Ibogaine for the treatment of multiple sclerosis

Abstract

A method for treating multiple sclerosis in patients in need and reducing associated lesions is described. This method involves administering to the patient a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of Provisional Patent Application No. 63 / 521,530, filed on June 16, 2023, under 35 U.S.C. § 119(e), the content of which is incorporated herein by reference.

Background Art

[0002] Field of Invention In one aspect, the present invention relates to the treatment of multiple sclerosis in a subject. In another aspect, the present invention relates to a pharmaceutical composition useful for the treatment of multiple sclerosis in a subject. In yet another aspect, the present invention relates to a pharmaceutical composition useful for the treatment of multiple sclerosis and reducing related lesions in a subject.

[0003] Prior Art Description Multiple sclerosis (MS) is generally known as an autoimmune disease of the central nervous system having characteristics of both autoimmunity and neurodegeneration. Approximately 400,000 people in the United States and 1.2 million people worldwide are affected. It is typically the leading cause of neurological disorders in young adults, which usually have relapses and remissions of neurological disorders and progress to a chronic stage with increasing difficulty in walking and coordination.

[0004] Studies have shown that nearly 50% of MS patients require walking aids 10 years after onset. Therefore, the impact of the direct medical costs and indirect economic costs of MS on society is huge, and it often burdens families with young children.

[0005] Drugs / agents currently used for MS treatment modify or suppress the body's immune system. These have been shown to moderately reduce the neurological relapses of the disease and, in some cases, delay the progression of neurological disorders, albeit incompletely.

[0006] Furthermore, drugs / agents for treating MS have not been reported to reduce MS - related lesions.

[0007] However, the vast majority of drugs / medications currently used for MS are constrained by various factors, including incomplete efficacy, side effects, and medical risks such as injection site reactions including skin necrosis; flu-like symptoms; depression; psychosis; hypersensitivity; allergic reactions; toxicity to the heart and other organs due to diabetes; cataracts; osteonecrosis; life-threatening opportunistic infections and the risk of malignancy. The presence of these side effects and risks prevents many MS patients from using these medications.

[0008] Therefore, there is an urgent need for safe, effective, well-tolerated, and more conveniently administered treatments / medications. Ideally, such treatments / medications would also alleviate the lesions associated with multiple sclerosis in patients. [Overview of the project]

[0009] The object of the present invention is to eliminate or mitigate at least one of the drawbacks of the prior art described above.

[0010] Another object of the present invention is to provide a novel method for treating multiple sclerosis.

[0011] Therefore, in one aspect, the present invention provides a method for treating multiple sclerosis in patients in need and reducing associated lesions, the method comprising administering to the patient a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

[0012] Surprisingly, it was discovered that ibogaine can be used to treat multiple sclerosis in patients and, at the same time, reduce associated lesions. [Modes for carrying out the invention]

[0013] Detailed description of preferred embodiments Various terms used throughout this specification are intended to have the following meanings:

[0014] "To improve" means to reduce, suppress, alleviate, mitigate, prevent, or stabilize the onset or progression of a disease.

[0015] An "analog" refers to a molecule that is not identical but possesses similar functional or structural characteristics. For example, ibogaine analogs have specific modifications that enhance the function of ibogaine while retaining its physiological activity compared to a reference compound. Such modifications can increase the oral availability or half-life of the analog.

[0016] In this specification, "comprise," "comprising," "containing," and "having" may have the meanings recognized under U.S. patent law, and may mean "include" or "including"; similarly, "consisting essentially of" or "consisting essentially" also has the meaning recognized under U.S. patent law, and this term is open-ended, allowing for the existence of something beyond what is described, as long as the basic or novel characteristics of what is described are not altered by the existence of something beyond what is described, but excluding aspects of the prior art.

[0017] The “effective dose” refers to the amount necessary for symptom improvement compared to an untreated patient. The effective dose of the active compound used in the implementation of this invention for treatment varies depending on the method of administration, the patient’s age, weight, and health condition. Ultimately, the attending physician or veterinarian will determine the appropriate dose and administration regimen. Such a dose is called the “effective” dose.

[0018] "Disease" means any condition or disorder that impairs or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include multiple sclerosis.

