(19) TZZ Z __T

(11) EP 2 609 921 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: (2006.01) (2006.01) 03.07.2013 Bulletin 2013/27 A61K 31/58 A61P 7/10

(21) Application number: 13161401.8

(22) Date of filing: 25.02.2010

(84) Designated Contracting States: (72) Inventor: Miller, Guy M. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Mountain View, CA California 94043 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR (74) Representative: Sexton, Jane Helen J A Kemp (30) Priority: 25.06.2009 US 269627 P 14 South Square Gray’s Inn (62) Document number(s) of the earlier application(s) in London WC1R 5JJ (GB) accordance with Art. 76 EPC: 10792467.2 / 2 445 519 Remarks: This application was filed on 27-03-2013 as a (71) Applicant: Ampere Life Sciences, Inc. divisional application to the application mentioned Mountain View, CA 94043 (US) under INID code 62.

(54) Treatment of pervasive developmental disorders with tocotrienols or tocotrienol enriched extracts

(57) Methods of treating or suppressing Pervasive a subject in need thereof a therapeutically effective Developmental Disorders (PDDs) including; Autistic Dis- amount of a tocotrienol, a tocotrienol ester, a tocotrienol order, Asperger’s Disorder, Childhood Disintegrative ether, a tocotrienol enriched extract or mixtures thereof. Disorder (CDD), Rett’s Disorder, and PDD-Not Other- wise Specified (PDD-NOS) comprising administering to EP 2 609 921 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 609 921 A1 2

Description ron (2000) 28 (2): 355-63). [0006] Autism is a complex serious developmental dis- CROSS-REFERENCE TO RELATED APPLICATIONS ability that interferes with, among other things, the normal development of the brain in the areas of social interaction [0001] This application claims priority benefit of United 5 and communication skills and which causes severely re- States Provisional Patent Application No. 61/269,627 stricted interests and repetitive behavior. Typically, au- filed June 25, 2009. The content of that application is tistic children and adults have difficulties in verbal and hereby incorporated by reference herein in its entirety. non-verbal communication, social interactions, and lei- sure or play activities. Autism can include language dis- FIELD OF THE INVENTION 10 orders with impaired understanding, echolalia, pronom- inal reversal (such as using "you" instead of "I" or "me" [0002] The application discloses methods useful for when referring to one’s self), rituals and compulsive phe- treatment, prevention, or suppression of diseases, de- nomena, and uneven intellectual development with men- velopmental delays, and symptoms of Pervasive Devel- tal retardation. Autistic children are also at increased risk opmental Disorders including Autistic Spectrum Disor- 15 of developing seizure disorders, especially during their ders, with tocotrienols, tocotrienol esters, tocotrienol teen years. Autism typically appears during the first three ethers, tocotrienol enriched extracts, or mixtures thereof. years of life and is the result of a neurological disorder that affects the functioning of the brain. BACKGROUND OF THE INVENTION [0007] The overall incidence of autism is, for the most 20 part, globally consistent. Indeed, autism knows no racial, [0003] Pervasive Developmental Disorder (PDD) is a ethnic, or social boundaries, and family income, lifestyle, category of neurological disorders characterized by se- and educational levels do not affect the chance of au- vere and pervasive impairment in several areas of de- tism’s occurrence. However, it has been found to be four velopment, including social interaction and communica- times more prevalent in boys than girls. On the other tions skills. The five disorders under PDD are Autistic 25 hand, Rett’s Disorder is more prevalent in girls than boys. Disorder, Asperger’s Disorder, Childhood Disintegrative [0008] Since being first described by Dr. Leo Kanner Disorder (CDD), Rett’s Disorder, and PDD-Not Other- in 1943, the understanding of autism has grown tremen- wise Specified (PDD-NOS). Specific diagnostic criteria dously. Although autism is defined by a certain set of for each of these disorders can be found in the Diagnostic behaviors, it is a spectrum disorder in that its symptoms & Statistical Manual of Mental Disorders (DSM-IV-TR) 30 and characteristics can be present in a wide variety of as distributed by the American Psychiatric Association combinations, from mild to severe. Therefore, autistic (APA). Autistic Spectrum Disorder (ASD) is an umbrella children and adults can exhibit any combination of the term that is used to represent a broad heterogeneous behaviors in any degree of severity. Two individuals, both disorder by collectively grouping autistic disorder, As- with the same diagnosis, may have varying skills and perger’s Disorder and PDD-NOS. 35 display very different actions. Those only mildly affected [0004] Autism, the most common of the Pervasive De- may exhibit slight delays in language or communication velopmental Disorders, affects an estimated 1 in approx- and may face greater challenges in social interactions. imately 150 births. Estimates of the prevalence of ASD For example, one may have difficulty initiating and/or are in the range of 6.5 to 6.6 per 1000 based on Autism maintaining a conversation. Communication by autistic and Developmental Disab ilities Monitoring Network Sur- 40 children or adults is often displayed as talking at others veillance (Year 2002). Indeed, as of 2003-2004, as many (for example, a monologue on a favorite subject that con- as 1.5 million Americans are believed to have some form tinues despite attempts by others to interject comments). of autism. Autism is a childhood encephalopathy char- [0009] Autism seems to cause those affected by it to acterized by deficiencies in social interaction and com- process and respond to information in unique ways. In munication and by repetitive and stereotyped behaviors. 45 some individuals with PDD including Autism, aggressive Based on statistics from the U.S. Department of Educa- and/or self-injurious behavior may exist. The following tion and other governmental agencies; autism is growing traits, as identified by the ASA, may also be present in at a rate of 10-17 percent per year. At these rates, the persons with autism: insistence on sameness or resist- Autism Society of America (ASA) estimates that the prev- ance to change; difficulty in expressing needs; (i.e. uses alence of autism could easily reach 4 million Americans 50 gestures or pointing instead of words); repeating words in the next decade. or phrases in place of normal, responsive language; [0005] Of the other four PDD forms, Asperger’s syn- laughing, crying, or showing distress for reasons not ap- drome is closest to autism in signs and likely causes; parent to others; preferring to be alone or an aloof man- Rett’s disorder and childhood disintegrative disorder ner; tantrums; difficulty in mixing with others; may not share several signs with autism, but may have unrelated 55 wanting to cuddle or be cuddled; little or no eye contact; causes; PDD not otherwise specified (PDD-NOS) is di- unresponsive to normal teaching methods; sustained agnosed when the criteria are not met for a more specific odd play; spinning objects; inappropriate attachments to disorder (Lord C, et al. "Autism spectrum disorders" Neu- objects; apparent over-sensitivity or under-sensitivity to

2 3 EP 2 609 921 A1 4 pain; no real fears of danger; marked physical over-ac- may cause a gagging reflex. Some children or adults with tivity or extreme under-activity; uneven gross/fine motor autism are particularly sensitive to sound, so that even skills;and/or non- responsiveness to verbal cues (i.e. acts the most ordinary daily noises are painful. as if deaf although hearing tests in normal range). [0014] Although there is no single known cause for au- [0010] People with autism have social impairments 5 tism, it is generally accepted that it is caused by abnor- that appear early in childhood and continue through malities in brain structure or function. The shape and adulthood. Autistic infants show less attention to social structure of the brain in autistic versus non-autistic chil- stimuli, smile and look at others less often, and respond dren showdifferences whenbrain scans areviewed. Cur- less to their own name. Autistic toddlers have more strik- rently the links between heredity, genetics and medical ing social deviance; for example, they have less eye con- 10 problems are being investigated by researchers, as well tact and anticipatory postures and are more likely to com- as a number of other theories. The theory of a genetic municate by manipulating another person’s hand (Volk- basis of the disorder is supported by the fact that, in many mar F, et al "Autism in infancy and early childhood" Annu families, there appears to be a pattern of autism or related Rev Psychol (2005) 56: 315-36.) Three- to five-year-old disabilities. While no one gene has been identified as autistic children are less likely to exhibit social under- 15 causing autism, researchers are searching for irregular standing, approach others spontaneously, imitate and re- segments of genetic code that autistic children may have spond to emotions, communicate nonverbally, and take inherited. While researchers have not yet identified a sin- turns with others. However, they do form attachments to gle trigger that causes autism to develop, it also appears their primary caregivers. (Sigman M, et al. "Early detec- that some childrenare bornwith a susceptibilityto autism. tion of core deficits in autism" Ment Retard Dev Disabil 20 [0015] Other researchers are investigating the possi- Res Rev. (2004) 10 (4): 221-33). They display moder- bility that under certain conditions, a cluster of unstable ately less attachment security than usual, although this genes may interfere with brain development resulting in feature disappears in children with higher mental devel- autism. Still other researchers are investigating problems opment or less severe autism spectrum disorders. Older during pregnancy or delivery as well as environmental children and adults with ASD perform worse on tests of 25 factors such as viral infections, metabolic imbalances, face and emotion recognition (Sigman M. et al, see su- and exposure to environmental chemicals. Yet other re- pra). Contrary to common belief, autistic children do not searchers are investigating the link between autism and prefer to be alone. Making and maintaining friendships chemical toxicity, in particular with the mercury-contain- often proves to be difficult for those with autism. For them, ing vaccine preservative thimerosal. the quality of friendships, not the number of friends, pre- 30 [0016] Some cases of autism have been associated dicts how lonely they are. with several different organic conditions, including bioen- [0011] Unlike those with autism, people with Asperg- ergetic metabolism deficiency suggested by the detec- er’s syndrome are not usually withdrawn around others; tion of high lactate levels in some patients (Coleman M. they approach others, even if awkwardly, for example by et al, Autism and Lactic Acidosis, J. Autism Dev Disord., engaging in a one-sided, long-winded speech about a 35 (1985) 15: 1-8; Laszlo et al Serum serotonin, lactate and favorite topic while being oblivious to the listener’s feel- pyruvate levels in infantile autistic children, Clin. Chim. ings or reactions, such as signs of boredom or haste to Acta (1994) 229:205-207; and Chugani et al., Evidence leave. of altered energy metabolism in autistic children, Progr. [0012] About a third to a half of individuals with autism Neuropsychopharmacol Biol Psychiat., (1999) 23: does not develop enough natural speech to meet their 40 635-641) and by nuclear magnetic resonance imagining daily communication needs; (Noens I, et al, "The Com- as well as positron emission tomography scanning which For: an instrument for the indication of augmentative documented abnormalities in brain metabolism. Al- communication in people with autism and intellectual dis- though the mechanism of hyperlactacidemia remains un- ability". J Intellect Disabil Res (2006) 50 (9): 621-32.) known, a likely possibility involves mitochondrial oxida- Differences in communication may be present from the 45 tive phosphorylation dysfunction in neuronal cells. A first year of life, and may include delayed onset of bab- small subset of autistic patients diagnosed with deficien- bling, unusual gestures, diminished responsiveness, and cies in complex I or III of the respiratory chain have been the desynchronization of vocal patterns with the caregiv- reported in the literature (see Oliveira, G., Developmental er. In the second and third years, autistic children have Medicine & Child Neurology (2005) 47 185-189; and Fili- less frequent and less diverse babbling, consonants,50 pek, PA et al., Journal of Autism and Developmental Dis- words, and word combinations; their gestures are less orders (2004) 34:615-623.) However, in many of the cas- often integrated with words. Autistic children are less like- es of autism where there is some evidence of mitochon- ly to make requests or share experiences, and are more drial dysfunction, there is an absence of the classic fea- likely to simply repeat others’ words or reverse pronouns. tures associated with mitochondrial disease, such as mi- [0013] For individuals with autism, sensory integration 55 tochondrial pathology in muscle biopsy (see Rossignol, problems are common. In particular, their senses may D.A. et al., Am J. Biochem. & Biotech, 4 (2) 208-217). be either over- or under-active. The fuzz of a kiwi may [0017] The main goals of treatment are to lessen as- actually be experienced as painful; a sweet, fruity smell sociated deficits and family distress, and to increase

