US20100092447A1 - Methods and compositions for the treatment of symptoms of prion diseases - Google Patents

Methods and compositions for the treatment of symptoms of prion diseases Download PDF

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US20100092447A1
US20100092447A1 US12/573,353 US57335309A US2010092447A1 US 20100092447 A1 US20100092447 A1 US 20100092447A1 US 57335309 A US57335309 A US 57335309A US 2010092447 A1 US2010092447 A1 US 2010092447A1
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method
pharmaceutical composition
chymotrypsin
prion disease
patient
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Joan M. Fallon
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Curemark LLC
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/465Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/47Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/48Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482Serine endopeptidases (3.4.21)
    • A61K38/4826Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/48Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4873Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896Neurological disorders, e.g. Alzheimer's disease
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y301/00Hydrolases acting on ester bonds (3.1)
    • C12Y301/01Carboxylic ester hydrolases (3.1.1)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y302/00Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21001Chymotrypsin (3.4.21.1)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21004Trypsin (3.4.21.4)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22Cysteine endopeptidases (3.4.22)
    • C12Y304/22002Papain (3.4.22.2)
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90Enzymes; Proenzymes
    • G01N2333/914Hydrolases (3)
    • G01N2333/948Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/976Trypsin; Chymotrypsin
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/28Neurological disorders
    • G01N2800/2814Dementia; Cognitive disorders
    • G01N2800/2828Prion diseases
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/52Predicting or monitoring the response to treatment; Prognosis

Abstract

A therapeutic composition for the treatment of the symptoms of prion diseases and the method for preparing the therapeutic agents is disclosed. The therapeutic composition is a stable pharmaceutical composition comprising one or more digestive and/or pancreatic enzymes. The therapeutic composition may be manufactured by a variety of encapsulation technologies. Delivery of the therapeutic composition may be made orally, through injection, by adherence of a medicated patch or other method. Further, a method of using fecal chymotrypsin level as a biomarker for the presence of a prion disease, or the likelihood of an individual to develop a prion disease is disclosed.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application claims priority under 35 U.S.C. §119 to U.S. Provisional Application 61/102818, filed Oct. 3, 2008, incorporated by reference in its entirety herein.
  • TECHNICAL FIELD
  • This disclosure relates to a treatment for the symptoms of prion diseases, and more particularly, to the use of pharmaceutical compositions comprising one or more digestive enzymes, such as one or more pancreatic enzymes, in the treatment of the symptoms of prion diseases. The disclosure also relates to a method of making pharmaceutical compositions comprising one or more digestive enzymes. The disclosure further relates to the use of an individual's fecal chymotrypsin level as a diagnostic marker for determining whether an individual has a prion disease, as well as to predict whether an individual will be beneficially treated with the described pharmaceutical compositions.
  • BACKGROUND OF THE INVENTION
  • Dysautonomias can result in symptoms in which one or more areas of the body are innervated by the autonomic nervous system. While some dysautonomias are well known, other conditions have yet to be determined as a dysautonomia.
  • Symptoms of known dysautonomias include: palpitations, chest pain, tachycardia, excessive fatigue, severe fluctuations in blood pressure, excessive sweating, fainting, exercise intolerance, shortness of breath, visual disturbances including blurred vision, tunneling, and double vision, migraines, dizziness, insomnia, gastrointestinal problems including diarrhea, and constipation, bloody stools, fainting/near fainting, frequent urination, convulsions, and cognitive impairment. Secondarily others symptoms such as depression, dysthymia, obsessive compulsive tendencies, and difficulty with ambulation and other symptoms may also be a part of the dysautonomic picture.
  • Conditions such as familial dysautonomia (FD), also known also as Riley-Day syndrome, Parkinson's disease, Guillaine-Barre syndrome (GBS), Dopamine-b-Hydroxalase deficiency, baroreflex failure, Guillaine-Barre Syndrome, neuroblastoma and other tumors which affect the neuroendocrine system, Aromatic L-Amino Acid Decarboxylase deficiency, Tetrahydrobiopterin deficiency, Familial Paraganglioma syndrome, “Shy-Drager Syndrome,” also referred to as “Multiple System Atrophy” or MSA, Neurally Mediated Syncope, also known as Neurocardiogenic Syncope, fetal fatal insomnia (FFI), diabetic cardiovascular neuropathy, hereditary sensory and autonomic neuropathy type III (HSAN III), Menke's disease, monoamine oxidase deficiency states, and other disorders of dopamine metabolism, dysautonomic syndromes and disorders of the cardiovasular system, Chaga's disease, diabetic autonomic failure, and pure autonomic failure, are well known as conditions associated with or primarily due to a dysautonomia.
