WO2013139861A1 - Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders - Google Patents

Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders Download PDF

Info

Publication number
WO2013139861A1
WO2013139861A1 PCT/EP2013/055834 EP2013055834W WO2013139861A1 WO 2013139861 A1 WO2013139861 A1 WO 2013139861A1 EP 2013055834 W EP2013055834 W EP 2013055834W WO 2013139861 A1 WO2013139861 A1 WO 2013139861A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
autistic
children
bacterial
dna
Prior art date
Application number
PCT/EP2013/055834
Other languages
French (fr)
Inventor
Luc Montagnier
Corinne SKORUPKA
Philippe Raymond
Philippe BOTTERO
Original Assignee
Luc Montagnier
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Luc Montagnier filed Critical Luc Montagnier
Priority to US14/386,215 priority Critical patent/US10039777B2/en
Publication of WO2013139861A1 publication Critical patent/WO2013139861A1/en
Priority to US16/055,868 priority patent/US20190134073A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria

Definitions

  • the present invention relates to methods and pharmaceutical compositions for the treatment of Autistic Syndrome Disorders.
  • Infantile Autistic Syndrome Disorders include a wide range of abnormalities including a genuine incapacity to organise affective relations, behavioural anomalies in reciprocal social interactions, verbal and non verbal communication, limited interest in the surrounding environment associated with stereotyped movements and repetitive plays (Kanner, 1943; Levy and Hyman, 1993; Levy and Hyman, 2005; Adrien et al, 2001 ; Blanc et al, 2005; Bourreau et al, 2009). Research to date indicates that a genetic predisposition may play a role in the disease but one or more environmental factors must be in place for symptoms to occur including environmental contaminants and possibly maternal exposures during gestation (Persico and Bourgeron, 2006; Bourgeron, 2009; Patterson, 2002).
  • the present invention relates to a method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof with an effective amount of at least one antibacterial agent.
  • the present invention relates to a method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof with an effective amount of at least one antibacterial agent.
  • the subject is diagnosed with autism.
  • autism denotes a family of disorders of neural development that is characterized by impaired social interaction and communication, restricted and repetitive behaviour accompanied with other deficits. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; how this occurs is not well understood.
  • the two other autism spectrum disorders (ASD) are Asperger syndrome, which lacks delays in cognitive development and language, atypical autism, diagnosed when full criteria for the other two disorders are not met, and PDD-NOS when pervasive developmental disorder are not specified.
  • the subject has been previously diagnosed with a latent bacterial infection.
  • said latent bacterial infection may be detected by detecting the presence of bacterial 16S sequence in a blood sample obtained from the subject (e.g. by RT- PCR) or by performing the method as described in WO2007068831 or in US2012024701 in the blood sample, such as described in EXAMPLE 1 or 2.
  • antibacterial agent has its general meaning in the art. Antibacterial agents kill or inhibit the growth or function of bacteria.
  • a large class of antibacterial agents is antibiotics. Any kind of antibiotics may used according to the invention, but use of broadspectrum antibiotics are particularly desirable.
  • a broad spectrum antibiotic for use in the invention is one that possesses activity against both grampositive and gram-negative organisms. Exemplary broad spectrum antibiotics for use in the invention include compounds falling within the following chemical classifications or categories: aminoglycosides, macrolides, ketolides, quinolones, tetracyclines, sulfonamides, and beta- lactams (including the cephalosporins).
  • a broad spectrum antibiotic for use in the invention is one demonstrating a degree of anti-microbial activity comparable to that of any of the herein described aminoglycosides, macrolides, ketolides, quinolones, tetracyclines, sulfonamides, or beta-lactams, in particular, against species falling within four or more different microbial genuses selected from Actinomyces, Bacillus, Bordetella, Borrelia, Campylobacter, Chlamydia, Clostridium, Corynebacterium, Cryptosporidium, Entamoeba, Enterobacter, Escherichia, Gardnerella, Haemophilus, Klebsiella, Legionella, Leishmania, Moraxella, Mycobacterium, Mycoplasma, Neisseria, Nocardia, Proteus, Providencia, Pseudomonas, Salmonella, Serpulina, Serratia, Shigella, Staphylococcus, Str
  • Tetracyclines belongs to a class that shares a four-membered ring structure composed of four fused 6-membered (hexacyclic) rings. The tetracyclines exhibit their activity by inhibiting the binding of the aminoacyl tR A to the 30S ribosomal subunit in susceptible bacteria.
  • Tetracyclines for use in the invention include chlortetracycline, demeclocycline, doxycycline, minocycline, oxytetracycline, chlortetracycline, methacycline, mecocycline, tigecycline, limecycline, and tetracycline.
  • the tetracyclines are effective against many known organisms including a-hemo lytic streptococci, nonhemolytic streptococci, gramnegative bacilli, rickettsiae, spirochetes, Mycoplasma, and Chlamydia.
  • Aminoglycosides are compounds derived from species of Streptomyces or Micomonospora bacteria and are primarily used to treat infections caused by gram-negative bacteria. Drugs belonging to this class all possess the same basic chemical structure, i.e., a central hexose or diaminohexose molecule to which two or more amino sugars are attached by a glycosidic bond.
  • the aminoglycosides are bactericidal antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis. They are active primarily against aerobic gram-negative bacilli and staphylococci.
  • Aminoglycoside antibiotics for use in the invention include amikacin (Amikin®), gentamicin (Garamycin®), kanamycin (Kantrex®), neomycin (Mynatidin®), netilmicin (Netromycin®), paromomycin (Humatin®), streptomycin, and tobramycin (TOBI Solution®, TobraDex®).
  • the macrolides are a group of polyketide antibiotic drugs whose activity stems from the presence of a macro lidc ring (a large 14-, 15-, or 16-membered lactone ring) to which one or more deoxy sugars, usually cladinose and desosamine, are attached.
  • Macrolides are primarily bacteriostatic and bind to the 50S subunit of the ribosome, thereby inhibiting bacterial synthesis. Macrolides are active against aerobic and anaerobic gram positive cocci (with the exception of enterococci) and against gram-negative anaerobes.
  • Macrolides for use in the invention include azithromycin (Zithromax®), clarithromycin (Biaxin®), dirithromycin (Dynabac®), erythromycin, clindamycin, josamycin, roxithromycin and lincomycin.
  • ketolides Another type of broad spectrum ant ibiotic.
  • the ketolides belong to a new class of semi-synthetic 14-membered ring macrolides in which the erythromycin macrolactone ring structure and the D-desosamine sugar attached at position 5 are retained, however, replacing the L-cladinose5 moiety and hydroxyl group at position 3 is a3-keto functional group.
  • the ketolides bind to the 23S rR A, and their mechanism of action is similar to that of macrolides (Zhanel, G.
  • ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes, and possess excellent activity against Streptococcus spp. including mefA and ermB-producing Streptococcus pneumoniae, and Haemophilus influenzae.
  • Representative ketolides for use in the invention include telithromycin (formerly known as HMR-3647), HMR 3004, HMR 3647, cethromycin, EDP-420, and ABT-773.