3 5 EP 2 609 921 A1 6 quality of life and functional independence. No single methods of treating patients exhibiting symptoms of Per- treatment is best and treatment is typically tailored to the vasive Developmental Disorders, particularly symptoms child’s needs.Intensive, sustained specialeducation pro- of autism with therapies that are safe and can be easily grams and behavior therapy early in life can help children administered to children. acquire self-care, social, and job skills, (Myers SM, et al. 5 "Management of children with autism spectrum disor- SUMMARY OF THE INVENTION ders" Pediatrics (2007) 120 (5): 1162-82) and Angley M, et al. "Children and autism-part 1-recognition and phar- [0023] The present invention provides methods that macological management" Aust Fam. Physician (2007) can reduce, ameliorate or treat the symptoms of Perva- 36 (9): 741-4) and often improve functioning and de-10 sive Developmental Disorders, particularly symptoms of crease symptom severity and maladaptive behaviors ; autism in a human patient. Briefly, the methods and com- (Rogers SJ, et al., . "Evidence-based comprehensive positions comprise administering a physiologically or treatments for early autism" J Clin. Child Adolesc. Psy- therapeutically effective amount of a tocotrienol, a tocot- chol. (2008) 37 (1): 8-38). rienol ester, a tocotrienol ether, a tocotrienol enriched [0018] Medications have not been proven to correct 15 extract or composition, or mixtures thereof, in sufficient deficits of ASDs and are not the primary treatment. They quantities to reduce, ameliorate or treat at least one of are used to treat problems associated with autism disor- the symptoms of Pervasive Developmental Disorders, ders, such as associated maladaptive behaviors or psy- particularly symptoms of autism, preferably all of the chiatric comorbidities that may interfere with educational symptoms of Pervasive Developmental Disorders, par- progress, socialization, health or safety and quality of life. 20 ticularly of autism. When administered to human patients More than half of U.S. children diagnosed with autistic suffering from Pervasive Developmental Disorders, par- disorders are prescribed psychoactive drugs or anticon- ticularly from autism, without restriction on the normal vulsants, with the most common drug classes being anti- diet of the patients, the compositions and methods may depressants, stimulants, and antipsychotics.(Oswald reduce or improve one or more symptoms of Pervasive DP, et al. "Medication use among children with autism 25 Developmental Disorders, particularly symptoms of au- spectrum disorders". J Child Adolesc Psychopharmacol tism, such as increased eye contact, better enunciation (2007) 17 (3): 348-55.) Aside from antipsychotics, there and use of pronouns, less fatigue, singing a song with is scant reliable research about the effectiveness or safe- the melody and words together and the entire song un- ty of drug treatments for children, adolescents or adults derstandable, playing with age appropriate friends, fewer with ASD. A person with ASD may respond atypically to 30 tantrums, better sleep patterns, improved politeness and medications, the medications can have adverse effects, coordination, being more loving, acknowledging another and no known medication relieves autism’s core symp- individual’s emotion, and increased voice and word as- toms of social and communication impairments. Alterna- sociation. In some embodiments the composition com- tive nutritional therapies for autistic children may include prises alpha-tocotrienol or esters or ethers or mixtures Idebenone and CoQ10, because of their superior anti- 35 thereof, particularly the formulation comprises alpha-to- oxidant properties, but no studies have been performed cotrienol. In other embodiments, the composition com- to prove their efficacy. prises a tocotrienol enriched extract. [0019] US Patent Publication 2005/0203066 discloses [0024] In another aspect, the invention embraces a compounds, compositions and methods for treatment of method of reducing, ameliorating or treating the symp- developmental delay in cognitive, motor, language, ex- 40 toms associated with, or of treating or suppressing Per- ecutive function or social skills with a pyrimidine nucle- vasive Developmental Disorder (PDD), including of Au- otide precursor, but it does not disclose any compounds, tistic Disorder, Asperger’s Disorder, Childhood Disinte- compositions or methods of treatment with compounds grative Disorder (CDD), Rett’s Disorder, and PDD-Not of the present invention. Otherwise Specified (PDD-NOS) in a patient in need of [0020] Krajcovicova-Kudlackova et al, Bratisl Lek45 such treatment by administering a therapeutically or Listy, (2009), 110(4): 247-250 have shown that plasma physiologically effective amount of formulation compris- concentrations of exogenous antioxidants such as Vita- es a therapeutically effective amount of one or more min E and A and lycopene in autistic subjects are insuf- agents selected from the group consisting of alpha-to- ficient. cotrienol, beta-tocotrienol, gamma-tocotrienol, delta-to- [0021] Co-owned US provisional patent application 50 cotrienol, or mixtures thereof. USAN 61/191,696 titled "Treatment of Pervasive Devel- [0025] In some embodiments, the tocotrienol is essen- opment Disorders with Redox-active Therapeutics," Pat- tially pure alpha-tocotrienol. In other embodiments the ent Cooperation Treaty tocotrienol application is an alpha-tocotrienol enriched composition PCT/US2009/056254, andU.S. patentapplication USAN of tocotrienols also optionally including beta-tocotrienol, 12/555,700 disclose the use of certain redox- active com- 55 delta-tocotrienol and gamma-tocotrienol, but with less pounds for the treatment or suppression of pervasive de- than 40%, less than 30%, less than 25%, less than 20%, velopment disorders. less than 15%, less than 10%, less than 5% or less than [0022] Thus, there is an unmet need for improved 2% tocopherol or no detectable tocopherol. In some em-

4 7 EP 2 609 921 A1 8 bodiments, the tocotrienol is alpha- tocotrienol essentially [0029] In other embodiments, the tocotrienol ester is free of tocopherol. In the spirit of the invention, "essen- selected from alpha-tocotrienol succinate, beta-tocotrie- tially free of tocopherol" means less than 20%, less than nol succinate, gamma-tocotrienol succinate, delta- tocot- 15%, less than 10%, less than 5% or less than 2% of rienol succinate; alpha- tocotrienol acetate, beta- tocotrie- tocopherol of the total tocotrienol/tocopherol weight. In 5 nol acetate, gamma- tocotrienol acetate, delta- tocotrienol other embodiments the tocotrienol is an alpha- tocotrienol acetate; alpha-tocotrienol nicotinate, beta-tocotrienol enriched composition of tocotrienols also optionally in- nicotinate, gamma-tocotrienol nicotinate, delta-tocotrie- cluding beta-tocotrienol, delta-tocotrienol and gamma- nol nicotinate; alpha-tocotrienol phosphate, beta-tocot- tocotrienol, but with less than 40%, less than 30%, less rienol phosphate, gamma-tocotrienol phosphate, delta- than 25%, less than 20%, less than 15%, less than 10%, 10 tocotrienol phosphate, alpha-tocotrienol glutamate, be- less than 5% or less than 2% alpha- tocopherol or no de- ta-tocotrienol glutamate, gamma-tocotrienol glutamate, tectable alpha-tocopherol. In some embodiments, the to- delta-tocotrienol glutamate, alpha-tocotrienol linoleate, cotrienol is alpha- tocotrienol essentially free of alpha- to- beta-tocotrienol linoleate, gamma-tocotrienol linoleate, copherol. In the spirit of the invention, "essentially free delta-tocotrienol linoleate, alpha-tocotrienol palmitate, of alpha-tocopherol" means less than 20%, less than 15 beta-tocotrienol palmitate, gamma- tocotrienol palmitate, 15%, less than 10%, less than 5% or less than 2% of delta-tocotrienol palmitate, alpha-tocotrienol aspartate, alpha-tocopherol of the total tocotrienol/tocopherol beta-tocotrienol aspartate, gamma-tocotrienol aspar- weight. tate, and delta-tocotrienol aspartate. [0026] In another aspect, the invention embraces a [0030] In particular embodiments, the tocotrienol ester method of reducing, ameliorating or treating the symp- 20 is selected from alpha-tocotrienol succinate, alpha-tocot- toms associated with, or of treating or suppressing Per- rienol acetate, alpha-tocotrienol nicotinate, alpha-tocot- vasive Developmental Disorder (PDD), including of Au- rienol phosphate, alpha-tocotrienol glutamate, alpha-to- tistic Disorder, Asperger’s Disorder, Childhood Disinte- cotrienol linoleate, alpha-tocotrienol palmitate, and al- grative Disorder (CDD), Rett’s Disorder, and PDD-Not pha-tocotrienol aspartate. In another embodiment, the Otherwise Specified (PDD-NOS) in a patient in need of 25 tocotrienol ester is alpha-tocotrienol acetate. In another such treatment by administering a therapeutically or embodiment, the tocotrienol ester is alpha-tocotrienol physiologically effective amount of one or more agents succinate. In another embodiment, the tocotrienol ester selected from the group consisting of alpha-tocotrienol is alpha-tocotrienol nicotinate. In another embodiment, esters, beta-tocotrienol esters, gamma-tocotrienol es- the tocotrienol ester is alpha- tocotrienol glutamate. In an- ters, delta-tocotrienol esters, and mixtures thereof. 30 other embodiment, the tocotrienol ester is alpha-tocot- [0027] In another aspect, the invention embraces a rienol phosphate. In another embodiment, the tocotrienol method of reducing, ameliorating or treating the symp- ester is alpha-tocotrienol palmitate. In another embodi- toms associated with, or of treating or suppressing Per- ment, the tocotrienol ester is alpha-tocotrienol linoleate. vasive Developmental Disorder (PDD), including of Au- In another embodiment, the tocotrienol ester is alpha- tistic Disorder, Asperger’s Disorder, Childhood Disinte- 35 tocotrienol aspartate. grative Disorder (CDD), Rett’s Disorder, and PDD-Not [0031] In other embodiments, the tocotrienol ester is a Otherwise Specified (PDD-NOS) in a patient in need of polyethoxylated alpha-tocotrienol, polyethoxylated be- such treatment by administering a therapeutically or ta-tocotrienol, polyethoxylated gamma-tocotrienol, or physiologically effective amount of one or more agents polyethoxylated delta-tocotrienol. In some embodi- selected from the group consisting of alpha-tocotrienol 40 ments, the tocotrienol ester is polyethoxylated alpha-to- ethers, beta-tocotrienol ethers, gamma-tocotrienol cotrienol. In other embodiments, the tocotrienol ester is ethers, delta-tocotrienol ethers, and mixtures thereof. In alpha-tocotrienol polyethylene glycol succinate. some embodiments, the tocotrienol ether is a polyethox- [0032] In another aspect, the invention embraces a ylated tocotrienol. In some embodiments, the tocotrienol method of reducing, ameliorating or treating the symp- ether is a polyethoxylated alpha-tocotrienol ether, a pol- 45 toms associated with, or of treating or suppressing Per- yethoxylated beta-tocotrienol ether, a polyethoxylated vasive Developmental Disorder (PDD), including of Au- gamma-tocotrienol ether, a polyethoxylated delta-tocot- tistic Disorder, Asperger’s Disorder, Childhood Disinte- rienol ether, and mixtures thereof. grative Disorder (CDD), Rett’s Disorder, and PDD-Not [0028] In some embodiments, the tocotrienol ester is Otherwise Specified (PDD-NOS) in a patient in need of selected from the group consisting of an acetic acid ester, 50 such treatment by administering a therapeutically or a nicotinic acid ester, a phosphate ester, a glutamic acid physiologically effective amount of formulation compris- ester, a linoleic acid ester, a palmitic acid ester, an as- ing a therapeutically effective amount of a an enriched partic ester, and a succinic acid ester. In other embodi- tocotrienol extract of palm oil, rice bran oil, barley or an- ments, the tocotrienol is a polyethoxylated tocotrienol. In natto. In another embodiment the formulation of the other embodiments the tocotrienol is a tocotrienol poly- 55 present invention comprises an enriched tocotrienol ex- ethylene glycol succinate derivative. In other embodi- tract from palm oil, as sold by Carotech, Golden Hope ments, including any of the foregoing embodiments, the Bioorganic, Carotech, Davos Life Science, Beijing Ging- tocotrienol ester is alpha-tocotrienol ester. ko Group, Eisai, Eastman Corporation or Palm Nutraceu-