[0019] The ranges described herein are understood to be abbreviated notations for all values ​​within the range. For example, 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0020] In this specification, terms such as “treat,” “treating,” and “treatment” refer to reducing or improving a disorder and / or related symptoms. It is recognized, but is not excluded, that treating a disorder or condition does not require the complete elimination of the disorder, condition, or related symptoms.

[0021] Unless otherwise specified or the context makes it clear, the term "or" is understood to be inclusive in this specification. Unless otherwise specified or the context makes it clear, the terms "a, an" and "the" are understood to be singular or plural in this specification.

[0022] Unless otherwise specified or made clear from the context, the term “about” in this specification is understood to mean within the normal range of acceptable values ​​in the art, for example, within two standard deviations of the mean. “About” can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the indicated value. Unless otherwise made clear from the context, all numerical values ​​shown in this specification are modified by the term “about.”

[0023] Usage The present invention provides a method for treating multiple sclerosis and related diseases and / or disorders or symptoms thereof, said method comprising administering to a subject (e.g., a mammal such as a human) a therapeutically effective amount of a pharmaceutical composition comprising a compound represented by a formula herein (e.g., ibogaine and ibogaine analogs). Thus, one aspect is a method for treating a subject afflicted with or susceptible to a multiple sclerosis disease or its symptoms. This method comprises administering to a mammal, under conditions in which the disease or disorder or its symptoms are treated, an amount of ibogaine or an ibogaine analog sufficient to treat the disease or disorder or its symptoms.

[0024] The methods herein comprise administering to a subject (including a subject identified as needing treatment) an amount of a compound described herein or a composition described herein effective to produce such an effect.

[0025] Identifying a subject needing treatment can be at the discretion of the subject or a medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0026] The treatment methods of the present invention (including prophylactic treatment) generally comprise administering to a subject (e.g., an animal, a human), including a mammal that needs it, a therapeutically effective amount of a compound herein such as a compound represented by a formula herein. Treatment is suitably administered to a subject afflicted with, susceptible to, or at risk of a disease, disorder, or its symptoms, particularly a human.

[0027] Determination of these "at risk" subjects can be made by an objective or subjective determination by a diagnostic test or by the opinion of the subject or a healthcare provider (e.g., genetic testing, enzyme or protein markers, markers (defined herein), family history, etc.).

[0028] In one embodiment, the present invention provides a method for monitoring the progress of treatment. The method comprises determining or performing diagnostic measurements (e.g., screening, assay) of a diagnostic marker (marker) (e.g., a precisely delineated target, protein, or indicator thereof modulated by the compounds herein) in a subject who has or is susceptible to a disorder or symptom associated with multiple sclerosis, wherein the subject has been administered an amount of the compounds herein sufficient to treat the disease or symptom. The level of the marker determined by this method can be compared to known levels of the marker in a healthy, normal control or other patient to demonstrate the disease status of the subject.

[0029] In a preferred embodiment, the measurement of a second level of the target marker is performed at a later time than the determination of the first level, and these two levels are compared to monitor the course of the disease or the effectiveness of the treatment. In a preferred embodiment, the pre-treatment level of the target marker is measured before initiating the treatment of the present invention; the pre-treatment level of the marker can then be compared to the level of the target marker after initiation of treatment for the purpose of determining the effectiveness of the treatment.

[0030] The present invention further relates to methods for the treatment and / or prevention of multiple sclerosis, including, for subjects requiring the use of the compounds and compositions described in the specification, other diseases / disorders affecting the nervous system (e.g., central, peripheral) or muscles, including symptoms associated with multiple sclerosis and / or symptoms thereof.

[0031] The subject matter of the present invention is mammals, such as humans or veterinary animals, that exhibit and / or suffer from or have been diagnosed with the diseases / disorders described herein. The term "veterinary animals" refers to animals treated or cared for by a veterinarian and includes companion animals (pets) and livestock, such as cats, dogs, and horses (e.g., racehorses). Other mammals, such as non-human primates like mice, rats, rabbits, and monkeys, used as experimental models for MS, are also within the scope of the present invention (e.g., experimental allergic encephalomyelitis (EAE)).

