WO2008021970A2

WO2008021970A2 - Treatment of motor neuron disease, including certain neurological disorders, motor neuropathies and chronic inflammatory diseases

Info

Publication number: WO2008021970A2
Application number: PCT/US2007/075609
Authority: WO
Inventors: William K. Reid
Original assignee: Reid William K
Priority date: 2006-08-09
Filing date: 2007-08-09
Publication date: 2008-02-21
Also published as: WO2008021970A3

Abstract

The invention relates to a method of treating a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease. In an embodiment of the invention the treatment includes a treatment consisting essentially of treating a patient suffering from a fungal infection, including, for example, the administration of a therapeutically effective amount of one or more antifungal agents.

Description

TREATMENT OF MOTOR NEURON DISEASE, INCLUDING CERTAIN NEUROLOGICAL DISORDERS, MOTOR NEUROPATHIES AND CHRONIC

INFLAMMATORY DISEASES

Cross-Reference to Related Applications

[0001] This application claims priority to US Provisional Application No. 60/836,382,

filed August 9, 2006 and US Provisional Application No. 60/917,526, filed May 11, 2007, the disclosures of which are incorporated herein by reference in their entirety.

Background of the Invention

[0002] The present invention relates to new methods of treating motor neuron diseases,

such as ALS.

[0003] Amyotrophic Lateral Sclerosis (ALS, sometimes called Lou Gehrig's disease, Maladie de Charcot or 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.

According to a review by Rowland, L. P. et al. that appeared in the N. E. J. Med. (2001) 344(22): 1688-1700, 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.

[0004] "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

columns of the spinal cord due to degeneration and gliosis of the corticospinal columns. The upper motor neuron findings result in overactive tendon reflexes, Hoffman's sign, clonus and Babinski signs.

[0005] If only the lower motor neurons are involved it is the variant progressive spinal muscular atrophy. If the upper motor neurons are more involved then it is called primary lateral sclerosis. But at autopsy both lower and upper motor neurons show involvement. [0006] Other motor neuron disorders that could mimic symptoms of ALS include, but are not limited to, myasthenia gravis and cervical spondylotic myelopathy. A particularly difficult differential is multifocal motor neuropathy with positive GMl ganglioside antibodies, which responds to IV gammaglobulin. Treatment of the foregoing disorders is also contemplated by the invention.

[0007] Thus the invention contemplates the treatment of motor neuron disease, including certain neurological disorders, motor neuropathic disorders, chronic inflammatory diseases, autoimmune disorders and . These conditions (in addition to those already described above) include, but are not limited to, Parkinson's Disease, Guillain-Barre Syndrome, Porphyria, Systemic Lupus Erythematosus and Multiple Sclerosis. In addition, 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.

Summary of the Invention

[0008] 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. In an embodiment of the invention, those certain neurological disorders, include chronic idiopathic neurological diseases. It has been surprisingly discovered that such patients can be treated by the administration of one or more active ingredients that are effective against, or otherwise antagonize the effects of, mycotoxin-producing organisms. Not wishing to be bound by theory, 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. In a preferred embodiment of the invention, a patient present symptoms of disease is treated with an effective amount of one or more anti- fungal agents.

Detailed Description of the Invention

[0009] 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. However, sometimes 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. In any event, the patient is infected or colonized by one or more types of opportunistic fungi. Normally these 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. [0010] The selective motor paralysis could be due to the selective damage to mitochondria with ATP depletion. Of the known mycotoxins, 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. Labs will report fungal infections without further speciation assuming it is insignificant. Physicians will write off a fungal infection as "colonization" without recommending further treatment for the diagnosed patient. Prior to the method of the invention it was widely believed that fungi are usually benign and simply "colonize" without causing pathology.

[0011] It is believed by the inventor that many motor neuron disease are forms of mycotoxicosis caused by mycotoxins released from opportunistic fungi colonizing the orifices of the human body. For discussion of mycotoxicosis, please see, J. W. Bennett & M. Klich, Clinical Microbiology Reviews (July 2003) 16(3):497-516. In the past 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. [0012] 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. 400) from Fusarium, Myrothecium, Phomopsis, Stachybotrys, Trichoderma, Trichothecium and other species h. Zearalenone (molecular weight ca. 300) from Fusarium species i. Other mycotoxins such as yellow rice toxins [0013] One embodiment of the present invention relates to treatment of fungi that cause opportunistic infection. Such 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. media, 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.

