Methods for treating nervous system disorders with antipurinergic agents - Patents.com

Abstract

The present invention provides compositions and methods for treating nervous system disorders in mammals. These compositions and methods include administering an effective amount of an antipurinergic agent according to a pharmacokinetic and / or pharmacodynamic method that includes a loading dosing regimen followed by a maintenance dosing regimen on demand to achieve efficacy taking into account the dynamic non-linear relationship between efficacy and blood levels of the antipurinergic agent. Compositions and methods for treating nervous system disorders in mammals, such as cognitive, social or behavioral disorders, are described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 236,155, filed August 23, 2021, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention provides compositions and methods for treating nervous system disorders in mammals, particularly useful for maximizing therapeutic efficacy while minimizing undesirable side effects. These compositions and methods involve administering an effective amount of an antipurinergic agent according to a pharmacokinetic and / or pharmacodynamic dosing regimen. The dosing regimen includes a loading dose regimen followed by a maintenance dose regimen as needed to achieve optimal blood levels, taking into account a previously unknown dynamic, nonlinear relationship between drug efficacy and blood levels over time. Each loading dose in the loading dose regimen contains about 3 mg / kg to about 30 mg / kg of the antipurinergic agent and is administered as a single dose or as multiple doses, each administered at a frequency ranging from about once daily to about once every three months. Each maintenance dose in the maintenance dose regimen contains about 1 mg / kg to about 15 mg / kg of the antipurinergic agent and is administered at a frequency ranging from about three times daily to about once every three months. Due to the non-linear correlation between efficacy and blood levels, the dosing regimens and dosage levels of the present invention would not have been predicted based on previously disclosed dose-response linearity. [Background technology]

[0003] Background of the Invention Neurological disorders, whether mild or severe in their manifestations, affect many individuals in the United States and around the world. These disorders have an impact beyond the individual patient, affecting families, caregivers, and society at large.

[0004] Nervous system disorders include cognitive disorders, social or behavioral disorders, nervous system and neurodevelopmental disorders, psychiatric disorders, neurological disorders, and central nervous system (CNS) disorders. These nervous system disorders include, among others, autism spectrum disorder (ASD), fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), post-traumatic stress syndrome (PTSD), Tourette syndrome (TS), Parkinson's disease, Angelman syndrome (AS), and nervous system and central nervous system (CNS) disorders associated with COVID-19 and other viruses (e.g., Epstein-Burchandise virus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including the manifestations of CNS disorders often associated with Lyme disease and other tick-borne diseases, as well as their long-term effects. It should be noted that this list of nervous system disorders is exemplary, and there are many other nervous system disorders that could benefit from the present invention.

[0005] Current treatments for these exemplified disorders are limited and often target specific symptoms, such as seizures, anxiety, depression, attention deficit / hyperactivity, sleep disorders, and cognitive impairment. While much research has been done in this field, and new or known therapeutic agents exist for such treatment, it is not always clear how to safely and effectively administer these agents. As shown in the examples, it is demonstrated herein that antipurinergic agents can be administered to treat these disorders according to pharmacokinetic and pharmacodynamic treatment regimens that would not have been predicted before. These agents are administered at doses and frequencies not previously disclosed or anticipated in the scientific literature, which has led to the discovery of a dynamic, nonlinear correlation between drug efficacy and blood levels over time.

[0006] Autism is associated with a combination of genetic and environmental factors, and its incidence in the United States is reported to be approximately 1 in 60 children. The estimated global prevalence of autism is approximately 25 million. Autism is also known as autism spectrum disorder (ASD) because it encompasses a wide range of symptoms characterized by challenges with social skills, repetitive behaviors, speech, and nonverbal communication. In 2013, the American Psychiatric Association merged four distinct autism diagnoses into a single diagnosis: autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Signs and symptoms of autism typically appear by the age of 2 or 3. Autism spectrum disorder is a condition related to brain development that can affect how a person perceives and socializes with others, leading to problems with social interaction and communication. The disorder may also include restrictive and repetitive behavioral patterns.

[0007] Research shows that early intervention for autism spectrum disorder can result in positive outcomes, as described in the following references: Chaste P, Leboyer M (2012). "Autism risk factors: genes, environment, and gene-environment interactions". Dialogues in Clinical Neuroscience. 14(3):281-92. PMC 3513682. PMID 23226953; and Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report, Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014 Surveillance Summaries / April 27, 2018 / 67(6);1-23.

[0008] Currently, there is no cure for autism spectrum disorder, and no U.S. FDA-approved medications to treat the core symptoms. According to the diagnostic criteria of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-V), the core symptoms of autism spectrum disorder include: persistent deficits in social and emotional reciprocity that make it difficult to develop, maintain, and understand relationships; deficits in verbal and nonverbal social communication; and restricted and repetitive patterns of behavior, interests, or movements. Individuals with ASD often have many accompanying (i.e., non-core) symptoms, including increased or decreased reactivity to sensory input or an unusual interest in sensory aspects of the environment, clinically significant impairment in current functioning in social, occupational, or other important areas, cognitive impairment, impulsivity, attention-deficit and hyperactivity symptoms, sleep disturbances, gastrointestinal complaints and food / chemical sensitivities, abnormal eating habits, depression, mood disorders, anxiety, seizures, irritability, emotional outbursts, and sometimes violent behavior that may be directed toward self or others.

[0009] Despite the frequent occurrence of these core symptoms, current treatment focuses on treating some of the accompanying non-core symptoms with various drugs, such as antipsychotics, anti-anxiety drugs, antidepressants, stimulants, or drugs for insomnia.Frequently occurring non-core symptoms include depression, seizures, anxiety, sleep disorders, hyperactivity, and difficulty concentrating.In addition, behavioral therapy, occupational therapy, speech therapy, and other non-pharmacological interventions are used.However, the exact cause of autism is not fully understood, and therefore, it is a challenge for new drug development programs.

[0010] Fragile X syndrome (FXS) is a rare genetic neurodevelopmental disorder affecting approximately 1 in 4,000 people in the United States. It is associated with highly variable cognitive and behavioral manifestations and shares many overlapping features with ASD. The syndrome is an X-linked disorder, meaning that a genetic mutation occurs on the X chromosome. In FXS, a trinucleotide repeat expansion is present in the FMR1 gene. A trinucleotide expansion is a specific genetic mutation in which a sequence of three nucleotide base pairs is improperly repeated multiple times. In FXS, the repeated trinucleotide sequence is cytosine-guanine-guanine (CGG). Typically, this DNA segment is repeated 5 to approximately 40 times. In individuals with FXS, this segment is repeated more than 200 times. This excess repeat typically results in the absence of functional FMR1 mRNA transcripts, and the protein normally encoded by this transcript, fragile X mental retardation protein (FMRP), is also absent.

[0011] Fragile X-associated tremor / ataxia (FXTAS) is a disorder distinct from, but genetically related to, FXS. It is a rare, "adult-onset," inherited neurodegenerative disorder that typically affects men over the age of 50. Women make up a small proportion of the FXTAS population and tend to have milder symptoms. FXTAS affects the nervous system and progresses at different rates in different individuals.

[0012] While patients with FXS have a "full mutation" in the FMR1 gene (usually well over 200 CGG trinucleotide repeats), patients with FXTAS are considered "carriers" of a premutation in the FMR1 gene, with CGG trinucleotide repeats ranging from 55 to 200. The function of the FMR1 gene is to produce a protein (FMRP) that is important for brain development and for maintaining and regulating synaptic connections between neurons. Researchers believe that (for unknown reasons) the premutation results in overproduction of FMR1 mRNA (containing the expanded repeat). Researchers also suspect that high levels of mRNA may be responsible for the signs and symptoms of FXTAS, but further research is needed to confirm these hypotheses.

[0013] Patients with FXTAS typically experience symptoms after age 55. Premutation carriers, especially men, are more likely to experience symptoms as they age; this likelihood reaches 75% by age 75 for premutation men. Symptoms, including memory loss, slowed speech, tremor, and a shuffling gait, progress gradually, with interference with daily activities due to tremor and falls occurring approximately 10 years after the onset of the first symptoms. Dependence on a cane or walker occurs approximately 15 years after the first symptom of disability. Some individuals with FXTAS exhibit a gradual progression (i.e., symptoms plateau for a period of time, followed by a sudden worsening) in which symptoms worsen more rapidly with acute illness, major surgery, or other major daily stressors.

[0014] The prevalence of FXTAS is unknown, but current estimates suggest that in families where someone already has fragile X, approximately 30%–40% of male FMR1 premutation carriers over the age of 50 will eventually demonstrate some features of FXTAS. There is no FDA-approved treatment for FXTAS, and currently used treatments address only the symptomatic nature of the condition, rather than targeting the pathophysiology itself.

[0015] Myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) can be debilitating. Chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME) or the combined term myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), is a complex, variable, and exhausting long-term medical condition. ME / CFS can cause worsening symptoms after physical or mental activity, known as post-exertional malaise (PEM). Patients with ME / CFS also often have sleep disturbances, joint and muscle pain, cognitive impairment, and significant orthostatic effects. Patients with ME / CFS often have a significantly reduced functional ability to complete routine daily activities.

[0016] Post-traumatic stress disorder (PTSD) is classified as an anxiety disorder and can be debilitating. PTSD can develop after a person is exposed to a traumatic event, such as war, sexual assault, or other significant traumatic event. PTSD symptoms can include hypervigilance, irritability, anger, depression, disturbing thoughts, emotions, dreams, or other intrusive recollections of the traumatic event, as well as mental or physical distress in response to cues associated with the trauma. PTSD symptoms can persist for long periods of time and result in significant impairment of functioning.

[0017] Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple physical movements, or motor tics, and at least one vocal tic. TS typically develops during childhood or adolescence. Tics are typically preceded by unwanted, uncontrollable urges or sensations in the affected muscles. Examples of these tics include eye blinking, coughing, throat clearing, sniffing, and facial movements. While the exact cause is unknown, TS is thought to involve a combination of genetic and environmental factors. More specifically, dysfunctional involvement of neural circuits between the basal ganglia and related structures in the brain may exist. Currently, there is no cure for TS. Haloperidol (Haldol), pimozide (Orap), and aripiprazole (Abilify) are the only drugs currently approved by the U.S. Food and Drug Administration (FDA) to treat tics, but all of these drugs have significant long-term side effects.

[0018] Parkinson's disease (PD) is a degenerative disorder of the nervous system that affects the motor system. The exact cause of the disease is unknown, and both genetic and environmental factors may contribute. PD motor symptoms include tremor, rigidity, slowness of movement, and difficulty walking. These motor symptoms are also known as parkinsonism or parkinsonism syndrome. Cognitive, mood, and behavioral symptoms may also be present, including depression, anxiety, blunted affect, dementia, sleep disorders, and sensory disturbances. The physical neurological changes associated with PD are related to the death of dopaminergic neurons in the substantia nigra, a region of the midbrain. This cell death is associated with dopamine deficiency.

[0019] Angelman syndrome (AS), also known as Angelman syndrome, is a genetic disorder affecting the nervous system. Physical characteristics of this syndrome include microcephaly (i.e., small head). In addition to physical features such as a small head, telecanthus or dystopia canthorum (i.e., increased distance between the inner eyelid angles), a wide mouth, and hands with tapered fingers, abnormal wrinkles, and broad thumbs, this syndrome is accompanied by severe intellectual disability, developmental disorders (e.g., lack of functional speech), seizures (e.g., epileptic seizures), balance and movement problems, and sleep problems. Electroencephalograms (EEGs) of individuals with AS are also typically abnormal. However, individuals with AS have happy personalities, are affectionate, and seek social interaction. Currently, there is no available treatment for AS. Seizures can be controlled with the use of one or more anticonvulsant medications. However, because people with AS often have multiple types of seizures, determining the level and type of anticonvulsant medication needed to establish control presents challenges.

[0020] Lyme disease (sometimes abbreviated as LD) is an infectious disease caused by the bacteria Borrelia burgdorferi and Borrelia mayonii, which are primarily carried by blacklegged or deer ticks. It is transmitted to the bloodstream by the bite of infected ticks. Borrelia burgdorferi, a gram-negative bacterial species that can exist as a spirochete, is the primary causative agent of the disease. A common sign of Lyme disease infection is an expanding, red, circular rash known as erythema migrans, which appears at the site of the tick bite approximately one week after the bite. Early symptoms of infection can include fever, headache, and fatigue. If untreated, the infection can progress to more severe neurological manifestations, such as loss of ability to move one or both sides of the face, joint pain, severe headache with neck stiffness, heart palpitations, tingling and electric shock pain, memory loss, and fatigue.

[0021] Coronavirus disease 2019, also known as COVID-19, is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in Wuhan, Hubei Province, China, in 2019. Common symptoms of coronavirus infection include fever, cough, fatigue, shortness of breath, and loss of smell and taste. While the majority of cases result in mild symptoms that resolve within two weeks, some cases can progress to viral pneumonia, multiple organ failure, cytokine storm, and permanent tissue and organ damage, including lung, heart, and kidney damage, and death. The disease can be particularly severe, with poor outcomes for those most at risk. Some of the more serious risk factors for severe COVID-19 disease include asthma, chronic lung disease, diabetes, serious cardiac conditions, chronic kidney disease treated with dialysis, severe obesity, people aged 65 years or older, people in nursing homes or long-term care facilities, and immunocompromised individuals (such as patients undergoing cancer chemotherapy, immunological treatments, or transplant recipients). However, there is growing evidence of long-term illness characterized by nervous system (CNS) complications, pulmonary, cardiac, and renal impairment, and neurological manifestations in patients with previous COVID-19 infection. There is no direct correlation between the severity of the initial COVID-19 infection and subsequent long-term sequelae. See Ali A Asadi-Pooya and Leila Simani, “Central nervous system manifestations of COVID-19: A systematic review,” J Neurol Sci, 2020 Jun 15;413:116832. doi:10.1016 / j.jns.2020.116832. Epub 2020 Apr 11. Many of these symptoms are associated with what is commonly known as “long COVID,” a condition characterized by long-term sequelae that emerge or persist after the typical recovery period.

[0022] Antipurinergic drugs constitute a family of compounds that antagonize purinergic receptors, which are among the most abundant receptors in living organisms. These receptors appeared early in evolution and are involved in regulating cellular function. There are three known distinct classes of purinergic receptors, known as P1, P2X, and P2Y receptors. Purinergic signaling is a form of extracellular signaling. This signaling is mediated by purine nucleotides and nucleosides, such as adenosine and adenosine triphosphate (ATP). This signaling involves activation of purinergic receptors within and / or nearby cells, thereby regulating cellular function. Purinergic receptors in the central nervous system play an important role in synaptic processes and mediate intercellular communication between neurons and glial cells in response to the release of adenosine triphosphate (ATP) or adenosine.

