WO2008021970A2 - Traitement d'une maladie des motoneurones, incluant certains troubles neurologiques, des neuropathies motrices et des maladies inflammatoires chroniques - Google Patents

Traitement d'une maladie des motoneurones, incluant certains troubles neurologiques, des neuropathies motrices et des maladies inflammatoires chroniques Download PDF

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WO2008021970A2
WO2008021970A2 PCT/US2007/075609 US2007075609W WO2008021970A2 WO 2008021970 A2 WO2008021970 A2 WO 2008021970A2 US 2007075609 W US2007075609 W US 2007075609W WO 2008021970 A2 WO2008021970 A2 WO 2008021970A2
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patient
treating
disease
charcoal
motor
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WO2008021970A3 (fr
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William K. Reid
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Reid William K
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to new methods of treating motor neuron diseases
  • ALS Amyotrophic Lateral Sclerosis
  • Lou Gehrig's disease Maladie de Charcot or motor neurone disease
  • motor neurone disease is a progressive, almost invariably fatal neurological disease.
  • ALS is a progressive illness with combined degeneration of the lower and upper motor neurons. It was first described by J. M. Charcot in 1874.
  • ALS has two meanings. In the first it is a collection of adult-onset diseases with progressive degeneration of motor neurons. In the second sense, ALS refers to a specific form of motor neuron disease with both upper and lower motor neuron signs.
  • Amyotrophic refers to the muscle atrophy, weakness and fasciculations found in the lower motor neuron deficits.
  • Lateral sclerosis refers to the hardening of the lateral
  • the invention contemplates the treatment of motor neuron disease, including certain neurological disorders, motor neuropathic disorders, chronic inflammatory diseases, autoimmune disorders and .
  • These conditions include, but are not limited to, Parkinson's Disease, Guillain-Barre Syndrome, Porphyria, Systemic Lupus Erythematosus and Multiple Sclerosis.
  • the present invention includes the therapeutic treatment of neurologic diseases resembling Amyotrophic Lateral Sclerosis or Parkinsonism, Autoimmune Disorders similar to Systemic Lupus Erythematosis, and Hypercoagulable disorders such as Lupus Anticoagulant disorder or Anti Phospholipid Syndrome causing chronic thrombosis, pulmonary emboli, strokes, and heart attacks.
  • the invention is directed to the treatment of patients in need of treatment, generally, those who either have been diagnosed as suffering from or are presenting or exhibiting symptoms of a motor neuron disease or certain neurological disorders, motor neuropathies and chronic inflammatory diseases.
  • those certain neurological disorders include chronic idiopathic neurological diseases.
  • the inventor believes that a patient responding to the invention is suffering from a pathogenic condition that is brought about by chronic poisoning due to extended exposure to one or more mycotoxins produced by one or more pathogens, including a fungus.
  • a patient present symptoms of disease is treated with an effective amount of one or more anti- fungal agents.
  • the following aspects could also be involved in patients with ALS and other motor neuron diseases leading to slow relentless muscle paralysis or porphyria:
  • the patient is immunocompromised due to one or more factors, such as diabetes mellitus, radiation or environmental exposures to toxins.
  • a patient is not immunocompromised and becomes exposed to a fungus alone. Signs of immunosuppression could be depressed immunoglobulin production, lymphopenia and T- cell depletion.
  • This suppressed lymphocytic immune system is predisposed to "opportunistic" infections by fungi.
  • the patient is infected or colonized by one or more types of opportunistic fungi.
  • fungi would cause minimal illness and be walled off in a granuloma and calcified. However, due to the immunosuppression the fungi are able to survive in the lymphatic or nervous system - chronically or indefinitely, releasing a steady low level of mycotoxins, including but not limited to trichothecenes, which progressively poison the patient over years.
  • the selective motor paralysis could be due to the selective damage to mitochondria with ATP depletion.
  • the trichothecenes are especially potent and cause selective damage to mitochondria in motor neurons and skeletal muscle with ATP depletion and progressive muscular weakness and paralysis. Fungal or mycotic infections are often ignored as a cause of human disease given their ubiquity.
  • mycotoxicosis caused by mycotoxins released from opportunistic fungi colonizing the orifices of the human body.
  • mycotoxicosis please see, J. W. Bennett & M. Klich, Clinical Microbiology Reviews (July 2003) 16(3):497-516.
  • these opportunistic fungi were ignored due to their low invasive capacity.
  • One theory of the present invention is that these fungi with lower pathogenicity can cause human illness due to their release of potent toxins, if the fungus can survive or colonize especially the upper air ways.