[0032] In this specification, “multiple sclerosis” is used in accordance with the definition found in the accepted textbook in this field (Handbook of Multiple Sclerosis. 3rd Edition. Edited by Stuart D. Cook. Marcel Dekker, Inc., 2001). The diagnostic criteria used to identify subjects of multiple sclerosis are obvious to those skilled in the art. For example, those skilled in the art recognize that clinically defined multiple sclerosis is based on two episodes of neurological dysfunction separated in time and space. More recent diagnostic criteria for MS include the presence of characteristic areas on magnetic resonance imaging (MRI) of the head or neck.

[0033] Multiple sclerosis (MS) is a disease that often develops in young adulthood and is characterized by transient episodes of neurological dysfunction, such as vision loss, sensory changes, decreased motor function, and ataxia. These conditions fall within the scope of the present invention. The exact cause of multiple sclerosis is largely unknown, but it is thought to be the result of an autoimmune reaction against protein components of myelin, which form a sheath-like covering around nerve axons and promote electrochemical signaling in the central nervous system. Examples of such protein components include, but are not limited to, myelin basic protein, proteolipidoprotein, and myelin oligodendrocyte glycoprotein.

[0034] Common symptoms of multiple sclerosis and other diseases / disorders affecting nerves and muscles include, but are not limited to, weakness, muscle rigidity, burning pain, throbbing pain, aches and pains, balance disorders, weakness or fatigue, depression, visual impairment or blindness, headaches, loss of bowel or bladder control, ataxia or limb movement disorders, difficulty walking, difficulty with upper limb coordination, cognitive impairment, loss or paresthesia, muscle spasms or convulsions. Patients exhibiting these symptoms are within the scope of the present invention.

[0035] There are known subtypes of multiple sclerosis, generally defined by the symptom profile exhibited by the subject, including the onset, duration, and pattern of neurological dysfunction and / or impairment. Subjects suffering from MS subtypes are also within the scope of this invention.

[0036] Relapses in multiple sclerosis are the occurrence of a subtype of multiple sclerosis known as relapsing-remitting multiple sclerosis (RRMS), which is less frequent in secondary progressive multiple sclerosis (SPMS). In this specification, “relapse” is defined as the onset or worsening of neurological symptoms, usually lasting at least 48 hours, in the absence of any exacerbating factors such as fever or infection. Subjects experiencing relapses or suffering from RRMS are within the scope of this invention.

[0037] Relapses of multiple sclerosis include, but are not limited to, symptoms that may occur alone or in combination, such as increased or new onset of paralysis in the trunk or limbs, weakness in the trunk or limbs, ataxia, difficulty walking, decreased vision or double vision, pain in the face, trunk or limbs, difficulty urinating or defecating, sexual dysfunction, cognitive difficulties such as confusion, depression, psychosis or amnesia, dizziness or lightheadedness, fatigue, and muscle cramps or spasms.

[0038] Subjects exhibiting these symptoms fall within the scope of the present invention.

[0039] The goal of treating relapses is to halt the autoimmune processes associated with relapses and / or prevent or minimize residual nerve damage associated with incomplete remissions, which occur in a high proportion of patients. Particularly when the disease progresses from a relapsing-remitting phase (CPMS) to a chronic progressive phase, there is a significant risk of neurological disorders that lead to permanent and severe disability over time. Ten percent of patients have never experienced a relapse phase before the progressive phase, a condition known as primary progressive multiple sclerosis (PPMS). Untreated or uncontrolled relapses also carry a risk of progressing to SPMS, where progressive neurological disorders, including dementia, chronic vertigo, fatigue, visual impairment, motor dysfunction, sensory disturbances, bladder and bowel dysfunction, difficulty or inability to walk, ataxia, and pain, occur in the absence or reduced frequency of distinct seizures. SPMS and PPMS are poorly responsive to current drug therapies. CPMS and PPMS are also within the scope of this invention.

[0040] Ibogaine Ibogaine has been used for over 100 years as a plant-based preparation derived from the root bark of iboga tabernathe, as a crude preparation, as isolated ibogaine sold in France until around 1970, and more recently as a semi-synthetic ibogaine that can be produced from boacangin and other similar alkaloids. The therapeutic use of ibogaine is limited due to the potential for adverse side effects. For example, high doses of ibogaine can cause excitement and hallucinations, and may also induce transient ataxia and tremors. Typical doses of ibogaine cause these side effects in the majority of patients.