[0023] Chemical compounds that affect purinergic receptors are known. One of these, the compound suramin, was first synthesized in the early 1900s and has been found to have antipurinergic activity. Suramin is a drug used to treat trypanosomiasis, a parasitic disease caused by the protozoan Trypanosoma brucei, more commonly known as African sleeping sickness. This drug is also used to treat onchocerciasis, commonly known as river blindness. Because suramin has poor oral bioavailability, it is administered by intravenous injection. However, at doses required for the treatment of African sleeping sickness (trypanosomiasis), suramin causes several side effects. These side effects include nausea, vomiting, diarrhea, abdominal pain, and general discomfort. Other side effects include skin sensations such as formication or tingling, tenderness in the palms and soles of the feet, numbness in the extremities, watery eyes, rash, and photophobia. Furthermore, nephrotoxicity is common, as is peripheral neuropathy when the drug is administered at high doses. Regarding its pharmacokinetics, suramin is approximately 99–98% protein-bound in serum and has a half-life of 41–78 days, with an average of 50 days. Furthermore, suramin is not extensively metabolized and is eliminated by the kidney. Suramin is a large polyanionic naphthylurea compound with six negative charges at physiological pH. Due to these factors, suramin cannot readily diffuse across biological membranes and therefore cannot cross the blood-brain barrier or the blood-cerebrospinal fluid barrier. It is estimated that less than 1% of suramin crosses and enters the central nervous system. Therefore, for suramin to be used more effectively as a treatment for nervous system or central nervous system disorders, it would be desirable to minimize systemic levels of suramin by targeted delivery to brain tissue.

[0024] Recently, suramin has been reported to affect several multisystem abnormalities in mouse models of autism spectrum disorder. A small human trial was also conducted in boys diagnosed with autism spectrum disorder. See "Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model," Robert K. Naviaux, PLoS One. 2013;8(3):e57380, published online March 13, 2013. doi:10.1371 / journal.pone.0057380, PMCID: PMC3596371, PMID: 23516405. See also PCT Patent Application Publication No. WO2018 / 148580A1 to Vaughn et al., published August 16, 2018. See also Naviaux, R K et al., "Low-dose suramin in autism spectrum disorder: a small, phase I / II, randomized clinical trial," Annals of Clinical and Translational Neurology, 2017 May 26:4(7):491-505, available online December 16, 2017, and R K Naviaux, "Antipurinergic therapy for autism—An in-depth review," Mitochondrion 43, pp. 1-15 (2018). For example, suramin has only previously been studied in humans for neurodevelopmental conditions as a single dose of 20 mg / kg.

[0025] From the above, it is clear that the treatment of nervous system disorders remains challenging. Despite promising results from some early animal and human studies, it is recognized that much research remains needed to provide a safe and effective means of administering antipurinergic drugs such as suramin.

[0026] Based on limited data in the scientific literature, little guidance exists on how to select and administer these agents to achieve optimal therapeutic efficacy while minimizing undesirable side effects, whether for African sleeping sickness or neurological disorders such as autism. As can be seen from the data presented in the Examples herein, it has been discovered herein that the antipurinergic drug suramin can be administered at doses and frequencies not previously disclosed or contemplated, and that a dynamic, nonlinear correlation exists between drug efficacy and blood levels over time. In the present invention, antipurinergics can potentially be safely and effectively administered to achieve improvement in several behavioral deficits associated with the manifestations of CNS disorders such as ASD, FXS, FXTAS, ME / CFS, PTSD, TS, PD, and AS, as well as their long-term effects, including those associated with Lyme disease, COVID-19, and CNS disorders associated with other viruses (e.g., Epstein-Burkine herpesvirus 6 and 7, herpes simplex virus, cytomegalovirus, etc.). Compositions and methods for administering antipurinergics can provide improvements in behavioral measures of anxiety or anxiety-like behavior, willingness to explore the environment, social interaction, spatial learning and memory, irritability, agitation and / or crying, lethargy and / or social withdrawal, stereotypic behavior, hyperactivity and / or noncompliance, and restrictive and / or repetitive behavior. Furthermore, antipurinergics can potentially be safely and effectively administered according to pharmacokinetic and / or pharmacodynamic regimens to achieve appropriate levels of drug. Thus, the present invention has utility for treating CNS disorders such as neurodevelopmental conditions including, but not limited to, autism spectrum disorder, FXS, FXTAS, chronic fatigue syndrome (CFS), post-traumatic stress syndrome (PTSD), Tourette's syndrome (TS), Parkinson's disease (PD), Angelman syndrome (AS), and manifestations of CNS disorders associated with other viruses (e.g., Epstein-Burchandise virus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including their long-term effects. [Prior art documents] [Non-patent literature]

[0027] [Non-Patent Document 1] Naviaux, RK et al. Annals of Clinical and Translational Neurology (2017) 26:4(7):491~505 [Non-patent document 2] RKNaviaux, Mitochondrion (2018) 43, pp.1~15 Summary of the Invention [Means for solving the problem]

[0028] Summary of the Invention Compositions and methods are described for treating nervous system disorders in mammals, such as cognitive, social, or behavioral disorders, including neurodevelopmental disorders such as autism spectrum disorder, FXS, FXTAS, ME / CFS, PTSD, TS, Parkinson's disease, Angelman syndrome (AS), and manifestations of CNS disorders associated with Lyme disease, COVID-19, and other viruses (e.g., Epstein-Burk virus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including their long-term effects.

[0029] These compositions and methods involve administering an effective amount of an antipurinergic agent according to a pharmacokinetic and / or pharmacodynamic regimen, including a loading dosing regimen followed by a maintenance dosing regimen as needed. Each loading dose in the loading dosing regimen can contain about 3 mg / kg to about 30 mg / kg of the antipurinergic agent, administered as a single dose or as multiple doses, each administered at a frequency ranging from about once daily to about once every three months. Each maintenance dose in the maintenance dosing regimen can contain about 1 mg / kg to about 15 mg / kg of the antipurinergic agent, administered at a frequency ranging from about three times daily to about once every three months. These compositions and dosing regimens are particularly useful for maximizing therapeutic efficacy while minimizing potentially undesirable systemic side effects.

[0030] In some embodiments, the present invention provides a method of treating a nervous system disorder in a mammal in need thereof, comprising administering to said mammal a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, according to a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0031] In another aspect, the invention provides a method, wherein the multiple loading doses of (a)(ii) are administered at a frequency selected from the group consisting of once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose comprises about 3 mg / kg to about 30 mg / kg of the antipurinergic; and the multiple maintenance doses of (b) are administered at a frequency selected from the group consisting of three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose comprises about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0032] In another embodiment, the invention provides a method wherein the molar ratio of antipurinergic agent in each individual loading dose to antipurinergic agent in each maintenance dose is from about 1:1.25 to about 4:1.

[0033] In another embodiment, the invention provides a method wherein the percentage of antipurinergic agent in each individual loading dose is from about 125% to about 400% of the percentage of antipurinergic agent in each maintenance dose.

[0034] In another aspect, the invention provides a method further comprising a regimen in which the loading dose or doses of 3 mg / kg to about 30 mg / kg, defined as an initial loading dose or doses, are reduced to one or more lower intermediate loading doses prior to initiation of administration of the maintenance doses.

[0035] In another embodiment, the invention provides a method wherein the molar ratio of antipurinergic agent in each individual loading dose to antipurinergic agent in each maintenance dose is from about 1:1.05 to about 4:1.

[0036] In another embodiment, the invention provides a method wherein the percentage of antipurinergic agent in each individual loading dose is about 105% to about 400% of the percentage of antipurinergic agent in each maintenance dose.

[0037] In another aspect, the invention provides a method wherein an as-needed loading dosing regimen is administered until a Cmin plasma level of about 8 μg / ml to 24 μg / ml of the antipurinergic is achieved.

[0038] In another aspect, the invention provides a method wherein the maintenance dosing regimen is continued to maintain a Cmin plasma level of the antipurinergic agent of about 4 μg / ml to about 18 μg / ml.

[0039] In another aspect, the invention provides a method wherein an as-needed loading dosing regimen is administered until a Cmax plasma level of the antipurinergic of about 100 μg / ml to about 500 μg / ml, or about 150 μg / ml to about 450 μg / ml, or about 200 μg / ml to about 350 μg / ml is achieved.

[0040] In another aspect, the invention provides a method wherein the maintenance dosing regimen is continued to maintain a Cmax plasma level of the antipurinergic agent of about 50 μg / ml to about 300 μg / ml, or about 100 μg / ml to about 200 μg / ml, or about 125 μg / ml to about 175 μg / ml.

[0041] In another aspect, the invention provides a method wherein an as-needed loading dosing regimen is administered until an AUC for plasma levels of the antipurinergic of about 1500 to about 7000 μg*day / L, or about 1700 to about 6500 μg*day / L, or about 2000 to about 6000 μg*day / L is achieved.

[0042] In another aspect, the invention provides a method wherein the maintenance dosing regimen is continued until an AUC for plasma levels of the antipurinergic agent of about 700 to about 3000 μg*day / L, or about 900 to about 2000 μg*day / L, or about 1200 to about 1500 μg*day / L is achieved.

[0043] In another aspect, the invention provides a method wherein the mean plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen is about 20% to about 80% of the mean plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen.

[0044] In another aspect, the invention provides a method wherein the mean plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen is about 125% to about 400% of the mean plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen.

[0045] In another aspect, the invention provides a method wherein the C plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen is about 20% to about 80% of the C plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen.

[0046] In another aspect, the invention provides a method wherein the Cmin plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen is about 125% to about 400% of the Cmin plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen.

[0047] In another aspect, the invention provides a method wherein the Cmax plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen is about 20% to about 80% of the Cmax plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen.

[0048] In another aspect, the invention provides a method wherein the Cmax plasma level (concentration) of the antipurinergic agent achieved in the loading dosing regimen is about 125% to about 400% of the Cmax plasma level (concentration) of the antipurinergic agent achieved in the maintenance dosing regimen.

[0049] In another aspect, the invention provides a method wherein the AUC of the antipurinergic agent achieved in the maintenance dosing regimen is about 20% to about 80% of the AUC of the antipurinergic agent achieved in the loading dosing regimen.

[0050] In another aspect, the invention provides a method wherein the AUC of the antipurinergic agent achieved in the loading dosing regimen is about 125% to about 400% of the AUC of the antipurinergic agent achieved in the maintenance dosing regimen.

[0051] In another aspect, the invention provides a method wherein at least one of the PK parameters selected from the group consisting of a Cmin of about 8 μg / ml to about 24 μg / ml, a Cmax of about 100 μg / ml to about 500 μg / ml, or an AUC of about 1500 to about 7000 μg*day / L is achieved for an as-needed loading dose.

[0052] In another aspect, the invention provides a method wherein at least one of the PK parameters selected from the group consisting of a Cmin of about 4 μg / ml to about 18 μg / ml, a Cmax of about 50 μg / ml to about 300 μg / ml, or an AUC of about 700 to about 3000 μg*day / L is achieved for the maintenance dose.

[0053] In another aspect, the invention provides a method wherein the mammal is a human.

[0054] In another aspect, the present invention provides a pharmacokinetic method.

[0055] In another embodiment, the present invention provides a method for adjusting loading and maintenance doses according to efficacy and / or safety / tolerability endpoints using pharmacokinetic methods.

[0056] In another aspect, the present invention provides a method for treating a rheumatoid arthritis, wherein the efficacy endpoint is: a) anxiety or anxiety-like behavior, b) a willingness to explore the environment; c) social interaction; d) spatial learning and memory; e) learning and memory; f) irritability, agitation and / or crying; g) lethargy and / or withdrawal; h) stereotypic behavior; i) hyperactivity and / or noncompliance, and j) Restrictive and / or repetitive behaviors wherein the mammal is ameliorated of at least one impairment, symptom, or behavioral manifestation of a neurological disorder selected from the group consisting of:

[0057] In another aspect, the invention provides a method, wherein said efficacy endpoint is an improvement in said mammal of at least one impairment, symptom, or behavioral manifestation of said neurological disorder selected from the group consisting of difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0058] In another aspect, the present invention provides a pharmacodynamic method.

[0059] In another aspect, the invention provides a method for adjusting loading and maintenance doses according to efficacy and / or safety / tolerability endpoints using pharmacodynamic methods.

[0060] In another aspect, the present invention provides a method for treating a rheumatoid arthritis, wherein the efficacy endpoint is: a) anxiety or anxiety-like behavior, b) a willingness to explore the environment; c) social interaction; d) spatial learning and memory; e) learning and memory; f) irritability, agitation and / or crying; g) lethargy and / or withdrawal; h) stereotypic behavior; i) hyperactivity and / or noncompliance, and j) Restrictive and / or repetitive behaviors wherein the mammal is ameliorated of at least one impairment, symptom, or behavioral manifestation of a neurological disorder selected from the group consisting of:

[0061] In another aspect, the invention provides a method, wherein said efficacy endpoint is an improvement in said mammal of at least one impairment, symptom, or behavioral manifestation of said neurological disorder selected from the group consisting of difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0062] In another aspect, the invention provides a method wherein the nervous system disorder is selected from the group consisting of a nervous system disorder, a psychiatric disorder, or a neurological disorder.

[0063] In another aspect, the invention provides a method wherein the mammal is a human.

[0064] In another aspect, the present invention provides a method, wherein said nervous system, psychiatric or neurological disorder is selected from the group consisting of autism spectrum disorder (ASD), Fragile X syndrome (FXS), Fragile X-associated tremor / ataxia syndrome (FXTAS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), post-traumatic stress syndrome (PTSD), Tourette's syndrome (TS), Parkinson's disease (PD), Angelman syndrome (AS), nervous system and central nervous system (CNS) disorders associated with viral infections, including chronic Lyme disease and other nervous system disorders associated with tick-borne illnesses, and their long-term effects.

[0065] In another aspect, the invention provides a method wherein the disorder is selected from ASD, FXS, FXTAS, or ME / CFS.

[0066] In another aspect, the invention provides a method wherein the nervous system disorder is autism spectrum disorder (ASD).

[0067] In another aspect, the invention provides a method, wherein said autism spectrum disorder is selected from the group consisting of autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome.

[0068] In another aspect, the invention provides a method wherein the disorder is FXS.

[0069] In another aspect, the invention provides a method wherein the disorder is FXTAS.

[0070] In another aspect, the invention provides a method wherein the disorder is ME / CFS.

[0071] In another aspect, the invention provides a method wherein the disorder is PTSD.

[0072] In another aspect, the invention provides a method wherein the disorder is TS.

[0073] In another aspect, the invention provides a method wherein the disorder is PD.

[0074] In another aspect, the invention provides a method wherein the disorder is AS.

[0075] In another aspect, the invention provides a method wherein the disorder is a manifestation associated with Lyme disease.

[0076] In another aspect, the invention provides a method, wherein the disorder is a symptom associated with a virus selected from the group consisting of SARS-CoV-2 (COVID-19), Epstein-Burkine herpesvirus 6 and 7, herpes simplex virus, and cytomegalovirus, or a symptom associated with the long-term effects of a virus.

