kidneys were normal ( Figure 8 ). Disappearance of the brush border (dark grey arrows), nuclear shedding (grey arrows), and blebbing of tubular epithelial cells (black arrows) were observed in kidneys treated with PTX but not in kidneys isolated from animals treated with PTX + 4-AP.

[0385] The results of this experiment show that 4-AP co-treatment also prevents the multifaceted histological renal damage caused by PTX exposure. This surprising result suggests that 4-AP-mediated protection against chemotherapy also exists in tissues of the non-neural system. These results further confirm the data provided in Table 1.

[0386] Example 9: 4-AP exposure prevents PTX-induced changes in the central nervous system

[0387] Another important tissue that is damaged by anticancer agents, radiation, and other forms of toxicity is the central nervous system (CNS). The CNS is affected by many anticancer treatments, radiation, and multiple toxic insults. This damage can lead to changes in multiple neurological and / or cognitive functions, and prevention of this damage is of great medical importance. The lack of interventions to prevent this damage is even greater than possible interventions for other parts of the body.

[0388] One of the first signs of CNS damage is the increased expression of glial fibrillary acid protein (GFAP). The increase of GFAP indicates the activation of astrocytes, and the response to any of inflammation, various physical injuries and to chemical damage (such as exposure to chemotherapeutic agents) is enhanced (e.g. Liu, et al., Paclitaxel-activated astrocytesproduce mechanical allodynia in mice by releasing tumor necrosis factor-αandstromal-derived cell factor 1.J.Neuroinflammation 2019; 16: 209; Masocha, Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice. PeerJ 2015 3: e1350).

[0389] To determine whether 4-AP treatment could prevent the increase in PTX-induced reactive inflammatory responses in the brain as detected by increased expression of glial fibrillary acid protein (GFAP), the triple-negative murine breast cancer cell line E0771 was inoculated into 16-week-old female C57BL / 6 mice. When tumors were palpable, mice were injected with paclitaxel and saline, 4-AP, both, or saline as a control. Paclitaxel (35 mg / kg) was injected on the first day, and 4-AP and water were injected every day. Mice were sacrificed on the ninth day, and their brains were perfused and harvested. Coronal cryosections were performed on the brains.

[0390] Mouse brain sections were stained with anti-GFAP antibodies and then with fluorescent secondary antibodies and analyzed by immunofluorescence. Images of the corpus callosum (the major myelin bundle of the CNS) were taken by confocal microscopy and analyzed using Image-J. These experiments showed that PTX treatment was associated with increased GFAP expression ( Fig. 9 ). In mice co-treated with 4-AP, the increase in GFAP expression induced by PTX exposure was greatly reduced.

[0391] Example 10: 4-AP's protective effect against chemotherapeutic toxicity is selective for normal cells

[0392] Another unexpected property of 4-AP is that its ability to protect against chemotherapeutic agents with different mechanisms of action is selective for normal tissues (i.e., non-transformed cells), while 4-AP does not provide protection against cancer cells. This result was also unpredictable because many survival mechanisms are the same in normal cells and cancer cells. This surprising result is critical because protecting cancer cells would greatly reduce the value of 4-AP as a cancer therapeutic in cancer treatment. In addition, protection against cancer cells would also limit the use of 4-AP because many toxic insults associated with this patent increase cancer risk (including, for example, chemotherapeutic agents, radiation, and agricultural chemicals).

[0393] To investigate the effects of 4-AP treatment on cancer cells, 4-AP was co-applied with either paclitaxel or cisplatin to the extensively studied E0771 murine breast cancer cell line and A549 human lung cancer cell line over a dose-response curve that was expanded over a 20-fold range. Cells were exposed to paclitaxel or cisplatin for 5 days in the presence or absence of 1 mM 4-AP. This concentration of 4-AP is commonly used in in vitro studies and greatly exceeds the concentration that can be achieved in vivo. This higher dose will increase the likelihood of detecting protective activity.

[0394] Fig.10 The presence of 4-AP was shown to fail to protect cancer cells from cisplatin and even appeared to increase sensitivity to low-dose paclitaxel. Thus, this example reveals a surprising result: the ability of 4-AP to protect a variety of normal tissues from the toxic effects of cisplatin and paclitaxel is unusually selective and does not apply to cancer cells.

[0395] Example 11. Analysis of serum 4-AP levels revealed that 4-AP treatment can prevent changes in renal function.

