WO2018112106A1 - Procédés et compositions de traitement de la maladie de parkinson - Google Patents

Procédés et compositions de traitement de la maladie de parkinson Download PDF

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Publication number
WO2018112106A1
WO2018112106A1 PCT/US2017/066218 US2017066218W WO2018112106A1 WO 2018112106 A1 WO2018112106 A1 WO 2018112106A1 US 2017066218 W US2017066218 W US 2017066218W WO 2018112106 A1 WO2018112106 A1 WO 2018112106A1
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Prior art keywords
malassezial
agent
disease
parkinson
subject
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PCT/US2017/066218
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English (en)
Inventor
Matthew Carl LAWYER
Carl Henry LAWYER
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Cove Bio Llc
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Priority to CA3046501A priority Critical patent/CA3046501A1/fr
Priority to AU2017376458A priority patent/AU2017376458A1/en
Priority to MX2019007041A priority patent/MX2019007041A/es
Priority to EP17880499.3A priority patent/EP3554496A4/fr
Priority to JP2019551927A priority patent/JP2020502269A/ja
Priority to CN201780086331.3A priority patent/CN110753543A/zh
Publication of WO2018112106A1 publication Critical patent/WO2018112106A1/fr
Priority to US16/439,164 priority patent/US20200061018A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention is directed to the fields of pharmaceutical science and clinical medicine.
  • Various embodiments relate generally to methods and compositions for the prevention, mitigation, or treatment of Parkinson's disease.
  • methods and compositions for preventing, mitigating, or treating Parkinson's disease by administering to a subject in need thereof an effective amount of an anti-malassezial agent are provided herein.
  • the anti-malassezial agent may be any substance that has a biocidal and/or biostatic activity for Malassezia fungi.
  • the anti-malassezial agent is an antifungal compound selected from the group consisting of zinc pyrithione, ciclopirox olamine, a polyene (e.g., amphotericin B), an azole (e.g., ketoconazole, itraconazole, fluconazole, and
  • Voriconazole an allylamine (e.g., terbinafine), a morpholine (e.g., amorolfine), a sulfonamide (e.g., sulfacetamide), a glucan synthesis inhibitor or any combination thereof.
  • an allylamine e.g., terbinafine
  • a morpholine e.g., amorolfine
  • a sulfonamide e.g., sulfacetamide
  • glucan synthesis inhibitor or any combination thereof.
  • the antifungal agent is preferably a lipase inhibitor.
  • the lipase inhibitor is orlistat or cetilistat, or any combination thereof.
  • the antifungal compound may be in the form of a topical agent, an intranasal agent, an oral agent, a systemic agent, an antimetabolite and mixtures thereof.
  • the anti-malassezial agent is a debridement compound, such as a wash solution.
  • the debridement compound is a hypertonic saline solution.
  • the anti-malassezial agent is an anti-inflammatory compound.
  • the anti-inflammatory agent is ibuprofen or betamethasone.
  • the anti-malassezial agent is an antiseptic compound.
  • the antiseptic compound is a laundry composition.
  • the anti-malassezial agent is a UV light therapy.
  • the present invention relates to pharmaceutical compositions for the treatment, mitigation, or prevention of Parkinson's disease comprising an anti- malassezial agent.
  • the present invention relates to methods for treatment, mitigation, or prevention of Parkinson's disease, comprising administering to a patient in need thereof a pharmaceutical composition of the invention.
  • Some preferred embodiments comprise pharmaceutical compositions for treating Parkinson's disease, comprising a therapeutically effective amount of an anti-malassezial agent and a pharmaceutically acceptable carrier.
  • Figure 1 shows a graphical depiction of homology of leucine-rich repeats between Malassezia and the human LRRK2.
  • Figure 2 shows a graphical depiction of the Malassezial enzyme gene sequences for myxalamid polyketide synthase MxaB and epothilone polyketide synthase D.
  • Figure 3 shows a graphical depiction of the homology of polyketide synthetase genes between Malassezia and Beauveria.
  • Figure 4 Shows a graphical depiction of the phylogenetic tree of relative evolutionary branching among various fungi discussed in the present disclosure.
  • the present invention is based on the inventors surprising and unexpected discovery that Malassezia is a cause of Parkinson's disease.
  • Malassezia produce brain penetrant mycotoxins that cause apoptosis and cell death of the nigral dopaminergic neurons (nigral melanocytes) located in the substantia nigra of the midbrain. Reduction of these neurons is a known cause of attenuation in striatal dopamine efflux correlating positively with increased severity of Parkinson's disease.
  • the inventors performed comparative genomic analyses of Malassezia species and other sources of human fungal infection.
  • Malassezial enzymes that produce Malassezial brain-penetrant mycotoxins are encoded and expressed in the genomes of Malassezia known to infect the human skin (epidermis) as well as the human gastrointestinal tract (endodermis).
  • Malassezia globosa, Malassezia pachy derma, and Malassezia sympodialis have been discovered by the inventors to each contain the genes for myxalamid polyketide synthase MxaB and epothilone polyketide synthase D ( Figure 2), enzymes that produce brain-penetrant mycotoxins epothilone D and myxalamid.
  • the brain-penetrant mycotoxin epothilone D destabilizes cellular microtubule function of neurons. Reduced microtubule stability in nigral neurons is known to be associated with Parkinson's disease.
  • the brain-penetrant mycotoxin myxalamid inhibits respiratory electron transport chain function at mitochondrial complex 1. Inhibition of respiratory electron transport chain function at mitochondria complex 1 in nigral neurons is a known to be associated with Parkinson's disease.
  • Malassezia produces and secretes malassezin, which is a brain-penetrant mycotoxin known to cause apoptosis and cell death in human primary epidermal melanocytes.
  • Nigral melanocytes share the same embryological precursor origin (i.e., neural crest cells) as these epidermal melanocytes. Parkinson's disease has a known positive correlation between severity of disease and cell death of the pigmented nigral neurons in the midbrain.
  • Myxobacteria are known to produce and secrete mycotoxins that have human cell toxicity.
  • Sorangium cellulosum produces and secretes Ixabepilone, an epothilone analog that is commercially manufactured and sold under the brand name IXEMPRA by Bristol-Myers Squibb (New
  • LRRK2 Leucine-rich repeat kinase 2
  • PARK8 is an enzyme that in humans is encoded by the PARK8 gene and is a member of the leucine-rich-repeat kinase family of genes.
  • Variants of the human LRRK2 gene are associated with an increased risk of acquiring Parkinson's disease. People with pathogenic LRRK2 mutations (e.g., G2019S, R1441G,
  • Y1699C, R114C, R1441H, and I2020T are at increased risk of acquiring Parkinson's disease as compared to the general population.
  • Malassezia genes encode homologous leucine-rich repeats in malassezial proteins as found in the human LRRK2 gene ( Figure 1).
  • the inventors have discovered that entomopathogenic fungus Beauveria bassiana encodes polyketide synthetase enzymes that share homology with polyketide synthetase enzymes encoded in Malassezia globosa, Malassezia pachy derma ( Figure 3) and Malassezia sympodialis genomes.
  • Beauveria bassiana is known to infect insects and produces mycotoxins that enter the central nervous system of the insects to cause symptoms similar to Parkinson's disease, namely involuntary muscle contractions, prostration with tremors, and eventually paralysis followed by death.
  • the inventors have discovered that chiropteratopathogenic fungus
  • Pseudogymnoascus destructans encodes polyketide synthetase enzymes that share homology with polyketide synthetase enzymes encoded in the Malassezia globosa genome. Pseudogymnoascus destructans is known to infect bats and produces mycotoxins that enter the central nervous system of the bats to cause symptoms similar to Parkinson's disease.
  • Curacin A is known to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation of microtubules. Curacin A has also been characterized as a potent antiproliferative cytotoxic compound with known anti-neoplastic activity for several human cell lines.
  • Seborrhea and seborrheic dermatitis are common early symptoms of Parkinson's disease. Accordingly, the Malassezia responsible for the seborrhea and seborrheic dermatitis may cause the susceptibility, onset, development or progression in the Parkinson's disease state and symptoms. Mycotoxins produced by Malassezia are known to cause the redness and scaling symptoms of seborrheic dermatitis. It has been discovered through clinical observation coupled with deductive reasoning that increased seborrhea and worsening seborrheic dermatitis in patients with Parkinson's disease has a significant positive correlation with higher frequency of relapse or acceleration in progression of active Parkinson's disease.