[0077] In another aspect, the invention provides a method wherein said autism spectrum disorder is manifested by one or more symptoms selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0078] In another aspect, the invention provides a pharmacokinetic and / or pharmacodynamic method used to adjust loading and maintenance doses, as needed, according to efficacy endpoints based on improvement in the human as assessed according to the Autism Behavior Checklist (ABC), the Autism Diagnostic Observation Schedule (ADOS), the Autism Treatment Evaluation Checklist (ATEC), the Childhood Autism Rating Scale (CARS), the Clinical Global Impression (CGI) scale, the Clinical Global Impression Severity (CGI-S) scale, the Clinical Global Impression Improvement (CGI-I) scale, or the Interpersonal Responsiveness Scale (SRS).

[0079] In another aspect, the invention provides a pharmacokinetic and / or pharmacodynamic method to be used to adjust loading and maintenance doses as needed according to efficacy endpoints based on improvement in the human as assessed according to the Autism Behavior Checklist (ABC).

[0080] In another aspect, the present invention provides a method, wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, pharmaceutically acceptable salts, esters, prodrugs, and solvates thereof, and combinations thereof.

[0081] In another aspect, the present invention provides a method, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

[0082] In another aspect, the present invention provides a method wherein the pharmaceutically acceptable salt is selected from alkali metal salts, alkaline earth metal salts, and ammonium salts.

[0083] In another aspect, the invention provides a method wherein the salt is a sodium salt.

[0084] In another aspect, the invention provides a method wherein the salt is a hexasodium salt.

[0085] In another embodiment, the present invention provides a method wherein the composition is administered nasally or intranasally (IN).

[0086] In another embodiment, the present invention provides a method wherein the composition is administered intravenously (IV).

[0087] In another aspect, the present invention provides a kit for treating a nervous system, psychiatric or neurological disorder in a mammal in need thereof, comprising: (a) a first component for administering the composition according to an on-demand loading dosing regimen; (b) a second component for administering the composition according to a subsequent maintenance dosing regimen; and or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, comprising an effective amount of an antipurinergic agent comprising:

[0088] In another aspect, the invention provides a kit further comprising labeling instructions for administering the composition.

[0089] In another aspect, the present invention provides a kit comprising: (a) the first component for the on-demand loading dosing regimen comprises: (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the second component for the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0090] In another aspect, the present invention provides a kit, wherein the multiple loading doses of (a)(ii) are administered at a frequency selected from the group consisting of once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose contains about 3 mg / kg to about 30 mg / kg of the antipurinergic; and the multiple maintenance doses of (b) are administered at a frequency selected from the group consisting of three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose contains about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0091] In another aspect, the present invention provides a method of inhibiting or modulating purinergic receptors in a mammal in need thereof, comprising administering to said mammal a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, in accordance with a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0092] In another aspect, the invention provides a method wherein said antipurinergic agent is a selective inhibitor, antagonist or modulator of said purinergic receptor.

[0093] In another aspect, the invention provides a method, wherein said purinergic receptor is selected from the group consisting of a P1 receptor, a P2X receptor and a P2Y receptor.

[0094] In another aspect, the invention provides a method wherein said purinergic receptor is a P1 receptor.

[0095] In another aspect, the present invention relates to a method for treating rheumatoid arthritis, wherein the P1 receptor is A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A19, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, 2A , A 2B and A3.

[0096] In another aspect, the invention provides a method wherein said purinergic receptor is a P2X receptor.

[0097] In another aspect, the present invention provides a method wherein said P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7.

[0098] In another aspect, the present invention provides a method, wherein said P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X3 and P2X7.

[0099] In another aspect, the present invention provides a method wherein said P2X receptor subtype is P2X3.

[0100] In another aspect, the present invention provides a method wherein said P2X receptor subtype is P2X7.

[0101] In another aspect, the invention provides a method wherein the purinergic receptor is a P2Y receptor.

[0102] In another aspect, the present invention provides a method for treating a pulmonary artery disease, wherein the P2Y receptor is P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 The present invention provides a method for detecting a P2Y receptor subtype selected from the group consisting of:

[0103] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (two times) selectivity for P2X receptors over P1 receptors or over P2Y receptors, or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about 100-fold (10-fold), or at least about 1000-fold (1000-fold), or at least about 10,000-fold (10,000-fold).

[0104] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2Y receptors over P1 receptors or over P2X receptors.

[0105] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2X or P2Y receptors over P1 receptors.

[0106] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X3 receptor subtype over P1 receptors or over PY receptors.

[0107] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X7 receptor subtype over P1 receptors or over PY receptors.

[0108] In another aspect, the present invention provides compositions useful for practicing the methods described herein.

[0109] In another aspect, the invention provides the use of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, in the manufacture of a medicament for practicing the methods described herein.

[0110] In another aspect, the present invention provides a kit for treating a nervous system, psychiatric or neurological disorder in a mammal in need thereof, comprising: (a) a first component for administering the composition according to an on-demand loading dosing regimen; (b) a second component for administering the composition according to a subsequent maintenance dosing regimen; and or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0111] In another aspect, the present invention provides a kit further comprising labeling instructions for administering the composition comprising an antipurinergic, wherein the antipurinergic is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0112] In another aspect, the present invention provides a kit comprising: (a) the first component for the on-demand loading dosing regimen comprises: (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the second component for the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic; The kit is provided wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0113] In another aspect, the invention provides a kit, wherein the multiple loading doses of (a)(ii) are each administered at a frequency selected from the group consisting of once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose comprises about 3 mg / kg to about 30 mg / kg of an antipurinergic; and the multiple maintenance doses of (b) are each administered three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, or once every three months, , three times a month, twice a month, once a month, once every two months, or once every three months, wherein each loading dose comprises about 1 mg / kg to about 15 mg / kg of an antipurinergic agent, wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0114] In another aspect, the present invention provides a kit for treating a nervous system, psychiatric or neurological disorder in a mammal in need thereof, comprising: (a) a first component for administering the composition according to an on-demand loading dosing regimen; (b) a second component for administering the composition according to a subsequent maintenance dosing regimen; and or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, The kit provides a method for treating a rheumatoid arthritis, the method comprising administering to a subject a rheumatoid arthritis, the antipurinergic agent being suramin.

[0115] In another aspect, the invention provides a kit further comprising labeling instructions for administering the composition comprising an antipurinergic agent, wherein the antipurinergic agent is suramin.

[0116] In another aspect, the present invention provides a kit comprising: (a) the first component for the on-demand loading dosing regimen comprises: (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the second component for the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic; The kit provides a method for treating a rheumatoid arthritis, the method comprising administering to a subject a rheumatoid arthritis, the antipurinergic agent being suramin.

[0117] In another aspect, the present invention provides a kit, wherein the multiple loading doses of (a)(ii) are each administered at a frequency selected from the group consisting of once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose comprises about 3 mg / kg to about 30 mg / kg of the antipurinergic; and the multiple maintenance doses of (b) are each administered at a frequency selected from the group consisting of three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, and each loading dose comprises about 1 mg / kg to about 15 mg / kg of the antipurinergic; The kit provides a method for treating a rheumatoid arthritis, the method comprising administering to a subject a rheumatoid arthritis, the antipurinergic agent being suramin.

[0118] In another aspect, the present invention provides a method of inhibiting or modulating purinergic receptors in a mammal in need thereof, comprising administering to said mammal a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, in accordance with a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about 3 times daily to about once every 3 months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of an antipurinergic; wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0119] In another aspect, the present invention provides a method wherein the antipurinergic agent is a selective inhibitor, antagonist, or modulator of the purinergic receptor, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0120] In another aspect, the present invention provides a method, wherein the purinergic receptor is selected from the group consisting of a P1 receptor, a P2X receptor, and a P2Y receptor, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0121] In another aspect, the present invention provides a method, wherein the purinergic receptor is a P1 receptor and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0122] In another aspect, the present invention relates to a method for treating rheumatoid arthritis, wherein the P1 receptor is A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A19, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, 2A , A 2B and A3, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0123] In another aspect, the present invention provides a method, wherein the purinergic receptor is a P2X receptor and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0124] In another aspect, the present invention provides a method, wherein the P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567 and KN-62, and combinations thereof.

[0125] In another aspect, the present invention provides a method, wherein the P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X3 and P2X7, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0126] In another aspect, the present invention provides a method, wherein the P2X receptor subtype is P2X3 and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0127] In another aspect, the present invention provides a method, wherein the P2X receptor subtype is P2X7 and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0128] In another aspect, the present invention provides a method, wherein the purinergic receptor is a P2Y receptor and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0129] In another aspect, the present invention provides a method for treating a pulmonary artery disease, wherein the P2Y receptor is P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0130] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2X receptors over P1 receptors or over P2Y receptors, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0131] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2Y receptors over P1 receptors or over P2X receptors, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0132] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2X or P2Y receptors over P1 receptors, and wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0133] In another aspect, the present invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X3 receptor subtype over P1 receptors or over PY receptors, and wherein the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0134] In another aspect, the present invention provides a method, wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X7 receptor subtype over P1 receptors or over PY receptors, and the antipurinergic agent is selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, and combinations thereof.

[0135] In another aspect, the present invention provides a method of inhibiting or modulating purinergic receptors in a mammal in need thereof, comprising administering to said mammal a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, in accordance with a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about 3 times daily to about once every 3 months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of an antipurinergic; wherein the antipurinergic is suramin.

[0136] In another aspect, the invention provides a method wherein said antipurinergic agent is a selective inhibitor, antagonist or modulator of said purinergic receptor, wherein said antipurinergic agent is suramin.

[0137] In another aspect, the invention provides a method wherein the purinergic receptor is selected from the group consisting of a P1 receptor, a P2X receptor and a P2Y receptor, and the antipurinergic agent is suramin.

[0138] In another aspect, the invention provides a method wherein the purinergic receptor is a P1 receptor and the antipurinergic agent is suramin.

[0139] In another aspect, the present invention relates to a method for treating rheumatoid arthritis, wherein the P1 receptor is A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A19, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, 2A , A 2B and A3, and the antipurinergic agent is suramin.

[0140] In another aspect, the invention provides a method wherein the purinergic receptor is a P2X receptor and the antipurinergic agent is suramin.

[0141] In another aspect, the present invention provides a method wherein the P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and the antipurinergic is suramin.

[0142] In another aspect, the present invention provides a method wherein the P2X receptor is selected from a P2X receptor subtype selected from the group consisting of P2X3 and P2X7, and the antipurinergic is suramin.

[0143] In another aspect, the invention provides a method wherein the P2X receptor subtype is P2X3 and the antipurinergic is suramin.

[0144] In another aspect, the invention provides a method wherein the P2X receptor subtype is P2X7 and the antipurinergic is suramin.

[0145] In another aspect, the invention provides a method wherein the purinergic receptor is a P2Y receptor and the antipurinergic agent is suramin.

[0146] In another aspect, the present invention provides a method for treating a pulmonary artery disease, wherein the P2Y receptor is P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 and the antipurinergic agent is suramin.

[0147] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2X receptors over P1 receptors or over P2Y receptors, and wherein the antipurinergic agent is suramin.

[0148] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2Y receptors over P1 receptors or over P2X receptors, and wherein the antipurinergic agent is suramin.

[0149] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for P2X or P2Y receptors over P1 receptors, and wherein the antipurinergic agent is suramin.

[0150] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X3 receptor subtype over P1 receptors or over PY receptors, and wherein the antipurinergic agent is suramin.

[0151] In another aspect, the invention provides a method wherein the antipurinergic agent has at least about two-fold (2-fold), or at least about five-fold (5-fold), or at least about ten-fold (10-fold), or at least about one hundred-fold (10-fold), or at least about one thousand-fold (1000-fold), or at least about ten,000-fold (10,000-fold) selectivity for the P2X7 receptor subtype over P1 receptors or over PY receptors, and wherein the antipurinergic agent is suramin.

[0152] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, for use in a method for treating a nervous system disorder in a mammal in need thereof, wherein said composition is administered according to a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic; and (b) the subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0153] These and other aspects of the present invention will become apparent from the disclosure herein. [Brief explanation of the drawings]

[0154] [Figure 1] Figure 1 shows the pre- and post-dose plasma concentrations of suramin in individual children after a 10 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route.

[0155] [Figure 2]Figure 2 shows the pre- and post-dose plasma concentrations of suramin in individual children after a 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route.

[0156] [Figure 3] Figure 3 shows the change in the pharmacokinetic parameter C (μg / mL) of suramin versus baseline Aberrant Behavior Checklist (ABC) score in individual children after a 10 or 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 4, 5, and 7) after intravenous administration. The solid line is the locally weighted (Loess) regression line representing the trend in C versus ABC score.

[0157] [Figure 4] Figure 4 shows the change in the pharmacokinetic parameter AUC (μg*day / mL) of suramin versus baseline Aberrant Behavior Checklist (ABC) score in individual children after a 10 or 20 mg / kg dose of suramin at days 1, 28, 56, and 96 (visits 4, 5, and 7) after intravenous administration. The solid line is a locally weighted (Loess) regression line representing the trend in AUC versus ABC score.

[0158] [Figure 5] Figure 5 shows the pharmacokinetic parameters of suramin in individual children after a 10 or 20 mg / kg dose of suramin, mean quartile Cmin (μg / mL) versus visit, at days 1, 28, 56, and 96 (visits 4, 5, and 7) after administration of the intravenous route.

[0159] [Figure 6] Figure 6 shows the pharmacokinetic parameters of suramin in individual children after a 10 or 20 mg / kg dose of suramin, mean quartile AUC (μg*day / mL) versus visit, on days 1, 28, 56, and 96 (visits 4, 5, and 7) after administration by the intravenous route.

[0160] [Figure 7]Figure 7 shows the pharmacokinetic parameters of suramin Tmax (days), Cmax (μg / mL) and AUC (μg*day / mL) versus age (years) in individual children after a 10 mg / kg dose of suramin on days 1, 28, 56 and 96 (visits 4, 5 and 7) after administration by the intravenous route.

[0161] [Figure 8] Figure 8 shows the pharmacokinetic parameters of suramin Tmax (days), Cmax (μg / mL) and AUC (μg*day / mL) versus body mass index (BMI) in individual children after a 10 mg / kg dose of suramin on days 1, 28, 56 and 96 (visits 4, 5 and 7) after administration by the intravenous route.

[0162] [Figure 9] Figure 9 shows the pharmacokinetic parameters of suramin Tmax (days), Cmax (μg / mL) and AUC (μg*day / mL) versus age (years) in individual children after a 20 mg / kg dose of suramin on days 1, 28, 56 and 96 (visits 4, 5 and 7) after administration by the intravenous route.

[0163] [Figure 10] Figure 10 shows the pharmacokinetic parameters of suramin Tmax (days), Cmax (μg / mL) and AUC (μg*day / mL) versus body mass index (BMI) in individual children after a 20 mg / kg dose of suramin on days 1, 28, 56 and 96 (visits 4, 5 and 7) after administration by the intravenous route.

[0164] [Figure 11] FIG. 11 shows the Aberrant Behavior Checklist core change from baseline by suramin blood concentration level quartiles.