  • quinolone class Yet another type of broad spectrum ant ibiotic for use in the invention is the quinolone class. Structurally, the quinonolones possess a 1 ,4 dihydro-4-oxo-quinolinyl moiety bearing an essential carboxyl group at position 3. Functionally, the quinolones inhibit prokaryotic type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV, through direct binding to the bacterial chromosome.
  • Quinolones for use in the invention span first, second, third and fourth generation quinolones, including fluoroquinolones.
  • Such compounds include nalidixic acid, cinoxacin, oxolinic acid, flumequine, pipemidic acid, rosoxacin, norfloxacin, lomefloxacin, ofloxacin, enrofloxacin, ciprofloxacin, enoxacin, amifloxacin, fleroxacin, gatifloxacin, gemifloxacin, clinafloxacin, sitafloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin.
  • Additional quinolones suitable for use in the invention include those described in Hooper, D., and Rubinstein, E., "Quinolone Antimicrobial Agents, Vd Edition ", American Society of Microbiology Press, Washington D.C. (2004).
  • a broad spectrum antibiot ic for use in the invention may also be a sulfonamide.
  • Drugs belonging to the sulfonamide class all possess a sulfonamide moiety, — SO2NH2, or a substituted sulfonamide moiety, where one 15 of the hydrogens on the nitrogen is replaced by an organic substituent.
  • Illustrative N-substituents include substituted or unsubstitutedthiazole, pyrimidine, isoxazole, and other functional groups.
  • Sulfonamide antiobiotics all share a common structural feature, i.e., they are all benzene sulfonamides, 20 meaning that the sulfonamide functionality is directly attached to a benzene ring.
  • sulfonamide ant ibiot ics is similar to p-amino benzoic acid ( PABA), a compound that is needed in bacteria as a substrate for the enzyme, dihydroptroate synthetase, for the synthesis of tetrahydro- 25 folic acid.
  • PABA p-amino benzoic acid
  • the sulfonamides function as antibiotics by interfering with the metabolic processes in bacteria that require PABA, thereby inhibiting bacterial growth and activity.
  • Sulfonamide ant ibiotics for use in the invention include the following: mafenide, phtalylsulfathiazole, succinylsulfathiazole, sulfacetamide, sulfadiazine, sulfadoxine, sulfamazone, sulfamethazine, sulfamethoxazole, sulfametopirazine, sulfametoxypiridazine, sulfametrol, sulfamonomethoxine, sulfamylon, sulfanilamide, sulfaquinoxaline, sulfasalazine, sulfathiazole, sulfisoxazole, sulfisoxazole diolamine, and sulfaguanidine.
  • beta-lactams are also suitable for use in the invention.
  • All members of this broad spectrum antibiotic class possess a beta-lactam ring and a carboxyl group, resulting in 55 similarities in both their pharmacokinetics and mechanism of action.
  • the majority of clinically useful beta-lactams belong to either the penicillin group or the cephalosporin group, including cefamycins and oxacephems.
  • the beta-lactams also include the carbapenems and monobactams. Generally speaking, beta-lactams inhibit bacterial cell wall synthesis.
  • beta-lactarns act by inhibiting D-alanyl-D-alanine transpeptidase activity by forming stable esters with the carboxyl of the open lactam ring attached to the hydroxyl group of the enzyme target site. Beta-lactams are extremely effective and typically are of low toxicity. As a group, these drugs are active against many grampositive, gram-negative and anaerobic organisms.
  • Drugs falling into this category include 2-(3-alanyl)clavam, 2-hydroxymethylclavam, 7-methoxycephalosporin, epi- thienamycin, acetyl-thienamycin, amoxicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, bacampicillin, blapenem, carbenicillin, carfecillin, carindacillin, carpetimycin A and B, cefacetril, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefmetazole, cefminox
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • antibacterial agents e.g. antibiotics
  • the subjected undergoes a sustained administration with the antibacterial agent.
  • the subject is administered with the antibacterial agent for 1, 2, 3, 4 or 5 weeks.
  • the subject may also be administered with antifungal agents or anti-parasitic agents.
  • the subject is administered with the antibacterial agent optionally in combination with anti-fungal or or anti-parasitic agents following the typical regiment : for 3 weeks per month during the 3 first months of treatment, then 15 days per month during the following three months, then 15 days every 2 months during the following 6 months and finally 3 or 4 courses of 10 days treatment the following years.
  • the antibacterial agent may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the antibacterial agent of the invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the antibacterial agent of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
  • parenteral administration such as intravenous or intramuscular injection
  • other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration ; liposomal formulations ; time release capsules ; and any other form currently used.
  • Example 1 The technology as described in WO2007068831 or in US2012024701 allows the detection of aqueous structures induced by certain DNA molecules that emit low frequency electromagnetic signals. These DNA sequences "sensors" are present in most bacteria potentially pathogenic in humans and induce nano structures present in blood plasma or in certain dilutions of DNA extracted from plasma or blood cells. By performing said method the inventors demonstrate that detection of a latent bacterial infection (but not viral infection) can be made for 70 to 90% of autistic children who were included in the study. Interestingly, in a blind study, the sole autistic child that were considered as negative for the presence of a latent bacterial infection was treated with antibiotics in a long-term manner. In another example, a child who had signals saw them reduced after treatment and clinical improvement.
  • autism and its related disorders have become a major health problem worldwide. In most developed and even in developing countries, their incidence has been growing to more than 1% of the total child population.
  • the present example describes the abnormal presence of bacterial DNA in the blood of the majority of autistic children studied, and in particular of bacterial DNA identical or close to that of the Sutterella genus.
  • This DNA may originate from bacterial or viral DNA sequences. Filtration of the DNA solution by 100 nM porosity filters allows one to detect structures derived from bacterial DNA.
  • Filtration at 20 nM porosity allows one to detect small structures derived from DNA of small DNA viruses and HIV DNA.
  • Table A Distribution of EMS and Sutterella PCR in Autistic Children and healthy controls (French - Italian cohort)
  • N Number of patients
  • Results The treatment was interrupted for 17% of the children due to side effects. Slow or jagged progression was observed for 28%> of the children. Rapide and regular progression was observed for 55%> of the children (Tables 1 and 2). More particularly, in the first month, improvement in physical signs can be noticed. In a second time, behavioural symptoms are improved in a progressive manner. In a third time, mental progression can resume its course to where it was interrupted (psychomotrocity, learning, communication, and language and graphics). Administration of antibiotics, regular at the beginning, may become less frequent when improvement are observed and finally may be interrupted with an annual control. In some cases, the clinical improvement obtained is durable and persists after cessation of treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof an effective amount of antibacterial agent.

