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WO2025208209A1 - Utilisation d'ibogaïne dans le traitement d'un accident vasculaire cérébral du système nerveux central - Google Patents

Utilisation d'ibogaïne dans le traitement d'un accident vasculaire cérébral du système nerveux central

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Publication number
WO2025208209A1
WO2025208209A1 PCT/CA2025/050462 CA2025050462W WO2025208209A1 WO 2025208209 A1 WO2025208209 A1 WO 2025208209A1 CA 2025050462 W CA2025050462 W CA 2025050462W WO 2025208209 A1 WO2025208209 A1 WO 2025208209A1
Authority
WO
WIPO (PCT)
Prior art keywords
ibogaine
method defined
dosage
microdose
stroke
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CA2025/050462
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English (en)
Inventor
Jonathan Edward DICKINSON
Jose INZUNZA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ambio Life Sciences Inc
Original Assignee
Ambio Life Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ambio Life Sciences Inc filed Critical Ambio Life Sciences Inc
Publication of WO2025208209A1 publication Critical patent/WO2025208209A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/24—Apocynaceae (Dogbane family), e.g. plumeria or periwinkle

Definitions

  • CNS stroke is a group of encephalic disorders generated by pathological processes at the vascular level of the central nervous system. It is characterized by the modification of blood flow in one of the cephalic regions and is classified into two subtypes: ischemic and hemorrhagic. Ischemia is generated by the formation of a clot which obstructs blood flow in one of the cerebral vessels, occlusion of blood vessels can be transient or permanent manifestation. Hemorrhage involves the rupture of one of the vessels responsible for encephalic irrigation, causing an accumulation of blood product in the cerebral parenchyma or in the subarachnoid space (Lizano Salas, M., Me Donald Molina, C., & Tully Sancho, S. (2020).
  • Standard interventions following CNS stroke events include surgical vascular procedures, thrombolytic medications that break down plaque resulting from vascular occlusion, and blood pressure management, followed by ongoing physiotherapy. These therapies have been effective in reducing mortality and morbidity, but not in reversing cellular damage or disability once it occurs. In other instances, treatments like hyperbaric oxygen therapy, stem cell therapy, and transcranial magnetic stimulation have been shown to reduce inflammation, promote neurogenesis, and restore blood flow to the affected brain areas, resulting in modest improvements to disability.
  • ibogaine can be used to concurrently treat CNS stroke and reduce its associated lesions in a patient.
  • ameliorate decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • an ibogaine analog retains the biological activity of ibogaine, while having certain modifications that enhance the analog's function relative to the reference compound. Such modifications could increase the analog's oral availability, or half-life.
  • an effective amount is meant the amount of a required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • treat refers to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • the present invention provides methods of treating CNS stroke and related diseases and/or disorders or symptoms thereof which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formulae (e.g., ibogaine and ibogaine analogs, and all of their anomers) herein to a subject (e.g., a mammal such as a human).
  • a subject e.g., a mammal such as a human
  • a method of treating a subject suffering from or susceptible to CNS stroke or symptoms thereof includes the step of administering to the mammal a therapeutic amount of an amount of ibogaine or an ibogaine analog sufficient to treat the disease or disorder or symptom thereof, under conditions such that the disease or disorder is treated.
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect.
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • the therapeutic methods of the invention in general comprise administration of a therapeutically effective amount of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human.
  • a subject e.g., animal, human
  • Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof.
  • the invention provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target delineated herein modulated by a compound herein, a protein or indicator thereof, etc.) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with CNS stroke, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof.
  • the level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.
  • the invention further relates to methods for treatment and/or prevention of CNS stroke, including symptoms associated with CNS stroke, and/or other disease/disorder affecting the nervous system (e.g. central, peripheral) or muscle including symptoms thereof, in a subject in need thereof using the compounds and compositions described herein.
  • CNS stroke including symptoms associated with CNS stroke, and/or other disease/disorder affecting the nervous system (e.g. central, peripheral) or muscle including symptoms thereof, in a subject in need thereof using the compounds and compositions described herein.
  • Subject within the scope of the present invention is a mammal, such as a human or a veterinary animal, exhibiting symptoms and/or suffering from, or diagnosed with, diseases/disorders described herein.
