Treating neurological diseases with antifungals

June 15, 2008

There is good information in this report regarding the use of antifungal drugs

to treat neurological illnesses. I would be interested to know if the doctors

in this group have any experience with this.

http://www.wipo.int/pctdb/en/wo.jsp?wo=2008021970 & IA=WO2008021970 & DISPLAY=DESC

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. & 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

AdsorbaR 150C (150 grams of activate charcoal) and AdsorbaR 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.

June 16, 2008

The posting below is rather interesting for what it is, a patent application to

derive the applicant rights to license anti-fungal treatment for motor-neuron

illnesses. The invention is not a new drug, just new uses for a wide array of

existing drugs. There is no mention of any peer reviewed medical journal

publication to support any of his claims. If anyone is aware of such, it might

give credence to the many claims made, rather than simply triggering false

hopes.

Treating neurological diseases with antifungalsPosted by: " "

brianc8452@... brianc8452Date: Sun Jun 15, 2008 2:46 pm ((PDT)) There is

good information in this report regarding the use of antifungal drugs to treat

neurological illnesses. I would be interested to know if the doctors in this

group have any experience with this.

http://www.wipo.int/pctdb/en/wo.jsp?wo=2008021970 & IA=WO2008021970 & DISPLAY=DESC

TREATMENT OF MOTOR NEURON DISEASE, INCLUDING CERTAIN NEUROLOGICAL DISORDERS,

MOTOR NEUROPATHIES AND CHRONICINFLAMMATORY 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