[0014] 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. Examples of treatments for opportunistic fungal infections include administration of anti-fungal agents as well as blood filtration to remove toxins generated by fungi. Examples of 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. [0015] In the broader sense, the aforementioned mechanism could explain many chronic, idiopathic illnesses such as multiple sclerosis, Parkinsonism, Guillain-Barre Syndrome. The common relationship between these diseases is that many infections can survive in humans for years and cause pathology by releasing potent toxins without obvious growth and direct physical damage. Due to the balance of apparent survival of the infection in a hostile environment within the human body, the organism causes indirect toxicity by releasing blood-borne poisons.

[0016] Major groups of toxins which may be implicated in this discovery include, but are not limited to, those described further, below.

[0017] Aflatoxins produced by Aspergillus species, they 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. [0018] 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.

[0019] 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.

[0020] 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. In particular, in the available patients, there is a steadily increasing anion-gap metabolic acidosis, as well as rising red cell protoporphyrins.

Antifungal Treatment

[0022] In one embodiment of the present invention, 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. Alternatively, oral binding agents (i.e. bile acid sequestrate) like cholestyramine, to bind up mycotoxin, are administered. The patients may also be subjected to hemodialysis with resins selected to remove mycotoxins. One or more of the preceding treatment regimens can also be combined. Preferably, the mycotoxins levels of the patient are tracked using available methods, using e.g., blood or urine samples of the patient. Optionally, one can measure ATP levels in muscles and spinal cord using, e.g., NMR/MRI - P31 scans. [0023] 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. Other 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, naftifϊne, 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, griseofulvin, amorolfme, butenafine, nystatin and combinations thereof. The package insert sheets of the previously listed antifungal sheets, as well as the product reference sheets of all antifungal agents approved by the FDA, are hereby incorporated by reference. In one aspect of the invention, 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. Particularly useful antifungal agents are those that are capable of treating members of the genus Fursarium, which can cause opportunistic infections and produces the toxin trichothecenes. [0024] Dosages are given in the levels typically prescribed in the art. For example, antifungal regimens are commonly prescribed in line with regimens known in the art. For voraconazole, 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. Alternatively, invra venous dosages of VFEND can be given, such as 3 to 6 mg/kg every 12 hours. For Amphotericin, 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.

Blood Filtration Treatment

[0025] Treatment with a charcoal column, also known as charcoal hemoperfusion or active charcoal hemoperfusion, can aid patients as well. 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. For example 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. For example at a blood flow rate of 100-400 ml/min, preferably 250ml/min, 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.

[0026] Additionally, hepatic assistant devices (HADs) and extracorporeal liver support devices, which perform hemodialysis, can be used with the method of treatment of the present invention. Examples of HADs included 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. In addition, for those patients who do not show results with antifungal agent administration, sometimes therapeutic results can be achieved with HADs or charcoal haemoperfusion.

Long Term Fiber and Charcoal Treatment

[0027] In addition, 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.

[0028] For 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. [0029] For activated charcoal, patient is administered activated powdered charcoal, preferably added to the fiber, preferably about once or twice a month. In order to prevent vitamin and mineral depletion, 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). Also need increase amounts of calcium or dairy products. 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.

Other Diseases

[0031] In general patients suffering from other diseases, besides ALS, that are chronic idiopathic or chronic idiopathic neurologic disorders such as multiple sclerosis, parkinsonism, Guillain Barre and porphyria can benefit from the antifungal treatment of the invention.

Detection of Mycotoxins

[0032] Measurement of blood for mycotoxins using mass spectroscopy can confirm the diagnosis of mycotoxicosis. In particular, 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...

[0033] All references cited in this specification are incorporated by reference herein in their entirety.

Example 1

[0034] 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.

[0035] Patient was placed on a regimen of the antifungal voriconazole (VFEND) and hemoperfusion with activated charcoal. Voriconazole was administered orally, twice a day, at 200 mg per dosage. This treatment resulted in protoporphyrins returning to normal, resolution of anion gap, movement of left hand at wrist. Due to patient's insurance provider denying payment for treatment by antifungals, voriconazole and charcoal regimen was stopped, and patient returned to previous state in about two weeks, including elevated protoporphyrin levels, positive anion gap, and loss of movement of left hand.

Example 2

[0036] 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.

[0037] Patient was placed on a regimen according to the invention of voriconazole and cholestyramine. Voriconazole was administered orally, twice a day, at 300 mg per dosage. The administration of cholestyramine is optional. Patient displayed reduction in protoporphyrins, reduction anion gap metabolic acidosis, and elevated Kreb cycle metabolites. Antifungal therapy led to consistent improvement in the results of patient's lab tests with a reduction in his metabolic acidosis and red cell protoporphyrins. Patient began to move hands for the first time in years.