  • Prion diseases are rare. The general worldwide yearly incidence is approximately one case per million people. Thus, in the US, approximately 300 de novo cases of sporadic and genetic prion disease are observed per year. The genetically transmissible forms of prion disease are about one-tenth as common as the sporadic forms. This prevalence is comparable to that observed with the autosomal dominant forms of familial Alzheimer disease and amyotrophic lateral sclerosis (Lou Gehrig's disease).
  • Prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs); however, the order and/or predominance of these features and associated neurologic and psychiatric findings vary with prion disease subtype and/or PRNP mutation. The age at onset ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically five to seven years, but in rare cases more than ten years). Death generally results from infection, either by pneumonia (typically from aspiration) or urosepsis. Therapy is aimed at controlling symptoms that may cause discomfort. No cure for prion disease currently exists.
  • The three phenotypes classically associated with genetic prion disease (fCJD, GSS, and FFI), were defined by clinical and neuropathologic findings long before the molecular basis of this group of disorders was discovered. Although it is now recognized that these three phenotypes are part of a continuum and have overlapping features, it can be helpful to think of genetic human prion disease at least in part in terms of these phenotypes when providing individuals and families with information about the expected clinical course.
  • Familial Creutzfeldt-Jakob disease (fCJD). Progressive confusion and memory impairment occur first, followed by ataxia and myoclonus. The disease typically manifests between the ages of 30 and 50 years, although a few individuals present before age 30 or as late as the upper 80s. The course from onset to death ranges from a few months to five years. At the endstage of disease, the individual is generally bedbound, mute, and immobile, except for myoclonic jerks.
  • The cognitive impairment observed may initially be mild confusion or it may be specific for a particular cortical function, such as language or constructional abilities; however, the resultant picture is one of global dementia. As the disease progresses, neurobehavioral symptoms may vary considerably. Psychiatric features, including delusions and hallucinations, may also occur.
  • Ataxia may be either truncal or appendicular, manifesting either as an unsteady gait, clumsiness while carrying out commonly performed tasks (e.g., picking up the salt shaker while dining), or progressive dysarthria. As the ataxia progresses, the individual may fall repeatedly, necessitating the use of a wheelchair to prevent injury.
  • Myoclonus generally, but not always, occurs after cognitive impairment is evident. Myoclonus may begin focally in a single limb but eventually becomes generalized. “Startle myoclonus” may be elicited by simple acts such as clapping the hands or turning on the room lights. Even if warned of an impending noise, the individual cannot suppress the startle response.
  • Other neurologic signs and symptoms such as focal or generalized weakness, rigidity, bradykinesia, tremor, chorea, alien hand syndrome, stroke-like symptoms, visual disturbances, and seizures have been observed.
  • Gerstmann-Sträussler-Scheinker syndrome (GSS). GSS typically begins in the fourth to sixth decade with the insidious onset of cerebellar dysfunction, manifest as unsteady gait and mild dysarthria. Cognitive dysfunction is generally not apparent early on; however, with progression, bradyphrenia, or slowness of thought processing, may become evident. Pyramidal involvement with spasticity and/or extrapyramidal involvement with bradykinesia, increased muscle tone with or without cogwheeling, and masked facies are also common. Psychiatric or behavioral symptoms are atypical. The disease progresses at a relatively slow but relentless pace over the course of a few to seven or more years. Cerebellar dysfunction results in severe dysarthria, gait and appendicular ataxia, ocular dysmetria, and lack of coordination in swallowing. A decline in cognitive abilities, particularly of concentration and focus, becomes apparent with progression into the late stage of disease. In the terminal stage, the individual is bedridden from the disabling ataxia, unable to eat because of severe lack of coordination in swallowing, and unable to communicate because of the profound dysarthria; yet insight into his/her condition may remain. This pattern of progression relates to the cerebellar nature of this disease, with progression into the brain stem and eventually the cerebrum.
