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(WO/2008/021970) TREATMENT OF MOTOR NEURON DISEASE, INCLUDING

CERTAIN NEUROLOGICAL DISORDERS, MOTOR NEUROPATHIES AND CHRONIC

INFLAMMATORY DISEASESBiblio. DataDescription Claims National

PhaseNoticesDocuments Note: OCR Text

Note: Text based on automatic Optical

Character Recognition processes. Please

use the PDF version for legal matters TREATMENT OF MOTOR NEURON

DISEASE, INCLUDING CERTAIN NEUROLOGICAL DISORDERS, MOTOR

NEUROPATHIES AND CHRONIC

INFLAMMATORY DISEASES

http://www.wipo.int/pctdb/en/wo.jsp?

IA=WO2008021970 & wo=2008021970 & DISPLAY=DESC

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. & 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, naftifúne, 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. & 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.