  • the known mycotoxins include: a.
  • Aflatoxins (molecular weight ca. 300) from Aspergillus species b. Citrinin (molecular weight ca. 250) from Penicillium and Aspergillus species c. Ergot alkaloids (molecular weight ca. 600) from Claviceps d. Fumonisins (molecular weight ca. 600) from Fusarium species e. Ochratoxins (molecular weight ca. 400) from Aspergillus and Penicillum species f. Patulin (molecular weight ca. 200) from Penicillium species g. Trichothecenes (molecular weight ca.
  • One embodiment of the present invention relates to treatment of fungi that cause opportunistic infection.
  • fungi include members of the genus Fusarium.
  • Species of the Fusarium genus that are possible targets for the treatment methods of the present invention include Fusarium aquaeductuum, Fusarium aquaeductuum var.
  • Fusarium chlamydosporum Fusarium coeruleum, Fusarium dimerum, Fusarium graminearum, Fusarium incarnatum, Fusarium moniliforme, Fusarium napiforme, Fusarium oxysporum, Fusarium proliferatum, Fusarium sacchari, Fusarium semitectum, Fusarium solani, Fusarium sporotrichoides, Fusarium sub glutinans, Fusarium tabacinum, and Fusarium verticillioides.
  • the present invention also relates to treatment of a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease by treating the patient for an opportunistic fungal infection.
  • treatments for opportunistic fungal infections include administration of anti-fungal agents as well as blood filtration to remove toxins generated by fungi.
  • blood filtration include an albumin column, a hepatic assist device (HAD), charcoal filtration, chromatography or a hepatic assist device.
  • Guidance on treatment of toxicity and poison can be found in Brenner & Rector's The Kidney, 7th edition, 2004.
  • Sections of note in The Kidney that could be useful in the present invention include Chapter 62, Extracorporeal Treatment of Poisoning, and the sections entitled Urinary Alkanlinization and Acidification, Principles Governing Drug Removal by Extracorporeal Techniques, Dialysis Related Factors, Extracorporeal Techniques for Drug Removal, Hemoperfusion, Hemodialysis-Hemoperfusion, Table 62-6 Available Hemoperfusion Devices, Hemofiltration, and Continuous Renal Replacement Therapy.
  • the aforementioned mechanism could explain many chronic, idiopathic illnesses such as multiple sclerosis, Parkinsonism, Guillain-Barre Syndrome.
  • Aflatoxins produced by Aspergillus species are largely associated with commodities produced in the tropics and sub-tropics, such as groundnuts, other edible nuts, figs, spices and maize. Alflatoxin Bl is the most toxic.
  • Ochratoxin A is produced by Penicillium verrucosum, which is generally associated with temperate climates, and Aspergillus species which grows in warm humid conditions. Aspergillus ochraceus is found as a contaminant of a wide range of commodities including cereals and their products, fruit and a wide range of beverages and spices. Aspergillus carbonarius is the other main species associated in warm humid conditions found mainly on vine fruit and dried vine products particularly in the Mediterranean basin.
  • Patulin is associated with a range of fungal species and is found in moldy fruits, vegetables, cereals and other foods. It is destroyed by fermentation and so is not found in alcoholic drinks.
  • Fusarium toxins are produced by several species of the genus Fusarium, which infect the grain of developing cereals such as wheat and maize. They include a range of mycotoxins including the fumonisins, the trichothecenes, including deoxynivalenol, and zearalenone, the last two of which are very stable and can survive cooking. Diagnoses [0021] In diagnosing this type of patient, the following history should be considered. The patient might have been exposed to a sufficiently high amount of environmental toxins or have a history of exposures. The patient could have evidence of immunodeficiency or multiple opportunistic infections that have longevity.
  • Measurable toxins released by those infections that gradually increase in synchrony with the progression of the paralysis will be found in the patient.
  • ALS patients are treated with one or more anti-fungal agents.
  • Treatment with antifungal agents should help aid the anion-gap metabolic acidosis and red cell protoporphyrins return toward normal levels and, in parallel, reduce the clinical findings especially the motor paralysis.
  • oral binding agents i.e. bile acid sequestrate
  • cholestyramine to bind up mycotoxin
  • the patients may also be subjected to hemodialysis with resins selected to remove mycotoxins.
  • the mycotoxins levels of the patient are tracked using available methods, using e.g., blood or urine samples of the patient.