  • Fatal familial insomnia (FFI). FFI typically presents in midlife (40s to 50s) with the insidious or subacute onset of insomnia, initially manifest as a mild, then more severe, reduction in overall sleep time. When sleep is achieved, vivid dreams are common. A disturbance in autonomic function then emerges, which may manifest as elevated blood pressure, episodic hyperventilation, excessive lacrimation, sexual and urinary tract dysfunction, and/or a change in basal body temperature. Signs of brainstem involvement, such as decreased ability to gaze upward, double vision, jerky eye pursuit movements, or dysarthric speech may also appear in some individuals. With continued progression over the next few months, individuals develop truncal and/or appendicular ataxia. The speed of thought processing may be reduced, as is common in subcortical dementing states, and memory impairment may be variable; however, compared with other more prominent features of disease, cognitive capacity is relatively spared until late in the course. Advancing disease results in progressively greater loss of total sleep time, worsening ataxia, and more profound confusion, leading ultimately to an awake but stuporous state as death approaches. As with other forms of prion disease, debilitation leading to feeding difficulties and loss of airway protection is the most common immediate cause of death. The typical duration of disease is 12 to 16 months, with a range of a few months to five years.
  • Other prion diseases. About 10-15% of prion diseases are genetically transmissible, while the remainder occur from unknown risk factors or are acquired through infection with prions; these include sporadic Creutzfeldt-Jakob disease (sCJD), iatrogenic CJD (iCJD), variant CJD (vCJD), and sporadic fatal insomnia (sFI). Kuru, a prion disease associated with the practice of cannibalism in a primitive culture in New Guinea, is primarily of historical significance.
  • sCJD. The clinical and pathologic features of sCJD are the same as fCJD; however, the duration of disease is typically much shorter, on the average of six months or less, and the age at onset is later, typically after age 60 years.
  • sFI. The phenotype is the same as in FFI, including age at onset and duration of disease. sFI is much less common than FFI.
  • iCJD. Diagnosis of this form of prion disease requires the identification or strong association with administration of a biological extract or tissue contaminated with prions. Such sources have included injections of human growth hormone contaminated with prions (used prior to 1980), improperly decontaminated depth electrodes previously used in individuals with CJD, transplantation of corneas obtained from individuals with CJD, dura mater grafts contaminated with prions, and various poorly documented neurosurgical procedures.
  • vCJD. This prion disease represents a relatively new strain of CJD acquired by ingestion of beef or beef products contaminated with bovine spongiform encephalopathy (BSE), the prion disease of cattle (commonly known as mad cow disease). The typical clinical picture is that of a young adult or teen who develops behavioral changes and/or pain in the lower extremities that eventually lead to a progressive dementia with ataxia and myoclonus. The course is about 1.5 years. The EEG is often diffusively slow rather than periodic, and the 14-3-3 CSF protein test is more often negative than positive. Neuropathology reveals spongiform change spread diffusely throughout the brain and dense amyloid plaque deposition surrounded by a halo of vacuolation described as “florid plaques.
  • SUMMARY
  • It has been determined by the present inventor that the gastrointestinal tract of dysautonomic individuals is impaired, and that the proper levels of pancreatic enzymes and/or their precursors including the zymogens and bicarbonate ions are not present in sufficient quantities to allow proper digestion. While that impairment is relevant to the digestion of carbohydrates, fats and proteins, it is most specific and most severe with respect to protein digestion. Accordingly, while not being bound by theory, the present inventor believes that many, if not all, dysautonomias have a GI component, and thus that dysautonomias may actually have their etiology in gastrointestinal dysfunction. For example, with Guillaine-Barre syndrome, it is postulated that a GI pathogen is a causative factor in the formation of the Guillaine Barre dysautonomia. Similarly, it has been found by the present inventor that populations of autistic children suffer from GI disturbances and other conditions which are dysautonomic in nature. In general, these findings represent a possible link between the etiology of autism and autonomic dysfunction. Thus, the inventor believes that other dysautonomic conditions also have GI primary etiologies.
  • The symptoms of dysautonomic conditions, however, may have various manifestations due to the genetic makeup of the individuals suffering from the conditions. Various gene sequences in the genetic code of the individual will result in manifestation of certain diseases or symptoms that are expressed uniquely in each individual. For example, if amino acid pool deficits due to improper protein digestion and gastrointestinal dysfunction are manifested differently in different individuals, a “disease state” may appear different depending upon the genetic makeup of the individual. Neurological expression may be all that is seen in some individuals, whereas other manifestations may demonstrate a hybrid of gastrointestinal dysfunction as well as neurological or other dysfunctions.
  • Accordingly, while not bound by theory, the present inventor believes that prion diseases may have a dysautonomic component and that the etiology of prion diseases may be related to gastrointestinal dysfunction.