[0041] In the United States, ibogaine is classified as a Schedule I controlled substance. The use of ibogaine in humans is complicated by the extremely wide range of conventional dosages (0.01–1000 mg / kg body weight). Furthermore, the ranges commonly used to treat addiction (e.g., 15 mg / kg–20 mg / kg) can cause hallucinations and be fatal. Lotsof and Wachtel, Manual for Ibogaine Therapy: Screening, Safety, Monitoring & Aftercare (2nd revision, 2003), accessible at www.ibogaine.desk.nl / manual.html; Hoelen, et al. New Engl. J. Med. 360(3), 308 (2009), all of its methods, composition and teachings are incorporated herein by reference. See also the Clinical Guidelines for Ibogaine Assisted Detoxification: https: / / ibogaineguidelines.com.

[0042] "Ibogaine" refers to the following compound: [ka]

[0043] In this specification, when "ibogaine" is used, it should be understood that one or more polymorphs of ibogaine are available and considered. Ibogaine is isolated from Tabernanth iboga, a shrub native to West Africa. Ibogaine can also be synthesized by known methods; see, for example, Buchi, et al. (1966), J. Am. Chem Society, 88(13), 3099-3109. Unless otherwise specified, "ibogaine" in this specification refers to ibogaine, ibogaine derivatives, or their pharmaceutically acceptable salts and / or solvates. It may also refer to ibogaine mixtures, such as plant extracts of Tabernanthine, or other alkaloids contained therein, including ibogamine, ibogaline, tabernantine, colonolazine, boacangine, etc.

[0044] treatment method In a preferred embodiment, treatment involves an initial high dose of ibogaine followed by daily low doses for several days.

[0045] In a preferred embodiment, the initial high dose of ibogaine is selected from doses of approximately 3 to approximately 24 mg / kg, approximately 5 to approximately 21 mg / kg, preferably approximately 8 to approximately 18 mg / kg, preferably approximately 10 to approximately 15 mg / kg, and preferably approximately 12 to approximately 14 mg / kg (adjusted according to the patient's body weight).

[0046] At 13 mg / kg, a total of 1200 mg is preferred as the upper limit of the calculated initial high dose.

[0047] In some cases, a booster dose of 100-600 mg (usually 200-400 mg) may be administered one or more times at least 12 hours before or after a high dose of noribogaine to increase the level of the drug. This may be preferable if the patient feels the drug's effect is less than expected or if administration has been discontinued due to tolerability issues.

[0048] By combining these methods, it may be possible to provide patients who are highly sensitive or have difficulty tolerating with the drug to an equivalent or greater level of noribogaine over a period of time, achieving a level of saturation or greater.

[0049] In a preferred embodiment, the microdose of ibogaine is selected from doses of approximately 8 to 300 mg, approximately 10 to 200 mg, preferably approximately 12 to 150 mg, preferably approximately 15 to 80 mg, and preferably approximately 20 to 60 mg.

[0050] In a preferred embodiment, powdered ibogaine hydrochloride is combined with the vitamin in an appropriate ratio. In a preferred embodiment, vitamin C is included in the composition in the form of sodium ascorbate or calcium ascorbate. Preferably, the capsules are filled with the mixture in bulk and bottled.

[0051] Instructions for administration To obtain and enhance the benefits of noribogaine saturation, microdosing is preferably initiated 1 to 14 days after high-dose administration, more preferably 1 to 3 days after high-dose administration.

[0052] Microdosing may be continued to achieve psychotherapeutic effects and to increase exposure to ibogaine and noribogaine, and over time, it has the effect of reducing lesions. After 1-2 months, patients may be instructed to choose to interrupt their daily microdosing schedule, including a 1-4 week or 2-3 week hiatus, to reduce the accumulation of tolerance to the drug and to self-assess their current physical and mental condition. In these cases, patients are asked to record the number of days of administration for case studies.

[0053] You may discuss any medication treatments or changes in your health condition with your doctor at the clinic.

[0054] Patients are instructed to take one capsule daily in the morning. If the effect diminishes or is not significant after two weeks, the dosage may be gradually increased.