5 9 EP 2 609 921 A1 10 ticals. In some embodiments, and any of the foregoing reference to the remainder of this application, including embodiments the tocotrienol extract is Tocomin-50®. In the following detailed description. In addition, various ref- another embodiment, the formulation of the present in- erences are set forth herein that describe in more detail vention comprises an enriched tocotrienol extract from certain compositions, and/or methods; all such referenc- annatto. 5 es are incorporated herein by reference in their entirety. [0033] In some of the foregoing embodiments, the symptoms treated by the compounds of the present in- DETAILED DESCRIPTION OF THE INVENTION vention are selected from the group of symptoms con- sisting of eye contact avoidance, failure to socialize, at- [0040] The present invention provides methods and tention deficit, poor mood, hyperactivity, anxiety, stim- 10 compositions able to reduce the symptoms of Pervasive ming, poor comprehension, inappropriate speech, ab- Developmental Disorder including autistic spectrum dis- normal sound sensitivity, poor digestion, disrupted sleep, order in a patient. Briefly, the compositions and methods and perseveration, and where the decreased incidence comprise administering a tocotrienol, a tocotrienol ester, is measured relative to the incidence in the untreated a tocotrienol ether, a tocotrienol enriched extract or com- individual. 15 position, or mixtures thereof to a human patient in suffi- [0034] In one embodiment, the present invention pro- cient quantities to reduce the effects of the autistic dis- vides pharmaceutical or nutraceutical compositions able ease. An initial trial wherein a tocotrienol, a tocotrienol to reduce the symptomsof autism in a patient,comprising ester, a tocotrienol ether, a tocotrienol enriched extract a physiologically effective amount of a tocotrienol, a to- or composition, or mixtures thereof are administered to cotrienol ester, a tocotrienol ether, a tocotrienol enriched 20 human patients, without restriction on the normal diet of extract or composition, or mixtures thereof and a physi- the patients, would provide a significant number of the ologically acceptable carrier, adjuvant, excipient, buffer patients with a significant reduction of one or more symp- and diluent. toms, such as increased eye contact, better enunciation [0035] In still a further aspect, the present invention and use of pronouns, less fatigue, singing a song with provides foods, medical foods, dietary foods, functional 25 the melody and words together and the entire song un- foods, food supplements, or dietary supplements com- derstandable, playing with age appropriate friends, fewer prising compositions of a tocotrienol, a tocotrienol ester, tantrums, better sleep patterns, improved politeness and a tocotrienol ether, a tocotrienol enriched extract or com- coordination, being more loving, acknowledging another position, or mixtures thereof, and at least one of the group individual’s emotion, increased voice and word associa- consisting of a physiologically or nutritionally acceptable 30 tion. carrier, adjuvant, excipient, buffer and diluent. [0041] "Subject," "individual," or "patient" are used in- [0036] In yet another aspect, the invention also pro- terchangeably, and refer to a mammal, preferably a hu- vides articles of manufacture and kits containing materi- man. als useful for treating or suppressing autistic spectrum [0042] "Treating" a disease with the compounds and disorder. The invention also provides kits comprising a 35 methods discussed herein is defined as administering tocotrienol, a tocotrienol ester, a tocotrienol ether, a to- one or more of the compounds discussed herein, with or cotrienol enriched extract or composition, or mixtures without additional therapeutic agents, in order to reduce thereof. In some embodiments, the kit of the invention or eliminate either the disease or one or more symptoms comprises a container suitable for storing a tocotrienol, of the disease, or to retard the progression of the disease a tocotrienol ester, a tocotrienol ether, a tocotrienol en- 40 or of one or more symptoms of the disease, or to reduce riched extract or composition, or mixtures thereof. In the severity of the disease or of one or more symptoms some embodiments, the kit of the invention comprises a of the disease. "Suppression" of a disease with the com- container suitable for storing a tocotrienol, a tocotrienol pounds and methods discussed herein is defined as ad- ester, a tocotrienol ether, a tocotrienol enriched extract ministering one or more of the compounds discussed or composition, or mixtures thereof, and at least one of 45 herein, with or without additional therapeutic agents, in the group consisting of a physiologically or nutritionally order to suppress the clinical manifestation of the dis- acceptable carrier, adjuvant, excipient, buffer and dilu- ease, or to suppress the manifestation of adverse symp- ent. toms of the disease. The distinction between treatment [0037] In other aspects, the kits may be used for any and suppression is that treatment occurs after adverse of the methods described herein, including, for example, 50 symptoms of the disease are manifest in a subject, while to treat an individual with ASD disorder, or to suppress suppression occurs before adverse symptoms of the dis- an ASD disorder in an individual. ease are manifest in a subject. Suppression may be par- [0038] The present invention comprises multiple as- tial, substantially total, or total. Because the autism dis- pects, features and embodiments; where such multiple orders are inherited, genetic screening can be used to aspects, features and embodiments can be combined 55 identify patients at risk of the disease. The compounds and permuted in any desired manner. and methods of the invention can then be administered [0039] These and other aspects, features and embod- to asymptomatic patients at risk of developing the clinical iments of the present invention will become evident upon symptoms of the disease, in order to suppress the ap-

6 11 EP 2 609 921 A1 12 pearance of any adverse symptoms. contact, better enunciation and use of pronouns, less fa- [0043] "Therapeutic use" of the compounds discussed tigue, fewer tantrums, better sleep patterns, improved herein is defined as using one or more of the compounds politeness and coordination, and increased voice and discussed herein to treat or suppress a disease, as de- word association. In other words, the compositions are fined above. A "therapeutically effective amount" of a 5 able to effect an adequate reduction of one or more of compound is an amount of the compound, which, when the observable characteristics of autism by an amount administered to a subject, is sufficient to reduce or elim- that is observable to a human observer, such as a parent, inate either a disease or one or more symptoms of a physician or caretaker, without the use of special devices disease, or to retard the progression of a disease or of such as microscopes or chemical analytical devices. The one or more symptoms of a disease, or to reduce the 10 compositions reduce such symptoms by providing a severity of a disease or of one or more symptoms of a physiologically effective amount of a tocotrienol, a tocot- disease, or to suppress the clinical manifestation of a rienol ester, a tocotrienol ether, a tocotrienol enriched disease, or to suppress the manifestation of adverse extract or composition, or mixtures thereof and at least symptoms of a disease. A therapeutically effective one of the group consisting of a physiologically accept- amount can be given in one or more administrations. 15 able carrier, adjuvant, excipient, buffer and diluent, which [0044] A "physiologically effective amount" of an active terms are used in their ordinary sense to indicate sub- substance indicates an adequate amount of the active stances that assist in the packaging, delivery, absorption, substances to have a significant, externally observable or the physiological effect of the compounds. The phys- effect on the patient. Thus, such a physiologically effec- iologically acceptable carriers, adjuvants, excipients, tive amount affects one or more of the characteristics in 20 buffers and diluents are preferably nontoxic to recipients the patient without the need for special equipment to de- at the dosages and concentrations employed. Repre- termine the effect. For example, a physiologically effec- sentative samples include oil, water, isotonic saline so- tive amount of a compound of the present invention has lutions that are preferably buffered at physiological pH a significant, externally observable effect on the behavior (such as phosphate-buffered saline or Tris-buffered sa- of the patient by reducing one or more of the symptoms 25 line), mannitol, dextrose, glycerol, and ethanol, as well of autism or other pervasive developmental disorder. Ac- as selected polypeptides or proteins such as human se- cordingly, one can determine whether an adequate rum albumin, maltodextrin, L-lysine, lactase and other amount of the active substance has been administered carbohydratases, lipase and non-specific proteases by watching the patient and observing whether changes such as papain. The carrier, adjuvant, excipient, buffer, have occurred in the patient due to the active substance. 30 or diluent may be combined with the compositions dis- [0045] Esters of tocotrienols with aspartate can be es- closed herein to provide compositions either as liquid so- terified via the alpha-carboxy group of aspartate, the lutions or, preferably, in solid form. For example, when side-chain (gamma-carboxy) group of aspartate, or to- the compositions are to be administered orally, the com- cotrienols esterified at the alpha- carboxy group of aspar- positions may be produced in any of powder, tablet or tate can be mixed with tocotrienols esterified at the side- 35 capsule form. The compositions can also be adminis- chain carboxy group of aspartate in any ratio. Esters of tered as elixirs, liquids, solutions, suspension, emul- tocotrienols with glutamate can be esterified via the al- sions, soft gelatin capsules, and hard gelatin capsules. pha-carboxy group of glutamate, the side-chain (delta- The preparation of the above dosage forms are well carboxy) group of glutamate, or tocotrienols esterified at known in the art. the alpha-carboxy group of glutamate can be mixed with 40 [0048] The compositions of the present invention are tocotrienols esterified at the side- chain carboxy group of preferably administered orally, but may also be adminis- glutamate in any ratio. tered via other direct routes, such as rectal or, in the case [0046] The invention also includes all stereoisomers of pharmaceutically designed compositions, via transcu- of the compounds and their use in the methods, including taneous methods such as intraarterial, intramuscular, in- diastereomers and enantiomers. The invention also in- 45 traperitoneal, subcutaneous, intraocular, and intrave- cludes mixtures of stereoisomers in any ratio, including, nous. Other routes such as buccal/sublingual, nasal, top- but not limited to, racemic mixtures, and their use in the ical (such as transdermal), pulmonary and central nerv- methods. ous system (CNS) administration (such as intraspinal, [0047] In a first aspect, the present invention provides intraventricular or hypothalmic) may also be used, if de- compositions comprising a tocotrienol, a tocotrienol es- 50 sired. The compositions are typically administered to hu- ter, a tocotrienol ether, a tocotrienol enriched extract or man beings, but may also be administered to animals, composition, or mixtures thereof that are able to reduce preferably mammals, displaying symptoms similar to au- the symptoms of Pervasive Developmental Disorder tism. (PDD), including of Autistic Disorder, Asperger’s Disor- der, Childhood Disintegrative Disorder (CDD), Rett’s Dis- 55 Compounds of the present invention order, and PDD-Not Otherwise Specified (PDD- NOS) in a human patient. For example, the compositions are able [0049] One or more of the components of the formu- to reduce one or more symptoms, such as increased eye lation of the present invention are tocotrienols. Tocot-