  • Given the above, it is a goal of the present disclosure to provide therapeutic methods and pharmaceutical compositions for the treatment of the symptoms of prion diseases. It is also a goal of the present disclosure to provide therapeutic methods and pharmaceutical compositions for the treatment of Pervasive Development Disorders such as Autism, ADD, and ADHD, and for dysautonomias such as Familial Dysautonomia, Parkinson's, and Guillaine Barre Syndrome.
  • Another goal of the present disclosure is the provision of pharmaceutical compositions for the treatment of the above disorders, wherein the compositions comprise one or more digestive enzymes, e.g., one or more enzymes selected from amylases, proteases, cellulases, papaya, papain, bromelain, lipases, chymotrypsin, trypsin, and hydrolases. In some embodiments, the pharmaceutical compositions are lipid encapsulated.
  • Yet another goal of the present disclosure is to provide methods for making the described pharmaceutical compositions using methods such as: direct compression, microencapsulation, lipid encapsulation, wet granulation or other methods including the use of Prosolv® (silicified microcrystalline cellulose), and other known excipients and additives to accomplish microencapsulation, lipid encapsulation, direct compression, wet or dry granulation or other suitable technology.
  • A further goal of the present disclosure is to provide means to deliver the pharmaceutical compositions, which can include the use of rapid dissolution (rapid dissolve), time release, or other delivery methods including oral, injection, patch, or other method. Further, the delivery of the pharmaceutical compositions may be in the form of a tablet, capsule, sprinkles, sachet, or other oral delivery method.
  • An additional goal of the disclosure is to demonstrate the use of fecal chymotrypsin level as a biomarker for the presence of prion diseases, or the likelihood of an individual to develop prion diseases.
  • Accordingly, provided herein is a method for treating one or more symptoms associated with prion diseases in a patient diagnosed with a prion disease comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising one or more digestive enzymes. In some embodiments, the pharmaceutical composition may be lipid-encapsulated. In some embodiments, the one or more digestive enzymes comprise one or more enzymes selected from the group consisting of proteases, amylases, celluloses, sucrases, maltases, papaya, papain, bromelain, hydrolases, and lipases. In some embodiments, the one or more digestive enzymes comprise one or more pancreatic enzymes. In some embodiments, the pharmaceutical composition comprises one or more proteases, one or more lipases, and one or more amylases. In some embodiments, the one or more proteases comprise chymotrypin and trypsin.
  • The one or more digestive enzymes are, independently, derived from an animal source, a microbial source, or a plant source, or are synthetically prepared. In some embodiments, the animal source is a pig, e.g,. a pig pancreas.
  • In some embodiments, the pharmaceutical composition comprises at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain. In some embodiments, the pharmaceutical composition further comprises papaya. In some embodiments, the pharmaceutical composition comprises, per dose: amylases from about 10,000 to about 60,000 U.S.P; proteases from about 10,000 to about 70,000 U.S.P; lipases from about 4,000 to about 30,000 U.S.P; chymotrypsin from about 2 to about 5 mg; trypsin from about 60 to about 100 mg; papain from about 3,000 to about 10,000 USP units; and papaya from about 30 to about 60 mg.
  • In some embodiments, the pharmaceutical composition comprises at least one protease and at least one lipase, wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1. In some embodiments, the ratio of proteases to lipases ranges from about 4:1 to about 10:1.
  • In some embodiments, the one or more symptoms of prion diseases are selected from personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait. Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment and lose the ability to move or speak.
  • In some embodiments, the pharmaceutical composition is a dosage formulation selected from the group consisting of: pills, tablets, capsules, microcapsules, mini-capsules, time released capsules, mini-tabs, sprinkles, and a combination thereof.
  • Also provided is a method of diagnosing a patient comprising: obtaining a fecal sample from the patient; determining a level of chymotrypsin present in the fecal sample, wherein the determination is performed at 30° C.; and diagnosing the patient as having a prion disease if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient exhibits at least one symptom associated with a prion disease. In some embodiments, the fecal chymotrypsin level is between 8.4 and 4.2 U/gram. In some embodiments, the fecal chymotrypsin level is less than 4.2 U/gram. In some embodiments, the level of chymotrypsin present in the fecal sample is determined using an enzymatic photospectrometry method. In some embodiments, the method further comprises administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes if the patient is diagnosed as having a prion disease. In some embodiments, the method further comprises determining if the administration of the pharmaceutical composition reduces or ameliorates one or more symptoms associated with a prion disease.