  • Antifungal agents can be administered to the patient in need thereof for a time period sufficient for the mycotoxins levels in a patient to be reduced or to completely disappear or otherwise become undetectable. Typically patients show a response over one to two months. Samples from a patient, e.g., body fluid, such as blood or urine, can be obtained and tested for a reduction in the levels of mycotoxin.
  • Preferred antifungal agents include voraconazole (VFEND) and other antifungal agents that show activity against Fusarium infection.
  • antifungal agents that are contemplated for administration include fluconazole, amphotericin B, terbinafme, flucytosine, itraconazole, ketoconazole posaconazole, ravuconazole, pimaricin, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, amorolfme, butenafine HCl, naftif ⁇ ne, terbinafme, ciclopirox, olamine, haloprogin, tolnaftate, undecylenate, nikkomycin Z caspofungin, micafungin, anidulafungin, amphotericin B,lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD,) liposomal amphotericin B (L- AMB), liposomal nystatin, griseo
  • the antifungal agent is a prescription antifungal agent that is approved by the FDA. It is emphasized, however, that the invention is not limited to antifungal agents that are approved for marketing by the FDA. Any agent that exhibits antifungal activity is suitable for use in the invention. By antifungal activity is meant actually killing the fungus, disabling it, or acting to remove it or the mycotixins it produces from a patient by the action of binding, chelating and the like, separating or filtering the fungus or mycotoxins from a patient.
  • antifungal agents are those that are capable of treating members of the genus Fursarium, which can cause opportunistic infections and produces the toxin trichothecenes.
  • Dosages are given in the levels typically prescribed in the art.
  • antifungal regimens are commonly prescribed in line with regimens known in the art.
  • tablets are generally given orally, twice at day at a dosage of 300 mg/day.
  • a dosage range of administration of 20 mg to 400 mg, preferably 100 mg to 400 mg, given orally administered, once, twice or three times daily is also contemplated.
  • invra venous dosages of VFEND can be given, such as 3 to 6 mg/kg every 12 hours.
  • dosages should be tailored, as is known in the art, in accordance with patient tolerance. For example, 0.1- 0.8 mg/kg/day, up to 2.5 g total doses, are possible.
  • charcoal hemoperfusion also known as charcoal hemoperfusion or active charcoal hemoperfusion
  • Charcoal columns can be used under conditions that are standard in the art for treating those suffering from toxic ingestion, such as by eating poisonous mushrooms, for example amatoxin poisoning, or drug intoxication.
  • charcoal hemoperfusion can be carried out with a cartridge of activated charcoal.
  • Such charcoal can be coated with a membrane, such as cellulose, to reduce the undesirable deposition of blood components.
  • An example of such commercially available cartridges are Adsorba® 150C (150 grams of activate charcoal) and Adsorba® 300C (300 grams of activate charcoal).
  • Regimens for charcoal hemoperfusion can be based upon regimens already established for treatment of toxic ingestion.
  • treatment via French femoral catheters can be carried out for two to six hours a day, for two to five consecutive days.
  • Other types of columns such as resin columns and cartridges, and albumin columns and cartridges, are expected to have beneficial therapeutic effects. Hemoperfusion using affinity columns directed at the mycotoxins and charcoal cartridges or albumin cartridges can rapidly reduce the mycotoxin levels and result in remarkable improvement in the clinical findings.
  • the capacity to dialyze these toxins preferably occurs with molecules at or below 550 molecular weight and the majority of mycotoxins are accessible to this technique.
  • HADs hepatic assistant devices
  • extracorporeal liver support devices which perform hemodialysis
  • HADs hepatic assistant devices
  • extracorporeal liver support devices which perform hemodialysis
  • HADs include plasmapheresis devices, albumin dialysis devices, and molecular absorption recirculation systems.
  • HADs can be used to supplement ongoing treatment with antifungal agents or independently to treat patients without antifungal agents.
  • therapeutic results can be achieved with HADs or charcoal haemoperfusion.
  • the administration of fiber and activated powdered charcoal can be beneficial.
  • the patient is given increased doses of fiber, such a Metamucil.
  • the goal is to increase intake to up to 30 gm/day as the patient tolerates, and add the activated charcoal 1-2 times a month for 5 years or more.
  • This approach slowly removes poisons with minimal short term toxicity.
  • Long term the combination of high fiber and activated charcoal, can deplete multiple nutrients causing vitamin and mineral deficiencies. It is important over the long term to replete vitamins and minerals while monitoring for osteoporosis and vitamin deficiencies.