7 13 EP 2 609 921 A1 14 rienols belong to the vitamin E family and differ from the cotrienol phosphate, alpha-tocotrienol aspartate, alpha- tocopherols in the chemical nature of the side chain or tocotrienol glutamate, alpha-tocotrienol palmitate, alpha- tail and in their properties that are clearly distinct from tocotrienol nicotinate, and polyethoxylated alpha-tocot- those of the tocopherols. Tocotrienols are fat-soluble, rienol. water-insoluble oils and modulate several mechanisms 5 [0054] Some other formulations of the present inven- associated with the aging process and aging- related dis- tion particularly comprise tocotrienols from extracts of eases. palm oil, rice bran oil and barley. While synthetic and [0050] Tocotrienols have been shown to promote natural tocopherols are readily available in the market, healthy cholesterol levels, and exhibit neuroprotective ef- natural tocotrienols supply is limited, and generally com- fects, anti-oxidant activity and anti- cancer effects that are 10 prises a mixture of tocotrienols. Crude palm oil which is often not exhibited by tocopherols. There are three com- rich in tocotrienols (800-1500 ppm) offers a potential mercially used sources of tocotrienols - rice bran oil, palm source of natural tocotrienols. Carotech, Malaysia is an oil, and annatto bean. Annatto tocotrienol extracts con- industrial plant that is able to extract and concentrate tain, approximately, no alpha-tocotrienol, 90% of delta- tocotrienols from crude palm oil, by a process patented tocotrienol, 10% of gamma- tocotrienol, and no tocophe- 15 in U.S. Pat. No. 5,157,132. Tocomin-50® typically com- rols. Rice bran extract contains, approximately, less than prises about 25.32% mixed tocotrienols (7.00% alpha- 2% alpha-tocotrienol, 51.6% gamma-tocotrienol, and tocotrienol, 14.42% gamma tocotrienol, 3.30% delta to- 48% tocopherols. Palm oil extract contains, approximate- cotrienol and 0.6% beta tocotrienol), 6.90% alpha-toco- ly, 22.1 % alpha-tocotrienol, 10% delta-tocotrienol, pherol and other phytonutrients such as plant squalene, 45.7% gamma-tocotrienol, and 21.8% tocopherols. To- 20 phytosterols, co-enzyme Q10 and mixed carotenoids. cotrienols are often used in small quantities as antioxi- [0055] Some other formulations of the present inven- dants to prevent decomposition and enhance the stability tioncomprise tocotrienols from extracts ofannatto beans. of other components in formulations, but in the present [0056] Additional commercially available products that invention tocotrienols are used as one of the essential may be used in the present invention are for example, components of the medical food or dietary food for the 25 Nu Triene Tocotrienol® (30% content, a product of East- prevention and amelioration of Pervasive Developmental man Chemical Company), various Oryza® tocotrienol Disorder (PDD), including of Autistic Disorder, Asperg- products of different tocotrienol concentrations from er’s Disorder, Childhood Disintegrative Disorder (CDD), Oryza Oil & Fat Co. Ltd including Oryza tocotrienol-70 Rett’s Disorder, and PDD-Not Otherwise Specified with 70% total tocopherol/ tocotrienol content, and a total (PDD-NOS) in a human patient. 30 tocotrienol content of 40% including 14% of alpha- tocot- [0051] Some formulations of the present invention par- rienol and 24% gamma-tocotrienol, and Oryza tocotrie- ticularly comprise alpha-tocotrienol which can be pro- nol-90 with 90% total tocopherol/ tocotrienol content and duced synthetically or derived from one of the commer- a total tocotrienol content of 60%; Golden Hope Planta- cial sources mentioned above. A preferred process for tions Berhad Tocotrienol oil (70% content), Davos Life the production of essentially pure alpha-tocotrienol has 35 Science TRF (63% content) and Palm Nutraceuticals been described in co-owned US application USAN Sdn Bhd (89% content). Delta Tocotrienol- 92®(92% pure 12/606,923 titled "Process for Enrichment and Isolation by HPLC) is a commercially available product from Bei- of alpha-Tocotrienol and Derivatives" hereby incorporat- jing Gingko Group that may be also used in the present ed by reference in its entirety. invention. [0052] Syntheses of various members of the tocotrie- 40 [0057] Other methods for isolation or enrichment of to- nol family in the d,1- or (RS)-form have been published, cotrienol from certain plant oils and plant oil by-products see for example Schudel et al., Helv. Chim. Acta (1963) have been described in the literature. For some examples 46, 2517-2526; Mayer et al., Helv. Chim. Acta (1967) 50, of such isolation and purification processes, see for in- 1376-1393; Kabbe et al., Synthesis (1978), 888-889; Ka- stance Top et al., U.S. Pat. No. 5,190,618; Lane et al., jiwara et al., Heterocycles (1980) 14, 1995-1998; Urano 45 U.S. Pat No. 6,239,171; Bellafiore et al, U.S. Pat. No. et al., Chem. Pharm. Bull. (1983) 31, 4341-4345; Pearce 6,395,915; May et al., U.S. Pat. No. 6,656,358; Jacobs et al., J. Med Chem. (1992), 35, 3595-3606; and Pearce et al., U.S. Pat. No. 6,838,104; Sumner et al. Int. Pat. et al., J. Med. Chem. (1994). 37, 526-541. None of these Pub. WO 99/38860, Jacobs Int. Pat. Pub. WO reported processes lead to the natural form of the tocot- 2002/500054, and Bhaggan et al. Int. Pat. Pub. WO rienols,but ratherproduces racemicmixtures. Syntheses 50 2008/142433. of natural form d-tocotrienols have been published. See for example, Scott et al., Helv. Chim. Acta (1976) 59, Clinical Assessment of Autism 290-306; Sato et al., Japanese Patent No. 63063674; Sato et al., Japanese Patent No. 01233278; and Cou- [0058] Several biochemical markers have been asso- ladouros et al (US Patent No. 7,038,067). 55 ciated with Pervasive Developmental Disorders. These [0053] Some other formulations of the present inven- biomarkers can be monitored during treatment with the tion comprise tocotrienol esters selected from alpha-to- methods and compositions of the invention, in order to cotrienol acetate, alpha-tocotrienol succinate, alpha-to- assess efficacy of treatment.

8 15 EP 2 609 921 A1 16

[0059] Carnitine Deficiency: As documented by Fili- [0063] Antioxidant Proteins: Levels of major antioxi- pek, PA et al, in J, Autism Dev. Diosrd. (2004) 34:615-23 dant proteins namely, transferrin (iron-binding protein) serum carnitine levels on 100 children with autism were and ceruloplasmin (copper-binding protein) in the serum, investigated, concurrently with serum pyruvate, lactate, are significantly reduced in autistic children as compared ammonia, and alanine levels. Values of free and total 5 to their developmentally normal non-autistic siblings. A carnitine (p < 0.001), and pyruvate (p = 0.006) were sig- striking correlation was observed between reduced lev- nificantly reduced while ammonia and alanine levels els of these proteins and loss of previously acquired lan- were considerably elevated (p < 0.001) in the autistic guage skills in children with autism. These results indi- subjects. The relative carnitine deficiency in these pa- cating altered regulation of transferrin and ceruloplasmin tients, accompanied by slight elevations in lactate and 10 in autistic children who lose acquired language skills can significant elevations in alanine and ammonia levels be used as diagnosis of disease during evaluation of pa- would suggest that assessing pyruvate, lactate, carnitine tients. and ammonia levels may be useful when measured dur- ing routine evaluation of ASD children. Pharmaceutical, nutraceutical and nutritional formula- [0060] Lactic acid (lactate) levels: Some cases of au- 15 tions tism have been associated with abnormal levels of lactic acid, as pyruvate levels increase and pyruvate is con- [0064] The compounds described herein can be for- verted to lactate to maintain capacity for glycolysis (see mulated as pharmaceutical compositions by formulation Coleman, M. et al. Journal of Autism and Developmental with additives such as pharmaceutically acceptable ex- Disorders (1985) 15, 1-8.) Lactate levels can be meas- 20 cipients, pharmaceutically acceptable carriers, and phar- ured by taking samples of appropriate bodily fluids such maceutically acceptable vehicles, or as nutraceutical or as whole blood, plasma, or cerebrospinal fluid. Using nutritional formulations with additives such as nutraceu- magnetic resonance, lactate levels can be measured in tically or nutritionally acceptable excipients, nutraceuti- virtually any volume of the body desired, such as the cally or nutritionally acceptable carriers, and nutraceuti- brain. Whole blood, plasma, and cerebrospinal fluid lac- 25 cally or nutritionally acceptable vehicles. tate levels can be measured by commercially available [0065] Suitable pharmaceutically acceptable excipi- equipment such as the YSI 2300 STAT Plus Glucose & ents,carriers and vehicles include processing agentsand Lactate Analyzer (YSI Life Sciences, Ohio). drug delivery modifiers and enhancers, such as, for ex- [0061] Lipid Peroxidation: Lipid peroxidation has been ample, calcium phosphate, magnesium stearate, talc, found to be elevated in autism indicating that oxidative 30 monosaccharides, disaccharides, starch, gelatin, cellu- stress is increased in this disease. Lipid peroxidation can lose, methyl cellulose, sodium carboxymethyl cellulose, be measured by quantifying the levels of malonyldialde- dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrro- hyde (MDA), an end product of fatty acid oxidation. Sev- lidinone, low melting waxes, ion exchange resins, and eral assays exist for MDA in plasma, urine, and other the like, as well as combinations of any two or more there- specimens. Such assays include specific reagents for 35 of. Other suitable pharmaceutically acceptable excipi- UV detection by HPLC (Steghens, J. P., et al., Free Radic ents are described in "Remington’s Pharmaceutical Sci- Biol Med (2001) 31:242 and Pilz, J. Chromatogr B Bi- ences," Mack Pub. Co., New Jersey (1991), and "Rem- omed Sci appl (2000) 742:315 and capillary electro- ington: The Science and Practice of Pharmacy," Lippin- phoresis (Korizis, K. N. et al., Biomed Chromatogr 15: cott Williams & Wilkins, Philadelphia, 20th edition (2003) 287 (2001)). A variety of lipid peroxidation products in- 40 and 21st edition (2005), incorporated herein by refer- cluding MDA can be quantified using the thiobarbituric ence. acid reaction (K Fukanaga et al., Biomed Chromatogr [0066] A pharmaceutical composition can comprise a (1998)12:300). unit dose formulation, where the unit dose is a dose suf- [0062] Lipid peroxidation can also be quantified by ficient to have a therapeutic or suppressive effect. The measurement of urinary levels of isoprostane F(2a)-VI, 45 unit dose may be sufficient as a single dose to have a a marker of lipid peroxidation; 2,3-dinor-thromboxane B therapeutic or suppressive effect. Alternatively, the unit (2), which reflects platelet activation; and 6- keto-prostag- dose may be a dose administered periodically in a course landin F(1a), a marker of endothelium activation, by of treatment or suppression of a disorder. A unit dose means of gas chromatography-mass spectrometry in can contain a therapeutically effective amount of a com- subjects with autism and healthy control subjects. Meth- 50 position disclosed herein. Alternatively, a unit dose can ods of detecting oxidant stress- related products are like- contain a physiologically effective amount of a composi- wise known in the art. For example, enzyme immu- tion disclosed herein. noassay kits are commercially available from Cayman [0067] Pharmaceutical compositions containing the Chemical for determination of isoprostane F (2a)-VI (Cay- compounds of the invention may be in any form suitable man Chemical cat. no. 516301); for 2,3- dinor-thrombox- 55 for the intended method of administration, including, for ane B(2) (Cayman Chemical cat. no. 519051), and for 6- example, a solution, a suspension, or an emulsion. Liquid keto-prostaglandin F(1a) (Cayman Chemical cat. no. carriers are typically used in preparing solutions, suspen- 5152111). sions, and emulsions. Liquid carriers contemplated for