  • detecting the mycotoxins produced by microorganisms responsible for the seborrhea and seborrheic dermatitis can be used to detect the susceptibility, onset, development or progression in the Parkinson's disease state and symptoms.
  • the mycotoxins responsible for the seborrhea and seborrheic dermatitis may cause the susceptibility, onset, development or progression in the Parkinson's disease state and symptoms.
  • Intranasal Malassezia infection is a point of entry for Malassezial brain penetrant mycotoxins to access the central nervous system through the olfactory system.
  • the presence of intranasal Malassezial infection correlates with olfactory dysfunction, such as decreased odor detection, identification, and discrimination, which is a common early symptom of Parkinson's disease.
  • the present invention pertains, at least in part, to a method for treating a subject for Parkinson's disease by administering to the subject an effective amount of at least one compound or pharmaceutical composition of the invention.
  • the compound(s) or pharmaceutical composition(s) may also be useful for treating a
  • the present invention provides for simultaneously treating Parkinson's disease and Malassezia infection, which includes prophylactic measures to inhibit susceptibility and onset as well as curative measures to reduce or cure an ongoing or established Parkinson's disease or Malassezia infection.
  • the present invention provides a method for the prevention and/or treatment and/or mitigation of Parkinson's disease in a subject in need thereof including the step of administering to the subject therapeutically effective amount of a compound or pharmaceutical composition, comprising an anti-malassezial agent.
  • a subject in need of a compound or pharmaceutical composition comprising an anti-malassezial agent may suffer from motor symptoms and dysfunctions that include one or more of bradykinesia, rest tremor (such as pill-rolling tremor), rigidity, postural instability, gait difficult (e.g., shuffling gait), hypomimia (masked facies), hypokinetic dysarthria, hypophonia, palilalia, dysphagia, sialorrhea, decreased spontaneous eye blink rate, eyelid opening apraxia, hypometric saccades, impaired vestibuloocular reflex, impaired upward gaze and convergence, respiratory distress, micrographia, incontinence, restless legs syndrome, sleep apnea, dystonia, myoclonus,
  • Such patients in need of a compound or pharmaceutical composition comprising an anti-malassezial agent may also suffer from non-motor symptoms or dysfunctions that include one or more of cognitive and/or sensory dysfunction or impairment that include one or more of subcortical dementia, Lewy body dementia, psychomotor retardation, memory difficulty, learning and executive dysfunction (e.g., attention deficit disorder), language impairment, altered personality, impulse control dysfunction (e.g.
  • administration of the compound or pharmaceutical composition comprising an anti-malassezial agent treats one or more of the motor and/or non-motor symptoms of PD.
  • subject improvement is measured by methods known in the art (e.g., ADAS-cog, MDRS, MoCA, CDR, FAB, D-KEFS VF, HVLT, TPCT, MMSE, QTCS, VMI, BTA, NPI, CSDD, BPRS, ADCS-ADL, QOL-AD, DAD, SE-ADL, PDQ- 39, UPDRS, MDS-UPDRS, UPDRS-ADL, CGI, ADC-CGIC, CIBC-PLUS, and ZBI) and the response is statistically significant (e.g. test-retest reliability, Student's t-test, or the like).
  • methods known in the art e.g., ADAS-cog, MDRS, MoCA, CDR, FAB, D-KEFS VF, HVLT, TPCT, MMSE, QTCS, VMI, BTA, NPI, CSDD, BPRS, ADCS-ADL, QOL-AD, DAD,
  • the improvement e.g., amelioration or mitigation of Parkinson's disease and/or symptoms of Parkinson's disease
  • the improvement is measured with a subject's personal self-assessment and/or with the improvement measured by of the subject's caregiver or caregivers and/or with the improvement measured by the subject's healthcare provider or providers.
  • a subject can be an otherwise healthy individual who is at increased risk of acquiring Parkinson's disease because the person's genome contains a copy of the rs34637584(A) allele, a single nucleotide polymorphism (SNP) commonly referred to as the G2019S variant that is a well-known Parkinson's disease associated mutation rarely found in healthy, elderly people without Parkinson's disease and found with higher frequency in people with both the sporadic and familial types of Parkinson's disease. A person with a copy of the allele possesses a greatly increased chance of acquiring Parkinson's disease.
  • G2019S refers to the change from glycine
  • LRRK2 leucine-rich repeat kinase 2
  • PARK8 an enzyme that in humans is encoded by the PARK8 gene and is a member of the leucine-rich repeat kinase family of proteins.
  • Parkinson's disease associated mutations examples include variants rsl 12176450, rs35095275, rs34778348, rs3892097, rs287235, rs838552, rs283413, rsl l 868035, rsl057217, and rs6812193.
  • the invention provides methods of prophylactic treatment of Parkinson's disease by administering an effective amount of an anti-malassezial agent to a person with one or more mutations associated with increased risk of Parkinson's disease who has not acquired Parkinson's disease.
  • the term “treat” or “treated” or “treating” or “treatment” refer to any type of action that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease, or condition (e.g., Parkinson's disease), including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, and/or change in clinical parameters, disease or illness, etc., as would be well known in the art.
  • a disorder, disease, or condition e.g., Parkinson's disease
  • treatment includes therapeutic and/or prophylactic treatment of Parkinson's disease, the diminishment or alleviation of at least one symptom associated with Parkinson's disease (e.g., bradykinesia, rest tremor, rigidity, insomnia, dementia, abulia, anosmia, and sialorrhea), and the eradication of one or more symptoms of Parkinson's disease.
  • a symptom associated with Parkinson's disease e.g., bradykinesia, rest tremor, rigidity, insomnia, dementia, abulia, anosmia, and sialorrhea
  • treatment can be a remission or cure of the condition of having Parkinson's disease.
  • such treatment can provide simultaneous remission or cure for a Malassezial infection.
  • treatment includes the arresting or slowing of progression of
  • the stopping or slowing of the progression Parkinson's disease can be a decreased rate of increase in symptoms.
  • the decreased rate of increase in symptoms can be measured, for example, by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores over time.
  • MDS-UPDRS is a commonly used clinical neurological rating scale that quantitatively measures longitudinal course of Parkinson's disease severity.
  • prevention refers to prevention or delay of the onset of a disorder, disease, or condition (e.g., Parkinson's disease) and/or a decrease in the symptoms of Parkinson's disease in a subject relative to the symptoms of Parkinson's disease that would develop in the absence of the methods of the invention.
  • the prevention can be complete, for example, the total absence of Parkinson's disease in a subject.
  • the prevention can also be partial, such that the Parkinson's disease in a subject has reduced symptoms from that which would have occurred without the present invention.
  • prevention “prophylactic treatment”, and “prophylaxis” may be used interchangeable and are intended to refer to prevention.
  • the prophylactic treatment of Parkinson's disease in a subject comprises applying to the subject a composition comprising an anti-malassezial agent effective to prevent Malassezia fungi from infecting the subject, and/or to inhibit and/or kill a Malassezia fungi infection, so as to protect the subject from acquiring Parkinson's disease.
  • treating Parkinson's disease may include a preceding step of identifying a subject as being infected, suspected of being infected, or at risk of infection, with Malassezia fungi.
  • treating Parkinson's disease may include a preceding step of diagnosing a subject as being infected or at risk of infection, with a Malassezia fungi.
  • treating Parkinson's disease may include a preceding step of identifying a site of a subject (e.g., the human nose cavity) as being colonized, suspected of being colonized, or at risk of colonization, with a Malassezia fungi.
  • a site of a subject e.g., the human nose cavity
  • colonization is the presence or establishment of a fungus organism or population of fungi at a particular site or location (e.g., the scalp) and/or the expansion of the numbers of the fungus organism by replication or recruitment of additional fungi.
  • infection is encompassed by the term “colonization” and includes disease associated colonization and/or undesirable colonization.
  • the treatment, mitigation, or prevention for Parkinson's disease in a subject in need thereof comprises physical removal or reduction (e.g.
  • the physical removal of Malassezia at the location of infection can be carried out with any suitable surgical, mechanical or chemical means.
  • the means can be the use of a liquid, foam, gel, gel-solid, semi-solid compositions or gas applied at pressure to the location undergoing therapy.
  • the location may be contacted with an anti-malassezial agent.