[0165] [Figure 12] FIG. 12 shows the Aberrant Behavior Checklist total change from baseline by suramin blood concentration level quartiles.

[0166] [Figure 13]Figure 13 shows the Aberrant Behavior Checklist core change from baseline in patients with target blood levels of suramin (8-20 μg / mL at week 14).

[0167] [Figure 14] Figure 14 shows the total change in the Aberrant Behavior Checklist from baseline in patients with target blood concentration levels of suramin (8-20 μg / mL at week 14).

[0168] [Figure 15] FIG. 15 shows the total change (mean±SE) from baseline in the Aberrant Behavior Checklist by suramin blood level (BL). DETAILED DESCRIPTION OF THE INVENTION

[0169] definition As used herein, the following terms and abbreviations have the meanings indicated unless expressly stated to the contrary.

[0170] The term "ABC" as used herein refers to a rating scale for assessing autism known as the "Aberrant Behavior Checklist."

[0171] As used herein, the term "ADOS," also known as the "Autism Diagnostic Observation Schedule," is an instrument for diagnosing and assessing autism. The protocol consists of a series of structured and semi-structured tasks that involve social interaction between the examiner and the person being assessed.

[0172] As used herein, the term "ATEC," also known as the "Autism Treatment Evaluation Checklist," is a 77-item diagnostic assessment tool developed at the Autism Research Institute. The ATEC was originally designed to evaluate the effectiveness of autism treatments, but has also been used as a screening tool.

[0173] The term "AUC" as used herein, also known as "area under the curve," is a standard term in pharmacology, particularly pharmacokinetics. This term refers to the definite integral of the curve that describes the change in plasma drug concentration as a function of time. In practice, drug concentrations are measured at specific, discrete time points, and the trapezoidal rule is used to estimate the AUC. The AUC provides a measure of bioavailability and refers to the fraction of drug absorbed systemically. Knowing this, drug clearance can also be determined. The AUC reflects the actual body exposure to a drug after administration of a dose of the drug, usually expressed in mg. * h / L or μg * It is expressed in h / L (where "h" stands for time). Alternatively, AUC is expressed in mg * day / L or μg * It can be expressed in days / L. Note that the asterisk "*" in the units of AUC denotes multiplication; alternative notations use a dot "·" or a multiplication symbol "x." AUC can be determined or presented over a specified time range, such as 0 to time "t," or can be extrapolated to infinity, resulting in AUC 0-t and AUC 0-inf It is written as follows.

[0174] As used herein, the term "based on suramin active substance" is meant to provide a basis for determining or calculating the amount of suramin based on the molecular weight (i.e., molar mass) of suramin of 1297.26 grams / mole. This is an important consideration for determining the amount of suramin when it is delivered as a salt or other form with a different total molecular weight, such as the hexasodium salt, which has a molecular weight (i.e., molar mass) of 1429.15 grams / mole.

[0175] As used herein, the term "CARS" is a behavioral rating scale, also known as the "Childhood Autism Rating Scale," intended to aid in the diagnosis and assessment of autism.

[0176] As used herein, the term "CFS" is also known as "chronic fatigue syndrome."

[0177] As used herein, the term "CGI," also known as the "Clinical Global Impression" rating scale, is a measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of patients with psychological disorders. Additionally, aspects of the CGI rating scale are described as the "CGI-I" scale, which stands for clinical global impression improvement scale, and the "CGI-S" scale, which stands for clinical global impression severity scale.

[0178] As used herein, "C max The term "Cmin" is a standard term in pharmacology, particularly pharmacokinetics, to define the maximum (or peak) serum concentration a drug achieves in a particular compartment or test area of ​​the body after a drug is administered and before a second dose is administered. By comparison, Cmin is the minimum concentration of a drug in the blood after a given dose.

[0179] As used herein, the term "FXS" means Fragile X Syndrome.

[0180] As used herein, the term "FXTAS" means Fragile X-associated tremor / ataxia syndrome.

[0181] As used herein, the term "IN" means intranasal.

[0182] As used herein and described in more detail below, the term "loading dosing regimen" refers to a portion of the dosing regimen of the invention for delivering a loading dose of an antipurinergic. The loading dosing regimen may be on an as-needed basis. A loading dose is described in the pharmacokinetic literature as an initial, higher dose of a drug that may be given at the beginning of a course of treatment before being reduced to a lower maintenance dose.

[0183] As used herein, the term "long COVID" is also known as post-COVID-19 syndrome, acute sequelae of COVID-19, chronic COVID syndrome, and long-lasting COVID. As described in references, long COVID is a condition characterized by long-term sequelae that emerge or persist after the typical recovery period of coronavirus disease 2019. Long COVID can affect nearly every organ system, with sequelae including respiratory disorders, neurological and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia. A wide range of symptoms are commonly described, including fatigue, headache, shortness of breath, anosmia, parosmia, muscle weakness, low-grade fever, and cognitive impairment.

[0184] As used herein, the term "long-term" refers to the duration or onset of symptoms, or the appearance or persistence of neurological disorders associated with a disease or condition. For example, onset or symptoms may last from about 4 weeks to about 6 months, or in some cases even longer or chronically. Symptoms may not occur or appear for a period of time, and long-term is also intended to indicate that this period may be from about 4 weeks to about 6 months or longer from the onset of the underlying disease.

[0185] As used herein and described in more detail below, the term "maintenance dosing regimen" refers to the portion of the dosing regimen of the invention for delivering a maintenance dose of an antipurinergic agent. The maintenance dose is the amount of therapeutic agent administered to maintain a desired level of the agent in the blood.

[0186] As used herein, the term "ME" is also known as "myalgic encephalomyelitis."

[0187] As used herein, the term "ME / CFS" is also known as "myalgic encephalomyelitis / chronic fatigue syndrome."

[0188] As used herein, the term "nervous system disorder" includes the following non-limiting exemplary disease states, conditions, or disorders selected from the group consisting of autism spectrum disorder (ASD), fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), post-traumatic stress syndrome (PTSD), Tourette syndrome (TS), Parkinson's disease, Angelman syndrome (AS), and CNS disorders associated with COVID-19, including manifestations of nervous system and central nervous system (CNS) disorders often associated with Lyme disease and other tick-borne illnesses, as well as their long-term effects. The term "nervous system disorder" includes conditions involving the nervous system, such as conditions that cause neuroinflammation.

[0189] The term "pharmaceutically acceptable" is used herein with respect to the compositions, i.e., formulations, of the present invention, and with respect to pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of suramin and a pharmaceutically acceptable carrier. These carriers can include a wide variety of excipients. Pharmaceutically acceptable carriers are conventionally known carriers with an acceptable safety profile. The compositions are made using conventional formulation techniques. See, for example, Remington's Pharmaceutical Sciences, 17 th See, "Pharmaceutically Acceptable Salts," 17th edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Easton, PA, 17th edition, 1985. With regard to pharmaceutically acceptable salts, these are known and understood by those of ordinary skill in the art and are further described below.

[0190] As used herein, the term "pharmacodynamics" (PD) is used in its ordinary sense to refer to the pharmacodynamic aspects of drug delivery. By definition, pharmacodynamics (PD) is the study of how drugs affect living organisms, e.g., the effects of drugs on the biochemical processes of an organism.

[0191] As used herein, the term "pharmacokinetics" (PK) is used in its usual sense to refer to the pharmacokinetic aspects of drug delivery. By definition, pharmacokinetics (PK) is the study of how an organism affects a drug, for example, how and how quickly an organism metabolizes a drug. Pharmacokinetic parameters include Cmax, Cmin, Tmax, Tmin and AUC. Various ranges and ratios or combinations of these parameters can be used to adjust or optimize drug delivery.

[0192] As used herein, the term "PTSD" is also known as "post-traumatic stress disorder or syndrome."

[0193] As used herein, the term "SRS," also known as the "Social Responsiveness Scale," is a measure of autism spectrum disorder.

[0194] The term "subject" means a human patient or an animal in need of treatment or intervention for a nervous system disorder.

[0195] The term "therapeutically effective" refers to the amount of suramin required to provide a meaningful or demonstrable benefit, as understood by a physician, to a subject, such as a human patient, in need of treatment. Conditions targeted for treatment include, for example, autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome. For example, meaningful or demonstrable benefit can be assessed or quantified using various clinical parameters. Demonstration of benefit can include, but is not limited to, that provided by models, including in vitro models, in vivo models, and animal models. An example of such an in vitro model is the permeation of active drugs tested using cultured human airway tissue (EpiAirway AIR-100) to simulate permeation through the nasal mucosa.

[0196] As used herein, the term "Tmax" is a standard term in pharmacology, particularly pharmacokinetics, to define the maximum (or peak) serum concentration achieved by a drug in a specified compartment or test region of the body after the drug is administered and before the administration of a second dose. By comparison, "Tmin" is the time at which the minimum concentration is observed.

[0197] As used herein, the term "Tmin" is a standard term in pharmacology, particularly pharmacokinetics, to define the minimum (or trough) serum concentration that a drug achieves in a specified compartment or test region of the body after the drug is administered and before the administration of a second dose. By comparison, "Tmax" is the time at which the maximum concentration is observed.

[0198] As used herein, the term "TS" is also known as "Tourette's Syndrome."

[0199] Route of Administration: The U.S. Food and Drug Administration provides standards for a wide range of drug administration routes, or "routes of administration." For example, routes of administration include intravenous (IV), oral, transdermal, parenteral, buccal, intracerebral, intradermal, intraepidermal, intramuscular, intraperitoneal, intrathecal, IV, transdermal, rectal, respiratory (inhalation), and sublingual, among other "other" routes, as appropriate.

[0200] Standard routes of administration as described by the FDA, among others, are contemplated herein, as shown in Table 1 below (FDA Routes of Administration; retrieved from www.fda.gov; content as of November 14, 2017). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0201] The term "reducing" as used herein with respect to a dosing regimen means that the dose of an antipurinergic agent is gradually reduced from an initial loading dose in a loading dosing regimen to a final maintenance dose in a maintenance dosing regimen. This reduction or "reducing" constitutes a lower dose of the drug active than in the initial loading dose, but may include one or more intermediate loading doses at a higher level than in the maintenance doses. This "reducing" is in contrast to direct "reducing" dosing, in which there is a direct reduction to a maintenance dose after administration of one or more loading doses, with no intermediate doses present.

[0202] The terms "treat," "treating," or "treatment," as used herein, include alleviating, alleviating, or ameliorating a condition, such as autism and other nervous system disorders, prophylactically and / or therapeutically, or preventing or reducing the risk of developing a condition or showing symptoms of a condition, ameliorating or preventing the underlying cause of a symptom, inhibiting a condition, halting the onset of a condition, alleviating a condition, causing regression of a condition, or halting the symptoms of a condition.

[0203] In various embodiments, the methods of treatment using an antipurinergic or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, or a pharmaceutical composition of the invention also include use of an antipurinergic or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof in the manufacture of a medicament for the desired treatment, such as for a nervous system disorder.

[0204] Purinergic receptors Purinergic receptors (also referred to as "purinergic receptors") are a family of membrane receptors found in most mammalian tissues. There are three different known classes of purinergic receptors, known as P1, P2X, and P2Y receptors (also known as P1, P2X, and P2Y, respectively). Each of these receptor classes further comprises receptor subtypes, which are encoded by different genes. The P1 class is divided into the following subtypes: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79 ... 2A , A 2B and A3. The P2X class has the following subtypes: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7. The P2Y class has the following subtypes: P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 It has.

[0205] P2X and P2Y receptors are expressed in cells of the human central nervous system. P2X receptors are ATP-gated, nonselective cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. The P2X7 receptor subtype is a member of the P2X superfamily of purinergic receptors (P2X 1~7 P2X7 receptors are ligand-gated, nonselective cation channels that are members of the P2X7 subtype. The human P2X7 receptor was first cloned in 1997 and has since attracted considerable attention from numerous research groups in both academia and industry for its potential role in numerous neurological and neurodegenerative disorders. P2X7 receptors were first described on cells of hematopoietic origin (macrophages, microglia, and certain lymphocytes) and have also been found on cells of the nervous system, such as neurons, astrocytes, oligodendrocytes, and Schwann cells. Activation of the P2X7 receptor results in the upregulation of small cations (Na + , Ca 2+ and K. +) flux, release of the pro-inflammatory cytokines IL-1b and IL-18, and numerous downstream events. P2X7 receptors are activated by high concentrations of ATP, which are released in large amounts after cell injury. Pharmacological blockade of P2X7 receptors has been studied in animal models of neurological disorders, but their effects and significance remain largely unknown. Rachael Bartlett,Leanne Stokes and Ronald Sluyter.P2X7Antagonists in Models of Disease.Pharmacological Reviews July 1,2014,66(3)638-675;Sperlagh,B and Illes,P.The P2X7purinergic receptor:from physiology to neurological disorders.Trends in Pharmacological Sciences,October 2014,Vol 35,No 10; and Skaper, SD, Debetto, P., Giusti, P. The P2X7 purinergic receptor: from physiology to neurological disorders.FASEB J.24, 337-345 (2010).

[0206] It has now been found that the administration of antipurinergic agents which have an inhibitory, antagonistic or modulatory effect on one or more of these receptors can be useful in the treatment of nervous system disorders.

[0207] Antipurinergic drugs Purinergic signaling is an extracellular process mediated by purine nucleotides and nucleosides, such as adenosine and ATP. This process involves activation of purinergic receptors in cells and / or nearby cells, thereby regulating cellular function. The present invention is based on administering compounds with antipurinergic activity, such as antagonists, to treat or ameliorate symptoms and manifestations associated with nervous system disorders. Non-limiting examples of antipurinergic agents useful in the present invention include those selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, KN-62, and combinations thereof. Pharmaceutically acceptable salts, esters, prodrugs, solvates (including hydrates), and polymorphs are also considered within the scope of the present invention. In another embodiment, the antipurinergic agent can be administered in combination with other drugs, enhancers, adjuvants, penetration enhancers, etc.

[0208] Berberine In some embodiments, the present invention utilizes a therapeutically effective amount of berberine, which is believed to have potential antipurinergic activity. Berberine is a quaternary ammonium salt alkaloid compound derived from the protoberberine group of benzylisoquinoline alkaloids found in plants such as Berberis, e.g., Berberis vulgaris (barberry). This compound is typically isolated as a quaternary ammonium salt, as shown by the following structure: [ka]

[0209] Berberine corresponds to the CAS Registry Number 2086-83-1 and ChemSpider ID 2263. Berberine has the chemical formula C 20 H 18It is a yellow solid, corresponding to NO4, with a molar mass of 336.361 g / mol. Note that these molecular weight values ​​vary slightly depending on the atomic weight values ​​used in the calculation. One chemical name for berberine is benzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium, 5,6-dihydro-9,10-dimethoxy-.

[0210] Emodin In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic emodin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, to treat a nervous system disorder.