9 17 EP 2 609 921 A1 18 use in the practice of the present invention include, for genetically engineered designer foods, herbal products, example, water, saline, pharmaceutically acceptable or- and processed foods such as cereals, soups and bever- ganic solvent(s), pharmaceutically acceptable oils or ages. In a more technical sense, the term has been used fats, and the like, as well as mixtures of two or more to refer to a product isolated or purified from foods, and thereof. The liquid carrier may contain other suitable5 generally sold in medicinal forms not usually associated pharmaceutically acceptable additives such as solubiliz- with food and demonstrated to have a physiological ben- ers, emulsifiers, nutrients, buffers, preservatives, sus- efit or provide protection against chronic disease. Suita- pending agents, thickening agents, viscosity regulators, ble nutraceutically acceptable excipients may include liq- stabilizers, and the like. Suitable organic solvents in- uid solutions such as a solution comprising a vegetable- clude, for example, monohydric alcohols, such as etha- 10 and/or animal- and/or fish-derived oil. nol, and polyhydric alcohols, such as glycols. Suitable [0070] The compositions of the present invention can oils include, for example, soybean oil, coconut oil, olive be dissolved in a vegetable oil that is appropriate as a oil,safflower oil,cottonseed oil,and the like. Forparenter- food additive such as soybean oil, sunflower oil, olive oil al administration, the carrier can also be an oily ester or other similar oils derived usually from seeds. The dis- such as ethyl oleate, isopropyl myristate, and the like. 15 persion or emulsion can be dispersed or spray dried and Compositions of the present invention may also be in the agglomerated. form of microparticles, microcapsules, liposomal encap- [0071] The compositions of the present invention can sulates, and the like, as well as combinations of any two be administered in the form of an emulsified liquid solu- or more thereof. tion that can be delivered as concentrates or in unit dose [0068] The compositions, as described above, can be 20 packaging for immediate consumption. Some emulsifiers prepared as nutritional formulations such as foods, in- described in US Pat. 7,118,688 may be sorbitol egg yolk cluding medical or functional foods and dietary supple- phospholipids, and sorbitol and soybean phospholipids, ments. A "medical or functional food" is defined as being optionally comprising flavors such as chocolate. Other consumed as part of a usual diet which has been dem- examples of emulsifiers include, but are not limited to onstrated to have physiological benefits and/or to reduce 25 lecithin, preferably natural soy lecithin, polyoxyethylene the risk of chronic disease beyond basic nutritional func- stearate, polyoxyethylene sorbitan mono- oleate, polyox- tions. A "dietary supplement" is defined as a product that yethylene sorbitan monopalmitate, polyoxyethylene is intended to supplement the human diet and is typically sorbitan monostearate, polyoxyethylene sorbitan mon- provided in the form of a pill, capsule, tablet, or like for- olaurate, ammonium phosphatides, citric acid esters of mulation. By way of example, but not limitation, a dietary 30 mono- or di-glycerides of fatty acids, and tartaric acid supplement may include one or more of the following esters of mono- or di- glycerides of fatty acids. The emul- ingredients: vitamins, minerals, herbs, botanicals, amino sifier should be one that is effective at achieving an oil- acids, dietary substances intended to supplement the di- in-water emulsion. et by increasing total dietary intake, and concentrates, [0072] In one embodiment, the emulsion is formulated metabolites, constituents, extracts or combinations of 35 as a powder, wherein said emulsion is mixed with a pow- any of the foregoing. Dietary supplements may also be der substance and the formed suspension is spray dried incorporated into food stuffs, such as functional foods or freeze dried. Processes for such formulations are designed to promote health or to prevent disease or dis- known in the art, for example as described by Yokoi et orders. If administered as a medicinal preparation, the al., US Pat. No. 6,562,372. Dextrins such as cyclodextrin composition can be administered, either as a prophylaxis 40 or maltodextrin may be added for the pulverization of the or treatment, to a patient in any of a number of methods. emulsion. The subject compositions may be administered alone or [0073] The powder composition may contain a desired in combination with other pharmaceutical agents and can amount of carbohydrates. Water-based food composi- be combined with a physiologically acceptable carrier tions typically include between about 5.0% to about 35% thereof. The effective amount and method of administra- 45 by weight of carbohydrates. An exemplary carbohydrate tion of the particular formulation can vary based on the is Maltodextrin DE 10 because it provides a mild sweet- individual subject, the stage of disease, and other factors ener combined with a good source of carbohydrates. Mal- evident to one skilled in the art. During the course of the todextrins are derived from corn starches. They are clas- treatment, the concentration of the subject compositions sified by dextrose equivalent or DE, which is a measure may be monitored (for example, blood plasma levels may 50 of the reducing sugars present calculated as dextrose be monitored) to insure that the desired level is main- and expressed as a percentage of the total dry sub- tained. stance. Maltodextrins can go up to 20 DE. At and above [0069] The term "nutraceutical" has been used to refer 20 DE, the product is classified as Corn Syrup Solids. to any substance that is a food or a part of a food and The lower the DE, the less sweet and the more like starch provides medical or health benefits, including the pre- 55 the maltodextrin is. As the DE decreases from 20 to 1, vention and treatment of disease. Hence, compositions the maltodextrins also decrease in solubility. Above a DE falling under the label "nutraceutical" may range from iso- of 20, the product is corn syrup solids, is completely sol- lated nutrients, dietary supplements and specific diets to uble, and therefore imparts significant sweetness.

10 19 EP 2 609 921 A1 20

[0074] Alternatively the formulation of the present in- bran are the most preferred. The components of the in- vention can be administered in the form of a beverage soluble dietary fiber derived from these brans are known product. The liquid beverage of the invention may be pre- to be cellulose, hemicellulose and lignin. pared by the individual at ambient temperature by dis- [0080] The soluble dietary fibers may be film-forming solving for immediate consumption the powder as de- 5 hydrocolloid materials such as alginates, gums, pectin, scribed above, in a consumable liquid, such as water, mucilagesand similar plantexudates. Examplesof useful milk, carbonated drink, and fruit juice. Liquid composi- soluble fibers are arabic, tragacanth, karaya gum, ghatti tions for oral administration prepared in water or other gum, seaweed extracts including agar, alginates, carra- aqueous consumable vehicles can include solutions, geenans, and furcellaran; pectin; and mucilages such as emulsions, syrups and elixirs containing together with 10 psyllium. Dietary fiber should constitute about 2-15% of the active compounds, wetting agents, sweeteners, the carbohydrates. The ratio of insoluble to soluble fiber coloring agents and flavoring agents. Alternatively the can range from 50:50 to about 99:1 with ratios in the formulation of the present invention can be administered range of about 80:20 to about 99:1 preferred. The blend in the form of a beverage product ready to be consumed. of higher insoluble to soluble also adds to the improved [0075] The formulation of the present invention can be 15 taste characteristics of the food bar. administered in the form of a high protein food bar that [0081] Another delivery form of the formulations of the may be used to supplement protein intake particularly in present invention is packaged as a mixture, preferably individuals in need of such supplementation. The formu- microencapsulated, in small impermeable, disposable lation may be in the form of ready-to-eat packages. The packages such as packets (e.g., 11/2" x 2" in size) or formulation administered in the form of a high protein 20 small tubes (e.g., 1/4" diameter x 2" in length) which may food bar may contain carbohydrates and dietary fibers. be foil, plastic, or other disposable material under inert [0076] The term "protein source" includes but is not conditions. In some of these configurations, the contents limited to, plant proteins, animal proteins, proteins from of the packages containing the formulations are admin- single cell organisms and free amino acids. Sources of istered to the patient directly from the package or mixed protein for high protein food bars include, but are not25 with food or a cold consumable liquid. In another delivery limited to, proteins derived from milk, whey, beef, egg, form the solid composition of the present invention is legumes, peanut wheat, soy and combinations thereof, packaged in nitrogen sealed cans. such as whey protein, soy protein, casein, hydrolyzed [0082] Time-release or controlled release delivery sys- beef protein, hydrogenated peanut oil, and combinations tems may be used, such as a diffusion controlled matrix thereof. 30 system or an erodible system, as described for example [0077] The term "carbohydrate" includes simple (mono in: Lee, "Diffusion-Controlled Matrix Systems", pp. and disaccharides) and complex (polysaccharides) car- 155-198 and Ron and Langer, "Erodible Systems", pp. bohydrates. The simple carbohydrates may be any of the 199-224, in "Treatise on Controlled Drug Delivery", A. digestible carbohydratessuch as dextrose, fructose, high Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The fructose corn syrup, sucrose, maltose, high maltose corn 35 matrix may be, for example, a biodegradable material syrup, maltodextrin, lactose, glucose, oligosaccharides, that can degrade spontaneously in situ and in vivo for, high saccharides, corn starch, cellulose, or mixtures example, by hydrolysis or enzymatic cleavage, e.g., by thereof, depending on usage. Complex carbohydrates proteases. The delivery system may be, for example, a are provided by but not limited to sources as cereal grains naturally occurring or synthetic polymer or copolymer, such as wheat, oat, corn, barley, rice, rye, sorghum; leg- 40 for example in the form of a hydrogel. Exemplary poly- umes both mature and dry, such as soybeans; and nuts mers with cleavable linkages include polyesters, poly- such as peanuts, and the like. Cereal grains may also orthoesters, polyanhydrides, polysaccharides, poly act as sources of fiber, may be rolled, toasted, extruded (phosphoesters), polyamides, polyurethanes, poly(imi- and otherwise treated to add to the chew texture. docarbonates) and poly(phosphazenes). [0078] The carbohydrates can be in the form of grains, 45 [0083] The compounds of the invention may be admin- flakes, flours, and meals. Simple carbohydrates including istered enterally, orally, parenterally, sublingually, by in- fructose should constitute from about 30-60% of the car- halation (e.g. as mists or sprays), rectally, or topically in bohydrates. Complex carbohydrates should constitute dosage unit formulations containing conventional non- from about 40-70% of the carbohydrates. The blend of toxic pharmaceutically acceptable carriers, adjuvants, carbohydrates including fibers is selected to add to sus- 50 and vehicles as desired. For example, suitable modes of tained energy. administration include oral, subcutaneous, transdermal, [0079] Dietary fiber can be divided into two broad cat- transmucosal, iontophoretic, intravenous, intraarterial, egories: insoluble dietary fiber and water soluble dietary intramuscular, intraperitoneal, intranasal (e.g. via nasal fiber. Best suited are cereal bran and mixtures thereof mucosa), subdural, rectal, gastrointestinal, and the like, due to their relatively high insoluble dietary fiber content. 55 and directly to a specific or affected organ or tissue. For Those cereal brans useful in this invention are selected delivery to the central nervous system, spinal and epi- from the group consisting of rice, wheat, corn, barley, dural administration, or administration to cerebral ventri- rye, oats, pea and mixtures thereof. Wheat, oat and corn cles, can be used. Topical administration may also in-