  • a composition used in the physical removal of the Malassezial infection or used as a wash solution before, during or after the removal may contain an anti-malassezial agent. Accordingly, some embodiments provide a debridement composition, for use in the treatments and methods of the invention.
  • Such a debridement composition will typically be an aqueous sterile solution, and may additionally contain one or more abrasives (e.g., calcium carbonate, hydrated silica, hydrated aluminum oxide), detergents (e.g., nonoxynol-9, castile soap), and/or proteolytic enzymes (e.g. collagenase, elastase, pepsin, and trypsin).
  • abrasives e.g., calcium carbonate, hydrated silica, hydrated aluminum oxide
  • detergents e.g., nonoxynol-9, castile soap
  • proteolytic enzymes e.g. collagenase, elastase, pepsin, and trypsin.
  • the debridement composition is an aqueous solution comprising a mixture of non-iodized sodium chloride and purified or filtered water warmed to about 98 degrees Fahrenheit (37 degrees Celsius).
  • the aqueous solution may be hypertonic (e.g., 3% sodium chloride), isotonic (e.g., 0.9% sodium chloride) or hypotonic (e.g., 0.65% sodium chloride).
  • the aqueous solution may have other components including, for example, pH modifiers, buffers (e.g., sodium bicarbonate), local anesthetic agents, preservatives, flavoring agents, coloring agents, agents that promote wound healing, agents that stop bleeding and/or promote clot formation, and other therapeutic and non-therapeutic components.
  • administered includes routes of administration which allow the anti-malassezial agents to perform their intended function(s) of preventing, mitigating, or treating Parkinson disease in a subject.
  • routes of administration examples include parenteral (e.g., subcutaneous,
  • preferred routes of administration which may be used include injection, topical, oral, intranasal, intra-aural, subcutaneous, intravenous, inhalation and transdermal.
  • the anti-malassezial agent is administered in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier include those suitable for injection, topical, oral, intranasal, subcutaneous, intravenous, inhalation and/or transdermal administration.
  • an anti-malassezial agent may be coated with or contained within a material to protect it from natural conditions which may detrimentally affect the ability of the anti-malassezial agent to perform its intended function.
  • a sustained-release formulation may be designed to release the one or more anti-malassezial agents in a targeted part of the intestinal tract, mucosa (e.g., nasal passages), scalp, or respiratory tract, possibly over a period of time.
  • the administration of the anti-malassezial agent is done at dosages and for periods of time effective to prevent, mitigate, or treat Parkinson's disease or to reduce or obviate the risk of Parkinson's disease.
  • the daily dosage of the anti-malassezial agent is about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or higher.
  • the anti-malassezial agent is fluconazole and the daily dosage is 100 or 200 mg per day.
  • the anti-malassezial agent is administered daily for a period of at least four weeks, three months, at least four months, at least five months, at least six months, or longer.
  • the anti-malassezial agent is fluconazole, the daily dosage is 100 mg or 200 mg per day, and the period of administration is at least 4 weeks, two months, or three months.
  • the anti-malassezial agent is given once a week for at least three, four, eight, twelve, or more weeks.
  • the anti-malassezial agent is fluconazole and is administered at 300 mg once weekly for at least three, four or eight weeks.
  • the daily or weekly dosages of the anti-malassezial agent is administered orally.
  • fluconazole is administered orally at a daily dosage of 100 mg or 200 mg for at least four weeks, or at a weekly oral dosage of 300 mg for at least three, four or eight weeks. Dosage regimes may be adjusted for purposes of improving the therapeutic or prophylactic response of the anti-malassezial agent.
  • the first dose of the anti-malassezial agent given on day one of treatment is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or higher, followed by a daily dose of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or higher for at least three months.
  • the anti-malassezial agent is fluconazole
  • the starting dosage on day one of treatment is 400 mg given orally
  • the subsequent daily dosage is 200 mg per day given orally
  • the period of administration is at least three months.
  • Suitable pharmaceutical vehicles or dosage forms for injectable compositions, implants, and systemic administration are known.
  • the anti-malassezial agent may be administered intra-nasally and can be formulated into a variety of intranasal administrable compositions of the invention, such as washes, foams, gels, powders, and the like.
  • the intranasal administration comprises irrigating the nasal passages with an anti-malassezial agent.
  • the anti-malassezial agent is administered to a patient by exposing the deeper reaches of the nasal cavity to effective amounts of an anti-malassezial agent, orally (e.g., gargling with an anti- malassezial agent formulated as a mouthwash), by inhalation (including nasal inhalation) and/or by nasal spray or drops.
  • the anti-malassezial agent may be administered in the intra-aurally (i.e., the ear canal) and can be formulated into a variety of intra-aural administrable compositions of the invention, such as washes, foams, gels, powders, and the like.
  • the intra-aural administration comprises irrigating the ear canal with an anti-malassezial agent.
  • the anti-malassezial agent is administered to a patient by exposing the deeper reaches of the ear canal to effective amounts of an anti-malassezial agent, via swab stick application (e.g., Q-Tip containing an anti-malassezial agent formulated as a powder or gel), by ear wick (e.g., an ear wick impregnated with clotrimazole cream inserted into ear of patient by a physician in clinic and changed every third day for nine days), and/or by aural spray or drops.
  • swab stick application e.g., Q-Tip containing an anti-malassezial agent formulated as a powder or gel
  • ear wick e.g., an ear wick impregnated with clotrimazole cream inserted into ear of patient by a physician in clinic and changed every third day for nine days
  • the anti-malassezial agent is administered to a patient in conjunction with a drying agent. In some embodiments, the anti-malassezial agent is administered to a patient in conjunction with debridement of ear wax such as, for example, mechanical suctioning of the ear canal and/or application of Burow's solution or 5% aluminum acetate solution.
  • some examples of drops for use in treating Malassezia present in the ear include clotrimazole (e.g., in a I percent solution) or flumetasone pivalate (e.g. in a 0.02 percent solution) plus clioquinol (e.g., in a 1 percent solution).
  • an example of anti-malassezial cream for use in treating Malassezia present in the ear includes clotrimazole 1 percent cream.
  • the cream formulation suitable for treating Malassezia present in the ear is comprised of an anti-malassezial antifungal agent combined with benzyl alcohol, cetostearyl alcohol, cetyl esters wax, 2-octyldodecanol, polysorbate 60, purified water, and/or sorbitan monostearate.
  • an anti-malassezial agent is administered to a patient by a liquid stream lavage (also referred to as a "neti pot").
  • a liquid stream lavage also referred to as a "neti pot”
  • the anti-malassezial agent formulated as a solution is fed by gravity or slight pressure into one nostril and the composition exits the other nostril.
  • An artificial pressure may also be used to feed the solution.
  • An example of a device that creates artificial pressure to feed the solution is a pulsating irrigation device.
  • An example of a pulsating irrigation device is the Grossan HydroPulse manufactured by Hydro Med, Inc. (Los Angeles, California).
  • a water vapor (mist) and/or other vapor based composition is administered into the nose and onto the nasal sinus and/or contiguous/adjacent nasal structures (e.g., olfactory fossa, olfactory bulb, and cribriform plate).
  • the anti-malassezial agent may be administered topically to the skin and can be formulated into a variety of topically administrable compositions, such as lotions, solutions, suspensions, shampoos, foams, gels or ointments.
  • the anti-malassezial agent may be administered in any order.
  • the medication may be any medication known to the art to treat the symptoms of Parkinson's disease and is preferably selected from the group consisting of carbidopa-levodopa (e.g., Duopa), pramipexole (e.g., Mirapex), ropinirole (e.g., Requip) and rotigotine (e.g.
  • carbidopa-levodopa e.g., Duopa
  • pramipexole e.g., Mirapex
  • ropinirole e.g., Requip
  • rotigotine e.g.
  • apomorphine e.g., Apokyn
  • selegiline e.g., Zelapar
  • rasagiline e.g., Azilect
  • entacapone e.g., Comtan
  • tolcapone bromocriptine
  • benztropine e.g., Cogentin
  • trihexyphenidyl e.g., amantadine.
  • the co-administration of the anti-malassezial agent with another compound includes administration of the anti-malassezial agent first, followed by the compound and administration of the compound.
  • the co-administration of the anti-malassezial agent with another compound includes administration of the compound first, followed by the anti- malassezial agent.
  • the co-administration of the anti-malassezial agent with another compound includes administration of the anti-malassezial agent at the same time as the other compound.