[0055] Patients are instructed on potential tolerability, which is mostly related to dosage. Dosage later in the day, especially at night, may cause sleep disturbances. Increased sensitivity to caffeine and other medications may be observed. Contraindications to medication should be carefully monitored. Doses exceeding the mildest psychoactive effect are generally undesirable with daily administration.

[0056] The following non-limiting examples will be used to illustrate aspects of the present invention, but these should not be used to interpret or limit the scope of the present invention. [Examples]

[0057] Example 1 Patient A ("A") In August 2022, a 44-year-old man was admitted to Ambio Life Sciences ("Ambio") in Tijuana, Mexico, seeking ibogaine treatment for post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and traumatic brain injury (TBI) that occurred in 2013. Furthermore, the man reported periodic dizziness, which he attributed to heavy alcohol consumption.

[0058] Following treatment, the patient abstained from alcohol, and the dizziness subsided for two months. Upon relapse, the patient underwent further examinations and was diagnosed with relapsing-remitting multiple sclerosis (RRMS). The patient was prescribed dimethyl fumarate and vitamin D to help control symptom relapses, but was returned to treatment at Ambio in February 2023. At this point, the patient was experiencing progressive changes in fine motor mobility and coordination, nocturnal dizziness, and altered mental stagnation and short-term memory. Relationship anxiety and the possibility of divorce were strong additional factors in the patient's willingness to seek treatment.

[0059] Patient B (“B”) In February 2023, a 44-year-old woman contacted Ambio to inquire about ibogaine treatment. This patient had previously been diagnosed with complex post-traumatic stress disorder (CPTSD) associated with childhood trauma. Furthermore, she had a family history of MS and was diagnosed with secondary progressive multiple sclerosis (SPMS) in 2019. Since then, she had experienced progressive changes in fine motor mobility and coordination, increased pain and muscle rigidity, in addition to depression, anxiety, and fatigue.

[0060] Following the insertion of a subcutaneous baclofen pump, this patient developed significant gait impairment. Upon admission, the patient exhibited severe muscle rigidity, atrophy of the limbs and upper extremities, and required wheelchair use and transfer assistance. Prior to ibogaine treatment, B had explored all other treatment options. Despite reduced mobility, the patient continued to use baclofen and high doses of medical cannabis to manage pain. While these treatments helped manage certain symptoms, the rigidity progressed to the point where the patient could not participate in physical therapy.

[0061] method The treatments administered in each case included high-dose exposure to ibogaine hydrochloride (A: 1200 mg and B: 450 mg) during hospitalization in Ambio, followed by low-dose administration of 20 mg per day. The ibogaine used for treatment is semi-synthetically produced from voacangin extracted from Voacanga africana. Independent TLC analysis showed no impurities.

[0062] Neither Patient A nor Patient B discontinued their daily microdosing during the observation period.

[0063] Preparation and administration Ibogaine hydrochloride powder was administered in capsules, with additional doses given in 3 to 5 divided doses (A: 4 doses, B: 3 doses). An initial test dose of 200-600 mg / kg (usually 400 mg) was administered, followed by the remaining dose, divided into equal parts, starting 30-90 minutes later and continuing at 15-30 minute intervals. The objective was to ensure that the initially calculated dose was completely absorbed within the first two hours.

[0064] Adjustments for tolerability Some patients may be unable to or unwilling to complete the last dose measured, while others may be so overwhelmed by the effects that they feel they no longer need the stimulant.

[0065] Some patients experience little to no effect from the initial dose, even more than three hours later. A booster dose may be discussed for those who feel a stronger effect within 2.5 to 3 hours. This additional dose can be 2-5 mg / kg. A maximum dose of 1200 mg is sometimes preferred. This dose is added to the initial dose, increasing the total dose according to body weight.

[0066] Further adjustments In some cases, one or more test doses of 200-600 mg (usually 400 mg) may be administered at least 8 hours before a larger dose. This may be preferable in individuals who appear to be highly sensitive emotionally or physically, in order to more carefully observe their tolerance. This type of administration was performed on patient B.