  • Also provided is a method of identifying a patient likely to benefit from administration of a pharmaceutical composition comprising one or more digestive enzymes comprising: obtaining a fecal sample from the patient; determining a level of chymotrypsin present in the fecal sample, wherein the determination is performed at 30° C.; and identifying the patient as likely to benefit from administration of the pharmaceutical composition if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient is diagnosed with a prion disease. In some embodiments, the method further comprises determining if the patient exhibits one or more symptoms of a prion disease. In some embodiments, the benefit comprises a reduction or amelioration of one or more symptoms associated with a prion disease. In some embodiments, the method further comprises administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes.
  • Also provided is a pharmaceutical composition comprising one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1. In some embodiments, the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1. In some embodiments, the pharmaceutical composition is lipid encapsulated.
  • Also provided is a pharmaceutical composition comprising at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain. In some embodiments, the pharmaceutical composition further comprises papaya. In some embodiments, the ratio of total proteases to total lipases ranges from about 1:1 to about 20:1.
  • The features and advantages described herein are not all-inclusive and, in particular, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the drawings, specification, and claims. Moreover, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and not to limit the scope of the inventive subject matter.
  • DETAILED DESCRIPTION
  • The present disclosure provides pharmaceutical compositions and methods for treating symptoms associated with CRPS, Pervasive Development Disorders, and Dysautonomias. The pharmaceutical compositions described herein include one or more digestive enzymes, which are postulated by the present inventor to assist in proper digest protein and thus to ameliorate the gastrointestinal dysfunction that is associated with the described disorders.
  • In certain embodiments, the pharmaceutical compositions may include one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1. In some cases, the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1.
  • In some cases, a pharmaceutical composition for use herein comprises at least one amylase, at least one protease, and at least one lipase. In certain embodiments, the pharmaceutical composition includes multiple proteases, including, without limitation, chymotrypsin and trypsin. In certain embodiments, the composition can further include one or more hydrolases, papain, bromelain, papaya, celluloses, pancreatin, sucrases, and maltases.
  • The one or more enzymes can be independently derived from animal, plant, microbial, or synthetic sources. In some embodiments, the one or more enzymes are derived from pig, e.g.: pig pancreas.
  • One exemplary formulation for the treatment of the symptoms of prion diseases is as follows:
  • Amylase 10,000-60,000 U.S.P
      • Protease 10,000-70,000 U.S.P
      • Lipase 4,000-30,000 U.S.P
      • Chymotrypsin 2-5 mg
      • Trypsin 60-100 mg
      • Papain 3,000-10,000 USP units/mg
      • Papaya 30-60 mg
  • Additional formulations comprising one or more digestive enzymes may be advantageous including formulations in which the ratio of total proteases to total lipases (in USP units) is from about 1:1 to about 20:1. In some embodiments, the ratio of total proteases to total lipases is from about 4:1 to about 10:1. Such formulations are useful for treating symptoms of prion diseases as well as dysautonomias (e.g., familial dysautonomia, Parkinson's, Guillaine-Barre Syndrome, Aromatic-L-amino acid decarboxylase deficiency, tetrahydrobiopterin deficiency, familial paranganglioma syndrome; multiple system atrophy, dysautonomic symptoms associated with tumors such as pheochromocytoma, chemodectoma, and neuroblastoma; neurally mediated syncope, and SIDS) and pervasive development disorders such as autism, ADHD, ADD, and Asperger's.
  • Patients below the age of 18 are typically given a dosage such that the formulation would deliver at least 5,000 USP units of protease and no more than 10,000 USP units of lipase per kilogram weight of patient, per day. Beneficially, the formulation would deliver at least 5,000 USP units of protease and no more than 7,500 USP units of lipase per kilogram weight of patient per day. Patients above the age of 18 are typically given no less than 5,000 USP units of protease per kilogram weight of patient per day.
  • The dosage formulation may be administered by an oral preparation including, but not limited to, an encapsulated tablet, mini-tabs, microcapsule, mini-capsule, time released capsule, sprinkle or other methodology. In one embodiment, the oral preparation is encapsulated using lipid. Alternatively, the oral preparation may be encapsulated using enteric coating or organic polymers. A formulation may also be prepared using Prosolv® technology, direct compression, dry granulation, wet granulation, and/or a combination of these methods.