  • the term "therapeutically effective amount” or “effective amount” includes an amount of the therapeutic or treatment composition that provides a prophylactic or therapeutic benefit in the treatment, prevention, or management of a disease or a symptom of a disease.
  • the therapeutically effective amount may treat a disease or condition, a symptom of disease, or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease, the symptoms of disease, or the predisposition toward disease.
  • the term "therapeutically effective amount” or “effective amount” of the anti-malassezial agent includes an amount of the anti-malassezial agent that is sufficient in treating, mitigating, or preventing Parkinson's disease.
  • an "effective amount" of the anti- malassezial agent means an amount of the anti-malassezial agent to be administered necessary to treat or prevent a disease or disorder mediated by deficiency in nigral dopaminergic neurons.
  • "effective amount” of the anti-malassezial agent means the amount necessary to improve cognitive and/or motor function in a subject, or reduce a decline in cognitive and/or motor function.
  • "effective amount” of the anti-malassezial agent is the amount of the anti-malassezial agent required to prevent dopaminergic neuronal cell death in the substantia nigra.
  • "effective amount” is the amount of the anti-malassezial agent with sufficient biostatic or biocidal activity against Malassezia infection to diminish or alleviate a symptom of Parkinson's disease.
  • a therapeutically effective amount can be readily determined on an individual basis and will be based, in part, on the severity of Malassezia infection and the activity of the specific anti-malassezial agent.
  • a therapeutically effective amount of an anti- malassezial agent can be determined by one of ordinary skill in the art using no more than routine experimentation in clinical management of a subject.
  • the specific amount that is therapeutically effective may be readily determined by ordinary medical practitioner, and may vary depending on factors known in the art, such as, e.g.
  • the patient's history including genetic and medical history
  • sex age
  • patient's family history including genetic and medical history
  • the patient's history of previous treatment modalities of Parkinson's disease and/or Malassezia infection the patient's history of progression of Parkinson's disease, the stage of Parkinson's disease, genetic risk of Parkinson's disease, and the current administration of other therapeutic agents.
  • Another factor influencing clinical management of a subject is the patient's side effect profile history.
  • previous gastro-intestinal (GI) upset and/or elevated liver enzyme levels e.g., Alanine transaminase (ALT) and Aspartate transaminase (AST)
  • GI gastro-intestinal
  • ALT Alanine transaminase
  • AST Aspartate transaminase
  • previous antifungal compound use may influence the determination of a specific treatment regimen of a subject in need of treatment, mitigation, or prevention of Parkinson's disease.
  • the dosage ranges for the administration of are those that produce the desired effect. Generally, the dosage will vary with the age, weight, condition, and sex of the patient. and the extent of disease. A person of ordinary skill in the art, given the teachings of the present specification, may readily determine suitable dosage ranges.
  • a therapeutically effective amount of the anti-malassezial agent includes a precise dosage level determined by an attending physician or other health care provider and will depend upon well-known factors, including route of administration, and the age, body weight, sex, concomitant therapies, patient medical history including previous drug tolerances, general health of the patient; the nature, severity and clinical stage of Malassezia infection, and/or other clinical dosing factors known in the art.
  • anti-malassezial agent is any substance that has a significant biocidal and/or biostatic activity against Malassezia fungi for use in the treatment, mitigation, or prevention of Parkinson's disease.
  • the anti-malassezial agent inhibits the growth of one or more Malassezia organisms in a subject receiving said agent.
  • the anti-malassezial agent kills one or more Malassezia organisms in a subject receiving said agent.
  • the anti-malassezial agent is a substance that that has a biocidal and/or biostatic activity for Malassezia fungi. In further embodiments, the anti- malassezial agent is a substance that that has a biocidal and/or biostatic activity that is relatively specific and selective for Malassezia fungi.
  • anti-malassezial comprise anti-fungal compounds that have biocidal and/or biostatic activity for Malassezia fungi.
  • anti-fungal compounds examples include polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g., polyene antifungal drugs (e.g.
  • amphotericin B natamycin, rimocidin, nystatin, candicidin, hamycin, filipin, perimycin
  • imidazole antifungals e.g., miconazole, ketoconazole, climbazole, clotrimazole, econazole, enilconazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, lanoconazole, luliconazole, oxiconazole, sertaconazole, sulconazole, tioconazole), triazole antifungals (e.g., fluconazole, fosfluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole, albaconazole), thiazole antifungals (e.g., abafungin), ally
  • terbinafine, naftifine, butenafine, amorolfine echinocandin antifungals
  • echinocandin antifungals e.g. anidulafungin, caspofungin, micafungin
  • hydroxypyridones e.g., ciclopirox, piroctone olamine
  • tolnaftate chlovalicin
  • ovalicin fumagillin
  • sulfur lithium gluconate
  • lithium succinate zinc carbonate
  • polytar e.g., coal tar
  • a thiocarbamate e.g., tolnaftate
  • Whitfields ointment e.g., tolnaftate
  • Preferred anti-fungal compounds include lipase inhibitors.
  • Preferred lipase inhibitors include, but are not limited to, orlistat and cetilistat.
  • Preferably, lipase inhibitors are topically administered to a patient to treat disease in accordance with the invention.
  • amphotericin B is formulated as a liposomal amphotericin B, amphotericin B colloidal dispersion, amphotericin B lipid complex, deoxycholate amphotericin B, or amphotericin B oral suspension.
  • the anti-malassezial agent may be an antifungal drug that is administered via systemic routes of administration (e.g., amphotericin B, ketoconazole, fluconazole, fosfluconazole, itraconazole, posaconazole, voriconazole, and terbinafine).
  • the anti-malassezial agents will be an antifungal drug that is commonly administered as a non-systemic treatment (e.g., a topical treatment).
  • antifungal drugs include amphotericin B, natamycin, nystatin, candicin, hamycin, perimycin, miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, fosfluconazole, isavuconazole, ravuconazole, terconazole, albaconazole, abafungin, terbinafine, naftifine, butenafine, amorolfine, tolnaftate, ciclopirox, zinc pyrithione; sulfur; salicylic acid, benzoic acid, coal tar (polytar), and tretinoic acid.
  • antifungal agents examples include ciclopirox olamine, zinc pyrithione, amphotericin B, nystatin, ketoconazole, miconazole, fluconazole, itraconazole, and voriconazole.
  • the antifungal drug may be used in any convenient form, including any
  • references to disclosed antifungal drugs extends to any analogs thereof, compounds which mimic their activity, and/or isomeric form in which the compound may exist as well as mixtures of two or more isomers, e.g. racemic mixtures.
  • the invention contemplates compounds that inhibit fungal growth through an increase in copper at the location of the Malassezia infection.
  • anti -inflammatory compounds and antiseptic compounds may also be considered to be anti-malassezial agents to the extent that these compounds have biocidal and/or biostatic activity for Malassezia fungi and to the extent that administration of these compounds is not deleterious to the subject, even though anti-inflammatory compounds and antiseptic compounds have a broad spectrum of biocidal and/or biostatic activity that do not display appreciable specificity or selectivity for Malassezia fungi over other cell types (e.g. bacteria, archaea, protists, plants, and animals).
  • cell types e.g. bacteria, archaea, protists, plants, and animals.
  • the antiseptic compound mitigates, treats, or prevents Parkinson's disease by decreasing or preventing Malassezia from coming in contact with the subject in need of mitigation, treatment, or prevention of Parkinson's disease.
  • the antiseptic compound is formulated as a laundry composition comprising at least one antiseptic compound, the composition preferably being a laundry detergent or laundry conditioner.
  • the antiseptic compound of the laundry composition comprises a bleach solution.
  • antifungal compounds encompassed by the group of laundry compositions are well-known to those skilled in the art.
  • antifungal compounds for use in laundry compositions useful in the present invention and formulations thereof are disclosed in U.S. Pat. No. 7,987,539 (to Pestell et al), U.S. Pat. No. 4,235,599 (to Davis et al), and U.S. Pat. No. 6,228,127(to Reinehr et al), which are incorporated herein by reference in their entirety.
  • Anti-inflammatory compounds useful in the methods and compositions of the present invention include, but are not limited to, steroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • preferred anti-inflammatory compounds, useful in the present invention include ibuprofen and betamethasone.
  • a safe and effective amount of an anti-inflammatory compounds may be added to a composition of the present invention, preferably from about 0.1% to about 25%, more preferably from about 0.5% to about 20%, of the composition.