  • the fiber initially about 3 and 6 gm servings are mixed in room temperature water and then consumed. The dose is slowly increased over months to about 6 gm twice a day, then about 12 gm twice a day, then about 18 gm in the morning and about 12 gms at night. The patient should eventually have a regular bowel movement with every meal. Therefore, the preferred dosage range is from about 3 to 50 grams of fiber.
  • activated charcoal patient is administered activated powdered charcoal, preferably added to the fiber, preferably about once or twice a month.
  • patient should take double or triple doses of daily essential vitamins and minerals, such as B-Complex, Vitamins A, D, E, Omega Fatty Acids, Coenzyme Q, Folic Acid(3000-5000 meg/day), Pyridoxine 100 mg a day, and Magnesium Chloride or Oxide(400-800 mg/day).
  • daily essential vitamins and minerals such as B-Complex, Vitamins A, D, E, Omega Fatty Acids, Coenzyme Q, Folic Acid(3000-5000 meg/day), Pyridoxine 100 mg a day, and Magnesium Chloride or Oxide(400-800 mg/day).
  • Patients can be periodically checked for osteoporosis by methods known in the art such as Dex Scans. Known methods can be used to monitor the patients for vitamin and mineral deficiency. [0030] For charcoal, approximately 1 tablespoon can be administered.
  • Measurement of blood for mycotoxins using mass spectroscopy can confirm the diagnosis of mycotoxicosis.
  • new procedures can quantify these mycotoxins bound to serum proteins such as human albumin called Albumin Adducts, See Iwona Yikes, et al, Environ Health Perspectives 114(8): 1221-1226, Aug. 2006, Mycotoxin Adducts...
  • a 42 year old female was diagnosed with ALS. Patient had developed gradual onset of fasciculations, then weakness, then paralysis and became ventilator dependent. Only residual function was right distal phalanx of thumb and eyes. Exposure was at animal shelter, where patient was exposed to moldy dog food. Patient had markedly elevated protoporphyrins, positive anion gap metabolic acidosis and urine organic acids elevated with pattern consistent with mitochondrial damage.
  • Trichothecene level in urine was 13/18 and ELISA revealing the following antibodies in blood: aflatoxin, stachytoxin, trichothecene,T-2, mycophenolic acid, HSP70, ocratoxin, Stachyhemolysin, alternariol, chaetogloboside, vomitoxin.
  • a 52 year old male was diagnosed with ALS.
  • Patient was on ventilator with paralysis from neck down. Patient could move his chin only. Patient operates computer with head movement using dot on chin.
  • the trichothecene level in patient's urine was 10/18 and ELISA of blood showed stachytoxin, alternariol, aomitoxin, chaetoglobosins, trichothecene, mycophenolic acid, ochratoxin, and aspergillus.
  • Example 3 A 44 year old female was diagnosed with ALS. Fasciculations began with leg cramps and due to respiratory failure was placed on a ventilator. Patient had slurred speech, dysarthria, near complete paralysis except movement of hands partially. Elevated protoporphyrins but minimal to no acidosis. Trichothecene level was 9/18 and ELISA showed positives for alternariol, vomitoxin, T-2, chaetogloboside, stachytoxin, trichothecene, mycophenolic acid, aflatoxin, aspergillus hemolysis. [0039] Treatment similar to that described above provides positive results. Voriconazole was administered orally, twice a day, at 300 mg per dosage.
  • a 65 year old female with progressive neurologic disorder was diagnosed at first as Guillain-Barre and then as ALS. She is still ambulatory though cachectic and homebound with diffuse weakness. Trichothecene level in urine was 8/18. Patient was treated with itraconazole (SPORONOX) but apparently unsuccessful for reasons that are unknown.
  • a 69 year old male with progressive neurologic disorder was diagnosed with Parkinson's disease or ALS.
  • Patient had muscle weakness and difficulty walking.
  • Trichothecene level in 24 hr urine was 8/18 and ELISA of blood showed aspergillus, aflatoxin, ochratoxin, mycophenolic acid, trichothecene, stachyhemolysis, stachytoxin, cladosporium, chaetoglobosin, T-2, vomitoxin and alternariol.
  • patient was exposed to pathogens from a contaminated basement.
  • a 41 year old male was diagnosed with ALS.
  • Patient experienced gradual onset of weakness and was diagnosed with ALS after he could not turn light switches on and off.
  • Patient has dysarthria with slurred speech and is still ambulatory.
  • Trichothecene level was 11/18. Exposure is unknown.