Description

METHODS AND PHARMACEUTICAL COMPOSITIONS OF THE TREATMENT
OF AUTISTIC SYNDROME DISORDERS
FIELD OF THE INVENTION:
The present invention relates to methods and pharmaceutical compositions for the treatment of Autistic Syndrome Disorders.
BACKGROUND OF THE INVENTION:
Infantile Autistic Syndrome Disorders (ASD) include a wide range of abnormalities including a genuine incapacity to organise affective relations, behavioural anomalies in reciprocal social interactions, verbal and non verbal communication, limited interest in the surrounding environment associated with stereotyped movements and repetitive plays (Kanner, 1943; Levy and Hyman, 1993; Levy and Hyman, 2005; Adrien et al, 2001 ; Blanc et al, 2005; Bourreau et al, 2009). Research to date indicates that a genetic predisposition may play a role in the disease but one or more environmental factors must be in place for symptoms to occur including environmental contaminants and possibly maternal exposures during gestation (Persico and Bourgeron, 2006; Bourgeron, 2009; Patterson, 2002). It is suggested that genetic and environmental hazards will alter developmental programs leading to cortical and/or sub-cortical malformations and the formation of misplaced/ misconnected neuronal ensembles. The first symptoms occur before 3 years of age with most likely an earlier origin. There is at present no efficient biological/ pharmaceutical treatment to ASD.
SUMMARY OF THE INVENTION:
The present invention relates to a method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof with an effective amount of at least one antibacterial agent.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof with an effective amount of at least one antibacterial agent. In a particular embodiment, the subject is diagnosed with autism. As used herein, the term "autism" denotes a family of disorders of neural development that is characterized by impaired social interaction and communication, restricted and repetitive behaviour accompanied with other deficits. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; how this occurs is not well understood. The two other autism spectrum disorders (ASD) are Asperger syndrome, which lacks delays in cognitive development and language, atypical autism, diagnosed when full criteria for the other two disorders are not met, and PDD-NOS when pervasive developmental disorder are not specified.
In a particular embodiment, the subject has been previously diagnosed with a latent bacterial infection. Typically said latent bacterial infection may be detected by detecting the presence of bacterial 16S sequence in a blood sample obtained from the subject (e.g. by RT- PCR) or by performing the method as described in WO2007068831 or in US2012024701 in the blood sample, such as described in EXAMPLE 1 or 2.
As used herein the term "antibacterial agent" has its general meaning in the art. Antibacterial agents kill or inhibit the growth or function of bacteria. A large class of antibacterial agents is antibiotics. Any kind of antibiotics may used according to the invention, but use of broadspectrum antibiotics are particularly desirable. A broad spectrum antibiotic for use in the invention is one that possesses activity against both grampositive and gram-negative organisms. Exemplary broad spectrum antibiotics for use in the invention include compounds falling within the following chemical classifications or categories: aminoglycosides, macrolides, ketolides, quinolones, tetracyclines, sulfonamides, and beta- lactams (including the cephalosporins). In yet another embodiment, a broad spectrum antibiotic for use in the invention is one demonstrating a degree of anti-microbial activity comparable to that of any of the herein described aminoglycosides, macrolides, ketolides, quinolones, tetracyclines, sulfonamides, or beta-lactams, in particular, against species falling within four or more different microbial genuses selected from Actinomyces, Bacillus, Bordetella, Borrelia, Campylobacter, Chlamydia, Clostridium, Corynebacterium, Cryptosporidium, Entamoeba, Enterobacter, Escherichia, Gardnerella, Haemophilus, Klebsiella, Legionella, Leishmania, Moraxella, Mycobacterium, Mycoplasma, Neisseria, Nocardia, Proteus, Providencia, Pseudomonas, Salmonella, Serpulina, Serratia, Shigella, Staphylococcus, Streptococcus, Suterella, Toxoplasmosis, Treponem, and Tubercle.
The first type of broad spectrum antibiotic for use in the invention, are tetracyclines. Tetracyclines belongs to a class that shares a four-membered ring structure composed of four fused 6-membered (hexacyclic) rings. The tetracyclines exhibit their activity by inhibiting the binding of the aminoacyl tR A to the 30S ribosomal subunit in susceptible bacteria. Tetracyclines for use in the invention include chlortetracycline, demeclocycline, doxycycline, minocycline, oxytetracycline, chlortetracycline, methacycline, mecocycline, tigecycline, limecycline, and tetracycline. The tetracyclines are effective against many known organisms including a-hemo lytic streptococci, nonhemolytic streptococci, gramnegative bacilli, rickettsiae, spirochetes, Mycoplasma, and Chlamydia.
Another type of broad spectrum antibiotics for use in the invention is the aminoglycosides. Aminoglycosides are compounds derived from species of Streptomyces or Micomonospora bacteria and are primarily used to treat infections caused by gram-negative bacteria. Drugs belonging to this class all possess the same basic chemical structure, i.e., a central hexose or diaminohexose molecule to which two or more amino sugars are attached by a glycosidic bond. The aminoglycosides are bactericidal antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis. They are active primarily against aerobic gram-negative bacilli and staphylococci. Aminoglycoside antibiotics for use in the invention include amikacin (Amikin®), gentamicin (Garamycin®), kanamycin (Kantrex®), neomycin (Mycifradin®), netilmicin (Netromycin®), paromomycin (Humatin®), streptomycin, and tobramycin (TOBI Solution®, TobraDex®).