  • the exact amount of anti-inflammatory compound to be used in the methods and compositions will depend on the particular anti -inflammatory compounds utilized since such compounds vary widely in potency and toxicity.
  • Steroidal anti -inflammatory drugs include corticosteroids such as, alpha-methyl dexamethasone, dexamethasone-phosphate, hydrocortisone, hydroxyltriamcinolone clobetasol valerate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, flumethasone pivalate, fluclorolone desoxycorticosterone acetate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, paramethasone, prednisolone dexamethasone, dichlorisone, acetonide, fludrocortisone, prednisolone acetate, loteprednol etabonate, medrysone, amcinafel, amcinafide, betamethasone, chloroprednisone, chloroprednisone a
  • fluradrenolone acetonide clescinolone, , flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone
  • cyclopentylpropionate hydrocortamate, meprednisone, fluticasone propionate, rimexolone, and mometasone furoate.
  • a second class of anti-inflammatory compounds which is useful includes the nonsteroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs include, but are not limited to salicylates (e.g., acetylsalicylic acid, amoxiprin, methyl salicylate, choline salicylate, magnesium salicylate, and salicylamide), arylalkanoic acids (e.g., diclofenac), profens (e.g., ibuprofen, alminoprofen, benoxaprofen, carprofen, and naproxen), N- arylanthranilic acids, pyrazolidine derivatives (e.g., phenylbutazone), oxicams, cyclooxygenase-2 inhibitors (e.g., celecoxib) and sulphonanilides (e.g., nimesulide).
  • salicylates e.g., acetylsalicylic acid, amoxiprin,
  • a third class of anti-inflammatory compounds which is useful includes the topical calcineurin inhibitors.
  • Suitable topical calcineurin inhibitors include, but are not limited to tacrolimus and pimecrolimus.
  • anti-inflammatory compounds encompassed by the group of anti-inflammatory compounds are well-known to those skilled in the art. Mixtures and admixtures of anti- inflammatory compounds may also be employed, as well as the pharmaceutically - acceptable salts and esters of these compounds.
  • naturopathic anti-malassezial agents are useful in the methods and compositions of the present invention.
  • naturopathic compounds include but are not limited to cinnamics (e.g. cinnamon), vanilla (e.g. vanillin), tea tree oil, citronella, camphor, coconut (e.g., SEBCO), antioxidants
  • turmeric e.g., vitamin D
  • turmeric e.g., cypress extracts, lavender, colloidal silver, colloidal copper, colloidal zinc, limonene, lemon myrtle, lemongrass, neem seed, olive leaf extract, orange oil, palmarosa oil, patchouli oil, beeswax, honey, aloe vera, yoghurt-acidophilus-milk (YAM), acidophilus, yoghurt, phenylalanine, methylated spirits, seaweed, Allium cepa, and Allium sativum (e.g. allicin).
  • YAM yoghurt-acidophilus-milk
  • phenylalanine methylated spirits
  • seaweed Allium cepa
  • Allium sativum e.g. allicin
  • naturopathic agents are known to those skilled in the art. Mixtures and admixtures of naturopathic agents may also be employed, as well as the pharmaceutically-acceptable derivatives, extracts, oils, salts and esters of these agents.
  • the present invention encompasses the use of a single anti-malassezial agent or a plurality (e.g., mixture) of different anti-malassezial agents. Thus, for example, one anti- malassezial agent or a combination of different anti-malassezial agents (e.g. two or more) may be used.
  • the present invention provides anti-malassezial
  • phototherapeutics to mitigate, treat, or prevent Parkinson's disease in a subject in need thereof comprising irradiating a location with a Malassezia infection with sufficient electromagnetic radiation to inhibit the growth of or kill the Malassezia, wherein the radiation is administered from a minimum wavelength of about 350 nanometers (nm) to a maximum wavelength of about 450 nm.
  • the radiation is a wavelength of about 375, 380, 385, 390, 395, or 400 nm. More preferably the radiation is a wavelength of about 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395 nm. Even more preferably still the radiation is a wavelength of about 391.5 391.6,
  • anti-malassezial phototherapy refers to an artificial source of light of the frequencies of the present invention for use in mitigation, treatment, or prevention of
  • the frequency or frequencies of a given light source of the present invention can be across the entire range, a portion of the range or can be limited to a single frequency or band of frequencies within the range.
  • anti-malassezial phototherapy useful in the present invention include ultraviolet light therapy (phototherapy) comprising PUVA (psoralens plus ultraviolet A radiation), broadband UVA, broadband UVB, combined UVA and UVB, narrow-band UVB, or UVAl.
  • phototherapy is administered as a medium dose of UVAl in combination with a medium dose of narrow-band UVB.
  • the phototherapy is administered as a medium dose of UVAl in combination with a medium dose of narrow-band UVB administered within the range of
  • anti-malassezial phototherapy is a photo/antifungal combination therapy that is administered in combination with an anti-malassezial agent.
  • phototherapy is administered in combination with a topical anti-fungal compound such as selenium sulfide, ketoconazole, or miconazole.
  • Topical emollients e.g., propylene glycol
  • phototherapy may increase skin dryness.
  • a location is treated with separate light sources
  • a single dose exposure to light is from about 1 to
  • the subject is administered a dose exposure 2 to 5 times daily, once a day, 1 to 3 times weekly, or monthly.
  • the phototherapy is administered between four to six times per week.
  • the light source may be positioned very close or in contact with the body of the subject.
  • the light source is one that does not generate large amounts of heat when in use.
  • the light source is a light emitting diode (LED).
  • the light source is an LED light bulb having a light output of about 0.7 lumens at between 3 and 4 volts. In some
  • the light source is generated by a device that is hands-free, battery powered, and/or portable.
  • the light source is encompassed in a tanning lamp or bed well known in the art.
  • the anti-malassezial phototherapy mitigates, treats, or prevents Parkinson's disease by preventing Malassezia from coming in contact with a subject in need of mitigation, treatment, or prevention of Parkinson's disease.
  • the present invention pertains, at least in part, to compositions for treating
  • Parkinson's disease in a subject comprising an effective amount of an anti-malassezial agent or salt thereof and a pharmaceutically acceptable carrier.
  • compositions of the present invention may be made into a wide variety of product types.
  • Product types include, but are not limited to solutions, lotions, creams, beach products, gels, hydrogels, sticks, sprays, nebulizers, pads, plasters, ointments, pastes, mousses, foams, and cosmetics.
  • These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels, foams, and solids.
  • the topical pharmaceutical compositions of the present invention formulated as solutions typically include a pharmaceutically-acceptable aqueous or organic solvent.
  • compositions of the present invention may be prepared as a concentrate form, so that consumer products can be produced therefrom by simple dilution, without necessarily blending in of other formulating components.
  • the concentrate form is an article of commerce.
  • compositions of the present invention may be suitable for any route of administration which allows an anti-malassezial agent to perform the intended function of the anti-malassezial agent; namely preventing, mitigating, or treating
  • Non-limiting examples of routes of administration of pharmaceutical compositions of the present invention include topical, intranasal, systemic, or oral administration.
  • the pharmaceutical composition comprises an anti-malassezial agent and a pharmaceutically-acceptable carrier for use in the treatment, prevention, or mitigation of Parkinson's disease.
  • the pharmaceutical composition comprises an anti-malassezial agent and a pharmaceutically-acceptable carrier for use in the treatment, prevention, or mitigation of fatigue, particularly mental fatigue, associated with Parkinson's disease.
  • the pharmaceutical compositions of the present invention further comprise packaged pharmaceutical compositions to treat, mitigate, or prevent Parkinson's disease.
  • a packaged pharmaceutical composition (also referred to as a "kit") is intended to include at least one anti-malassezial agent, packaged with instructions (e.g., instructions for once a day administration, twice a day administration, etc.) for administering the anti- malassezial agent(s) as a treatment, mitigation, or prevention of Parkinson's disease.
  • the package can contain one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • the packaged pharmaceutical compositions include one or more containers holding one or more anti-malassezial agents, alone or in combination with one or more pharmaceutically acceptable carriers, along with instructions for use for the treatment, mitigation, and/or prevention of Parkinson's disease.
  • the packaged pharmaceutical composition may also include one or more medications known in the art to treat the symptoms of Parkinson's disease.
  • an anti-malassezial agent of the packaged pharmaceutical composition is a member of one of the preferred antifungal compounds described herein.