  • Fecal chymotrypsin level is a sensitive, specific measure of proteolytic activity, see e.g.: U.S. Pat. No. 6,660,831, incorporated by reference herein. Normal levels of chymotrypsin are considered be greater than 8.4 U/gram. Decreased values (less than 4.2 U/gram) suggest diminished pancreatic output (pancreatic insufficiency), hypoacidity of the stomach or cystic fibrosis. Elevated chymotrypsin values suggest rapid transit time, or less likely, a large output of chymotrypsin from the pancreas.
  • For the fecal chymotrypsin test, a stool sample is collected from each of the subjects. Each stool sample can be analyzed using an enzymatic photo spectrometry analysis to determine the level of fecal chymotrypsin in the stool; in some cases the assay is performed at 30° C., see e.g.: U.S. Pat. No. 6,660,831, incorporated by reference herein. Alternatively, other methods, such as the colorimetric method, use of substrates, use of assays, and/or any other suitable method may be used to measure the fecal chymotrypsin levels. The levels of fecal chymotrypsin in the samples of the individuals having a prion disease are compared to the levels of fecal chymotrypsin in individuals not diagnosed with a prion disease determine if the individuals having the prion disease would benefit from the administration of digestive enzymes.
  • The foregoing description of the embodiments of the invention has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of this disclosure. It is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.

Claims (49)

1. A method for treating one or more symptoms associated with a prion disease in a patient diagnosed with a prion disease comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising one or more digestive enzymes.
2. The method of claim 1 wherein the one or more digestive enzymes comprise one or more enzymes selected from the group consisting of proteases, amylases, celluloses, sucrases, maltases, papaya, papain, and lipases.
3. The method of claim 1 wherein the one or more digestive enzymes comprise one or more pancreatic enzymes.
4. The method of claim 2 wherein the proteases comprise chymotrypin and trypsin.
5. The method of claim 1 wherein the one or more digestive enzymes are, independently, derived from an animal source, a microbial source, or a plant source, or are synthetically prepared.
6. The method of claim 5 wherein the animal source is a pig.
7. The method of claim 1 wherein the pharmaceutical composition comprises at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain.
8. The method of claim 7 wherein the pharmaceutical composition further comprises papaya.
9. The method of claim 1 wherein the pharmaceutical composition comprises: amylases from about 10,000 to about 60,000 U.S.P, proteases from about 10,000 to about 70,000 U.S.P, lipases from about 4,000 to about 30,000 U.S.P, chymotrypsin from about 2 to about 5 mg, trypsin from about 60 to about 100 mg, papain from about 3,000 to about 10,000 USP units, and papaya from about 30 to about 60 mg.
10. The method of claim 1 wherein the pharmaceutical composition comprises at least one protease and at least one lipase, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1.
11. The method of claim 10 wherein the ratio of proteases to lipases ranges from about 4:1 to about 10:1.
12. The method of claim 1 wherein the one or more symptoms of the prion disease are selected from personality changes, psychiatric problems, lack of coordination, unsteady gait, myoclonus, unusual sensations, insomnia, confusion, memory problems, severe mental impairment, loss of the ability to move or speak, and a combination thereof.
13. The method of claim 1 wherein the pharmaceutical composition is a dosage formulation selected from the group consisting of: pills, tablets, capsules, microcapsules, mini-capsules, time released capsules, mini-tabs, sprinkles, and a combination thereof.
14. A method of diagnosing a patient comprising:
obtaining a fecal sample from the patient;
determining a level of chymotrypsin present in the fecal sample; and
diagnosing the patient as having a prion disease if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient exhibits at least one symptom associated with.
15. The method of claim 14 wherein the fecal chymotrypsin level is between 8.4 and 4.2 U/gram.
16. The method of claim 14 wherein the fecal chymotrypsin level is less than 4.2 U/gram.
17. The method of claim 14 wherein the level of chymotrypsin present in the fecal sample is determined using an enzymatic photospectrometry method.
18. The method of claim 14 further comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes if the patient is diagnosed as having the prion disease.
19. The method of claim 18 further comprising determining if the administration of the pharmaceutical composition reduces one or more symptoms associated with the prion disease.
20. The method of claim 19 further comprising comparing the post-administration measurement of one or more prion disease symptoms to a pre-administration measurement of the one or more prion disease symptoms.