Yet another type of broad spectrum antibiotic for use in the invention is a macroiicle. The macrolides are a group of polyketide antibiotic drugs whose activity stems from the presence of a macro lidc ring (a large 14-, 15-, or 16-membered lactone ring) to which one or more deoxy sugars, usually cladinose and desosamine, are attached. Macrolides are primarily bacteriostatic and bind to the 50S subunit of the ribosome, thereby inhibiting bacterial synthesis. Macrolides are active against aerobic and anaerobic gram positive cocci (with the exception of enterococci) and against gram-negative anaerobes. Macrolides for use in the invention include azithromycin (Zithromax®), clarithromycin (Biaxin®), dirithromycin (Dynabac®), erythromycin, clindamycin, josamycin, roxithromycin and lincomycin.
Also suitable for use in the present invention are the ketolides, another type of broad spectrum ant ibiotic. The ketolides belong to a new class of semi-synthetic 14-membered ring macrolides in which the erythromycin macrolactone ring structure and the D-desosamine sugar attached at position 5 are retained, however, replacing the L-cladinose5 moiety and hydroxyl group at position 3 is a3-keto functional group. The ketolides bind to the 23S rR A, and their mechanism of action is similar to that of macrolides (Zhanel, G. G.,et al.,Drugs, 2001 ; 61(4):443-98).The ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes, and possess excellent activity against Streptococcus spp. including mefA and ermB-producing Streptococcus pneumoniae, and Haemophilus influenzae. Representative ketolides for use in the invention include telithromycin (formerly known as HMR-3647), HMR 3004, HMR 3647, cethromycin, EDP-420, and ABT-773.
Yet another type of broad spectrum ant ibiotic for use in the invention is the quinolone class. Structurally, the quinonolones possess a 1 ,4 dihydro-4-oxo-quinolinyl moiety bearing an essential carboxyl group at position 3. Functionally, the quinolones inhibit prokaryotic type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV, through direct binding to the bacterial chromosome. Quinolones for use in the invention span first, second, third and fourth generation quinolones, including fluoroquinolones. Such compounds include nalidixic acid, cinoxacin, oxolinic acid, flumequine, pipemidic acid, rosoxacin, norfloxacin, lomefloxacin, ofloxacin, enrofloxacin, ciprofloxacin, enoxacin, amifloxacin, fleroxacin, gatifloxacin, gemifloxacin, clinafloxacin, sitafloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin. Additional quinolones suitable for use in the invention include those described in Hooper, D., and Rubinstein, E., "Quinolone Antimicrobial Agents, Vd Edition ", American Society of Microbiology Press, Washington D.C. (2004).
A broad spectrum antibiot ic for use in the invention may also be a sulfonamide. Drugs belonging to the sulfonamide class all possess a sulfonamide moiety, — SO2NH2, or a substituted sulfonamide moiety, where one 15 of the hydrogens on the nitrogen is replaced by an organic substituent. Illustrative N-substituents include substituted or unsubstitutedthiazole, pyrimidine, isoxazole, and other functional groups. Sulfonamide antiobiotics all share a common structural feature, i.e., they are all benzene sulfonamides, 20 meaning that the sulfonamide functionality is directly attached to a benzene ring. The structure of sulfonamide ant ibiot ics is similar to p-amino benzoic acid ( PABA), a compound that is needed in bacteria as a substrate for the enzyme, dihydroptroate synthetase, for the synthesis of tetrahydro- 25 folic acid. The sulfonamides function as antibiotics by interfering with the metabolic processes in bacteria that require PABA, thereby inhibiting bacterial growth and activity. Sulfonamide ant ibiotics for use in the invention include the following: mafenide, phtalylsulfathiazole, succinylsulfathiazole, sulfacetamide, sulfadiazine, sulfadoxine, sulfamazone, sulfamethazine, sulfamethoxazole, sulfametopirazine, sulfametoxypiridazine, sulfametrol, sulfamonomethoxine, sulfamylon, sulfanilamide, sulfaquinoxaline, sulfasalazine, sulfathiazole, sulfisoxazole, sulfisoxazole diolamine, and sulfaguanidine.
Also suitable for use in the invention are the broad spectrum antibiotics classified structurally as beta-lactams. All members of this broad spectrum antibiotic class possess a beta-lactam ring and a carboxyl group, resulting in 55 similarities in both their pharmacokinetics and mechanism of action. The majority of clinically useful beta-lactams belong to either the penicillin group or the cephalosporin group, including cefamycins and oxacephems. The beta-lactams also include the carbapenems and monobactams. Generally speaking, beta-lactams inhibit bacterial cell wall synthesis. More specifically, these antibiotics cause 'nicks' in the peptidoglycan net of the cell wall that allow the bacterial protoplasm to flow from its protective net into the surrounding hypotonic medium. Fluid then accumulates in the naked 65 protoplast (a cell devoid of its wall), and it eventually bursts, leading to death of the organism. Mechanistically, beta-lactarns act by inhibiting D-alanyl-D-alanine transpeptidase activity by forming stable esters with the carboxyl of the open lactam ring attached to the hydroxyl group of the enzyme target site. Beta-lactams are extremely effective and typically are of low toxicity. As a group, these drugs are active against many grampositive, gram-negative and anaerobic organisms. Drugs falling into this category include 2-(3-alanyl)clavam, 2-hydroxymethylclavam, 