Example 3 [0038] 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.

Example 4

[0040] 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.

Example 5

[0041] 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. Apparently, patient was exposed to pathogens from a contaminated basement.

[0042] Patient showed marked improvement in only two months of antifungal treatment, almost back to baseline. Interestingly, if the antifungal agents are stopped, there is a rapid return of the original symptoms. Exposure is unknown. Voriconazole was administered orally, twice a day, at 300 mg per dosage. Example 6

[0043] 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.

[0044] Patient was placed on a regimen of the anti fungal voriconazole (VFEND) and charcoal, as described above. Voriconazole was administered orally, twice a day, at 300 mg per dosage. Positive improvement in symptoms is observed eventually.

Example 7

[0045] 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.

Example 8

[0047] A 35 year old male was diagnosed with porphyria. Symptoms were chronic abdominal pain, personality disorder, and severe headaches. He was homebound unable to work due to symptoms. He was also hypercoagulable with recurring deep venous thrombosis. Trichothecene was 9-10/18. Patient's wife (Example 7) was exposed to fungus from building ventilation system. [0048] After about 3-6 months of treatment using voriconazole, amphotericin B, and cholestyramine he had almost complete resolution of his symptoms. Voriconazole was administered orally, twice a day, at 300 mg per dosage. Patient went back to work after over 10 years of the illness.

Example 9

[0049] Similarly, patients diagnosed with multiple sclerosis, Parkinson's Disease, Guillain-Barre Syndrome and lupus are shown to improve using the methods of the invention.

[0050] Preferred embodiments have been described above to illustrate certain aspects of the invention. The invention should not be construed, however, as being limited to the specific embodiments described, as a reader of ordinary skill will appreciate that the invention is broad and generic in concept.

Example 10

[0051] Four patients (3 ventilator-dependent) with a diagnosis of Motor Neuron Disease/ Amyotrophic Lateral Sclerosis were found to have colonization of their upper airways by toxogenic fungi. Cultures of the tracheostomy, lung, sinuses & nasal passages grew out fungi known to produce mycotoxins including Dematiaceous moulds, Fusarium, Alternarium, Cladosporium, Phoma, Aspergillus and Penicillium. Blood work in all 4 patients showed Protoporphyrinemia without evidence of Iron Deficiency, as well as an Anion-Gap Metabolic Acidosis. Twenty four hour urines for Organic Acids were positive for Citric Acid Cycle Metabolites. Muscle biopsies were consistent with Denervation pattern.

[0052] 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. Based on these findings, I would conclude that Colonization of the Upper Airways by Opportunistic Fungi can release significant levels Mycotoxins that exacerbate the clinical findings in patients with Amyotrophic Lateral Sclerosis. Reduction of the fungal colonization with anti-fungal agents and hemoperfusion with charcoal cartridgies can result in clinical improvement including a reduction in paralysis.

[0053] For a reference disclosing certain fungi known to produce mycotoxins, the reader is referred to J. W. Bennett & M. Klich, Mycotoxins, Clinical Microbiology Reviews (July 2003) 16(3):497-516, which also contains chemical structural information for certain mycotoxins. Indeed, certain mycotoxins, particularly macrocyclic trichothecenes, are known to produce adducts with human serum albumin ("HSA"). See, for example, Iwona Yikes et al. Environmental Health Perspectives (August 2006) 114(8): 1221-1226, which also contains a disclosure of a protocol for isolation of such mycotoxin-HSA adducts and their subsequent analysis and identification by selected techniques, including mass spectrometry. Hence, if desired, one can utilize 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. For a disclosure on extracorporeal treatment of poisoning, please see, for example, I. J. Chang et al. in Brenner & Rector's The Kidney, 7th Ed (2004), pg. 2733-2741, Chapter 62. The disclosures of all of the foregoing publications is incorporated in their entirety by reference herein. Other treatment regimens may also become apparent to one of ordinary skill once familiar with the aspects of the present invention.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising administering to the patient a therapeutically effective amount of one or more antifungal agents.

2. The method of claim 1 in which the symptoms include that of amyotrophic lateral sclerosis.

3. The method of claim 1 in which the symptoms include that of multiple sclerosis.

4. The method of claim 1 in which the symptoms include that of Parkinson's Disease.

5. The method of claim 1 in which the symptoms include that of Guillain-Barre Syndrome.

6. The method of claim 1 in which the one or more antifungal agents is selected from the group consisting of voraconazole, fluconazole, amphotericin B, terbinafme, flucytosine, itraconazole, ketoconazole posaconazole, ravuconazole, pimaricin, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, amorolfme, butenafine HCl, naftifine, 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, griseofulvin, amorolfme, butenafine and nystatin.