11 21 EP 2 609 921 A1 22 volve the use of transdermal administration such as formedby mono- ormulti- lamellarhydrated liquid crystals transdermal patches or iontophoresis devices. The term that are dispersed in an aqueous medium. Any non- toxic, parenteral as used herein includes subcutaneous injec- physiologically acceptable and metabolizable lipid capa- tions, intravenous, intramuscular, intrasternal injection, ble of forming liposomes can be used. The present com- or infusion techniques. The compounds are mixed with 5 positions in liposome form can contain, in addition to a pharmaceutically acceptable carriers, adjuvants, and ve- compound of the present invention, stabilizers, preserv- hicles appropriate for the desired route of administration. atives, excipients, and the like. The preferred lipids are Oral administration is a preferred route of administration, the phospholipids and phosphatidyl cholines (lecithins), and formulations suitable for oral administration are pre- both natural and synthetic. Methods to form liposomes ferred formulations. The compounds described for use 10 are known in the art. See, for example, Prescott, Ed., herein can be administered in solid form, in liquid form, Methods in Cell Biology, Volume XIV, Academic Press, in aerosol form, or in the form of tablets, pills, powder New York, N.W., p. 33 et seq (1976). mixtures, capsules, granules, injectables, creams, solu- [0088] In a preferred embodiment, the compositions tions, suppositories, enemas, colonic irrigations, emul- are provided to the patient as either a medical or dietary sions, dispersions, food premixes, and in other suitable 15 food or a food supplement. For example, when provided forms. The compounds can also be administered in lipo- as a food the compositions of the present invention are some formulations. The compounds can also be admin- combined with material primarily made up of protein, car- istered as prodrugs, where the prodrug undergoes trans- bohydrate and/or fat that is used in the body, preferably formation in the treated subject to a form which is thera- a human body, to sustain growth, repair, vital processes, peutically effective. Additional methods of administration 20 and to furnish energy. When provided as a food supple- are known in the art. ment, the compositions comprise selected substances [0084] Injectable preparations, for example, sterile in- such that they can be eaten at or about the same time jectable aqueous or oleaginous suspensions, may be for- as a food. The food supplements are generally eaten mulated according to the known art using suitable dis- within about one hour before or after the food is eaten, persing or wetting agents and suspending agents. The 25 typically within about one-half hour before or after the sterile injectable preparation may also be a sterile inject- food is eaten, preferably within about 15 minutes of when able solution or suspension in a nontoxic parenterally the food is eaten, and further preferably within one to five acceptable diluent or solvent, for example, as a solution minutes of the time the food is eaten. The food supple- in propylene glycol. Among the acceptable vehicles and ment can also be eaten at the same time as, or even with solvents that may be employed are water, Ringer’s so- 30 the food. lution, and isotonic sodium chloride solution. In addition, [0089] The invention also provides articles of manu- sterile, fixed oils are conventionally employed as a sol- facture and kits containing materials useful for treating vent or suspending medium. For this purpose any bland or suppressing PDD including Autism or for reducing the fixed oil may be employed including synthetic mono- or symptoms of one or more symptoms of PDD. The inven- di-glycerides. In addition, fatty acids such as oleic acid 35 tion also provides kits comprising of a tocotrienol, a to- find use in the preparation of injectables. cotrienol ester, a tocotrienol ether, a tocotrienol enriched [0085] Solid dosage forms for oral administration may extract or composition, or mixtures thereof. In some em- include capsules, tablets, pills, powders, and granules. bodiments, the kit of the invention comprises the contain- In such solid dosage forms, the active compound may er described above. be admixed with at least one inert diluent such as su- 40 [0090] In other aspects, the kits may be used for any crose, lactose, or starch. Such dosage forms may also of the methods described herein, including, for example, comprise additional substances other than inert diluents, totreat an individualwith a Pervasive Developmental Dis- e.g., lubricating agents such as magnesium stearate. In order, including an autistic spectrum disorder, or to sup- the case of capsules, tablets, and pills, the dosage forms press a Pervasive Developmental Disorder, such as an may also comprise buffering agents. Tablets and pills 45 autistic spectrum disorder in an individual. can additionally be prepared with enteric coatings. [0091] The amount of active ingredient that may be [0086] Liquid dosage forms for oral administration may combined with the carrier materials to produce a single include pharmaceutically acceptable emulsions, solu- dosage form will vary depending upon the host to which tions, suspensions, syrups, and elixirs containing inert the active ingredient is administered and the particular diluents commonly used in the art, such as water. Such 50 mode of administration. It will be understood, however, compositions may also comprise adjuvants, such as wet- that the specific dose level for any particular patient will ting agents, emulsifying and suspending agents, cyclo- depend upon a variety of factors including the activity of dextrins, and sweetening, flavoring, and perfuming the specific compound employed, the age, body weight, agents. body area, body mass index (BMI), general health, sex, [0087] The compounds of the present invention can 55 diet, time of administration, route of administration, rate also be administered in the form of liposomes. As is of excretion, drug combination, and the type, progres- known in the art, liposomes are generally derived from sion, and severity of the particular disease undergoing phospholipids or other lipid substances. Liposomes are therapy. The pharmaceutical unit dosage chosen is usu-

12 23 EP 2 609 921 A1 24 ally fabricated and administered to provide a defined final leucine, creatine, taurine and caffeine. concentration of drug in the blood, tissues, organs, or [0096] Other agents useful in combination with the other targeted region of the body. The therapeutically compounds and methods of the invention are com- effective amount or effective amount for a given situation pounds and/or drugs that have an effect on the neuro- can be readily determined by routine experimentation 5 transmitters, particularly serotonin and dopamine, that and is within the skill and judgment of the ordinary clini- include antidepressants, anti-anxiety drugs, antispas- cian. The composition can be administered once a day, modics, neuroleptics and atypical neuroleptics, and stim- twice a day or three times a day. The composition can ulants. Antidepressants include but are not limited to Se- be administered at the recommended maximum clinical lective Serotonin Reuptake Inhibitors (SSRIs) (fluoxetine dosage or at lower doses. Dosage levels of the active 10 (Prozac); fluvoxamine (Luvox); paroxetine (Paxil); ser- compounds in the formulation of the invention may be traline (Zoloft); citalopram (Celexa)); Tricyclic antide- varied so as to obtain a desired therapeutic response pressants (amitriptyline (Elavil); amitriptyline/chlo- depending on the severity of the disease and the re- rdiazepoxide (Limbitrol); amoxapine (Asendin); clomi- sponse of the patient. pramine (Anafranil); desipramine (Norpramin); doxepin [0092] Examples of dosages which can be used are 15 (Sinequan); imipramine (Tofranil); nortriptyline (Avenytl, an effective amount within the dosage range of about 0.1 Pamelor); protriptyline (Vivactil); trimipramine (Surmon- mg/kg to about 500 mg/kg body weight, 0.1 mg/kg to til)); MAO Inhibitors (moclobemide (Aurorex); phenelzine about 300 mg/kg body weight, or within about 1.0 mg/kg (Nardil); tranylcypromine sulfate (Parnate)); Buproprion; to about 100 mg/kg body weight, or within about 1.0 Lithium; Mirtazapine; Nefazodone (Serzone); Reboxet- mg/kg to about 50 mg/kg body weight, or within about 20 ine (Edronax); Venlafaxine (Effexor, Effexor XR); and 1.0 mg/kg to about 30 mg/kg body weight, or within about "natural" antidepressants such as St. John’s Wart. Anti- 1.0 mg/kg to about 10 mg/kg body weight, or within about anxiety drugs include but are not limited to alprazolam 10 mg/kg to about 100 mg/kg body weight, or within about (Xanax); chlordiazepoxide (Librium); clonazepam 50 mg/kg to about 150 mg/kg body weight, or within about (Klonopin); clorazepate (Tranxene); diazepam (Valium); 100 mg/kg to about 200 mg/kg body weight, or within25 lorazepam (Ativan); oxazepam (Serax); and prazepam about 150 mg/kg to about 250 mg/kg body weight, or (Centrax). Antispasmodic medications include but are within about 200 mg/kg to about 300 mg/kg body weight, not limited to carmazepine (Tegretol); clonazepam or within about 250 mg/kg to about 300 mg/kg body (Klonopin); ethosuximide (Zarontin); ethotoin (Pega- weight. Compounds of the present invention may be ad- none); fosphenytoin (Cerebyx); gabapentin (Neurontin); ministered in a single daily dose, or the total daily dosage 30 lamotrigine (Lamictal); mephenytoin (Mesantoin); phe- may be administered in divided dosage of two, three or nobarbital (Luminol, Solfoton); phenytoin (Dilantin); prim- four times daily. idone (Mysoline); toiramate (Topamax); valproic acid [0093] While the compounds of the invention can be (Depakene); divalproex sodium (Depakote, Depakote administered as the sole active pharmaceutical agent, Sprinkles); and Gabapentin (Neurontin). Stimulants in- they can also be used in combination with one or more 35 clude but are not limited to dextroamphetamine sulfate other agents used in the treatment or suppression of dis- (Das, Dexampex, Dexedrine, Dexedrine Spansules, orders. If compounds are administered together, they Dextrostat, Ferndex, Oxydess); dextroamphetamine/ need not be administered by the same route, or in the amphetamine (Adderall); methamphetamine (MTH); same formulation. However, they can be combined into methylphenidate hydrochloride (Ritalin); and pemoline one formulation as desired. 40 (Cyclert); and phenylpropanolamine (PPA). Atypical neu- [0094] In some embodiments, representative agents roleptics include but are not limited to clozapine (Cloz- are useful in combination with the compounds and meth- aril); olanzapine (Zyprexa); risperidone (Risperdal); ods of the invention for the treatment or suppression of quetiapine (Seroquel); and ziprasidone (Zeldox). PDD or ASD symptoms include, but are not limited to, [0097] The compounds disclosed herein for use in antioxidant compounds and/or drugs, such as but not 45 methods of the invention can be administered in combi- limited to carnitine, quercetine, mangosteen, acai, urid- nation with one or more minerals, such as, but not limited ine, N-acetyl cysteine (NAC), and glutathione. to, iron, calcium, potassium, zinc, manganese, phospho- [0095] In other embodiments, representative agents rous,chromium, magnesium,manganese, molybdenum, useful in combination with the compounds and methods tin, nickel, sulfur, selenium, copper, cobalt, chloride, flu- of the invention for the treatment or suppression of PDD 50 oride or iodide. The minerals may be administered in or ASD symptoms include one or more compounds se- large or trace amounts. The compounds can be admin- lected from alpha-lipoic acid, L-carnitine or acetyl L-car- istered together with the minerals in one formulation or nitine, Vitamin C, at least one of the B vitamins selected in different formulations. from vitamin B 1 (Thiamine), vitamin B2 (Riboflavin), vi- [0098] When additional active agents are used in com- tamin B3 (Niacin), vitamin B4 (Niacinamide), vitamin B5 55 bination with the compounds and methods of the present (Pantothenic acid), vitamin B6 (Pyridoxine), vitamin B8 invention, the additional active agents may generally be (Inositol), vitamin B9 (Folic acid), vitamin B10 (PABA) employed in therapeutic amounts as indicated in the Phy- and vitamin B12 (Cobalamins), N- acetyl cysteine (NAC), sicians’ Desk Reference (PDR) 53rd Edition (1999), or