7-methoxycephalosporin, epi- thienamycin, acetyl-thienamycin, amoxicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, bacampicillin, blapenem, carbenicillin, carfecillin, carindacillin, carpetimycin A and B, cefacetril, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefmetazole, cefminox, cefmolexin, cefodizime, cefonicid, cefoperazone, ceforamide, cefoselis, cefotaxime, cefotetan, cefotiam, cefoxitin, cefozopran, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cephalosporin C, cephamycinA, cephamycinC, cephalothin, chitinovorin A, chitinovorin B, chitinovorin C, ciclacillin, clavulanate salt, clavulanic acid, clometocillin, cloxacillin, cycloserine, deoxy pluracidomycin B and C, dicloxacillin, dihydro pluracidomycin C, epicillin, epithienamycin D, E, and F, ertapenem, faropenem, flomoxef, flucloxacillin, hetacillin, imipenem, lenampicillin, loracarbef, mecillinam, meropenem, metampicillin, meticillin (also referred to as methicillin), mezlocillin, moxalactam, nafcillin, northienamycin, oxacillin, panipenem, penamecillin, penicillin G, N, and V, phenethicillin, piperacillin, povampicillin, pivcefalexin, povmecillinam, prvmecillinam, pluracidomycin B, C, and D, propicillin, sarmoxicillin, sulbactam, sultamicillin, talampicillin, temocillin, terconazole, thienamycin, andticarcillin. By a "an effective amount" is meant a sufficient amount of the antibacterial agent to for treating autism at a reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Preferably, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
Combination of antibacterial agents (e.g. antibiotics) is encompassed by the present invention. In a particular embodiment, the subjected undergoes a sustained administration with the antibacterial agent. Typically, the subject is administered with the antibacterial agent for 1, 2, 3, 4 or 5 weeks. In a particular embodiment, the subject may also be administered with antifungal agents or anti-parasitic agents.
In a particular embodiment, the subject is administered with the antibacterial agent optionally in combination with anti-fungal or or anti-parasitic agents following the typical regiment : for 3 weeks per month during the 3 first months of treatment, then 15 days per month during the following three months, then 15 days every 2 months during the following 6 months and finally 3 or 4 courses of 10 days treatment the following years. The antibacterial agent may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
Preferably, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The antibacterial agent of the invention can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The antibacterial agent of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
In addition to the compounds of the invention formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration ; liposomal formulations ; time release capsules ; and any other form currently used.
The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
Example 1: The technology as described in WO2007068831 or in US2012024701 allows the detection of aqueous structures induced by certain DNA molecules that emit low frequency electromagnetic signals. These DNA sequences "sensors" are present in most bacteria potentially pathogenic in humans and induce nano structures present in blood plasma or in certain dilutions of DNA extracted from plasma or blood cells. By performing said method the inventors demonstrate that detection of a latent bacterial infection (but not viral infection) can be made for 70 to 90% of autistic children who were included in the study. Interestingly, in a blind study, the sole autistic child that were considered as negative for the presence of a latent bacterial infection was treated with antibiotics in a long-term manner. In another example, a child who had signals saw them reduced after treatment and clinical improvement. This correlation between disappearance of the signals of bacterial and clinical improvement on antibiotics shows that the infection is not a simple consequence but is one of the causes of autism and signal detection can serve as a biomarker in clinical trials. Example 2: Autism: the gut-blood-brain connection: Improved Methods for the
Detection and Diagnostic of Abnormal Bacteremia in Autistic Patients
Within a decade, autism and its related disorders have become a major health problem worldwide. In most developed and even in developing countries, their incidence has been growing to more than 1% of the total child population.
The reason for this continuous increase is unclear, but cannot be ascribed to genetic changes suddenly affecting the new generations. Rather, the increased exposure to changing environmental factors may be involved.
There is mounting indication that these environmental changes occurring at the intestinal level may allow the abnormal passage of bacteria or bacterial products in the blood circulation which could then reach the brain. There is also evidence that the blood-brain barrier can become more permeable, due also to environmental changes.
Recently, the group of Williams and Lipkin has described a significant increase of a particular genus belonging to a Gram negative family (Alcaligenaceae) , the bacteria Suttterella, in ileal biopsies of autistic children suffering from gastro-intestinal disturbance, as opposed to non-autistic children suffering of the same affection.
The present example describes the abnormal presence of bacterial DNA in the blood of the majority of autistic children studied, and in particular of bacterial DNA identical or close to that of the Sutterella genus.
This bacterial DNA is reduced by a long term antibiotic treatment of children which improves at the same time their clinical condition (example 3). The detection of bacterial DNA is done by the use of two technologies: a) One has already been described in several patent applications (WO2007068831 or in US2012024701).