[0211] Emodin is a hydroxyanthraquinone that is an orange solid at room temperature found in rhubarb and buckthorn. Emodin corresponds to the CAS Registry Number 518-82-1 and ChemSpider ID 3107. The IUPAC name for emodin is 1,3,8-trihydroxy-6-methylanthracene-9,10-dione.

[0212] The chemical formula of emodin is C 15 H 10 O. Therefore, emodin has a molecular weight (i.e., molar mass) of 270.240 grams / mole. Note that these molecular weight values ​​will vary slightly depending on the atomic weight values ​​used in the calculation. The chemical structure of emodin is shown below. [ka]

[0213] Pharmaceutically acceptable salts, esters, solvates and prodrugs of emodin are useful in the methods and compositions of the present invention. As used herein, "pharmaceutically acceptable salts, esters, solvates and prodrugs" refers to derivatives of emodin.

[0214] Pharmaceutically acceptable salts, esters, solvates and prodrugs of emodin can be prepared from parent compounds by conventional chemical methods.Generally, salts can be prepared by reacting the compound with a stoichiometric amount of a suitable base in water or an organic solvent, or in a mixture of the two, and generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.Pharmaceutically acceptable esters of emodin can be prepared by reacting with carboxylic acid and removing water.For example, one or more of the three phenolic groups can be esterified to form, for example, an acetate group.

[0215] A solvate of emodin means that one or more solvent molecules are associated with one or more molecules of emodin, including fractional solvates such as 0.5 and 2.5 solvates. The solvent can be selected from a wide range of solvents, including water, ethanol, isopropanol, and the like. Depending on the prodrug selected, emodin prodrugs can be prepared using conventional chemical methods. A prodrug is a drug or compound that is metabolized (i.e., converted in the body) into a pharmacologically active drug after administration. A prodrug can be designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo when such a prodrug is administered. In some classifications, esters are considered prodrugs.

[0216] In some embodiments of the present invention, it has been found to be advantageous to co-administer emodin with piperine. Piperine is the alkaloid responsible for the pungency of black pepper and long pepper. Piperine has the IUPAC name (2E,4E)-5-(2H-1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one, corresponding to CAS Registry Number 94-62-2 and ChemSpider Number 553590. Piperine has the molecular formula C 17 H 19 NO3 and has a molar mass of 285.343 g / mol, corresponding to the chemical structure shown below. [ka]

[0217] In some embodiments, emodin and piperine are administered in a weight ratio of 1 to 1. Other weight ratios of emodin to piperine can range from about 100:1 to about 1:100, or from about 10:1 to about 1:10, or from about 1:5 to about 5:1, or from about 1:2 to about 2:1, or from about 1:1.5 to about 1.5:1.

[0218] Slammin' In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, to treat a nervous system disorder.

[0219] Suramin is a sulfonic acid pharmaceutical compound with CAS Registry Number 145-63-1 and ChemSpider ID 5168. One of its chemical names is 1,3,5-naphthalenetrisulfonic acid, 8,8'-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]]bis-. This compound is used to treat African sleeping sickness (trypanosomiasis) and river blindness (onchocerciasis) and is known under the trade names Antrypol, 309 F, 309 Fourneau, Bayer 205, Germanin, Moranyl, Naganin, and Naganine. However, this drug has not been approved by the U.S. FDA. It is administered intravenously.

[0220] The half-life of suramin is reported to range from approximately 41 to 78 days, with an average of 50 days. See Phillips, Margaret A.; Stanley, Jr., Samuel L. (2011) "Chapter 50: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections." In Brunton, Laurence L.; Chabner, Bruce A.; Knollmann, Bjorn Christian (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.), McGraw Hill, pp. 1437-1438.

[0221] The chemical formula of suramin is C 51 H 40 NO 23S6. Therefore, the molecular weight (i.e., molar mass) of suramin is 1297.26 grams / mole. Suramin is typically delivered as a sodium sulfonate salt, such as the hexasodium salt, which has a molecular weight (i.e., molar mass) of 1429.15 grams / mole. Note that these molecular weight values ​​will vary slightly depending on which atomic weight values ​​are used in the calculation. The chemical structure of suramin is shown below. [ka]

[0222] Pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin are useful in the methods and compositions of the present invention. As used herein, "pharmaceutically acceptable salts, esters, solvates, and prodrugs" refers to derivatives of suramin. Examples of pharmaceutically acceptable salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of alkali metal salts include lithium, sodium, and potassium salts. Examples of alkaline earth metal salts include calcium and magnesium salts. Ammonium salts, such as NH4 + In addition to the ammonium salts themselves, various mono-, di-, tri-, and tetra-alkyl ammonium salts can be prepared. One or more alkyl groups of such ammonium salts can also be further substituted with groups such as hydroxyl groups to provide ammonium salts of alkanolamines. Ammonium salts derived from diamines such as 1,2-diaminoethane are contemplated herein. The hexasodium salt of suramin is useful herein.

[0223] Pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin can be prepared from the parent compound by conventional chemical methods. Generally, salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base in water or an organic solvent, or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, and acetonitrile are generally preferred. Esters of suramin can be prepared by reacting the parent compound with an alcohol and removing the water formed from the reaction. Alternatively, other methods can be used. Anywhere from one to all six of the sulfonic acid groups of suramin can be esterified to form monoesters to hexaester sulfonates.

[0224] A solvate of suramin refers to one or more solvent molecules associated with one or more suramin molecules, including fractional solvates such as 0.5 solvates and 2.5 solvates. Solvents can be selected from a wide range of solvents, including water, ethanol, isopropanol, and the like. Prodrugs of suramin can be prepared using conventional chemical methods, depending on the prodrug selected. Prodrugs are drugs or compounds that are metabolized (i.e., converted in the body) after administration to become pharmacologically active drugs. Prodrugs can be designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo upon administration of such prodrugs. In some classifications, esters are considered prodrugs, such as the esters of suramin described herein. Other types of prodrugs may include sulfonamide derivatives and anhydrides.

[0225] Additionally, various esters and prodrugs can include further derivatization to create polyethylene glycol (PEG) and polypropylene glycol (PPG) derivatives and mixed derivatives, examples of which are PEGylated derivatives.

[0226] Tangeretin In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic agonist tangeretin, or a pharmaceutically acceptable solvate or prodrug thereof, to treat a nervous system disorder.

[0227] Tangeretin is an O-polymethoxylated flavone found in tangerine and other citrus peels and used as a dietary supplement. Tangeretin corresponds to CAS Registry Number 481-53-8 and ChemSpider ID 61389. The IUPAC name for tangeretin is 5,6,7,8-tetramethoxy-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one.

[0228] The chemical formula of tangeretin is C 20 H 20 O7. Therefore, A-804598 has a molecular weight (i.e., molar mass) of 372.37 grams / mole. Note that these molecular weight values ​​vary slightly depending on the atomic weight values ​​used in the calculation. The chemical structure of tangeretin is shown below. [ka]

[0229] Pharmaceutically acceptable solvates and prodrugs of tangeretin are useful in the methods and compositions of the invention. As used herein, "pharmaceutically acceptable solvates and prodrugs" refers to derivatives of tangeretin.

[0230] Pharmaceutically acceptable solvates and prodrugs of tangeretin can be prepared from the parent compound by conventional chemical methods. A solvate of tangeretin means that one or more solvent molecules are associated with one or more molecules of tangeretin, including fractional solvates such as 0.5 and 2.5 solvates. Solvents can be selected from a wide range of solvents, including water, ethanol, isopropanol, and the like. Prodrugs of tangeretin can be prepared using conventional chemical methods, depending on the prodrug selected. Prodrugs are drugs or compounds that are metabolized (i.e., converted in the body) into pharmacologically active drugs after administration. Prodrugs can be designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo when such prodrugs are administered. In some classifications, amides are considered prodrugs.

[0231] A-438079 In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic A-438079 (also known as "A438079" or "A 438079") or a pharmaceutically acceptable salt, solvate, or prodrug thereof to treat nervous system disorders. For example, the hydrochloride salt of A-438079 is particularly useful.

[0232] A-438079 is reported to have activity as a P2X7 receptor antagonist at both human and rat P2X7 receptors. The compound has the chemical formula C 13It corresponds to H9Cl2N5 and has a molar mass of 306.15 g / mol (the monohydrochloride salt has a molar mass of 342.6 g / mol). Note that these molecular weight values ​​vary slightly depending on the atomic weight values ​​used in the calculation. One chemical name for A-438079 is 3-[[5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl]methyl]-pyridine, monohydrochloride. The compound corresponds to CAS Registry Number 899431-18-6. This compound is also known to form a hydrate. The structure of the hydrochloride salt is shown below. [ka]

[0233] A-839977 In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic A-839977 (also known as "A839977" or "A4839977"), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to treat a nervous system disorder.

[0234] A-839977 has been reported to have activity as a P2X7 receptor antagonist. The compound has the chemical formula C 13 It corresponds to H9Cl2N5 and has a molar mass of 413.26 g / mol. Note that these molecular weight values ​​will vary slightly depending on the atomic weights used in the calculation. One of the chemical names for A-839977 is 1-(2,3-dichlorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine. The compound corresponds to CAS Registry Number 870061-27-1 and its chemical structure is shown below. [ka]

[0235] A-804598 In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic A-804598 (also known as "A804598" or "A804598"), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to treat a nervous system disorder.

[0236] A-804598 is a cyanoguanidine P2X7 inhibitor corresponding to CAS Registry Number 1125758-85-1 and ChemSpider ID 26377919. One of the chemical names for A-804598 is N-cyano-N"-[(1S)-1-phenylethyl]-N'-5-quinolinyl-guanidine. The compound is described as a central nervous system-penetrant, competitive and selective P2X7 receptor antagonist with IC50 of 9 nM, 10 nM and 11 nM for mouse, rat and human P2X7 receptors, respectively.

[0237] The chemical formula of A-804598 is C 19 H 17 N5. Therefore, A-804598 has a molecular weight (i.e., molar mass) of 315.372 grams / mole. Note that these molecular weight values ​​will vary slightly depending on the atomic weight values ​​used in the calculation. The chemical structure of A-804598 is shown below. [ka]

[0238] Pharmaceutically acceptable salts, amides, solvates and prodrugs of A-804598 are useful in the methods and compositions of the present invention. As used herein, "pharmaceutically acceptable salts, amides, solvates and prodrugs" refers to derivatives of A-804598. Examples of pharmaceutically acceptable salts include, but are not limited to, strong acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and hydrogen sulfate.

[0239] Pharmaceutically acceptable salts, amides, solvates and prodrugs of A-804598 can be prepared from the parent compound by conventional chemical methods.Salts can generally be prepared by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid in water or an organic solvent, or in a mixture of the two, and generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.Amides can be prepared by reacting the parent compound with a carboxylic acid.

[0240] A solvate of A-804598 means that one or more solvent molecules are associated with one or more molecules of A-804598, including fractional solvates such as 0.5 and 2.5 solvates. The solvent can be selected from a wide range of solvents, including water, ethanol, isopropanol, and the like. Prodrugs of A-804598 can be prepared using conventional chemical methods, depending on the prodrug selected. Prodrugs are drugs or compounds that are metabolized (i.e., converted in the body) into pharmacologically active drugs after administration. Prodrugs can be designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo when such prodrugs are administered. In some classifications, amides are considered prodrugs.

[0241] JNJ-47965567 In some embodiments, the present invention utilizes a therapeutically effective amount of the antipurinergic drug JNJ-47965567, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to treat nervous system disorders. The compound has been shown to suppress epileptic seizures in a mouse model of epilepsy.

[0242] JNJ-47965567 is a selective P2X7 antagonist corresponding to CAS Registry Number 1428327-31-4. One of the chemical names of JNJ-47965567 is 2-(phenylthio)-N-[[tetrahydro-4-(4-phenyl-1-piperazinyl)-2H-pyran-4-yl]methyl]-3-pyridinecarboxamide.

[0243] The chemical formula of JNJ-47965567 is C 28 H 32 The compound is N4O2S. The compound has a molecular weight (i.e., molar mass) of 488.64 grams / mole. Note that these molecular weight values ​​will vary slightly depending on the atomic weight values ​​used in the calculation. The chemical structure of JNJ-47965567 is shown below. [ka]

[0244] KN-62 In some embodiments, the present invention utilizes a therapeutically effective amount of antipurinergic agent KN-62 or its pharmaceutically acceptable salt, solvate or prodrug for treating nervous system disorders.KN-62 is a derivative of isoquinoline sulfonamide and is reported to inhibit P2X7 receptor.

[0245] KN-62 corresponds to the CAS registry number 127191-97-3 and ChemSpider ID 4471558. The IUPAC name for JNJ-47965567 is 4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl]phenylisoquinolinesulfonic acid ester.

[0246] The chemical formula for KN-62 is C 38 H 35 It is N5O6S2 and has a molecular weight (i.e., molar mass) of 721.84 grams / mole. Note that these molecular weight values ​​will vary slightly depending on the atomic weight values ​​used in the calculation. The chemical structure of KN-62 is shown below. [ka]

[0247] Medication regimen Based on limited data in the scientific literature, little guidance exists on how to select and administer these agents to achieve optimal therapeutic efficacy while minimizing unwanted side effects, whether for African sleeping sickness or neurological disorders such as autism. For example, suramin has only been studied in humans for neurodevelopmental conditions at a single dose of 20 mg / kg. See RK Naviaux, "Antipurinergic therapy for autism—An in-depth review," Mitochondrion 43, pp. 1–15 (2018), available online December 16, 2017. Based on the data and outcomes from these studies, it was surprising to discover that optimal clinical efficacy is achieved based on a dynamic and nonlinear correlation between clinical efficacy and blood levels. Given the linear correlation between clinical efficacy and blood levels observed after a single dose of suramin, the methods and compositions of the present invention would not have been anticipated.

[0248] As can be seen from the data presented in the present examples, the antipurinergic drug suramin was administered at doses and frequencies not previously disclosed or anticipated, leading to the discovery of a dynamic, non-linear correlation between drug efficacy and blood levels over time.

[0249] The present invention provides compositions and methods for treating nervous system disorders in mammals. These compositions and methods involve administering an effective amount of an antipurinergic agent according to a pharmacokinetic and / or pharmacodynamic dosing regimen. The dosing regimen includes an on-demand loading dose regimen followed by a maintenance dose regimen. Each loading dose in the loading dose regimen contains about 3 mg / kg to about 30 mg / kg of the antipurinergic agent and is administered as a single dose or as multiple doses, each administered at a frequency ranging from about once daily to about once every three months. Each maintenance dose in the maintenance dose regimen contains about 1 mg / kg to about 15 mg / kg of the antipurinergic agent and is administered at a frequency ranging from about three times daily to about once every three months. These compositions and dosing regimens are particularly useful for maximizing therapeutic efficacy while minimizing potentially undesirable systemic side effects.

[0250] Because many of the antipurinergic drugs to be delivered have relatively long half-lives and / or protein binding, and maximizing efficacy while minimizing systemic side effects is highly desirable, the present invention utilizes a dosing regimen that takes into account both pharmacokinetic and pharmacodynamic considerations. For example, suramin is approximately 99-98% protein bound in serum and has a half-life of 41-78 days, with an average of 50 days. The dosing regimen of the present invention includes a loading dosing regimen followed by a maintenance dosing regimen, which may be on demand.