[0067] evaluation Patients' electrocardiograms, blood tests, and 18-item urinary drug screenings were evaluated. During high-dose administration, patients' hearts were continuously monitored for at least 12 hours, and metabolic support protocols, including drug therapy and IV therapy, were implemented.

[0068] Patient A was also evaluated by MRI before and after treatment. Both patients were evaluated by a psychologist and a physician. Psychological assessment included semi-structured interviews about the subjective effects of ibogaine, as well as the complete Multiple Sclerosis Quality of Life Inventory (MSQLI) collected over four weeks at baseline ("BL") and at one month ("1M") and two months ("2M") follow-up. Medical assessment included functional scales measuring physical disability, gait index, and the Comprehensive Disability Assessment Scale, collected at baseline and at two months follow-up.

[0069] observation Image diagnostic results Patient A's MRI images show a significant reduction in total demyelination. To the inventor's knowledge, there are no existing treatments for MS that have been shown to reduce lesions, and this is considered a significant finding.

[0070] Quantitative results The collected quantitative measures support the imaging findings and indicate corresponding improvements in symptoms. With few exceptions, both patients reported significant improvement across all measures at 1 month, and at 2 months, these improvements were either sustained or further improved.

[0071] Patient A showed the greatest decline in the MSQLI score (MFIS) related to fatigue effects (BL:52, 1M:29, 2M:4). At 2M, this patient had a complete resolution of fatigue symptoms and could explain the impact of fatigue on their quality of life. The same patient had completely resolved the minor bladder control issues reported at baseline (BL:4, 1M:0, 2M:0).

[0072] Patient B's greatest improvement was in the MSQLI Pain Experience Scale (PES) (BL:22, 1M:8, 2M:6). A significant decrease in the gait index score, which describes overall mobility, was also observed (BL:8, 1M:7, 2M:6). These results were largely attributable to the alleviation of severe muscle rigidity. The patient also noted considerable improvement in bladder score (BL:5, 1M:3, 2M:3) and bowel management (BL:6, 1M:5, 2M:2).

[0073] The MSQLI measures mental health in three ways: firstly, the impact of mental / emotional experiences on overall health and daily functioning (MF-36-MH); secondly, a measure of cognitive deficit (PDQ); and thirdly, an overall mental health score (MHI). While there was improvement in all of these measures between BL and 2M, the changes across all three measures were not necessarily directly correlated. The MF-36-MH score appeared to be either leveling off or showing a peak at time 1M (A: BL: 31.6, 1M: 54.7, 2M: 54.6; BL: 36.3, 1M: 54.5, 2M: 46.5). The PDQ score showed the most consistent linear improvement in both patients (A: BL: 42, 1M: 40, 2M: 33; B: BL: 40, 1M: 30, 2M: 25). MHI scores improved by 38–39% from baseline to 2 months in both patients, but the patterns were not consistent (A: BL: 41.7, 1M: 59.6, 2M: 57.8; B: BL: 22.7, 1M: 19.5, 2M: 31.3). In patient A, the improvement plateaued, similar to the PDQ score, while in patient B, there was a sharp decline at 1 month followed by a sharp increase at 2 months. The mean overall improvement rate in mental health scores for both patients was 44.2%.

[0074] Of the three scales used to measure physical disability, the gait index was negligible in patient A, who had no problems walking. The mean improvement rate in the other disability scores was 71.5% in patient A and 30% in patient B.

[0075] Example 2 In this example, gait recovery and spinal cord injury repair are evaluated using the model described in Fiander et al., Behavioural Brain Research, 317 (2017) 95-108. See also Chedrawe et al., Journal of Neuroimmunology, 321 (2018) 72-82.

[0076] Walking recovery We will evaluate the effects of vehicle and ibogaine on gait recovery in a mouse model of MS.

[0077] More specifically, walking recovery will be evaluated after administration of ibogaine preparations containing ibogaine and a vehicle. The control group will be established by evaluating walking recovery after administration of the vehicle alone.

[0078] Using modeled encephalitis and demyelination, motor gait analysis is performed before administration (-2 days) and after administration (7, 14, 21, 28, 35, and 42 days). Experimental autoimmune encephalomyelitis (EAE) is induced by injection of myelin oligodendrocyte glycoprotein (MOG) or proteolipidoprotein (PLP). To evaluate the ability of ibogaine to reverse gait impairment, either the vehicle alone (NEOBEE; 100 μl) or an ibogaine preparation (40 mg / kg) is administered orally on day 7 after gait measurement.