  • the packaged pharmaceutical compositions include a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of a pharmaceutical product or products, which notice reflects approval by the agency of manufacture, use or sale for human administration of a pharmaceutical composition of the present invention.
  • the packaged pharmaceutical compositions include package labeling identifying an anti-malassezial agent along with instructions for use of the anti- malassezial agent for the treatment, mitigation, and/or prevention of Parkinson's disease.
  • a pharmaceutical composition and/or packaged are provided.
  • composition of the present invention is sterilized.
  • phrases "pharmaceutically acceptable” refers to those compounds, dosage forms, materials, and/or compositions which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier includes a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the anti- malassezial agent within or to the subject such that the anti-malassezial agent can perform the anti-malassezial agent's intended function, e.g. to treat Parkinson's disease.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the anti- malassezial agent within or to the subject such that the anti-malassezial agent can perform the anti-malassezial agent's intended function, e.g. to treat Parkinson's disease.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • compositions of the present invention include but are not limited to lubricants, preservatives, stabilizers, solubilizers, penetrants, wetting agents, drying agents, bulking agents, fillers, emulsifiers, salts for influencing osmotic pressure, tonicity contributors (e.g., dextrose, mannitol, glycine and sodium chloride), buffers, antioxidants, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention or each other.
  • lubricants e.g., lubricants, preservatives, stabilizers, solubilizers, penetrants, wetting agents, drying agents, bulking agents, fillers, emulsifiers, salts for influencing osmotic pressure, tonicity contributors (e.g., dextrose, mannitol, glycine and sodium chloride), buffers, antioxidants, colorings, flavorings and
  • suitable pharmaceutically acceptable carriers include water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • the pharmaceutical composition comprising an anti- malassezial agent and a pharmaceutically acceptable carrier has a pH of greater than 4.0.
  • the pharmaceutical composition of the invention comprises an anti-malassezial agent, a pharmaceutically acceptable carrier, and a medication to treat the symptoms of Parkinson's disease.
  • the term "topical” includes references to formulations that are adapted for application to a body surface or body surfaces (e.g. the skin and mucous membranes).
  • Mucous membranes that may be mentioned in this respect include the mucosa of the vagina, the penis, the urethra, the bladder, the anus, the mouth (including the mucosa of the cheek, the soft palate, the under surface of tongue, the ceiling and floor of the mouth), the nose (including the nasal cavity, olfactory fossa, and cribiform plate), the throat (including the mucosa of the pharynx, the larynx, the trachea and the esophagus), the bronchi, the lungs, the eye (including the lacrimal duct and conjunctiva), the ear (including the inner ear canal), and the like.
  • Skin includes groin region (e.g. external genitals, anogenital area), scalp, scalp margin, neck, neckline, eyelids, eyebrow region, eyelashes, auricles, hairy areas of the head (e.g., eyelashes, eyebrows, mustache, beard), forehead, chin, cheeks, nail-beds (including fingers and toes), nasolabial folds, external ear canals, auricular areas, post-auricular creases, shoulders, elbows, back, sternal area, supra-stemal notch, supra-mammary area, mammary area (including areolar area), infra-mammary area, axillae, navel, and the like.
  • groin region e.g. external genitals, anogenital area
  • scalp scalp margin
  • neck neckline
  • eyelids eyebrow region
  • eyelashes eyelashes
  • auricles hairy areas of the head
  • hairy areas of the head e.g., eyelashes, eyebrow
  • Body surfaces include areas that are defined based on standard clinical/medical descriptions known in the art.
  • the so-called "danger triangle" of the face i.e., the area bounded by each lateral comer of the mouth to the bridge of the nose, including the nose and maxilla
  • a body surface is considered a body surface.
  • Topical administration includes methods of delivery to a body surface or body surfaces (e.g. the skin or mucous membranes). Topical administration involves any form of administration which involves a body surface or body surfaces (e.g. the skin or mucous membranes). Topical administration includes laying on or spreading a compound of the present invention on the skin (e.g. the scalp) of a subject.
  • topical formulations of the present invention will be applied in the range of once or twice or three or four or five times weekly up to once or twice or three or four or five times daily.
  • the topical formulation for use in the present invention may be in any form suitable for application to the body surface, such as a cream, lotion, sprays, solution, gel, hydrogel, foam, powder, ointment, paste, plaster, paint, shampoos, bio-adhesive, suspensions, aerosols, solids (e.g., bar soaps, deodorant), cosmetic formulations, and skin cleansing formulations, or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres.
  • a formulation may be used in combination with an occlusive over-layer.
  • the occlusive over-layer allows moisture evaporating from the body surface to be maintained within the formulation upon application to the body surface and thereafter.
  • the occlusive over- layer provides the skin or mucosal membrane of the subject with a protective barrier from the eternal environment.
  • Topical formulations include any formulation suitable for topical delivery of a composition of the invention.
  • Topical formulations may include those in which an active compound of the present invention is dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or non-aqueous gels, ointments, water-in-oil and oil-in- water emulsions).
  • a dermatological vehicle known in the art
  • constituents of such vehicles may comprise water, aqueous buffer solutions, non-aqueous solvents (e.g., ethanol, isopropanol, benzyl alcohol, propylene glycol, propylene glycol monolaurate, glycofurol and glycerol), oils (e.g.
  • a solubilising agent or solvent e.g. a beta-cyclodextrin, such as hydroxypropyl beta-cyclodextrin, an alcohol, a polyol (such as ethanol, propylene glycol or glycerol); a thickening agent (e.g. hydroxyethylcellulose); a gelling agent (e.g. a polyoxyethylene-polyoxypropylene copolymer); a preservative (e.g. benzyl alcohol, benzalkonium chloride, and chlorhexidine); and a pH buffering agent (e.g. such as a mixture of dihydrogen phosphate and hydrogen phosphate salts).
  • a solubilising agent or solvent e.g. a beta-cyclodextrin, such as hydroxypropyl beta-cyclodextrin, an alcohol, a polyol (such as ethanol, propylene glycol or glycerol); a thickening agent (e.g
  • aqueous solvent and “pharmaceutically - acceptable organic solvent” refer to a solvent, which is capable of having dispersed (or dissolved therein) the active compound, and possesses acceptable safety properties (e.g., desired irritation and sensitization characteristics).
  • Water is a typical aqueous solvent.
  • suitable organic solvents include: propylene glycol, butylene glycol, glycerol, butanediol, and mixtures thereof.
  • these solutions contain from about 0.01 % to about 50% of the active compound, more preferably from about 0.1 % to about 20%, and, for example, between about 0.1 % and 10% of the active compound; and from about 1% to about 80% of an acceptable aqueous or organic solvent, more preferably from about 1 % to about 30%.
  • the topical pharmaceutical compositions of the present invention are formulated as an aerosol for administration to the subject as a spray.
  • a propellant is added to the solution composition of the aerosol to improve the desired activity of the aerosol.
  • Topical pharmaceutical compositions of the present invention may be formulated as a solution comprising an emollient.
  • emollients refer to materials used for the prevention or relief of dryness, as well as for the protection of the skin.
  • such compositions contain from about 0.1 % to about 50% of the active compound and from about 2% to about 50% of a topical pharmaceutically-acceptable emollient.
  • a lotion can be made from a solution carrier system.
  • Lotions preferably comprise from about 0.1% to about 20%, more preferably from about 1% to about 5%, of the active compound; from about 1% to about 20%, preferably from about 5% to about 10%, of an emollient; and from about 50% to about 90%, preferably from about 60% to about 80%, water.
  • Another type of product that may be formulated from a solution carrier system is a cream.
  • a cream of the present invention would preferably comprise from about 0.1 % to about 20%, more preferably from about 1% to about 5%, of the active compound; from about 5% to about 50%, preferably from about 10% to about 20%, of an emollient, and from about 45% to about 85%, preferably from about 50% to about 75%, water.
  • An ointment may comprise a simple base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous). Ointments may also comprise absorption ointment bases which absorb water to form emulsions. Ointment carriers may also be water soluble. Typically, an ointment may also comprise from about 2% to about 10% of an emollient plus from about 0.1 % to about 2% of a thickening agent.
  • the carrier is formulated as an emulsion, from about 1 % to about 10%, preferably from about 2% to about 5%, of the carrier system comprises an emulsifier.
  • Emulsifiers may be nonionic, anionic or cationic.