[0251] Loading medication regimen Loading dosing regimens for delivery of antipurinergics can be on an as-needed basis. As noted above, a loading dose is described in the pharmacokinetic literature as an initial, higher dose of a drug that may be given at the beginning of a course of treatment before being reduced or tapered to a lower maintenance dose.

[0252] The optional loading dosing regimen can be selected from (i) delivery of a single loading dose administered once, or (ii) delivery of multiple loading doses, each administered at a frequency ranging from about once daily to about once every three months, with each loading dose containing about 3 mg / kg to about 30 mg / kg of an antipurinergic. In some embodiments, each loading dose can independently contain about 3 mg / kg to about 30 mg / kg of an antipurinergic. In some embodiments, each loading dose can contain the same or approximately the same amount of an antipurinergic, which can range from about 3 mg / kg to about 30 mg / kg of an antipurinergic.

[0253] In a further embodiment, the loading dosing regimen comprises multiple loading doses each administered at a frequency selected from the group consisting of once daily, four times weekly, three times weekly, twice weekly, weekly, three times monthly, twice monthly, monthly, every two months, or every three months, and each loading dose comprises from about 3 mg / kg to about 30 mg / kg of an antipurinergic.

[0254] Whether a loading dosing regimen is utilized, i.e., as needed, is within the skill and medical judgment of the prescribing medical professional based on the antipurinergic agent and the patient.

[0255] Other ranges for each dose in the loading dosing regimen can include about 5 mg / kg to about 25 mg / kg and about 10 mg / kg to about 20 mg / kg. Other ranges and non-integer values ​​of the antipurinergic can be selected.

[0256] These values ​​can be based on the active chemical agent of the antipurinergic to account for differences in salt and prodrug forms.

[0257] Maintenance medication regimen After administration of the antipurinergic agent according to an as-needed loading dosing regimen, the agent is then administered according to a maintenance dosing regimen. As noted above, the maintenance dose is the amount of therapeutic agent administered to maintain a desired level of the agent in the blood.

[0258] The maintenance dosing regimen is administered in multiple maintenance doses, each administered at a frequency ranging from about three times daily to about once every three months, with each maintenance dose comprising about 1 mg / kg to about 15 mg / kg of the antipurinergic.

[0259] In a further embodiment, the maintenance dosing regimen is selected such that multiple maintenance doses of antipurinergic are each administered at a frequency selected from the group consisting of three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, with each loading dose comprising from about 1 mg / kg to about 15 mg / kg of antipurinergic.

[0260] Selection of an appropriate maintenance dosing regimen is within the skill and medical judgment of the prescribing healthcare professional based on the antipurinergic agent and the patient.

[0261] Other ranges for each dose of the loading dosing regimen can include about 2 mg / kg to about 12 mg / kg and about 5 mg / kg to about 10 mg / kg. Other ranges and non-integer values ​​of the antipurinergic can be selected.

[0262] These values ​​can be based on the active chemical agent of the antipurinergic to account for molar mass differences of salt and prodrug forms.

[0263] composition Antipurinergic compositions may also be determined on a weight basis. In one embodiment, the compositions useful herein comprise from about 50% to about 99.99% by weight of an antipurinergic, or a pharmaceutical salt, ester, solvate, or prodrug thereof, based on the weight of the antipurinergic active agent. In another embodiment, the compositions herein comprise from about 1% to about 25% by weight of an antipurinergic, or a pharmaceutical salt, ester, solvate, or prodrug thereof, based on the weight of the antipurinergic active agent.

[0264] For compositions containing a specified amount or weight percentage of an antipurinergic, the purinergic is determined or calculated based on the actual amount of the antipurinergic moiety, on a molar mass basis, and does not include the additional weight provided by any counterion or ester, solvate, or prodrug moiety, if a salt, ester, solvate, or prodrug is used. In other words, the composition is based on the amount or weight percentage of the antipurinergic chemical moiety.

[0265] Methods of Treatment and Dosage Regimen The present invention utilizes a therapeutically effective amount of an antipurinergic agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for administering the antipurinergic agent to treat symptomatic manifestations of CNS disorders associated with Lyme disease, COVID-19, other viruses (e.g., Epstein-Burkine herpesvirus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including nervous system disorders such as autism spectrum disorder, FXS, FXTAS, ME / CFS, PTSD, TS, PD, AS, or their long-term effects.

[0266] The methods include, inter alia, the following routes of administration of an antipurinergic or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof to a human patient in need thereof, as appropriate: IV, oral, transdermal, parenteral, buccal, intracerebral, intradermal, intraepidermal, intramuscular, intraperitoneal, intrathecal, nasal, other, percutaneous, rectal, respiratory (inhalation), and sublingual.

[0267] A variety of dosage regimens may be prescribed in accordance with the present invention and used based on the skill and knowledge of the physician or other practitioner. The dosage and regimen may be appropriately modified based on the pharmacokinetic and pharmacodynamic parameters of the antipurinergic agent.

[0268] Treatment may be continued, at the discretion of the physician or practitioner, until the desired therapeutic benefit is achieved. In many cases, it is desirable to continue long-term or maintenance treatment.

[0269] Treatment evaluation The present invention provides methods for treating nervous system disorders such as autism spectrum disorder, FXS, FXTAS, CFS, PTSD, TS, PD, AS, for example, or long-term effects thereof, including those associated with Lyme disease or COVID-19 and other viruses (e.g., Epstein-Burchandise virus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), in which the symptom manifestations include one or more symptoms selected from difficulty communicating, difficulty interacting with others, disruptive and repetitive behaviors, motor tics, and vocal tics. In these disorders, patients may experience one or more symptoms or behavioral manifestations, or a) anxiety or anxiety-like behavior, b) a willingness to explore the environment; c) social interaction; d) spatial learning and memory; e) learning and memory; f) Irritability, agitation and / or crying; g) lethargy and / or social withdrawal; h) stereotypic behavior; i) hyperactivity and / or insubordination, or j) Restrictive and / or repetitive behaviors The study endpoint is often selected from the group consisting of:

[0270] Patients with symptomatic manifestations of CNS disorders associated with Lyme disease, COVID-19, other viruses (e.g., Epstein-Burkine herpesvirus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including autism spectrum disorder, FXS, FXTAS, CFS, PTSD, TS, PD, AS, or their long-term effects, can be evaluated using various rating scales to determine the level of severity of their disorder as well as any improvement or change upon administration of treatment.

[0271] For example, the present invention provides methods for treating symptomatic manifestations of CNS disorders associated with Lyme disease, COVID-19, other viruses (e.g., Epstein-Burkine herpesvirus 6 and 7, herpes simplex virus, cytomegalovirus, etc.), including autism spectrum disorder, FXS, FXTAS, CFS, PTSD, TS, PD, AS, or their long-term effects, comprising improving the patient's symptoms by a greater percentage compared to their pre-treatment symptoms. Improvement can be determined by comparing the patient's symptom assessment score to their symptom score before administration. Desirably, the treatment results in a 10% or greater improvement compared to the patient's score before administration of treatment.

[0272] Examples of rating scales for assessing autism spectrum disorders include those selected from the ABC, ADOS, ATEC, CARS CGI (CGI-S and CGI-I) and SRS.

[0273] The term "ABC" is a rating scale for assessing autism, known as the "Aberrant Behavior Checklist." On this scale, lower scores indicate greater improvement. The term "ADOS" is also known as the "Autism Diagnostic Observation Schedule." The protocol consists of a series of structured and semi-structured tasks involving social interactions between the examiner and the subject. The term "ATEC," also known as the "Autism Treatment Evaluation Scale," is a 77-item diagnostic assessment tool developed by the Autism Research Institute. The ATEC was originally designed to evaluate the effectiveness of autism treatments, but it is also used as a screening tool. The term "CARS," also known as the "Childhood Autism Rating Scale," is a behavioral rating scale intended to aid in the diagnosis and evaluation of autism. The term "CGI," also known as the "Clinical Global Impression" rating scale, is a measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of patients with psychological disorders. The term "SRS," also known as the "Interpersonal Responsiveness Scale," is used herein to measure autism spectrum disorders.

[0274] For example, the present invention provides methods in which a patient's ADOS score improves by 1.6 or more compared to the score before treatment administration, or the corresponding performance on a similar test improves. Further, the present invention provides methods in which the p-value of the improvement in ADOS score or similar test is 0.05 or less. In another embodiment, the present invention provides methods in which the size effect of the improvement in ADOS score or similar test is about 1 or more, or about 2.9 or more.

[0275] See Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985 Mar;89(5):485-91. PMID:3993694; and Kaat, AJ, Lecavalier, L. & Aman, MG. Validity of the Aberrant Behavior Checklist in Children with Autism Spectrum Disorder. J Autism Dev Disorder 44,1103-1116(2014).https: / / doi.org / 10.1007 / s10803-013-1970-0.

[0276] formulation In one aspect, a composition or formulation of the invention comprises an antipurinergic agent or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. These formulations can be prepared using standard formulation and mixing techniques well known to those skilled in the art of pharmaceuticals and formulations.

[0277] The antipurinergic agent may be selected from the group consisting of berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, pharmaceutically acceptable salts, esters, prodrugs, and solvates thereof, and combinations thereof.

[0278] Formulators will understand that excipients are used primarily to aid in the delivery of a safe, stable, functional pharmaceutical agent, serving not only as part of the overall vehicle for delivery, but also as a means for achieving effective absorption of the active ingredient by the recipient. Excipients may serve the same simple and straightforward role as inert fillers, or excipients used herein may be part of a pH stabilizing system or coating.

[0279] Pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared according to acceptable pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely interact with the active ingredient. Thus, a pharmaceutically acceptable carrier is one that is compatible with other ingredients in the formulation and is biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0280] The compounds of the present teachings can be administered intravenously, by injection, orally, parenterally, or via other routes of administration, neat or in combination with conventional pharmaceutical carriers. Suitable carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrants, or encapsulating materials. Oral formulations containing the compounds disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal tablet forms, troches, lozenges, and oral liquids, suspensions, or solutions. In powders, the carrier can be a finely divided solid that is mixed with the finely divided compound. In tablets, the compounds disclosed herein can be mixed with a carrier having the necessary compression properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets can contain up to 99% of the compound.

[0281] Capsules can contain a mixture of one or more compounds disclosed herein with an inert filler and / or diluent, such as pharmaceutically acceptable starch (e.g., corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flour, gelatin, gums, and the like.

[0282] Useful tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods using pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, gum acacia, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting point waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. Surface modifiers include nonionic and anionic surface modifiers.Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.The oral formulation herein can utilize standard delay or time-release formulations to alter the absorption of the compound.Oral formulations can also consist of administering the compound disclosed herein in water or fruit juice, optionally containing suitable solubilizers or emulsifiers.

[0283] Liquid carriers can be used in the preparation of solutions for oral or parenteral administration (e.g., intravenous, intramuscular, or other injection), including suspensions, emulsions, syrups, elixirs, and even for inhalation delivery. The compounds of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity adjusters, stabilizers, and osmolality adjusters. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives described herein, e.g., cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0284] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized, for example, by intramuscular, intraperitoneal, or subcutaneous injection. Sterile injections can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0285] The compounds described herein can be administered parenterally or intraperitoneally.The solution or suspension of these compounds or their pharmaceutically acceptable salts, hydrates or esters can be prepared in water, suitably mixed with surfactants such as hydroxyl-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol and their mixtures in oil.Under normal conditions of storage and use, these preparations typically contain preservatives to prevent the growth of microorganisms.

[0286] Pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.In some embodiments, this form can be sterile, and its viscosity allows it to flow through a syringe.This form is preferably stable under the conditions of manufacture and storage, and can be protected against the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

[0287] Pharmaceutical compositions can be in the form of unit dosage, for example, as vial, ampule, tablet, capsule, powder, liquid, suspension, emulsion, granule or suppository.In such form, pharmaceutical compositions can be subdivided into unit doses containing appropriate amounts of compound.Unit dosage form can be a packaged composition, for example, a packeted powder, vial, ampule, pre-filled syringe or a sachet containing liquid.Alternatively, unit dosage form can be a capsule or tablet itself, or any of these compositions in an appropriate number in a packaged form.Such dosage can be administered by any method that is useful for introducing compound into recipient's bloodstream, such as orally, via implant, parenterally (including intravenous, intraperitoneal and subcutaneous injection), rectally, vaginally and transdermally.

[0288] When administered for the treatment or inhibition of a specific disease state or disorder, it is understood that the effective dosage can vary depending on the specific compound used, the pharmaceutical composition formulated, the mode of administration, and the severity of the condition being treated, as well as various physical factors related to the individual being treated.In therapeutic applications, the compounds of the present teachings can be given to patients already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.The dosage used to treat a specific individual must typically be subjectively determined by the attending physician.Variables involved include the specific condition and its status, as well as the size, age and response pattern of the patient.

[0289] In some instances, it may be desirable to administer the compound directly to a patient's respiratory tract using devices such as, but not limited to, metered-dose inhalers, breath-actuated inhalers, multi-dose dry powder inhalers, pumps, squeeze-activated atomized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into liquid compositions, solid compositions, or aerosol compositions. Liquid compositions can illustratively contain one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered, for example, by a pump or squeeze-activated atomized spray dispenser. The solvent can be, for example, isotonic saline or bacteriostatic water. Solid compositions can illustratively be powder preparations containing one or more compounds of the present teachings mixed with lactose or other inert powders acceptable for intrabronchial use and can be administered, for example, by an aerosol dispenser or a device that breaks or punctures a capsule encapsulating the solid composition and delivers the solid composition for inhalation. The aerosol composition can illustratively include one or more compounds of the present teachings, a propellant, a surfactant, and a cosolvent, and can be administered, for example, by a metered-dose device. The propellant can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable propellant.

[0290] The compounds described herein can be administered transdermally, i.e., across the surface of the body and the inner linings of bodily passages, including epithelial and mucosal tissues. Such administration can be accomplished using compounds of the present teachings, including their pharmaceutically acceptable salts, hydrates, or esters, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0291] Transdermal administration can be achieved through the use of a transdermal patch containing a compound, such as the compounds disclosed herein, and a carrier that can be inert to the compound, non-toxic to the skin, and capable of delivering the compound through the skin into the bloodstream for systemic absorption.The carrier can take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices.Creams and ointments can be viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil.Pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.A variety of occlusive devices can be used to release the compound into the bloodstream, such as a semipermeable membrane covering a reservoir containing the compound, with or without a carrier, or a matrix containing the compound.Other occlusive devices are known in the literature.