13 25 EP 2 609 921 A1 26 such therapeutically useful amounts as would be known MTP) a total of 14.3 million cells (passage eight) were to one of ordinary skill in the art. re-suspended in 480 ml medium, corresponding to 100 [0099] The compounds of the invention and the other ml medium with 3,000 cells/ well. The remaining cells were therapeutically active agents disclosed herein for use in distributed in 10 cm cell culture plates (500,000 cells/ methods of the invention can be administered at the rec- 5 plate) for propagation. The plates were incubated over- ommended maximum clinical dosage or at lower doses. night at 37°C in an atmosphere with 95% humidity and

Dosage levels of the active compounds in the composi- 5% CO2 to allow attachment of the cells to the culture tions of the invention may be varied so as to obtain a plate. desired therapeutic response depending on the route of [0105] MTP medium (243 ml) was added to a well of administration, severity of the disease and the response 10 the microtiter plate. The test compounds were unfrozen, of the patient. When administered in combination with and 7.5 ml of a 5 mM stock solution was dissolved in the other therapeutic agents, the therapeutic agents can be well containing 243 ml medium, resulting in a 150m M formulated as separate compositions that are given at master solution. Serial dilutions from the master solution the same time or different times, or the therapeutic agents were made. The period between the single dilution steps can be given as a single composition. 15 was kept as short as possible (generally less than 1 sec- [0100] The invention will be further understood by the ond). following non-limiting example. [0106] Plates were kept overnight in the cell culture incubator. The next day, 10 ml of a 10 mM BSO solution Example were added to the wells, resulting in a 1 mM final BSO 20 concentration. Forty-eight hours later, three plates were ScreeningCompounds of the Invention in Human Dermal examined under a phase-contrast microscope to verify Fibroblasts from Autistic Patients that the cells in the 0% control (wells E1- H1) were clearly dead. The medium from all plates was discarded, and [0101] A screen was performed to identify compounds the remaining liquid was removed by gently tapping the effective for the amelioration of ASD. Test samples, and 25 plate inversed onto a paper towel. solvent controls were tested for their ability to rescue ASD [0107] 100 ml of PBS containing 1.2 mM Calcein AM fibroblasts stressed by addition of L-buthionine-(S, were then added to each well. The plates were incubated R)-sulfoximine (BSO). for 50-70 minutes at room temperature. After that time [0102] MEM (a medium enriched in amino acids and the PBS was discarded, the plate gently tapped on a vitamins, catalog no. Gibco 11965) and Fetal Calf Serum 30 paper towel and fluorescence (excitation/emission wave- were obtained from Invitrogen. Basic fibroblast growth lengths of 485 nm and 525 nm, respectively) was read factor and epidermal growth factor were purchased from on a Gemini fluorescence reader. Data was imported into PeproTech. Penicillin-streptomycin-glutamine mix, L- Microsoft Excel (EXCEL is a registered trademark of Mi- buthionine (S,R)-sulfoximine, and insulin from bovine crosoft Corporation for a spreadsheet program) and used 35 pancreas were purchased from Sigma. Calcein AM was to calculate the EC 50 concentration for each compound. purchased from Molecular Probes. Cell culture medium [0108] The compounds were tested three times, i.e., (ATP) was made by combining 75 ml Fetal Calf Serum, the experiment was performed three times, the passage 100 U/ml penicillin, 100m g/ml streptomycin, 2 mM number of the cells increasing by one with every repeti- glutamine, 10 ng/ml EGF, and 10 ng/ml bFGF; MEM EBS tion. was added to make the volume up to 500 ml. A 10 mM 40 [0109] The solvents (DMSO, ethanol, PBS) neither BSO solution was prepared by dissolving 444 mg BSO had a detrimental effect on the viability of non-BSO treat- in 200 ml of medium with subsequent filter-sterilization. ed cells nor did they have a beneficial influence on During the course of the experiments, this solution was BSO-treated fibroblasts even at the highest concentra- stored at +4°C. The cells were obtained from Dr. J.M. tion tested (1%). None of the compounds showed auto- Shoffner , Medical Neurogenetics, Atlanta, GA and were 45 fluorescence. The viability of non- BSOtreated fibroblasts grown in 10 cm tissue culture plates. Every week, they was set as 100%, and the viability of the BSO- and com- were split at a 1:3 ratio. pound-treated cells was calculated as relative to this val- [0103] The samples were supplied in 1.5 ml glass vials. ue. Alpha-tocotrienol exhibited protection against ASD

Thecompounds were diluted with DMSO, ethanol orPBS with an EC50 of less than about 50 nM. to result in a 5 mM stock solution. Once dissolved, they 50 [0110] The disclosures of all publications, patents, pat- were stored at -20°C. ent applications and published patent applications re- [0104] The samples were screened according to the ferred to herein by an identifying citation are hereby in- following protocol: A culture with ASD fibroblasts was corporated herein by reference in their entirety. started from a 1 ml vial with approximately 500,000 cells stored in liquid nitrogen. Cells were propagated in 10 cm 55 EMBODIMENTS OF THE INVENTION cell culture dishes by splitting every week in a ratio of 1:3 until nine plates were available. Once confluent, fibrob- [0111] The following embodiments are disclosed: lasts were harvested. For 54 micro titer plates (96 well-

14 27 EP 2 609 921 A1 28

1. A method of reducing the symptoms associated iment 8, wherein the patient in need of such treat- with, or of treating or suppressing Pervasive Devel- ment exhibits symptoms associated with Autistic opmental Disorders (PDDs) in a patient in need of Disorder, Asperger’s Disorder, Childhood Disinte- such treatment, comprising administering a thera- grative Disorder (CDD), Rett’s Disorder, and peutically or physiologically effective amount of a 5 PDD-Not Otherwise Specified (PDD-NOS). composition comprising tocotrienols, tocotrienol es- ters,tocotrienol ethers, tocotrienol enriched extracts, 10. The method or dietary food according to embod- or mixtures thereof. iment 8, wherein the medical or dietary food com- prises a therapeutically effective amount of one or 2. The method according to embodiment 1, wherein 10 more agents selected from the group consisting of the patient in need of such treatment exhibits symp- alpha-tocotrienol, beta-tocotrienol, gamma-tocotrie- toms associated with Autistic Disorder, Asperger’s nol, delta-tocotrienol and mixtures thereof. Disorder, Childhood Disintegrative Disorder (CDD), Rett’s Disorder, and PDD-Not Otherwise Specified 11. The method or dietary food according to embod- (PDD-NOS). 15 iment 10, wherein the medical or dietary food com- prises a therapeutically effective amount of alpha-to- 3. The method according to embodiment 1, wherein cotrienol. the composition comprises a therapeutically effec- tive amount of one or more agents selected from the 12. The method or dietary food according to embod- group consisting of alpha-tocotrienol, beta-tocotrie- 20 iment 8, wherein the medical or dietary food com- nol, gamma-tocotrienol, delta-tocotrienol and mix- prises a therapeutically effective amount of one or tures thereof. more agents selected from tocotrienol acetate, to- cotrienol succinate, tocotrienol phosphate, tocotrie- 4. The method according to embodiment 3, wherein nol aspartate, tocotrienol glutamate, tocotrienol the composition comprises a therapeutically effec- 25 palmitate, tocotrienol nicotinate, and polyethoxylat- tive amount of alpha-tocotrienol. ed tocotrienol.

5. The method according to embodiment 1, wherein 13. The method or dietary food according to embod- the composition comprises a therapeutically effec- iment 12, wherein the medical or dietary food com- tive amount of one or more agents selected from 30 prises a therapeutically effective amount of one or tocotrienol acetate, tocotrienol succinate, tocotrienol more agents selected from alpha-tocotrienol ace- phosphate, tocotrienol aspartate, tocotrienol gluta- tate, alpha-tocotrienol succinate, alpha-tocotrienol mate, tocotrienol palmitate, tocotrienol nicotinate, phosphate, alpha-tocotrienol aspartate, alpha- tocot- and polyethoxylated tocotrienol. rienol glutamate, alpha-tocotrienol palmitate, alpha- 35 tocotrienol nicotinate, and polyethoxylated alpha- to- 6. The method according to embodiment 5, wherein cotrienol. the composition comprises a therapeutically effec- tive amount of one or more agents selected from 14. The medical or dietary food according to embod- alpha-tocotrienol acetate, alpha-tocotrienol succi- iment 8, wherein the medical or dietary food com- nate, alpha-tocotrienol phosphate, alpha- tocotrienol 40 prises a therapeutically effective amount of a tocot- aspartate, alpha-tocotrienol glutamate, alpha-tocot- rienol enriched extract. rienol palmitate, alpha-tocotrienol nicotinate, and polyethoxylated alpha-tocotrienol. 15. Use of a therapeutically or physiologically effec- tive amount of a composition comprising tocot- 7. The method according to embodiment 1, where 45 rienols, tocotrienol esters, tocotrienol ethers, tocot- the composition comprises a therapeutically effec- rienol enriched extracts, or mixtures thereof for re- tive amount of a tocotrienol enriched extract. ducing the symptoms associated with, or for treating or suppressing Pervasive Developmental Disorders 8. A medical or dietary food for reducing the symp- (PDDs) in a patient in need of such treatment. toms associated with Pervasive Developmental Dis- 50 orders (PDDs) in a patient in need of such treatment, 16. The use according to embodiment 15, wherein said medical or dietary food comprising a therapeu- the patient in need of such treatment exhibits symp- tically or physiologically effective amount of a com- toms associated with Autistic Disorder, Asperger’s position comprising tocotrienols, tocotrienol esters, Disorder, Childhood Disintegrative Disorder (CDD), tocotrienol ethers, tocotrienol enriched extracts, or 55 Rett’s Disorder, and PDD-Not Otherwise Specified mixtures thereof. (PDD-NOS).