  • veterinary animal refers to any animal cared for, or attended to by, a veterinarian, and includes companion (pet) animals and livestock animals, for example, a cat, a dog, and a horse (e.g., a race horse).
  • companion animals and livestock animals for example, a cat, a dog, and a horse (e.g., a race horse).
  • Other mammals e.g., such as those used as experimental models for CNS stroke, mice, rats, rabbits, nonhuman primates, such as monkeys, are also within the scope of the invention (e.g. induced embolism, arterial occlusion, etc.).
  • CNS stroke is used as per the expert consensus definition (An Updated Definition of Stroke for the 21st Century: A Statement for Healthcare Professionals from the American Heart Association/ American Stroke Association. Sacco, R., 2013). Diagnostic criteria used to identify a subject with CNS stroke would be apparent to a person of skill in the art. For example, a skilled individual would appreciate that clinically defined CNS stroke is based on "brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury.” More recent diagnostic criteria for CNS stroke include the presence of characteristic areas on a computerized tomography (CT) scan or magnetic resonance imaging (MRI) scan.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • ICH Intracerebral Hemorrhage
  • CAA cerebral amyloid angiopathy
  • coagulopathies among other vascular diseases.
  • Hypertension-related vasculopathy is more related to ICH in non-lobar areas (such as basal ganglia, thalamus, cerebellum and brainstem), whereas CAA is usually more linked to lobar ICH.
  • risk factors such as advanced age, hypertension, CAA, smoking, excessive alcohol consumption, use of sympathomimetic drugs, anticoagulants and antiplatelet agents, contribute to the development of ICH (Tadi, P., Lui, F. (2024). Acute Stroke. StatPearls. Treasure Island, FL: StatPearls Publishing.).
  • Clinical symptoms resulting from the cellular damage following CNS stroke include hemiplegia, insensitivity, loss of tactile and vibratory sensations, balance disorders, drooping of the eyelid (ptosis), diminished reflexes, visual field problems, motor coordination difficulties (apraxia) and language disorders (aphasia). These symptoms are due to damage to the neurons and brain pathways involved.
  • Other diseases/disorders affecting nerves and muscles include, but are not limited to, weakness, muscle stiffness, pain, which can be burning, throbbing, aching, imbalance, asthenia or fatigue, depression, visual disturbances or loss, headache, loss of bowel or bladder control, ataxia of gait or limb movements, difficulty walking, difficulty with coordinated movements of the upper extremities, cognitive dysfunction, loss or aberrant sensation, muscle cramps or spasms, among others. Subjects exhibiting these symptoms are within the scope of the present invention. [0038] Although the treatment of acute stroke injury has improved significantly, reducing mortality and morbidity, it remains one of the leading contributors to global disability.
  • the hyperacute phase of treatment for CNS stroke (within the first 24 hours) focuses on minimizing mortality and the effect of brain injury. After this period, the focus is on treating any symptoms of disability.
  • certain drugs and rehabilitation methods are available that promote brain repair by increasing vascular connectivity, functionally reorganizing neurovascular networks. These treatments have very limited efficacy in their ability to restore cellular function in the affected areas.
  • An additional goal of ongoing treatment is to reduce the possibility of recurring CNS stroke events by closely managing blood pressure.
  • Ibogaine has been used as a botanical preparation from the root bark of Tabernanthe iboga for over 100 years both as a crude preparation; as a purified botanical drug that contains ibogaine and other alkaloids found in iboga root bark; as isolated ibogaine, which was marketed in France until about 1970; or more recently as semi -synthetic ibogaine that can be produced from voacangine or other similar alkaloids.
  • the therapeutic use of ibogaine in all of these preparations is limited due to potentially adverse side effects. For example, in larger dosages ibogaine exhibits stimulant and hallucinogenic properties, and in addition, can induce temporary ataxia and tremors. At conventional doses, ibogaine causes these side effects in a majority of patients receiving treatment.
  • ibogaine is classified as a Schedule I controlled substance.
  • the use of ibogaine in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, the ranges generally used to treat addiction (e.g., 15 mg/kg to 20 mg/kg) cause hallucinations and may be fatal.
  • the Global Ibogaine Therapy Alliance. accessed at http://ibogaineguidelines.com, which is incorporated herein by reference in its entirety for all of its methods, compositions and teachings.
  • ibogaine is mentioned herein, one more polymorphs of ibogaine can be utilized and are contemplated. Ibogaine is isolated from Tabernanthe iboga, a shrub of West Africa. Ibogaine can also be synthesized using known methods. See, e.g., Buchi, et al. (1966), J. Am. Chem Society, 88(13), 3099-3109 Unless specified otherwise, "ibogaine” as used herein refers to ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
  • ibogaine mixture such as a botanical extraction of Tabernanthe iboga, or other alkaloids found present in it, including ibogamine, ibogaline, tabemanthine, coronoradine, voacangine, etc.