  • a 41 year old female was diagnosed with systemic lupus erythematosis. Patient complained of mental confusion and weakness, and also had polyarthritis and chronic fatigue. Patient had been unsuccessfully treated with hydroxychloroquine sulfate (PLAQUENIL). The trichothecene level was 6/18. Patient had been likely exposed to fungus from building ventilation system; co-workers had also become ill. [0046] Patient was treated with Amphotericin B , Vfend and cholestyramine. Voriconazole was administered orally, twice a day, at 300 mg per dosage. Patient's ANA test for first time in years reverted to normal and all of her symptoms and signs resolved within a few months. However, stopping treatment had gradual recurrence of symptoms but not to previous severity.
  • Prolonged treatment over a month with anti-fungal agents including Voraconazole, Posaconazole and Caspofungin resulted in partial to complete correction of the protoporphyrinemia and the anion-gap metabolic acidosis.
  • Discontinuing the antifungal agents resulted in a rise in the protoporphyrin levels and anion-gap metabolic acidosis to the pre-treatment levels over a period of 2-4 weeks.
  • Hemoperfusion with Charcoal Cartridges with continued anti-fungal therapy resulted in significant improvement in their motor function.
  • biological samples e.g., blood, tissue, or urine samples
  • mass spectrometry to confirm the presence of mycotoxins in biological samples (e.g., blood, tissue, or urine samples) taken from subjects suffering from disease conditions implicated by the present invention.
  • biological samples e.g., blood, tissue, or urine samples

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Abstract

La présente invention concerne un procédé destiné à traiter un patient atteint, ou présentant des symptômes, d'une maladie des motoneurones, d'un trouble neurologique, d'une neuropathie motrice ou d'une maladie inflammatoire chronique. Un mode de réalisation de l'invention inclut un traitement consistant à traiter essentiellement un patient atteint d'une infection fongique, incluant, par exemple, l'administration d'une quantité thérapeutiquement efficace d'un ou de plusieurs agents antifongiques.
PCT/US2007/075609 2006-08-09 2007-08-09 Traitement d'une maladie des motoneurones, incluant certains troubles neurologiques, des neuropathies motrices et des maladies inflammatoires chroniques WO2008021970A2 (fr)

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CN114652735A (zh) * 2016-07-27 2022-06-24 凯斯西储大学 促进髓鞘形成的化合物和方法

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AU2009298112B2 (en) * 2008-10-02 2015-11-12 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
US20120172375A1 (en) * 2008-11-07 2012-07-05 Bruce Trapp Compounds and methods of promoting oligodendrocyte precursor differentiation
US10045972B2 (en) * 2014-06-18 2018-08-14 Biotheryx, Inc. Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases
JP2017523221A (ja) * 2014-08-04 2017-08-17 シルべストリ、 ファブリツィオ デ 多発性硬化症の治療におけるミノサイクリン、フルコナゾールおよびアトルバスタチンの単一丸剤／錠剤／カプセルでの使用
WO2016020944A1 (fr) * 2014-08-04 2016-02-11 Fabrizio De Silvestri Utilisation dans un comprimé/pilule/capsule unique de minocycline, de fluconazole et d'atorvastatine pour le traitement de la sclérose en plaques
US10610592B2 (en) 2014-08-04 2020-04-07 Fabrizio De Silvestri Treatment of multiple sclerosis
CN114652735A (zh) * 2016-07-27 2022-06-24 凯斯西储大学 促进髓鞘形成的化合物和方法
JP2020502269A (ja) * 2016-12-13 2020-01-23 コーブ バイオ エルエルシー パーキンソン病を治療するための方法及び組成物
CN110753543A (zh) * 2016-12-13 2020-02-04 海湾生物有限公司 用于治疗帕金森氏病的方法和组合物
EP3554496A4 (fr) * 2016-12-13 2020-05-13 Cove Bio LLC Procédés et compositions de traitement de la maladie de parkinson
KR101854762B1 (ko) 2017-03-10 2018-05-04 순천대학교 산학협력단 알테르나리올 모노메틸 에테르를 유효성분으로 포함하는 우울증 및 불안증의 예방 또는 치료용 조성물
CN109503393A (zh) * 2018-11-07 2019-03-22 江苏省农业科学院 一种高速逆流色谱制备伏马毒素b1标准品的方法
WO2020127059A1 (fr) * 2018-12-17 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de sulconazole en tant qu'inhibiteur de la furine
CN111760015A (zh) * 2020-01-21 2020-10-13 中南大学 米卡芬净在制备神经保护药物中的应用

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