[0292] The compound described herein can be administered rectally or vaginally in the form of conventional suppositories.Suppository preparations can be made from traditional materials, including cocoa butter and glycerin, with or without the addition of wax to change the melting point of suppository.Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0293] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0294] The pharmaceutical compositions herein may contain a permeation enhancer. Surprisingly, the following permeation enhancers have been found to increase transmucosal tissue penetration of suramin: methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol. The material methyl β-cyclodextrin (methyl-β-cyclodextrin) is also known by the CAS Registry Number 128446-36-6 and the trade name Methyl Betadex. The material caprylocaproyl macrogol-8 glyceride is also known by the CAS Registry Number 85536-07-8 and the trade name Labrasol® as caprylocaproyl polyoxyl-8 glyceride and PEG-8 caprylic / capric glyceride. The material 2-(2-ethoxyethoxy)ethanol is also known as diethylene glycol ethyl ether by the CAS Registry Number 111-90-0 and the trade names Carbitol™ and Transcutol® P. Permeation enhancers are generally used at about 40% by weight of the composition, with other useful ranges being from about 0.1% to about 90% by weight of the composition, or from about 1% to about 80% by weight of the composition, or from about 10% to about 75% by weight of the composition, or from about 25% to about 50% by weight of the composition.

[0295] The water in a composition is usually QS. The abbreviation QS stands for Quantum satis, meaning that you add just enough of an ingredient (in this case, water) to achieve the desired result, but no more.

[0296] Other ingredients may include various salts for osmolality control and viscosity increasing agents.

[0297] In one embodiment, the pharmaceutical composition is selected from a solution, suspension, or dispersion for administration as a spray or aerosol. In another embodiment, the formulation can be delivered as droplets using a dropper or applied directly to the nasal cavity. Other pharmaceutical compositions are selected from the group consisting of gels, ointments, lotions, emulsions, creams, foams, mousses, liquids, pastes, jellies, or tapes to be applied to the nasal cavity.

[0298] Useful herein are compositions in which the pharmaceutically acceptable carrier is selected from water or a mixture of water and other water-miscible ingredients. In the case of emulsions, the ingredients do not need to be miscible with water.

[0299] In other embodiments, the compositions can include a buffer to maintain the pH of the drug formulation, a pharmaceutically acceptable thickener, a humectant, and a surfactant. Buffers suitable for use in the present invention include, for example, hydrochloride, acetate, citrate, carbonate, and phosphate buffers.

[0300] The viscosity of the composition of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.Thickening agents that can be used according to the present invention include, for example, xanthan gum, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, sodium carboxymethylcellulose (Na CMC) and mixtures thereof.The concentration of the thickening agent depends on the selected agent and the desired viscosity.

[0301] Other suitable absorption enhancers known in the art may also be used in the present invention.

[0302] The compositions can also include absorption-enhancing components such as (i) surfactants; (ii) bile salts (including sodium taurocholate); (iii) phospholipid additives, mixed micelles, or liposomes; (iv) alcohols (including polyols, such as those discussed above, e.g., propylene glycol or polyethylene glycols such as PEG 3000); (v) enamines; (vi) nitric oxide donor compounds; (vii) long-chain amphiphilic molecules; (viii) small hydrophobic uptake enhancers; (ix) sodium or salicylic acid derivatives; (x) glycerol esters of acetoacetic acid; (xi) cyclodextrins or cyclodextrin derivatives; (xii) medium- or short-chain (e.g., C1-C12) fatty acids; and (xiii) chelating agents; (xiv) amino acids or salts thereof; and (xv) N-acetylamino acids or salts thereof. Solubility enhancers can increase the concentration of the drug or its pharmaceutically acceptable salt in the formulation. Useful solubility enhancers include, for example, alcohols and polyalcohols.

[0303] Tonicity agents can improve the tolerability of formulations in certain cases. A common tonicity agent is NaCl. Preferably, when the formulation is an isotonic intranasal dosage formulation, it contains about 0.9% NaCl (v / v) in the aqueous portion of the liquid carrier.

[0304] The thickener can improve the overall viscosity of the composition, preferably to a value close to that of the nasal mucosa. Suitable thickeners include methylcellulose, carboxymethylcellulose, polyvinypyrrolidone, sodium alginate, hydroxypropylmethylcellulose, and chitosan.

[0305] In the case of topical compositions, humectants or anti-irritants can improve the tolerability of the composition upon repeated application. Suitable compounds include, for example, glycerol, tocopherol, mineral oil, and chitosan.

[0306] Various additional ingredients can be used in the compositions of the present invention. The compositions can include one or more additional ingredients selected from preservatives, antioxidants, emulsifiers, surfactants or humectants, emollients, film-forming agents, or viscosity adjusters. These ingredients can be used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. These amounts can range from less than 1 weight percent to up to 90 weight percent, or even more than 99 weight percent.

[0307] In one embodiment, a preservative can be included. In another embodiment, an antioxidant can be included. In another embodiment, an emulsifier can be included. In another embodiment, an emollient can be included. In another embodiment, a viscosity modifier can be included. In another embodiment, a surfactant or humectant can be included. In another embodiment, a film-forming agent can be included. In another embodiment, the pharmaceutical composition is in a form selected from the group consisting of a gel, an ointment, a lotion, an emulsion, a cream, a liquid, a spray, a suspension, a jelly, a foam, a mousse, a paste, a tape, a dispersion, and an aerosol. These ingredients can be employed and used in concentrations appropriate for the formulation based on the knowledge of one skilled in the art of pharmaceuticals and formulations.

[0308] In another embodiment, at least one preservative may be incorporated, and may be selected from the group consisting of parabens (including butylparaben, ethylparaben, methylparaben, and propylparaben), acetone sodium bisulfite, alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, calcium acetate, calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, edetic acid, glycerin, hexetidine, imidurea, isopropyl alcohol, monothioglycerol The preservatives may be selected from the group consisting of pentetic acid, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propyl gallate, propylene glycol, sodium propylparaben, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfur dioxide, thimerosal, zinc oxide, and N-acetylcysteine, any other preservative known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amounts may range from less than 1 weight percent to 30 weight percent.

[0309] In another embodiment, the at least one antioxidant can be selected from the group consisting of acetone sodium bisulfite, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, dodecyl gallate, erythorbic acid, fumaric acid, malic acid, mannitol, sorbitol, monothioglycerol, octyl gallate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, and N-acetylcysteine, any other antioxidant known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation arts. The amounts can range from less than 1 weight percent to 30 weight percent.

[0310] In another embodiment, the at least one emulsifier is selected from the group consisting of acacia, agar, ammonium alginate, calcium alginate, carbomer, sodium carboxymethylcellulose, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, glyceryl monooleate, glyceryl monostearate, hectorite, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, lanolin, lanolin alcohol, lauric acid, lecithin, linoleic acid, magnesium oxide, medium chain triglycerides, methylcellulose, mineral oil, monoethanolamine, myristic acid, octyldodecanol, oleic acid, oleyl alcohol, palm oil, palmitic acid, pectin, phospholipids, poloxamer, polycarbophil, polyoxyethylene alkyl ether, polyoxyethylene castor The following may be selected from the group consisting of oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxyglycerides, potassium alginate, propylene glycol alginate, propylene glycol dilaurate, propylene glycol monolaurate, saponite, sodium borate, sodium citrate dihydrate, sodium lactate, sodium lauryl sulfate, sodium stearate, sorbitan esters, starch, stearic acid, sucrose stearate, tragacanth, triethanolamine, tromethamine, vitamin E polyethylene glycol succinate, wax, and xanthan gum, any other emulsifier known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amount of these ingredients can range from less than 1 weight percent to 30 weight percent.

[0311] In another embodiment, the at least one emollient is selected from the group consisting of almond oil, aluminum monostearate, butyl stearate, canola oil, castor oil, cetostearyl alcohol, cetyl alcohol, cetyl palmitate, cholesterol, coconut oil, cyclomethicone, decyl oleate, diethyl sebacate, dimethicone, ethylene glycol stearate, glycerin, glyceryl monooleate, glyceryl monostearate, isopropyl isostearate, isopropyl myristate, palmitic acid Can be selected from the group consisting of isopropyl alcohol, lanolin, lanolin alcohol, lecithin, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, palm kernel oil, palm oil, petrolatum, polyoxyethylene sorbitan fatty acid ester, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, squalene, sunflower oil, tricaprylin, triolein, wax, xylitol, zinc acetate, any other emollient known in the art, or combinations thereof.These ingredients can be employed and used in formulations at appropriate concentrations based on the knowledge of those skilled in the art of pharmaceuticals and formulations.These amounts can range from less than 1 weight percent to 60 weight percent.

[0312] In another embodiment, the at least one viscosity modifier is selected from the group consisting of acacia, agar, alginic acid, aluminum monostearate, ammonium alginate, attapulgite, bentonite, calcium alginate, calcium lactate, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, ceratonia, ceresin, cetostearyl alcohol, cetyl palmitate, chitosan, colloidal silicon dioxide, corn syrup solids, cyclomethicone, ethylcellulose, gelatin, glyceryl behenate, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose. The composition may be selected from the group consisting of cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, myristyl alcohol, octyldodecanol, palm oil, pectin, polycarbophil, polydextrose, polyethylene oxide, polyoxyethylene alkyl ether, polyvinyl alcohol, potassium alginate, propylene glycol alginate, pullulan, saponite, sodium alginate, starch, sucrose, sugar, sulfobutyl ether beta-cyclodextrin, tragacanth, trehalose, and xanthan gum, any other viscosity modifier known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amount can range from less than 1 weight percent to 60 weight percent.

[0313] In another embodiment, the at least one film-forming agent can be selected from the group consisting of ammonium alginate, chitosan, colophony, copovidone, ethylene glycol and vinyl alcohol graft copolymer, gelatin, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyvinyl acetate dispersion, polyvinyl acetate phthalate, polyvinyl alcohol, povidone, pullulan, pyroxylin, and shellac, any other film-forming agent known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation arts. These amounts can range from less than 1 weight percent up to about 90 weight percent, or even more than 99 weight percent.

[0314] In another embodiment, the at least one surfactant or wetting agent can be selected from the group consisting of docusate sodium, phospholipids, sodium lauryl sulfate, benzalkonium chloride, cetrimide, cetylpyridinium chloride, alpha-tocopherol, glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxyglycerides, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan ester, sucrose stearate, tricaprylin, and vitamin E polyethylene glycol succinate, any other surfactant or wetting agent known in the art, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amount can range from less than 1 weight percent to 30 weight percent.

[0315] In another embodiment, a buffering agent can be included. In another embodiment, an emollient can be included. In another embodiment, an emulsifier can be included. In another embodiment, an emulsion stabilizer can be included. In another embodiment, a gelling agent can be included. In another embodiment, a humectant can be included. In another embodiment, an ointment base or oily vehicle can be included. In another embodiment, a suspending agent can be included. In another embodiment, an acidulant can be included. In another embodiment, an alkalizing agent can be included. In another embodiment, a bioadhesive material can be included. In another embodiment, a coloring agent can be included. In another embodiment, a microencapsulating agent can be included. In another embodiment, a hardening agent can be included. These ingredients can be employed and used in the formulation at concentrations appropriate to the formulation based on the knowledge of those skilled in the pharmaceutical and formulation arts. These amounts can range from less than 1 weight percent up to 90 weight percent, or even more than 99 weight percent.

[0316] Those skilled in the pharmaceutical and formulation arts can determine appropriate concentrations of the essential and optional components of the compositions of the present invention.

[0317] These formulations may be prepared using standard formulation and compounding techniques well known to those skilled in the pharmaceutical and formulation arts.

[0318] Methods for preparing antipurinergic agents are also contemplated as part of the present invention and will be apparent to those skilled in the pharmaceutical and formulation arts using standard formulation and compounding techniques. [Example]

[0319] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given for illustrative purposes only and are not to be construed as limitations of the invention, since many variations thereof are possible without departing from the spirit and scope of the invention.

[0320] Example 1: Composition for intravenous administration The following compositions are prepared using standard reconstitution techniques. [Table 8]

[0321] The lyophilized antipurinergic agent is diluted with sterile water for injection to provide the desired aqueous solution for intravenous administration.

[0322] These compositions are useful for treating nervous system disorders.

[0323] *An example of such a composition is the commercially available Germanin® available from Bayer, which contains 1 g of lyophilized suramin per bottle for dilution with water.

[0324] Example 2: Oral administration composition The following compositions are prepared using standard mixing equipment and procedures. [Table 9] *Polyethoxylated castor oil, also known as Kolliphor EL.

[0325] The ingredients and water are combined with mixing to form a homogeneous solution, which can be packaged for oral administration.

[0326] These compositions are useful for treating nervous system disorders.

[0327] Example 3: Composition for intranasal delivery The following compositions are prepared using standard mixing equipment and procedures. [Table 10]

[0328] Dissolve the antipurinergic in the water with gentle mixing. Add the cyclodextrin with mixing until dissolved. Let the resulting solution stand for 2 hours before use.

[0329] The composition can be packaged in a spray bottle for intranasal administration.

[0330] Alternatively, compositions are prepared by replacing methyl β-cyclodextrin with an equal weight of caprylocaproyl macrogol-8 glyceride or 2-(2-ethoxyethoxy)ethanol.

[0331] These compositions are useful for treating nervous system disorders.

[0332] Example 4 A three-arm, prospective, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of two doses of suramin compared with placebo in boys with autism spectrum disorder (ASD) receiving standard treatment Results from this study demonstrate a dynamic, nonlinear correlation between antipurinergic blood levels and efficacy, as determined from assessments of ASD using the Aberrant Behavior Checklist (ABC) and suramin blood levels. See, for example, Figures 11-15. These results would not have been predicted based on the linearity of the dose-response previously disclosed.

[0333] summary Bioanalytical data for this pharmacokinetic analysis were obtained from a three-arm, prospective, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of two doses of suramin compared with placebo in boys with autism spectrum disorder (ASD) receiving standard treatment.

[0334] Approximately 52 study participants were enrolled and randomized to receive either 10 mg / kg suramin (Arm A), 20 mg / kg suramin (Arm B), or placebo (Arm C) in a targeted 1:1:1 ratio according to the randomization schedule, matched for age, ADOS (Autism Diagnostic Observation Scale), and NVIQ (Non-verbal IQ) across arms. This is the first time that multiple doses have been studied in patients with neurodevelopmental disorders and observed over an extended period of time. Previously, only a single 20 mg / kg dose had been described in ASD research. See RK Naviaux, "Antipurinergic therapy for autism—An in-depth review," Mitochondrion 43, pp. 1–15 (2018), available online December 16, 2017.

[0335] Each study participant had a total of seven visits: screening period (Visit 1, 14 days), randomization visit (Visit 2, Day 1), treatment follow-up visit (Visit 3, Day 14), treatment visit (Visit 4, Day 28), treatment visit (Visit 5, Day 56), end-of-treatment visit (Visit 6, Day 77), and EOS (Visit 7, Day 98). The window period for screening through Visit 2 was ±14 days (thus, study procedures could be performed over a 14-day period) and ±2 days for Visits 2 and beyond (thus, procedures could be performed over a 5-day period) (Visits 2–7). Table 2 below outlines the visit schedule. [Table 2]

[0336] Plasma samples were collected for suramin pharmacokinetic (PK) analysis at Visits 2, 4, 5, immediately before infusion, 1 hour after infusion, and Visit 7. Suramin concentrations were measured by high-performance liquid chromatography coupled to a tandem mass spectrometer with a lower limit of quantitation (LLoQ) of 1 μg / mL.