  • Ibogaine has complex pharmacology, which produce several therapeutic effects that are relevant to the treatment of stroke. Each of these effects, separately and together, are within the scope of the present invention.
  • the depolarization of cellular membranes induces the release from presynaptic terminals of excitatory amino acids such as glutamic acid or glutamate (Glu), in charge of opening calcium channels dependent on glutamatergic receptors such as acidoamino-3- hydroxy-5-methyl-4-Isoxazole (AMP A) and N-methyl-D-Aspartate (NMD A) in the postsynaptic neuron and subsequently, activate metabotropic receptors (diacylglycerol, inositol triphosphate, phosphocreatine) that help the release of calcium from intracellular deposits, producing an increase in calcium concentration (6).
  • excitatory amino acids such as glutamic acid or glutamate (Glu)
  • AMP A acidoamino-3- hydroxy-5-methyl-4-Isoxazole
  • Ibogaine increases glutamate production and almost completely inhibits glutamate uptake by cultured cortical astrocytes in mice (96%) and rats (97%) (Skolnick, P. (2001).
  • Capitulo 3 La ibogaina como antagonista del glutamato: relevancia para sus supuestas propiedades antiadictivas.
  • Los alcaloides quimica y biologia, 55-62.).
  • Extracellular glutamate concentrations are usually maintained at low levels by its Na-dependent transport into neurons and especially into astrocytes. Ibogaine inhibited both glutamate uptake by mouse cortical synaptosomes (neuronal transporters) and by mouse cortical astrocyte cultures.
  • Ibogaine has significant effects in inducing increased excitability and rapidity in the activation of parabrachial neurons, through depolarization, decreased rapid synaptic transmission dependent on non-NMDA receptors, involvement of dopamine receptor activation in its mechanisms of action ( Kombian, S. B., Saleh, T. M., Fiagbe, N. I., Chen, X., Akabutu, J. J., Buolamwini, J. K., & Pittman, Q. J. (1997). Ibogaine and a total alkaloidal extract of Voacanga africana modulate neuronal excitability and synaptic transmission in the rat parabrachial nucleus in vitro. Brain research bulletin, 44(5), 603-610.
  • ibogaine functions as a membrane modulator, activating growth factors that can increase synaptic transmission and excitability of damaged cells.
  • the treatment requires initially loading the system with ibogaine, followed by maintenance using smaller dosages that are continued over a number of days.
  • This loading can be achieved in one of three ways: through the administration of a flood dose, followed by microdosing; through the administration of mid-range dosages, followed by microdosing; or through a sustained period of microdosing.
  • the initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 3 to about 24 mg/kg, from about 5 to about 21 mg/kg, preferably from about 8 to about 18 mg/kg, preferably from about 10 to about 15 mg/kg, preferably from about 12 to about 14 mg/kg.
  • one or more booster dosages of 100-600 mg can be provided 12 hours or more before or after the flood in order to boost levels of noribogaine. This can be preferable in cases where the patient either felt less effect than desired from the medicine, or where dosing was interrupted for tolerability.
  • the equivalent or greater than a single flood dose over a period of time can be provided for patients with high sensitivity or tolerability issues, and achieve similar or greater saturation of noribogaine.
  • the microdose of ibogaine is selected from a dosing range of from about 8 to about 300 mg, from about 10 to about 200 mg, preferably from about 12 to about 150 mg, preferably from about 15 to about 80 mg, preferably from about 20 to about 60 mg.
  • powdered ibogaine hydrochloride is compounded to the appropriate ratio with vitamins.
  • a sodium ascorbate or calcium ascorbate form of Vitamin C is included in the composition.
  • capsules are filled with the mixture in bulk and bottled.
  • Physiotherapy and pain management allowed B to regain some motor control. However, when B was admitted for treatment at Ambio he continued to experience insensitivity in his right leg and foot, resulting in gait instability, as well as baseline pain levels of 8-9 on a 10-point scale. This made it difficult for B to operate a vehicle without sudden jerky movements and hard braking.
  • Powdered ibogaine hydrochloride was administered in capsule form and divided into 3 to 5 (A: 4, B: 4) dosages.
  • An initial test dose of 200-600mg (typically 400mg) was administered, followed by equal divisions of the remainder beginning after 30-90 minutes, and continuing then at 15-30-minute intervals. The intent is to ingest the complete initially calculated dose within a 2-hour window.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Botany (AREA)
  • Vascular Medicine (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Mycology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement des effets post-aigus de l'accident vasculaire cérébral du SNC chez un patient en ayant besoin. La méthode comprend l'administration au patient d'une quantité thérapeutiquement efficace d'ibogaïne, d'un extrait botanique d'iboga, d'un dérivé d'ibogaïne, ou d'un sel et/ou solvate pharmaceutiquement acceptable de celle-ci.
PCT/CA2025/050462 2024-04-01 2025-04-01 Utilisation d'ibogaïne dans le traitement d'un accident vasculaire cérébral du système nerveux central Pending WO2025208209A1 (fr)