  • Lotions and creams can be formulated as emulsions as well as solutions.
  • lotions comprise from about 0.1% to about 20%, more preferably from about 1 % to about 5%, of the active compound; from about 1% to about 20%, preferably from about 5% to about 10%, of an emollient; from about 25% to about 75%, preferably from about 45% to about 95%, water; and from about 0.1 % to about 10%, preferably from about 0.5% to about 5%, of an emulsifier.
  • Such creams would preferably comprise from about
  • 0.1 % to about 20% more preferably from about 1 % to about 5%, of the active compound; from about 1 % to about 20%, preferably from about 5% to about 10%, of an emollient; from about 20% to about 80%, preferably from about 30% to about 70%, water; and from about 1% to about 10%, preferably from about 2% to about 5%, of an emulsifier.
  • Single emulsion topical preparations such as lotions and creams, of the oil- in- water type and water-in-oil type are known in the cosmetic art and are useful in the present invention.
  • Micro-emulsion carrier systems are also useful in the present invention. These carrier systems are preferably combined with from about 1% to about 10% of the active compound.
  • a method of formulating a gel or a cosmetic stick is by adding a suitable amount of a thickening agent to a cream or lotion formulation.
  • compositions of this invention may also be present in the compositions of this invention. These include humectants, proteins and polypeptides, preservatives and an alkaline agent.
  • topical compositions herein can contain conventional cosmetic adjuvants, such as dyes, opacifiers (e.g., titanium dioxide), pigments, and fragrances.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, pills, wafers, tablets, lozenges, cachets, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient.
  • a compound of the present invention may also be administered as an electuary, bolus, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate, dicalcium phosphate), and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, (e.g., carboxymethylcellulose, gelatin, sucrose and acacia); humectants (e.g. glycerol); disintegrating agents (e.g. agar- agar, calcium carbonate, tapioca starch); solution-retarding agents (e.g. paraffin);
  • pharmaceutically acceptable carriers e.g., sodium citrate, dicalcium phosphate
  • fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid
  • binders e.g., carboxymethylcellulose, gelatin, sucrose and acacia
  • humectants e.g
  • absorption accelerators include wetting agents (e.g. cetyl alcohol); absorbents (e.g. kaolin); lubricants (e.g., talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate); and coloring agents).
  • wetting agents e.g. cetyl alcohol
  • absorbents e.g. kaolin
  • lubricants e.g., talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate
  • coloring agents e.g., talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate
  • coloring agents e.g., talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate
  • coloring agents e.g., talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate
  • compositions may also comprise suitable buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin or gelatin-type capsules (e.g., employing such excipients as lactose, high molecular weight polyethylene glycols, and the like).
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder, lubricant, inert diluent, preservative, disintegrant, and/or surface- active or dispersing agent.
  • Molded tablets may be made, for example, by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the pharmaceutical compositions of the invention therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • the solid dosage forms may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the
  • compositions of the invention only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions suitable for use include polymeric substances and waxes.
  • the active compound may also be formulated in a micro-encapsulated form.
  • Liquid dosage forms for oral administration of an active compound include pharmaceutically acceptable emulsions, micro-emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof).
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate
  • oral, intranasal, or ophthalmic compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • antifungal pharmaceutical formulations suitable for use in the present inventions are well known in the art.
  • descriptions of a variety of antifungal pharmaceutical formulations known in the art are found in: U.S. Pat. No. 7,101,889 (to Kaczvinsky, Jr. et al), U.S. Pat No. 6897033 (to Dawson et al.) U.S. Pat. No. 6,656,928 (to McAdden), U.S. Pat. No. 6,046,176 (to Segal et al.), U.S. Pat. No. 6,558,710 (to Godfrey), U.S. Pat. No. 7,820,720 (to Cevc et al), U.S. Pat. No. 4,006,222
  • Examples of commercially available antifungal pharmaceutical formulations suitable for use in the present invention include: NIZORAL (ketoconazole 2% cream or shampoo), KENOZOLE-B (ketoconazole 2% & Beclomethasone 0.025% cream), MONISTAT (miconazole nitrate 2% cream), LAMISIL (terbinafine 1% solution or cream), ABELCET (amphotericin B 5mg/mL lipid complex injection), LITHIODERM (lithium gluconate 8% gel), EFALITH (lithium succinate 8%/zinc sulfate 0.05% cream), LOTRIMIN (clotrimazole ⁇ cream, lotion, or solution), NOXAFIL (posaconazole 40 mg/mL oral suspension) and LOPROX (ciclopirox olamine 1% shampoo, gel, or cream),
  • CANESTEN clotrimazole 1% cream
  • HEAD&SHOULDERS Zinc Pyrithione 1% shampoo
  • SELSU BLUE Senium sulfide 1% shampoo
  • amphotericin B for the treatment, mitigation, or prevention of Parkinson's disease is formulated as amphotericin B for injection which is a sterile, nonpyrogenic, lyophilized cake (which may partially reduce to powder following manufacture) providing 50 mg amphotericin B and 41 mg sodium desoxycholate buffered with 20.2 mg sodium phosphates (consisting of mono and dibasic sodium phosphate, phosphoric acid and sodium hydroxide). Crystalline amphotericin B is insoluble in water; therefore, the active compound is solubilized by the addition of sodium desoxycholate to form a mixture which provides a colloidal dispersion for intravenous infusion following reconstitution. At the time of manufacture the air in the vial is replaced by nitrogen as a preservative.
  • kits that can be used for preventing, inhibiting, treating, or otherwise providing a therapy for inhibiting Parkinson's disease.
  • the kit may be useful for subjects diagnosed as being susceptible to or having Parkinson's disease.
  • kits can include components described herein and/or in the claims.
  • a kit can include an absorbent medium having an anti- malassezial agent.
  • a kit can include a shower glove having the anti-malassezial agent in an absorbent region.
  • the absorbent medium can be a sponge having the anti-malassezial agent.
  • the kit can provide articles of commerce and methods of marketing hair care compositions that can be used for a therapy for Parkinson's disease.
  • the article of commerce comprises: (1) a container; (2) a skin care composition contained within said container, wherein said skin care composition comprises an anti-malassezial agent; and, optionally, (3) a communication, wherein said communication communicates that use of said skin care composition can reduce the chance of becoming susceptible to Parkinson's disease or of developing Parkinson's disease.
  • the communication can provide information of the link between a malassezial infection and becoming susceptible to Parkinson's disease or becoming diagnosed with
  • the present invention provides methods of marketing skin care compositions that can be used to reduce the chance of becoming susceptible to
  • Parkinson's disease or of developing Parkinson's disease by inhibiting, preventing, or treating a malassezial infection.
  • the method comprises: (a) offering for sale a skin care composition comprising an anti-malassezial agent; (b) communicating that said composition can be used to reduce the chance of becoming susceptible to Parkinson's disease or of developing Parkinson's disease by inhibiting, preventing, or treating a malassezial infection.
  • the skin care composition contains an antifungal for treating a malassezial infection for the purposes of inhibiting, preventing, or treating someone susceptible to or having Parkinson's disease and dandruff.
  • Suitable containers can include, but are not limited to, bottles, tottles, tubes, pouches, blister packs, boxes, tubs, jars, and cans.
  • containers can include primary containers, which contain the hair care composition itself, or secondary containers, which contain at least one primary container that contains the composition.
  • set of graphics or “graphics” refers to the text and/or pictorial images that are disposed on a container.
  • disposed on means integral with and/or located on the container and can include, but is not limited to, disposed directly thereon (e.g., printed directly on the container), disposed indirectly thereon (e.g., printed on a sticker that is affixed to the outer portion of the container), and/or applied to the container by any other suitable means (e.g., sprayed, bonded, drawn, painted, printed, or molded).
  • communication means a message, and can include but is not limited to a printed (e.g., printed material attached directly or indirectly to the container), electronic, or broadcast message.
  • the marketing described herein for a skin care product can be applied to any product that includes an anti-malassezial agent for treating a malassezial infection for the purpose of inhibiting, preventing, or treating someone susceptible to Parkinson's disease or someone having Parkinson's disease.
  • Such products may be nasal products, hair products, ear products, cleaning products for nasal, skin, hair, ear, or other location, or the like. Additional information can be found in US 20120258185 and/or US20080059313, which both are incorporated herein by specific reference in their entirety.