[0337] A summary of the mean pharmacokinetic parameters is summarized in Tables 3A-3D.

[0338] Study design and sample collection The study design consisted of three parallel treatment arms, i.e., three double-blind treatment groups randomized in a 1:1:1 ratio to receive either 10 mg / kg suramin (arm A) or 20 mg / kg suramin (arm B) or placebo (arm C).

[0339] See study design in Table 4.

[0340] Pharmacokinetic parameters PK parameters were estimated with Watson LIMS software (version 7.5) using a non-compartmental pharmacokinetic (PK) approach consistent with an intravenous route of administration. All parameters were generated from individual suramin concentrations in plasma obtained from children at Visits 1, 4, 5, and 7. All concentration values ​​were expressed in μg / mL, and all time points were expressed as days provided by the bioanalytical testing facility. Nominal dose concentrations and sample collection times were used. Plasma concentration-time area under the curve (AUC) estimates were calculated for profiles with at least quantifiable post-dose and pre-dose values ​​before the next dosing opportunity. The maximum observed plasma concentration (C max ) and C max Time (T max ) was determined directly from the data. C was determined by dividing the pharmacokinetic parameters by the corresponding values ​​in the low dose group and comparing with the corresponding fold change in dose. max and AUC 0~96日 The dose proportionality ratio for

[0341] Pharmacokinetic sample concentrations Control dose: After administration by the intravenous route, pre- and post-dose plasma concentrations were measured in individual children after a 0 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7). All measurements for this control were below the limit of quantitation (<1 μg / mL).

[0342] All samples collected from the control group had reported concentrations below the lowest level of quantitation (BLQ). For the other groups, all samples collected at time 0 at the start of the study were below the lowest level of quantitation. The other time points had quantifiable concentrations for all samples submitted.

[0343] Table 5 shows pre- and post-dose plasma concentrations in individual children after a 10 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route.

[0344] Table 6 shows the pre- and post-dose plasma concentrations in individual children after a 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route.

[0345] A general agreement was observed between dose level and measured plasma concentrations. See Figures 1 and 2. These figures show that as dose levels increased, higher plasma concentrations were measured.

[0346] Pharmacokinetic analysis Pharmacokinetic parameters were estimated using a non-compartmental approach consistent with the intravenous infusion route of administration, using individual suramin concentrations in plasma and nominal times.

[0347] See Table 7.

[0348] For area under the curve (AUC) estimation, post-dose and pre-dose measured plasma concentrations were required before the next dosing event. For this study, samples for pharmacokinetic analysis were collected on days 1, 28, 56, and 96.

[0349] Whenever possible, standard deviations and coefficients of variation were determined by Watson LIMS software. For analyses not supported by Watson (i.e., custom comparisons), Excel was used, and statistics determined by the Excel algorithm were reported. Note that in all cases, standard deviations and coefficients of variation could not be calculated if there were fewer than three data points.

[0350] Mean pharmacokinetic parameters Pharmacokinetic parameters for the two dose levels, 10 and 20 mg / kg, are summarized in Tables 3A-3D. Route of administration was intravenous infusion over 30 minutes at Visits 2, 4, and 5.

[0351] T max had a median of 28 days and ranged from 1 to 56 days for both the 10 and 20 mg / kg dose groups, occurring 1 hour after injection on those days.

[0352] Suramin C max and AUC 0~96 Systemic exposure, as assessed by C, increased with increasing dose levels of 10 and 20 mg / kg. max The increase in AUC was less than dose-proportional over the dose range of 10 mg / kg to 20 mg / kg. 0~96日 The values ​​were proportional to the dose.

[0353] The mean values ​​are shown in Tables 3A to 3D.

[0354] C max The maximum plasma concentration assessed by AUC was shown to be less than dose-proportional. 0~96 Systemic exposure, as assessed by , was shown to be approximately dose proportional. Because only pre-dose, 1 hour post-dose, and pre-dose samples were collected, the exact distribution and elimination curves could not be determined, and therefore the AUC 0~∞ and T 1 / 2Extrapolated parameters such as α, β, and β could not be determined. Note that the 10 mg dose group did not show significant accumulation, which may be due to a half-life shorter than 28 days at this low dose level. The fact that the 20 mg dose group showed accumulation implies that at higher dose levels, the half-life exceeds 28 days, likely due to limited renal clearance. The data also showed that adverse effects such as visible rash or vomiting in suramin-treated patients occurred primarily in the 20 mg / kg dose group, with only one event occurring in the lower 10 mg / kg group. The minimum observed AUC in the 20 mg / kg dose group was higher than the maximum AUC value in the 10 mg / kg dose group. T max , C max and AUC were observed to have weak or no correlation with age and body mass index (BMI). Suramin accumulation was also observed in the high-dose group of 20 mg / kg. Greater changes in ABC scores from baseline were observed at lower exposures. Table 3A-3D: Summary of mean pharmacokinetic parameters of suramin in children after a 10 or 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 4, 5, and 7) after intravenous route administration [Table 3A] [Table 3B] [Table 3C] [Table 3D] Table 4: Pharmacokinetic subset experimental study design and sample collection [Table 4] a PK samples were collected immediately before and 1 hour after infusion. Table 5: Pre- and post-dose plasma concentrations in individual children after a 10 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route [Table 5] Table 6: Pre- and post-dose plasma concentrations in individual children after a 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 2, 4, 5, and 7) after administration by the intravenous route [Table 6] Table 7. Mean pharmacokinetic parameters (and standard deviation, SD) in children after a 10 mg or 20 mg / kg dose of suramin on days 1, 28, 56, and 96 (visits 4, 5, and 7) after administration by the intravenous route. [Table 7]

[0355] Incorporation by Reference The complete disclosure of each patent document, including certificates of amendment, patent application documents, scientific articles, government reports, websites, and other references referred to herein, is incorporated herein in its entirety for all purposes. In the event of a conflict in terminology, the present specification will control.

[0356] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are to be considered in all respects illustrative rather than limiting of the invention described herein. In various embodiments of the methods and compositions of the present invention, when the term "comprising" is used in reference to recited method steps or composition components, it is also contemplated that the method and composition consist essentially of or consist of the recited steps or components. Furthermore, the order of steps or the order for performing particular actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0357] In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification will prevail.

[0358] Additionally, it should be recognized that, because certain components may further react or be converted into additional materials upon mixing, in certain instances the composition may be described as consisting of the components prior to mixing.

[0359] All percentages and ratios used herein are by weight unless otherwise specified. While the mass of an object is often referred to as its weight in everyday usage, and most frequently for scientific purposes, it is recognized that mass technically refers to the amount of matter in an object, while weight refers to the force an object experiences due to gravity. Also, in common usage, the "weight" (mass) of an object is determined when the object is "weighed" (massed) on a scale or balance.

Claims

1. 1. A pharmaceutical composition for use in a method of treating a nervous system disorder in a mammal in need thereof, comprising an effective amount of an antipurinergic agent or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein said pharmaceutical composition is administered according to a dosing regimen comprising (a) an as-needed loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the on-demand loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of the antipurinergic; and (b) said subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of said antipurinergic.

2. 2. The pharmaceutical composition of claim 1, wherein the multiple loading doses in (a)(ii) are administered at a frequency selected from once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, each loading dose comprising about 3 mg / kg to about 30 mg / kg of the antipurinergic; and the multiple maintenance doses in (b) are administered at a frequency selected from the group consisting of three times daily, twice daily, once daily, four times weekly, three times weekly, twice weekly, once weekly, three times monthly, twice monthly, once monthly, once every two months, or once every three months, each loading dose comprising about 1 mg / kg to about 15 mg / kg of the antipurinergic.

3. 10. The pharmaceutical composition of claim 1, wherein the molar ratio of said antipurinergic agent in each individual loading dose to said antipurinergic agent in each maintenance dose is from about 1:1.25 to about 4:

1.

4. 10. The pharmaceutical composition of claim 1, further comprising a regimen in which one or more loading doses of 3 mg / kg to about 30 mg / kg, defined as one or more initial loading doses, are reduced to one or more lower intermediate loading doses prior to initiation of administration of the maintenance doses.

5. A loading dosing regimen, (i) the loading dosing regimen is administered to obtain a Cmin plasma level of the antipurinergic agent of about 8 μg / ml to 24 μg / ml, and the maintenance dosing regimen is continued to maintain a Cmin plasma level of the antipurinergic agent of about 4 μg / ml to about 18 μg / ml; or (ii) the loading dosing regimen is administered to obtain a Cmax plasma level of the antipurinergic agent of about 100 μg / ml to about 500 μg / ml, or about 150 μg / ml to about 450 μg / ml, or about 200 μg / ml to about 350 μg / ml, and the maintenance dosing regimen is continued to maintain a Cmax plasma level of the antipurinergic agent of about 50 μg / ml to about 300 μg / ml, or about 100 μg / ml to about 200 μg / ml, or about 125 μg / ml to about 175 μg / ml; or (iii) the loading dosing regimen is administered to obtain an AUC for plasma levels of the antipurinergic agent of about 1500 to about 7000 μg*day / L, or about 1700 to about 6500 μg*day / L, or about 2000 to about 6000 μg*day / L, and the maintenance dosing regimen is continued until an AUC for plasma levels of the antipurinergic agent of about 700 to about 3000 μg*day / L, or about 900 to about 2000 μg*day / L, or about 1200 to about 1500 μg*day / L is achieved. The pharmaceutical composition of claim 1.

6. the mean plasma level of the antipurinergic agent achieved during the maintenance dosing regimen is about 20% to about 80% of the mean plasma level of the antipurinergic agent achieved during the loading dosing regimen; or the mean plasma level of the antipurinergic agent achieved during the loading dosing regimen is from about 125% to about 400% of the mean plasma level of the antipurinergic agent achieved during the maintenance dosing regimen; The pharmaceutical composition of claim 1.

7. the Cmin plasma level of the antipurinergic agent achieved during the maintenance dosing regimen is about 20% to about 80% of the Cmin plasma level of the antipurinergic agent achieved during the loading dosing regimen; or the Cmin plasma level of the antipurinergic agent achieved during the loading dosing regimen is from about 125% to about 400% of the Cmin plasma level of the antipurinergic agent achieved during the maintenance dosing regimen; The pharmaceutical composition of claim 1.

8. the Cmax plasma level of the antipurinergic agent achieved during the maintenance dosing regimen is about 20% to about 80% of the Cmax plasma level of the antipurinergic agent achieved during the loading dosing regimen; or the Cmax plasma level of the antipurinergic agent achieved during the loading dosing regimen is from about 125% to about 400% of the Cmax plasma level of the antipurinergic agent achieved during the maintenance dosing regimen; The pharmaceutical composition of claim 1.

9. the AUC of the antipurinergic agent achieved during the maintenance dosing regimen is about 20% to about 80% of the AUC of the antipurinergic agent achieved during the loading dosing regimen; or the AUC of the antipurinergic agent achieved in the loading dosing regimen is about 125% to about 400% of the AUC of the antipurinergic agent achieved in the maintenance dosing regimen; The pharmaceutical composition of claim 1.

10. At least one of the PK parameters selected from the group consisting of a Cmin of about 8 μg / ml to about 24 μg / ml, a Cmax of about 100 μg / ml to about 500 μg / ml, or an AUC of about 1500 to about 7000 μg*day / L is achieved for the as-needed loading dose; or At least one of the following PK parameters is achieved for said maintenance dose: a Cmin of about 4 μg / ml to about 18 μg / ml, a Cmax of about 50 μg / ml to about 300 μg / ml, or an AUC of about 700 to about 3000 μg*day / L; The pharmaceutical composition of claim 1.

11. The pharmaceutical composition of claim 1 , wherein the mammal is a human.

12. Using the method, a) anxiety or anxiety-like behavior, b) willingness to explore the environment; c) social interaction; d) spatial learning and memory; e) learning and memory; f) irritability, agitation and / or crying; g) lethargy and / or withdrawal; h) stereotypic behavior; i) hyperactivity and / or noncompliance, and j) Restrictive and / or repetitive behaviors 12. The pharmaceutical composition of claim 11, wherein the loading dose and the maintenance dose are adjusted according to efficacy and / or safety / tolerability endpoints selected from the group consisting of:

13. 12. The pharmaceutical composition of claim 11, wherein the nervous system disorder is selected from autism spectrum disorder (ASD), fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), post-traumatic stress syndrome (PTSD), Tourette's syndrome (TS), Parkinson's disease (PD), Angelman syndrome (AS), nervous system and central nervous system (CNS) disorders associated with viral infections, including chronic Lyme disease and other nervous system disorders associated with tick-borne diseases, and their long-term effects.

14. 2. The pharmaceutical composition of claim 1, wherein the antipurinergic agent is selected from berberine, emodin, suramin, tangeretin, A-438079, A-839977, A-804598, JNJ-47965567, and KN-62, pharmaceutically acceptable salts, esters, prodrugs, and solvates thereof, and combinations thereof.

15. 2. The pharmaceutical composition of claim 1, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

16. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable salt is selected from alkali metal salts, alkaline earth metal salts and ammonium salts.

17. 17. The pharmaceutical composition of claim 16, wherein the salt is a sodium salt.

18. 18. The pharmaceutical composition of claim 17, wherein the salt is a hexasodium salt.

19. 2. The pharmaceutical composition of claim 1, wherein the composition is administered nasally or intranasally (IN).

20. 10. The pharmaceutical composition of claim 1, wherein the composition is administered intravenously (IV).

21. 1. A kit for treating a nervous system, psychiatric or neurological disorder in a mammal in need thereof, said kit comprising first and second components for administering a pharmaceutical composition comprising an effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, and optionally instructions for administering said pharmaceutical composition; (a) the first component comprises the composition administered according to a loading dosing regimen selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of the antipurinergic; and (b) the second component comprises the composition administered according to a subsequent maintenance dosing regimen selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of the antipurinergic; kit.

22. 1. A pharmaceutical composition for inhibiting or modulating a purinergic receptor in a mammal in need thereof, comprising an antipurinergic agent or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein said pharmaceutical composition is administered according to a dosing regimen, said dosing regimen comprising (a) a loading dosing regimen and (b) a subsequent maintenance dosing regimen; (a) the loading dosing regimen is selected from (i) a single loading dose administered once, or (ii) multiple loading doses each administered at a frequency ranging from about once daily to about once every three months, wherein each loading dose comprises from about 3 mg / kg to about 30 mg / kg of the antipurinergic; and (b) said subsequent maintenance dosing regimen is selected from a plurality of maintenance doses each administered at a frequency ranging from about three times daily to about once every three months, each maintenance dose comprising from about 1 mg / kg to about 15 mg / kg of said antipurinergic.

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