9. The medical or dietary food according to embod- 17. The use according to embodiment 15, wherein

15 29 EP 2 609 921 A1 30

the composition comprises a therapeutically effec- palmitate, tocotrienol nicotinate, and polyethoxylat- tive amount of one or more agents selected from the ed tocotrienol. group consisting of alpha-tocotrienol, beta-tocotrie- nol, gamma-tocotrienol, delta-tocotrienol and mix- 6. A composition according to claim 5, for use as de- tures thereof 5 fined in said claim, wherein the composition com- prises a therapeutically effective amount of one or 18. The use according to embodiment 17, wherein more agents selected from alpha-tocotrienol ace- the composition comprises a therapeutically effec- tate, alpha-tocotrienol succinate, alpha-tocotrienol tive amount of alpha-tocotrienol. phosphate, alpha-tocotrienol aspartate, alpha- tocot- 10 rienol glutamate, alpha-tocotrienol palmitate, alpha- 19. The use according to embodiment 15, wherein tocotrienol nicotinate, and polyethoxylated alpha- to- the composition comprises a therapeutically effec- cotrienol. tive amount of one or more agents selected from alpha-tocotrienol acetate, alpha-tocotrienol succi- 7. A composition according to claim 1, for use as de- nate, alpha-tocotrienol phosphate, alpha- tocotrienol 15 fined in said claim, wherein the composition com- aspartate, alpha-tocotrienol glutamate, alpha-tocot- prises a therapeutically effective amount of a tocot- rienol palmitate, alpha-tocotrienol nicotinate, and rienol enriched extract. polyethoxylated alpha-tocotrienol. 8. A medical or dietary food for use in reducing the 20. The use according to embodiment 15, wherein 20 symptoms associated with a Pervasive Develop- the composition comprises a therapeutically effec- mental Disorder (PDD) in a patient in need of such tive amount of a tocotrienol enriched extract. treatment, said medical or dietary food comprising a therapeutically or physiologically effective amount of a composition comprising a tocotrienol, a tocotrienol Claims 25 ester, a tocotrienol ether, a tocotrienol enriched ex- tract, or a mixture thereof. 1. A composition comprising a tocotrienol, a tocotrienol ester, a tocotrienol ether, a tocotrienol enriched ex- 9. A medical or dietary food according to claim 8, for tract, or a mixture thereof, for use in reducing the use as defined in said claim, wherein the patient in symptoms associated with, or in treating or sup-30 need of such treatment exhibits symptoms associ- pressing, a Pervasive Developmental Disorder ated with Autistic Disorder, Asperger’s Disorder, (PDD) in a patient in need of such treatment. Childhood Disintegrative Disorder (CDD), Rett’s Dis- order, or PDD- Not Otherwise Specified (PDD- NOS). 2. A composition according to claim 1, for use as de- fined in said claim, wherein the patient in need of 35 10. A medical or dietary food according to claim 8, for such treatment exhibits symptoms associated with use as defined in said claim, wherein the medical or Autistic Disorder, Asperger’s Disorder, Childhood dietary food comprises a therapeutically effective Disintegrative Disorder (CDD), Rett’s Disorder, or amount of one or more agents selected from alpha- PDD-Not Otherwise Specified (PDD-NOS). tocotrienol, beta-tocotrienol, gamma-tocotrienol, 40 delta-tocotrienol and mixtures thereof. 3. A composition according to claim 1, for use as de- fined in said claim, wherein the composition com- 11. A medical or dietary food according to claim 10, for prises a therapeutically effective amount of one or use as defined in said claim, wherein the medical or more agents selected from alpha-tocotrienol, beta- dietary food comprises a therapeutically effective tocotrienol, gamma-tocotrienol, delta-tocotrienol 45 amount of alpha-tocotrienol. and mixtures thereof. 12. A medical or dietary food according to claim 8, for 4. A composition according to claim 3, for use as de- use as defined in said claim, wherein the medical or fined in said claim, wherein the composition com- dietary food comprises a therapeutically effective prises a therapeutically effective amount of alpha- 50 amount of one or more agents selected from tocot- tocotrienol. rienol acetate, tocotrienol succinate, tocotrienol phosphate, tocotrienol aspartate, tocotrienol gluta- 5. A composition according to claim 1, for use as de- mate, tocotrienol palmitate, tocotrienol nicotinate, fined in said claim, wherein the composition com- and polyethoxylated tocotrienol. prises a therapeutically effective amount of one or 55 more agents selected from tocotrienol acetate, to- 13. A medical or dietary food according to claim 12, for cotrienol succinate, tocotrienol phosphate, tocotrie- use as defined in said claim, wherein the medical or nol aspartate, tocotrienol glutamate, tocotrienol dietary food comprises a therapeutically effective

16 31 EP 2 609 921 A1 32

amount of one or more agents selected from alpha- tocotrienol acetate, alpha-tocotrienol succinate, al- pha-tocotrienol phosphate, alpha-tocotrienol aspar- tate, alpha-tocotrienol glutamate, alpha-tocotrienol palmitate, alpha-tocotrienol nicotinate, and poly- 5 ethoxylated alpha-tocotrienol.

14. A medical or dietary food according to claim 8, for use as defined in said claim, wherein the medical or dietary food comprises a therapeutically effective 10 amount of a tocotrienol enriched extract.

15. A medical or dietary food suitable for reducing the symptoms associated with a Pervasive Develop- mental Disorder (PDD) in a patient in need of such 15 treatment, said medical or dietary food comprising a therapeutically or physiologically effective amount of a composition comprising a tocotrienol, a tocotrienol ester, a tocotrienol ether, a tocotrienol enriched ex- tract, or a mixture thereof. 20

25

30

35

40

45

50

55

17 EP 2 609 921 A1

18 EP 2 609 921 A1

19 EP 2 609 921 A1

20 EP 2 609 921 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 61269627 B [0001] • US 6239171 B, Lane [0057] • US 20050203066 A [0019] • US 6395915 B, Bellafiore [0057] • US AN61191696 A [0021] • US 6656358 B, May [0057] • US 2009056254 W [0021] • US 6838104 B, Jacobs [0057] • US AN12555700 A [0021] • WO 9938860 A, Sumner [0057] • JP 63063674 B [0052] • WO 2002500054 A, Jacobs [0057] • JP 01233278 A [0052] • WO 2008142433 A, Bhaggan [0057] • US 7038067 B, Couladouros [0052] • US 7118688 B [0071] • US 5157132 A [0054] • US 6562372 B, Yokoi [0072] • US 5190618 A, Top [0057]

Non-patent literature cited in the description

• LORD C et al. Autism spectrum disorders. Neuron, • OSWALD DP et al. Medication use among children 2000, vol. 28 (2), 355-63 [0005] with autism spectrum disorders. J Child Adolesc Psy- • VOLKMAR F et al. Autism in infancy and early child- chopharmacol, 2007, vol. 17 (3), 348-55 [0018] hood. Annu Rev Psychol, 2005, vol. 56, 315-36 • KRAJCOVICOVA-KUDLACKOVA et al. Bratisl Lek [0010] Listy, 2009, vol. 110 (4), 247-250 [0020] • SIGMAN M et al. Early detection of core deficits in • SCHUDEL et al. Helv. Chim. Acta, 1963, vol. 46, autism. Ment Retard Dev Disabil Res Rev., 2004, vol. 2517-2526 [0052] 10 (4), 221-33 [0010] • MAYER et al. Helv. Chim. Acta, 1967, vol. 50, • NOENS I et al. The ComFor: an instrument for the 1376-1393 [0052] indication of augmentative communication in people • KABBE et al. Synthesis, 1978, 888-889 [0052] with autism and intellectual disability. J Intellect Dis- • KAJIWARA et al. Heterocycles, 1980, vol. 14, abil Res, 2006, vol. 50 (9), 621-32 [0012] 1995-1998 [0052] • COLEMAN M. et al. Autism and Lactic Acidosis. J. • URANO et al. Chem. Pharm. Bull., 1983, vol. 31, Autism Dev Disord., 1985, vol. 15, 1-8 [0016] 4341-4345 [0052] • LASZLOet al. Serum serotonin, lactate and pyruvate • PEARCE et al. J. Med Chem., 1992, vol. 35, levels in infantile autistic children. Clin. Chim. Acta, 3595-3606 [0052] 1994, vol. 229, 205-207 [0016] • PEARCEet al. J.Med. Chem., 1994, vol. 37, 526-541 • CHUGANI et al. Evidence of altered energy metab- [0052] olism in autistic children. Progr. Neuropsychophar- • SCOTT et al. Helv. Chim. Acta, 1976, vol. 59, macol Biol Psychiat., 1999, vol. 23, 635-641 [0016] 290-306 [0052] • OLIVEIRA, G. Developmental Medicine & Child Neu- • FILIPEK, PA et al. J, Autism Dev. Diosrd., 2004, vol. rology, 2005, vol. 47, 185-189 [0016] 34, 615-23 [0059] • FILIPEK, PA et al. Journal of Autism and Develop- • COLEMAN, M. et al. Journal of Autism and Devel- mental Disorders, 2004, vol. 34, 615-623 [0016] opmental Disorders, 1985, vol. 15, 1-8 [0060] • ROSSIGNOL, D.A. et al. Am J. Biochem. & Biotech, • STEGHENS, J. P. et al. Free Radic Biol Med, 2001, vol. 4 (2), 208-217 [0016] vol. 31, 242 [0061] • MYERS SM et al. Management of children with au- • PILZ, J. Chromatogr B Biomed Sci appl, 2000, vol. tism spectrum disorders. Pediatrics, 2007, vol. 120 742, 315 [0061] (5), 1162-82 [0017] • KORIZIS, K. N. et al. Biomed Chromatogr, 2001, vol. • ANGLEY M et al. Children and autism-part 1-recog- 15, 287 [0061] nition and pharmacological management. Aust Fam. • K FUKANAGA et al. Biomed Chromatogr, 1998, vol. Physician, 2007, vol. 36 (9), 741-4 [0017] 12, 300 [0061] • ROGERS SJ et al. Evidence-based comprehensive • Remington’s Pharmaceutical Sciences. Mack Pub. treatments for early autism. J Clin. Child Adolesc. Co, 1991 [0065] Psychol., 2008, vol. 37 (1), 8-38 [0017]

21 EP 2 609 921 A1

• Remington: The Science and Practice of Pharmacy. • Treatise on Controlled Drug Delivery. Marcel Dekker, Lippincott Williams & Wilkins, 2003 [0065] Inc, 1992 [0082] • REMINGTON: THE SCIENCE AND PRACTICE OF • Methods in Cell Biology. Academic Press, 1976, vol. PHARMACY. 2005 [0065] XIV, 33 [0087] • LEE. Diffusion-Controlled Matrix Systems, 155-198 • Physicians’ Desk Reference (PDR. 1999 [0098] [0082] • DR. J.M. SHOFFNER. Medical Neurogenetics, At- •RON; LANGER. Erodible Systems, 199-224 [0082] lanta, GA [0102]

22