[0396] In addition, the data provided in Table 1 show that the circulating 4-AP levels analyzed 1 hour after intraperitoneal injection were not different in mice treated with 4-AP alone and mice treated with 4-AP + PTX, indicating that 4-AP can prevent PTX-induced changes in renal function. 4-AP was injected intraperitoneally at the specified time points after the start of treatment. Mice received PTX on day 0 of the experiment, half of which were also injected with 4-AP at this time, and were injected daily at a dose of 1 mg / kg thereafter. Blood samples were drawn on days 3 and 7 after the start of the experiment and 1 hour after the injection of 4-AP. The circulating levels of 4-AP were determined by HPLC analysis. As shown, there was no difference in the amount of 4-AP detected in the circulation of mice treated with 4-AP alone or with PTX + 4-AP, whether on day 3 or day 7. Since 4-AP is cleared by the kidneys, this further indicates that 4-AP can prevent PTX-induced changes in renal function.

[0397] Table 1. Circulating 4-AP levels in mice treated with 4-AP alone and with 4-AP + PTX.

[0398]

[0399]

[0400] The disclosure of each patent, patent application and publication cited herein is hereby incorporated by reference in its entirety. Although the present invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the present invention may be devised by other skilled in the art without departing from the true spirit and scope of the present invention. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

Claims

1. A method for preventing, alleviating or treating tissue damage or tissue dysfunction caused by toxic insult in a subject in need thereof, The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

2. A method of reducing or reversing tissue damage, oxidative damage, scarring, or any combination thereof in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof; and The tissue damage, oxidative damage, scarring, or any combination thereof is caused by toxic insult.

3. A method for restoring, improving or enhancing at least a portion of tissue function in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof; and The tissue function is reduced by toxic insults.

4. The method of claim 3, wherein the tissue function is motor function, sensory function, cognitive function, visual function, auditory function, kidney function, hematopoietic system function, normal skin function, salivary gland function, liver function, gallbladder function, gastrointestinal (GI) function, sexual function, or any combination thereof.

5. A method of restoring, improving or enhancing myelination in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof; and The myelination is reduced or modulated by toxic insults.

6. A method for preventing, alleviating or treating mitochondrial damage or mitochondrial dysfunction caused by toxic insult in a subject in need thereof, The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

7. A method for preventing, ameliorating or treating axonal damage or axonal dysfunction caused by toxic insult in a subject in need thereof, The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

8. A method of preventing, ameliorating or treating at least one gait abnormality caused by a toxic insult in a subject in need thereof, The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

9. A method of enhancing tissue regeneration, cell survival, or a combination thereof in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof; and The subject is exposed to at least one toxic insult.

10. The method of claim 9, wherein the tissue is kidney tissue, liver tissue, heart tissue, lung tissue, brain tissue, central nervous system tissue, peripheral nervous tissue, gastrointestinal tract tissue, intestinal tissue, visual system tissue, auditory system tissue, skin tissue, bladder tissue, reproductive system tissue, hematopoietic system tissue, musculoskeletal tissue, or any combination thereof.

11. A method for preventing, alleviating or treating chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one potassium channel blocker or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug, pharmaceutically acceptable salt or derivative thereof.

12. The method of claim 11, wherein the chemotherapy-induced peripheral neuropathy (CIPN) is taxane-induced CIPN (P-CIPN), cisplatin-induced CIPN (CisIPN), anticancer agent-induced CIPN, platinum-based antineoplastic agent-induced CIPN, vinca alkaloid-induced CIPN, epothilone-induced CIPN, proteasome inhibitor-induced CIPN, immunomodulatory drug-induced CIPN, or any combination thereof.

13. The method of any one of claims 1-12, wherein the at least one potassium channel blocker comprises 4-aminopyridine, a derivative of 4-aminopyridine, or a combination thereof.

14. The method of claim 13, wherein the derivative of 4-aminopyridine is a compound having the structure of formula (I) or an analog, racemate, tautomer, isomer, enantiomer, diastereomer, prodrug or pharmaceutically acceptable salt thereof; Where R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, amine, hydroxyl, alkoxy, carboxyl or any combination thereof; and Where R 1 , R 2 , R 3 , R 4 and R 5 Optionally substituted.

15. The method of any one of claims 1, 2 or 14, wherein the tissue damage is renal tissue damage, liver tissue damage, cardiac tissue damage, lung tissue damage, brain tissue damage, central nervous system damage, peripheral nerve tissue damage, peripheral neuropathy, nephropathy, chemotherapy-induced peripheral neuropathy (CIPN), radiation-induced peripheral neuropathy (RIPN), chemotherapy-induced nephrotoxicity (CINT), chemotherapy-induced neutropenia, radiation-induced neutropenia, gastrointestinal tissue damage, intestinal tissue damage, visual system tissue damage, auditory system tissue damage, skin tissue damage, bladder tissue damage, reproductive system tissue damage, hematopoietic system tissue damage, or any combination thereof.