[0079] For walking data on days 14, 21, 28, 35, and 42, a statistical comparison will be performed between animals treated with vehicle alone and those treated with ibogaine using a two-way repeated-measures ANOVA followed by Sidac's multiple comparison test.

[0080] Spinal cord injury repair After gait measurement on day 42, spinal cord injury and the expression of metabolic enzymes, mitochondria, neurotrophic factors, and myelin-related genes will be quantified in the spinal cord. In subgroups of EAE mice, plasma and cortical ibogaine and noriibogaine levels will be measured using LC-MS-MS at 1, 4, and 24 hours after oral administration of ibogaine preparations.

[0081] Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is used to measure mRNA levels of phosphoglycerate kinase, malonate dehydrogenase, aldolase A, enolase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, copper-zinc superoxide dismutase, complex IV subunit, and myelin-related genes (MOG, MAG, and PLP2) in the spinal cord. Eriochrome cyanine staining is used to detect myelin, and histological examination is performed using immunohistochemistry to label oligodendrocyte precursor cells, oligodendrocytes, neurons, and axons in the spinal cord isolated from another mouse. Computer-aided image analysis is then used to quantify these markers. Statistical analysis is performed using the Mann-Whitney U test. Power analysis suggests that in 6 mice / group, a predicted 50% difference between means with a 15% standard deviation is detectable with 100% precision at α=0.05.

[0082] The present invention is described with reference to exemplary embodiments and examples, but this description is not intended to be constrained. Therefore, various modifications of the exemplary embodiments and other embodiments of the present invention will be apparent to those skilled in the art with reference to this specification. For this reason, the claims are considered to cover all such modifications or embodiments.

[0083] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each publication, patent, or patent application is specifically and individually suggested to be incorporated by reference in whole.

Claims

1. A method for treating multiple sclerosis in a patient in need and reducing associated lesions, comprising administering to the patient a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

2. The method according to claim 1, wherein the treatment comprises an initial high dose of ibogaine and subsequent multiple low doses of ibogaine.

3. The method according to claim 2, wherein the initial high dose of ibogaine is selected from a dose of approximately 3 to approximately 24 mg / kg (adjusted according to the patient's body weight).

4. The method according to claim 2, wherein the initial high dose of ibogaine is selected from a dose of approximately 5 to approximately 21 mg / kg (adjusted according to the patient's body weight).

5. The method according to claim 2, wherein the initial high dose of ibogaine is selected from a dose of approximately 8 to approximately 18 mg / kg (adjusted according to the patient's body weight).

6. The method according to claim 2, wherein the initial high dose of ibogaine is selected from a dose of about 10 to about 15 mg / kg (adjusted according to the patient's weight).

7. The method according to claim 2, wherein the initial high dose of ibogaine is selected from a dose of about 12 to about 14 mg / kg (adjusted according to the patient's body weight).

8. The method according to any one of claims 2 to 7, wherein the initial high dose of ibogaine does not exceed 1200 mg.

9. The method according to any one of claims 2 to 8, wherein the micro-administration of ibogaine is selected from a dose of about 8 to about 300 mg.

10. The method according to any one of claims 2 to 8, wherein the micro-administration of ibogaine is selected from a dose of about 10 to about 200 mg.

11. The method according to any one of claims 2 to 8, wherein the micro-administration of ibogaine is selected from a dose of about 12 to about 150 mg.

12. The method according to any one of claims 2 to 8, wherein the micro-administration of ibogaine is selected from a dose of about 15 to about 80 mg.

13. The method according to any one of claims 2 to 8, wherein the micro-administration of ibogaine is selected from a dose of about 20 to about 60 mg.

14. The method according to any one of claims 2 to 13, wherein the micro-administration of ibogaine is performed daily.

15. The method according to any one of claims 2 to 14, wherein the microadministration of ibogaine is performed for about one week to about four weeks.

16. The method according to any one of claims 2 to 14, wherein the microadministration of ibogaine is performed for approximately two to three weeks.

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