  • Example 1 A 55-year old female patient visits her physician complaining seborrheic dermatitis of the scalp, neck, shoulders, and face. Patient suffers from Parkinson's disease that was diagnosed about 7 months ago presenting with initial presenting symptoms of anosmia, tremor, and bradykinesia. Patient is administered oral fluconazole lOOmg daily, topical clotrimazole 1% cream applied to the location of the seborrheic dermatitis twice daily, and tretinoin 0.04% cream applied to the location daily. This treatment regimen is continued for three months. At this time, patient examination demonstrates the seborrheic dermatitis infection is completely eradicated. At a 3-month follow-up from successful treatment of seborrheic dermatitis infection patient reports anosmia, has resolved. In addition, the Parkinson's disease symptoms of tremor and bradykinesia have decreased significantly.
  • Example 2 A 30-year old male subject is determined by genetic testing to possess LRRK2 gene mutation G2019S which is associated with an increased risk of Parkinson's disease. Subject is administered zinc pyrithione formulated as a shampoo once daily. The zinc pyrithione shampoo is applied to the entire surface of the body excluding mucosal membranes. The shampoo is the commercially available Noble Formula Zinc
  • the shampoo comprises zinc pyrithione 2% prepared with purified water, sodium laureth sulfate, sodium laurel sulfate, glycol stearate, propylene glycol, sodium chloride, methyl paraben,
  • the shampoo is applied to the subject daily as prophylactic treatment for the prevention of Parkinson's disease.
  • the subject is followed up with clinical exam visits semi-annually over 7 years with no symptoms of Parkinson disease present on examination for the duration of follow-up.
  • Example 3 A 49-year old male patient is clinically evaluated by a physician for deterioration of health because of his progression of symptoms of Parkinson's disease which include tremor, speech dysfunction, aberrant personality changes, abulia, and difficulties with mentation. Patient has no overt symptoms of Malassezia infection. However, clinical examination reveals that patient has anosmia and nasal sinusitis.
  • Clinical laboratory testing is performed with results positive for Malassezia infection demonstrated by microscopy morphologic findings and positive growth on Dixon agar media plating (glycerol mono-oleate, or Sabouraud dextrose agar, covered with a layer of olive oil and incubated at 37°C), with identification further confirmed by matrix-assisted laser desorption ionizati on-time of flight mass spectrometry and multiplex polymerase chain reaction.
  • Patient is treated with an intravenous administration of a commercially available amphotericin formulation of amphotericin B deoxycholate at 1.0 mg/kg/day in combination with a twice daily treatment regimen of intranasal aqueous saline solution.
  • the solution comprises a mixture of 1 teaspoon of baking soda, 1.5 teaspoons of salt, and 1 quart sterilized distilled water.
  • the solution is administered intranasally using a pulsating irrigation device.
  • the pulsating irrigation device sends a gentle pulse of the solution into the nose via a nasal irrigation tip that can reach into and contact with the upper nasal passages.
  • the amphotericin B treatment regimen is discontinued after 3 weeks.
  • the total amount of amphotericin B administered to the patient over the course of treatment is about 1.8 grams.
  • the nasal wash is continued to be administered to the patient indefinitely on a once daily basis. Routine follow-up is conducted by the physician 6 months after completion of the amphotericin B treatment course.
  • Progression of Parkinson's disease is halted in the patient as measurement with the MDS-UPDRS.
  • Patient's caregiver reports that patient has "returned to being his normal self again” with improved mood, improved affect, decreased fatigue, decreased abulia, and improved mentation.
  • Patient self-reporting of amelioration of symptoms is consistent with caregiver reports.
  • the subject of the case study was a genotypic male, approximately age 50, who received a formal clinical diagnosis of idiopathic Parkinson disease approximately 5 years ago.
  • the subject displayed classical signs and symptoms of Parkinson disease including masked facies, cogwheel rigidity, pill-rolling tremor, and bradykinesia.
  • the subject described a complete anosmia (i.e. the inability to perceive odor or a lack of functioning olfaction).
  • the subject had no known uncontrolled medical conditions (e.g., known active hepatic disease, inadequately treated hypertension, congestive heart failure).
  • the subject was not taking carbidopa-levodopa therapy or any other dopaminergic replacement pharmacologics.
  • the subject had no known contraindication or allergy to fluconazole or zinc pyrithione in any form.
  • fluconazole 400 mg (2 capsules); subsequently, the subject orally ingested 200 mg (1 capsule) a day for the remainder of a 3-month treatment period.
  • the subject also washed his head, neck, and shoulders every third day with a shampoo containing 1% zinc pyrithione for the entire 3- month treatment period.
  • results The subject reported complete restoration of his sense of smell during week 4 of treatment. The restoration of his sense of smell continued for duration of treatment. The subject reported no worsening of symptoms as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) over the 3 month treatment duration. Further treatment for an additional 1 month beyond the 3 month treatment period resulted in improved mood during week 4 of treatment. The improved mood continued for the duration of treatment.
  • MDS-UPDRS Movement Disorder Society - Unified Parkinson's Disease Rating Scale
  • Parkinson's Disease with a modified Hoehn and Yahr stage 3 or less Patients may be on stable doses of carbidopa-levodopa therapy for at least 1 month prior to baseline and expected to maintain a stable dose for the duration of the study. Patients with
  • Each treatment group is comprised of 12 subjects.
  • the environment is sanitized by removing any humidifiers.
  • further environmental sanitation is performed by replacing (preferred) or washing pillow(s), pillow-case(s), bed sheets, blankets, towels, undergarments, socks, hats, etc. at least twice weekly.
  • An air purifier with HEPA filter is present in the bedroom (e.g., GERMGUARDIAN® AC4825 Purifier).
  • Patients are assigned treatment from a predetermined randomization schedule. Half the patients are instructed to shampoo every third day with a shampoo containing 1% zinc pyrithione from an unlabeled bottle and avoid all other shampoos. These same patients also take active fluconazole that has been over-encapsulated. The other half of patients are instructed to shampoo every third day with a shampoo not containing 1% zinc pyrithione in an unlabeled bottle and avoid all other shampoos. These same patients also take a capsule containing an inert substance.
  • Fluconazole capsules contain 200 mg of drug each. On Day 1, subjects take 400 mg
  • the shampoo contains zinc pyrithione 1%. Subjects are instructed to shampoo every third day (or at least twice weekly) for entire 3 -month treatment period.
  • MDS-UPDRS Parkinson's Disease Rating Scale

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Abstract

L'invention concerne des procédés et des compositions permettant de traiter, d'atténuer ou de prévenir la maladie de Parkinson par l'administration d'un agent anti-malassezia.
PCT/US2017/066218 2016-12-13 2017-12-13 Procédés et compositions de traitement de la maladie de parkinson WO2018112106A1 (fr)

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CA3046501A CA3046501A1 (fr) 2016-12-13 2017-12-13 Procedes et compositions de traitement de la maladie de parkinson
AU2017376458A AU2017376458A1 (en) 2016-12-13 2017-12-13 Methods and compositions for treating Parkinson's disease
MX2019007041A MX2019007041A (es) 2016-12-13 2017-12-13 Metodos y composiciones para tratar la enfermedad de parkinson.
EP17880499.3A EP3554496A4 (fr) 2016-12-13 2017-12-13 Procédés et compositions de traitement de la maladie de parkinson
JP2019551927A JP2020502269A (ja) 2016-12-13 2017-12-13 パーキンソン病を治療するための方法及び組成物
CN201780086331.3A CN110753543A (zh) 2016-12-13 2017-12-13 用于治疗帕金森氏病的方法和组合物
US16/439,164 US20200061018A1 (en) 2016-12-13 2019-06-12 Methods and compositions for treating parkinson's disease

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CN113005086A (zh) * 2021-02-01 2021-06-22 中国科学院遗传与发育生物学研究所 埃博霉素D和Apol8在调控神经干细胞定向神经元分化中的应用

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CN115813841B (zh) * 2023-01-10 2023-09-05 广东迪美新材料科技有限公司 去屑止痒组合物及制备方法、应用，洗发水及制备方法

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WO2020264076A1 (fr) * 2019-06-28 2020-12-30 The Procter & Gamble Company Méthode de traitement augmenté par la lumière
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CN113005086B (zh) * 2021-02-01 2022-10-28 中国科学院遗传与发育生物学研究所 埃博霉素D和Apol8在调控神经干细胞定向神经元分化中的应用

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