21. A method of identifying a patient likely to benefit from administration of a pharmaceutical composition comprising one or more digestive enzymes comprising:
obtaining a fecal sample from the patient;
determining a level of chymotrypsin present in the fecal sample; and
identifying the patient as likely to benefit from administration of the pharmaceutical composition if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient is diagnosed with a prion disease.
22. The method of claim 21 further comprising determining if the patient exhibits one or more symptoms of the prion disease.
23. The method of claim 21 wherein the benefit comprises a reduction in one or more symptoms associated with the prion disease.
24. The method of claim 21 wherein the level of chymotrypsin present in the fecal sample is determined using an enzymatic photospectrometry method.
25. The method of claim 21 further comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes.
26. A pharmaceutical composition comprising one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1.
27. The pharmaceutical composition of claim 26 wherein the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1.
28. A pharmaceutical composition comprising at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain.
29. The pharmaceutical composition of claim 28 wherein the pharmaceutical composition further comprises papaya.
30. The pharmaceutical composition of claim 28 wherein the ratio of total proteases to total lipases ranges from about 1:1 to about 20:1.
31. A pharmaceutical preparation for treating an individual exhibiting one or more symptoms of a prion disease comprising a therapeutically effective amount of a digestive enzyme.
32. The pharmaceutical preparation of claim 31 wherein the digestive enzyme is selected from the group consisting of: amylase, lipase, protease, and a combination thereof.
33. The pharmaceutical preparation of claim 31 wherein the digestive enzyme is further selected from the group consisting of: chymotrypsin, trypsin, papaya, papain, and a combination thereof.
34. The pharmaceutical preparation of claim 31 wherein the enzyme is derived from a source selected from the group consisting of animal enzymes, plant enzymes, synthetic enzymes, and a combination thereof.
35. The pharmaceutical preparation of claim 31 wherein the preparation is manufactured using a technology selected from the group consisting of Prosolv® technology, enteric coating, lipid encapsulation, direct compression, dry granulation, wet granulation, and a combination thereof.
36. The pharmaceutical preparation of claim 31 wherein the preparation is administered orally via a dosage formulation selected from the group consisting of: pills, tablets, capsules, microcapsules, mini-capsules, time released capsules, mini-tabs, sprinkles, and a combination thereof.
37. The pharmaceutical preparation of claim 32 wherein the amount of amylase ranges from 10,000 to 60,000 USP units/mg.
38. The pharmaceutical preparation of claim 32 wherein the amount of protease ranges from 10,000 to 70,000 USP units/mg.
39. The pharmaceutical preparation of claim 32 wherein the amount of lipase ranges from 4,000 to 30,000 USP units/mg.
40. The pharmaceutical preparation of claim 33 wherein the amount of pancreatin ranges from 2,000 to 6,000 USP units/mg.
41. The pharmaceutical preparation of claim 33 wherein the amount of chymotrypsin ranges from 2 to 5 mg.
42. The pharmaceutical preparation of claim 33 wherein the amount of papain ranges from 3,000 to 10,000 USP units/mg.
43. The pharmaceutical preparation of claim 33 wherein the amount of papaya ranges from 30 to 60 mg.
44. The pharmaceutical preparation of claim 33 wherein the amount of trypsin ranges from 60 to 100 mg.
45. The pharmaceutical preparation of claim 31 wherein a symptom of the prion disease is ameliorated.
46. The pharmaceutical preparation of claim 31 wherein the symptom of the prion disease is selected from the group consisting of: personality changes, psychiatric problems, lack of coordination, unsteady gait, myoclonus, unusual sensations, insomnia, confusion, memory problems, severe mental impairment, loss of the ability to move or speak, and a combination thereof.
47. A method of treating an individual having a prion disease with a therapeutically effective amount of digestive enzymes comprising the steps of:
measuring a level of fecal chymotrypsin in a stool sample of the individual;
comparing the level of fecal chymotrypsin with a normal fecal chymotrypsin level; and
administering the digestive enzymes to the individual if the level of fecal chymotrypsin in the individual is less than the normal fecal chymotrypsin level.
48. The method of claim 47 further comprising the steps of:
administering the digestive enzymes to the individual in order to promote protein digestion; and
administering the digestive enzymes to the individual in order to ameliorate a symptom of the prion disease.
49. The method of claim 47 wherein the stool sample is measured using a technique selected from the group consisting of: enzymatic photospectrometry, colorimetry, treatment with substrates, assays, and a combination thereof.
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