In short, it consists in measuring the intensity of the electromagnetic signals emitted by some high water dilutions of DNA extracted from the plasma of such patients.
This DNA may originate from bacterial or viral DNA sequences. Filtration of the DNA solution by 100 nM porosity filters allows one to detect structures derived from bacterial DNA.
Filtration at 20 nM porosity allows one to detect small structures derived from DNA of small DNA viruses and HIV DNA.
In the case of autistic patients, we have found that a majority of those who do possess in their plasma some DNA sequences inducing nano structures able to emit EMS. Since filtration at 100 nM was required, these nano structures are presumed to be of bacterial origin.
This technology, in its present state, does not yet permit us to distinguish between bacterial species since the signals are similar.
However there are indications that the signals also contain the specific information for transmitting particular DNA sequences. This phenomenon has been reproduced in several independent laboratories. b) the classical technology, Polymerase Chain Reaction (PCR) to identify the species of bacteria involved.
In a first approach, we used primers able to detect all types of Gram positive bacteria which yielded a majority of positive signals in a cohort of 22 autistic children but not in the same number of healthy children of matching age.
We also designed primers to recognize the group of Gram negative bacteria, based also on the 16 S ribosomal DNA. However our controls with pure sterile water were always positive due to the presence of small fragments contaminating bacterial DNA in various samples of that water, whatever its treatment.
Finally we used primers specific for the Sutterella genus and have clear-cut results : a large majority of the plasma of autistic children yielded a specific DNA band of the required size (260 bp) and sequencing of the bands confirm that they belong to two closely related families (Alcaligenaceae and Burkholderiaceae) . Less frequently, we could detect Borrelia sequences, the agent of Lyme disease, by primers specific for its 16 S ribosomal DNA.
Table A: Distribution of EMS and Sutterella PCR in Autistic Children and healthy controls (French - Italian cohort)
Figure imgf000013_0001
EMS = Electromagnetic Signals
N = Number of patients
PCR = Polymerase Chain Reaction.
Example 3: Clinical study
Study: 97 children were included in the study: children diagnosed with autism (n=73), atypical autism (n=10), Dravet syndrome (n=4), Rett syndrome (n=2), Asperger syndrome (n=3), epilepsy with mental retardation (n=3) and Gilles de la Tourette syndrome (n=2). 88% of the children were aged between 2,5 years old and 12 years old (min = 15 months old and max = 29 years old). Said children were administered with broad spectrum antibiotics for 3 weeks: for children older than 8 years old with macrolides and children older less than 8 years with tetracyclins. Furthemore the children were administered with an antifungal agent (Triflucan) and with anti-parasitic agents (Fluvermal and Flagyl). Nutritional and immunological deficiencies were also corrected.
Results: The treatment was interrupted for 17% of the children due to side effects. Slow or jagged progression was observed for 28%> of the children. Rapide and regular progression was observed for 55%> of the children (Tables 1 and 2). More particularly, in the first month, improvement in physical signs can be noticed. In a second time, behavioural symptoms are improved in a progressive manner. In a third time, mental progression can resume its course to where it was interrupted (psychomotrocity, learning, communication, and language and graphics). Administration of antibiotics, regular at the beginning, may become less frequent when improvement are observed and finally may be interrupted with an annual control. In some cases, the clinical improvement obtained is durable and persists after cessation of treatment.
Table 1 Rapid Slow progression Insufficient Tretament progression progression interrupted
Autism (n=73) 41 (56%) 19 (26%) 8 (11%) 5 (7%)
Atypical (n=10) 7 3
DRAVET (EMSN) 2 2
(n=4)
RETT (n=2) 1 1 epilepsy with mental 1 1 1
retardation (n=3)
Asperger (n=3) 3
Gilles de la Tourette 1 1
syndrome (n=2)
TOTAL = 97 53 (55%) 27 (28%) 12 (12%) 5 (5%)
Table 2 Rapid Slow progression Insufficient Tretament progression progression interrupted
Autistic children < 7 32 6 3 4
years old (n=45) (71%) (13%) (7%) (9%)
Autistic children > 9 13 5 1
7 years old (n=28) (32%) (46%) (18%) (4%)
REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.
Adrien JL, Rossignol-Deletang N, Martineau J, Couturier G, Barthelemy C (2001) Regulation of cognitive activity and early communication development in young autistic, mentally retarded, and young normal children. Dev Psychobiol 39: 124-136.
Blanc R, Adrien JL, Roux S, Barthelemy C (2005) Dysregulation of pretend play and communication development in children with autism. Autism 9:229-245.
Bourgeron T (2009) A synaptic trek to autism. Curr Opin Neurobiol 19:231-234.
Bourreau Y., Roux S., Gomot M., Bonnet-Brilhault F., Barthelemy C. (2009)
Validation of the repetitive and restricted behaviour scale in autism spectrum disorders. European Child and adolescent psychiatry, Nov 18(11): 675-682.
Kanner L. (1943) Autistic disturbances of affective contact. Nervous Child 2: 217-50
Levy SE, Hyman SL (1993) Pediatric assessment of the child with developmental delay. Pediatr Clin North Am 40:465-477.
Levy SE, Hyman SL (2005) Novel treatments for autistic spectrum disorders. Ment Retard Dev Disabil Res Rev 11 : 131-142.
Patterson PH (2002) Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Curr Opin Neurobiol 12: 115-118.
Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29:349-358.