7. The method of claim 1 in which the one or more antifungal agents are administered for at least two months.

8. The method of claim 1 which further comprises administering to the patient a therapeutically effective amount of an oral binding or chelating agent.

9. The method of claim 8 in which the oral binding or chelating agent is selected from the group consisting of charcoal, cholestyramine, or both.

10. The method of claim 1 or 8 which further comprises subjecting the patient to hemodialysis.

11. A method of treating a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising: (a) testing a fluid sample of a patient for the presence of one or more mycotoxins, and (b) administering to the patient a therapeutically effective amount of an anti-fungal agent.

12. The method of claim 11 which further comprises monitoring the levels of the one or more mycotoxins in the patient undergoing treatment.

13. The method of claim 11 in which the one or more mycotoxins is selected from the group consisting of trichothecene, alphatoxin, ochratoxin, stachytoxin, alternariol, aomitoxin, chaetoglobosins, mycophenolic acid, Patulin, fumonisin, deoxynivalenol, deoxynivalenol (DON), ochratoxin, T-2, DAS and zearalenone.

14. The method of claim 11 which further comprises administering to the patient a therapeutically effective amount of an oral binding agent or chelating resin.

15. The method of claim 11 which further comprises subjecting the patient to hemodialysis.

16. The method of claim 11 in which the symptoms include that of porphyria.

17. The method of claim 1 in which the symptoms include that of Systemic Lupus Erythematosus.

18. The method of claim 1 which further comprises subjecting the patient to a hepatic assistant device (HAD) or extracorporeal liver support device.

19. The method of claim 8 which further comprises subjecting the patient to a hepatic assistant device (HAD) or extracorporeal liver support device.

20. The method of claim 18 in which the device is a plasmapheresis device, charcoal resin column, albumin dialysis device, or molecular absorption recirculation system.

21. The method of claim 1 in which the device is a plasmapheresis device, charcoal resin column, albumin dialysis device, or molecular absorption recirculation system.

22. A method of treating a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising: (a) diagnosing that a patient is suffering from ALS, Parkinson's Disease, Guillain-Barre Syndrome, Porphyria, Systemic Lupus Erythematosus, or Multiple Sclerosis, (b) testing a fluid sample of the patient for the presence of one or more mycotoxins, and (c) administering to the patient a therapeutically effective amount of an anti-fungal agent.

23. A method of treating a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising administering to the patient between about 3 to 50 grams a day of fiber.

24. The method of claim 22 which further comprises administering activated charcoal at least once a month.

25. A method of treating a patient diagnosed with a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising treating the patient for an opportunistic fungal infection.

26. The method of claim 25 in which the treatment includes administration of an anti-fungal agent.

27. The method of claim 25 in which the treatment includes blood filtration.

28. The method of claim 27 in which the blood filtration includes the use of an albumin column, a hepatic assist device (HAD), charcoal filtration, chromatography, a hepatic assist device, or combinations thereof.

29. The method of claim 28 in which the blood filtration includes the use of an albumin column.

30. A method of treating a patient diagnosed with a patient diagnosed with or exhibiting symptoms of a motor neuron disease, neurological disorder, motor neuropathy, or chronic inflammatory disease comprising treating the patient for an opportunistic fungal infection.

31. The method of claim 30 in which the treatment includes administration of an anti-fungal agent.

32. The method of claim 30 in which the treatment includes blood filtration.

33. The method of claim 32 in which the blood filtration includes the use of an albumin column, a hepatic assist device (HAD), charcoal filtration, chromatography or a hepatic assist device.

34. The method of claim 33 in which the blood filtration includes the use of an albumin column.

35. A method of treating a patient diagnosed with a patient diagnosed with or exhibiting symptoms of neurologic diseases resembling Amyotrophic Lateral Sclerosis or Parkinsonism, Autoimmune Disorders resembling to Systemic Lupus Erythematosis, or Hypercoagulable disorders resembling Lupus Anticoagulant disorder or Anti Phospholipid Syndrome disease comprising treating the patient for an opportunistic fungal infection.

36. The method of claim 35 in which the treatment includes administration of an anti-fungal agent.

37. The method of claim 35 in which the treatment includes blood filtration.

38. The method of claim 37 in which the blood filtration includes the use of an albumin column, a hepatic assist device (HAD), charcoal filtration, chromatography, a hepatic assist device, or combinations thereof.

39. The method of claim 38 in which the blood filtration is by the use of an albumin column.