16. The method of claim 15, wherein the chemotherapy-induced peripheral neuropathy (CIPN) is taxane-induced CIPN (P-CIPN), cisplatin-induced CIPN (CisIPN), anticancer agent-induced CIPN, platinum-based antineoplastic agent-induced CIPN, vinca alkaloid-induced CIPN, epothilone-induced CIPN, proteasome inhibitor-induced CIPN, immunomodulatory drug-induced CIPN, or any combination thereof.

17. The method of any one of claims 1, 2, or 14, wherein the tissue injury is multiple tissue injury, multiple organ tissue injury, or any combination thereof.

18. The method of any one of claims 1-14, wherein the toxic insult is an acute toxic insult, a chronic toxic insult, or any combination thereof.

19. The method of any one of claims 1-14, wherein the toxic insult comprises exposure to damaging levels of radiation along the electromagnetic spectrum.

20. The method of any one of claims 1-14, wherein the toxic insult is a non-biological substance, a non-naturally occurring compound, a toxin, an agent used to treat cancer, a chemotherapeutic agent, a biological response modifier, radiation, or any combination thereof.

21. The method of claim 20, wherein the chemotherapeutic agent comprises a platinum-based anti-tumor agent, a vinca alkaloid agent, an epothilone agent, a taxane agent, a proteasome inhibitor, an immunomodulatory drug, or any combination thereof.

22. The method of claim 20, wherein the toxic insult comprises at least one environmental toxicant.

23. The method of claim 20, wherein the radiation comprises radiation from radiation cancer treatment, radiation from nuclear power accidents, radiation from nuclear waste exposure, radiation from the use of radioactive materials in military applications, or any combination thereof.

24. The method of any one of claims 1-14, wherein the toxic lesions include at least a first toxic lesion and a second toxic lesion, wherein the first toxic insult is a chemotherapeutic agent, radiation, or a combination thereof; and The second toxic insult is a chemotherapeutic agent, radiation, or a combination thereof.

25. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject prior to the toxic insult.

26. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject at the time of the toxic insult.

27. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject after the toxic insult.

28. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject more than once.

29. The method of any one of claims 1-14, wherein a therapeutically effective amount of the pharmaceutical composition is repeatedly administered to the subject for about 1 day to about 100 years.

30. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject systemically, topically, or a combination thereof.

31. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject by intraperitoneal injection, intravenous injection, intramuscular injection, intrathecal injection, subcutaneous injection, sublingual administration, inhalation, oral administration, transdermal administration, application to the outside of the body in liquid form, application to the outside of the body in ointment form, application to the outside of the body in bandage form, or any combination thereof.

32. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject at a dose of about 1 mg / day to about 1,000 mg / day of the potassium channel blocker.

33. The method of claim 32, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject at a dosage of about 2.5 mg / day to about 40 mg / day of the potassium channel blocker.

34. The method of claim 32, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject at a dosage of about 40 mg / day to about 100 mg / day of the potassium channel blocker.

35. The method of any one of claims 1-14, wherein the therapeutically effective amount of the pharmaceutical composition is co-administered with at least one anticonvulsant agent or a combination thereof.

36. The method of claim 35, wherein the at least one anticonvulsant is a barbiturate, a benzodiazepine Bromide, carbamate, carboxamide, fatty acid, fructose or its derivatives, gamma-aminobutyric acid (GABA) or its analogs, hydantoin, oxazolidinedione, propionate, pyrimidinedione, pyrrolidine, succinimide, sulfonamide, triazine, urea, valproamide or any combination thereof.

37. The method of any one of claims 1-36, wherein the method also enhances the repair or regeneration of endogenous stem cells, enhances the repair or regeneration of transplanted stem cells, enhances the repair or regeneration of progenitor cells, promotes neurogenesis, enhances cell survival, reduces scar formation, reduces lesion size, reduces oxidative damage, or any combination thereof.

38. A method of identifying a subject responsive to administration of 4-aminopyridine to prevent, alleviate or treat tissue damage or tissue dysfunction caused by toxic insult in a subject in need thereof, The method comprises the following steps: a) administering to the subject 1 to 5 therapeutically effective amounts of a pharmaceutical composition comprising 4-aminopyridine, a derivative of 4-aminopyridine, or a combination thereof; b) evaluating the subject for symptoms of tissue damage or tissue dysfunction caused by toxic insult; as well as c) when the symptoms of the tissue damage or tissue dysfunction caused by the toxic insult are improved in the subject, the subject is identified as responsive to the administration of 4-aminopyridine to prevent, alleviate or treat the tissue damage or tissue dysfunction caused by the toxic insult.

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