Claims

CLAIMS:
1. A method for the treatment of an autistic syndrome disorder comprising administering to a subject in need thereof with an effective amount of at least one antibacterial agent.
2. The method according to claim 1 wherein the subject was previously diagnosed with a latent bacterial infection.
PCT/EP2013/055834 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders WO2013139861A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US14/386,215 US10039777B2 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US16/055,868 US20190134073A1 (en) 2012-03-20 2018-08-06 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP12305326.6 2012-03-20
US201361773016P 2013-03-05 2013-03-05
US61/773,016 2013-03-05

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2013/055834 Continuation WO2013139861A1 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US14/386,215 Continuation US10039777B2 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders

Related Child Applications (4)

Application Number Title Priority Date Filing Date
PCT/EP2013/055834 Continuation WO2013139861A1 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US14/386,215 Continuation US10039777B2 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US14/386,215 A-371-Of-International US10039777B2 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US16/055,868 Continuation US20190134073A1 (en) 2012-03-20 2018-08-06 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders

Publications (1)

Publication Number Publication Date
WO2013139861A1 true WO2013139861A1 (en) 2013-09-26

Family

ID=47913432

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/055834 WO2013139861A1 (en) 2012-03-20 2013-03-20 Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders

Country Status (2)

Country Link
US (2) US10039777B2 (en)
WO (1) WO2013139861A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10039777B2 (en) 2012-03-20 2018-08-07 Neuro-Lm Sas Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
WO2018235082A1 (en) * 2017-06-20 2018-12-27 Ben Noon Alon Compositions comprising an anti-inflammatory drug and a dicer activator for use in the treatment of neuronal diseases
US10980780B2 (en) 2017-06-20 2021-04-20 Neurosense Therapeutics Ltd. Methods and compositions of anti-inflammatory drug and dicer activator for treatment of neuronal diseases

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7001593B2 (en) 2015-08-11 2022-01-19 コグノア， インコーポレイテッド Methods and devices for determining developmental progress using artificial intelligence and user input
US11972336B2 (en) 2015-12-18 2024-04-30 Cognoa, Inc. Machine learning platform and system for data analysis
EP3539033B1 (en) 2016-11-14 2024-10-02 Cognoa, Inc. Methods and apparatus for evaluating developmental conditions and providing control over coverage and reliability
JP7324709B2 (en) * 2017-02-09 2023-08-10 コグノア，インク． Platforms and systems for digital personalized medicine
US20220254461A1 (en) * 2017-02-09 2022-08-11 Cognoa, Inc. Machine learning algorithms for data analysis and classification
WO2020198065A1 (en) 2019-03-22 2020-10-01 Cognoa, Inc. Personalized digital therapy methods and devices

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001093904A1 (en) * 2000-06-05 2001-12-13 The United States Of America As Represented By The Department Of Veterans Affairs Method of treating gastrointestinal diseases associated with species of genus clostridium
WO2007068831A2 (en) 2005-12-14 2007-06-21 Luc Montagnier Method for characterising a biologically active biochemical element by analysing low frequency electromagnetic signals
US20100069399A1 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceutical, Inc. Arylpiperazine modulators of d2 receptors, 5-ht1a receptors, and/or 5-ht2a receptors
US20120024701A1 (en) 2010-06-24 2012-02-02 Luc Montagnier General procedure for the identification of dna sequences generating electromagnetic signals in biological fluids and tissues