Applications Claiming Priority (2)

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US202463572643P 2024-04-01 2024-04-01
US63/572,643 2024-04-01

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WO2025208209A1 true WO2025208209A1 (fr) 2025-10-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629307A (en) * 1989-10-20 1997-05-13 Olney; John W. Use of ibogaine in reducing excitotoxic brain damage
WO2022235514A1 (fr) * 2021-05-04 2022-11-10 Mind Medicine, Inc. Administration de psychotropes par liposome
WO2023012691A1 (fr) * 2021-08-03 2023-02-09 Pike Therapeutics, Inc. Administration posologique transdermique d'agents pharmaceutiques
WO2024059713A2 (fr) * 2022-09-14 2024-03-21 The Board Of Trustees Of The Leland Stanford Junior University Compositions d'alcaloïdes de l'iboga et méthohdes de traitement

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629307A (en) * 1989-10-20 1997-05-13 Olney; John W. Use of ibogaine in reducing excitotoxic brain damage
WO2022235514A1 (fr) * 2021-05-04 2022-11-10 Mind Medicine, Inc. Administration de psychotropes par liposome
WO2023012691A1 (fr) * 2021-08-03 2023-02-09 Pike Therapeutics, Inc. Administration posologique transdermique d'agents pharmaceutiques
WO2024059713A2 (fr) * 2022-09-14 2024-03-21 The Board Of Trustees Of The Leland Stanford Junior University Compositions d'alcaloïdes de l'iboga et méthohdes de traitement

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