Family Cites Families (271)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4458066A (en) 1980-02-29 1984-07-03 University Patents, Inc. Process for preparing polynucleotides
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4861719A (en) 1986-04-25 1989-08-29 Fred Hutchinson Cancer Research Center DNA constructs for retrovirus packaging cell lines
US4710384A (en) 1986-07-28 1987-12-01 Avner Rotman Sustained release tablets made from microcapsules
US5879680A (en) 1987-12-23 1999-03-09 The United States Of America As Represented By The Department Of Health And Human Services Cloned DNA for synthesizing unique glucocerebrosidase
US5278056A (en) 1988-02-05 1994-01-11 The Trustees Of Columbia University In The City Of New York Retroviral packaging cell lines and process of using same
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5236838A (en) 1988-12-23 1993-08-17 Genzyme Corporation Enzymatically active recombinant glucocerebrosidase
US6451600B1 (en) 1989-12-22 2002-09-17 Genzyme Corporation Enzymatically active recombinant glucocerebrosidase
IT1229203B (en) 1989-03-22 1991-07-25 Bioresearch Spa USE OF 5 METHYLTHETRAHYDROPHOLIC ACID, 5 FORMYLTHETRAHYDROPHOLIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE ACTIVE IN THE THERAPY OF MENTAL AND ORGANIC DISORDERS.
US5179023A (en) 1989-03-24 1993-01-12 Research Corporation Technologies, Inc. Recombinant α-galactosidase a therapy for Fabry disease
US5328470A (en) 1989-03-31 1994-07-12 The Regents Of The University Of Michigan Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5670488A (en) 1992-12-03 1997-09-23 Genzyme Corporation Adenovirus vector for gene therapy
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
GB9022788D0 (en) 1990-10-19 1990-12-05 Cortecs Ltd Pharmaceutical formulations
US5401650A (en) 1990-10-24 1995-03-28 The Mount Sinai School Of Medicine Of The City University Of New York Cloning and expression of biologically active α-galactosidase A
AU663702B2 (en) 1991-03-06 1995-10-19 Board Of Regents, The University Of Texas System Methods and compositions for the selective inhibition of gene expression
US5747469A (en) 1991-03-06 1998-05-05 Board Of Regents, The University Of Texas System Methods and compositions comprising DNA damaging agents and p53
US6410010B1 (en) 1992-10-13 2002-06-25 Board Of Regents, The University Of Texas System Recombinant P53 adenovirus compositions
US5252479A (en) 1991-11-08 1993-10-12 Research Corporation Technologies, Inc. Safe vector for gene therapy
US5580578A (en) 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
CA2156725A1 (en) 1993-02-22 1994-09-01 Warren S. Pear Production of high titer helper-free retroviruses by transient transfection
US5458142A (en) 1993-03-19 1995-10-17 Farmer; Edward J. Device for monitoring a magnetic field emanating from an organism
FR2712812B1 (en) 1993-11-23 1996-02-09 Centre Nat Rech Scient Composition for the production of therapeutic products in vivo.
US20030191061A1 (en) 1994-03-31 2003-10-09 Brewitt Barbara A. Treatment methods using homeopathic preparations of growth factors
IT1270594B (en) 1994-07-07 1997-05-07 Recordati Chem Pharm CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF LIQUID SUSPENSION MOGUISTEIN
IL116816A (en) 1995-01-20 2003-05-29 Rhone Poulenc Rorer Sa Cell for the production of a defective recombinant adenovirus or an adeno-associated virus and the various uses thereof
US7048906B2 (en) 1995-05-17 2006-05-23 Cedars-Sinai Medical Center Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions
US5686311A (en) 1995-06-23 1997-11-11 The Children's Mercy Hospital Diagnosis of autism and treatment therefor
US6013516A (en) 1995-10-06 2000-01-11 The Salk Institute For Biological Studies Vector and method of use for nucleic acid delivery to non-dividing cells
US5721118A (en) 1995-10-31 1998-02-24 The Regents Of The University Of California, San Diego Mammalian artificial chromosomes and methods of using same
CN101028523A (en) 1995-11-30 2007-09-05 德克萨斯州立大学董事会 Method and compositions for the diagnosis and treatment of cancer
US6025155A (en) 1996-04-10 2000-02-15 Chromos Molecular Systems, Inc. Artificial chromosomes, uses thereof and methods for preparing artificial chromosomes
US6458574B1 (en) 1996-09-12 2002-10-01 Transkaryotic Therapies, Inc. Treatment of a α-galactosidase a deficiency
US6083725A (en) 1996-09-13 2000-07-04 Transkaryotic Therapies, Inc. Tranfected human cells expressing human α-galactosidase A protein
US6020310A (en) 1997-05-19 2000-02-01 Repligen Corporation Method for assisting in differential diagnosis and treatment of autistic syndromes
US6210666B1 (en) 1997-10-21 2001-04-03 Orphan Medical, Inc. Truncated α-galactosidase A to treat fabry disease
US6187309B1 (en) 1999-09-14 2001-02-13 Milkaus Laboratory, Inc. Method for treatment of symptoms of central nervous system disorders
US6998255B1 (en) 1999-09-24 2006-02-14 Solvay Pharmaceuticals B.V. Human G-protein coupled receptor
EP1140123A4 (en) 1999-11-12 2006-03-15 Karen M Slimak Use of tropical root crops in effective intervention strategies for treating difficult and complex cases and chronic diseases
WO2001041707A2 (en) 1999-12-08 2001-06-14 Vanderbilt University Modulation of in vivo glutamine and glycine levels in the treatment of autism
US6632429B1 (en) 1999-12-17 2003-10-14 Joan M. Fallon Methods for treating pervasive development disorders
EP1257541B1 (en) 2000-01-11 2008-09-03 Molecular Insight Pharmaceuticals, Inc. Polypharmacophoric agents
US20060183776A9 (en) 2000-03-03 2006-08-17 Eisai Co., Ltd. Liquid dosage formulations of donepezil
US6188045B1 (en) 2000-04-03 2001-02-13 Alto-Shaam, Inc. Combination oven with three-stage water atomizer
EP1287135A2 (en) 2000-05-18 2003-03-05 Bayer Aktiengesellschaft Regulation of human follicle stimulating hormone-like g protein-coupled receptor
AU2001281791A1 (en) 2000-05-30 2001-12-11 Bayer Aktiengesellschaft Regulation of human lgr4-like g protein-coupled receptor
US6783757B2 (en) 2000-06-01 2004-08-31 Kirkman Group, Inc. Composition and method for increasing exorphin catabolism to treat autism
US20040170617A1 (en) 2000-06-05 2004-09-02 Finegold Sydney M. Method of treating diseases associated with abnormal gastrointestinal flora
US20040062757A1 (en) 2001-06-05 2004-04-01 Finegold Sydney M. Method of testing gastrointestinal diseases associated with species of genus clostridium
EP1332215A2 (en) 2000-10-06 2003-08-06 Bayer Aktiengesellschaft Regulation of human secretin receptor-like gpcr
WO2002029052A2 (en) 2000-10-06 2002-04-11 Bayer Aktiengesellschaft Regulation of human secretin receptor-like gpcr
AU2002212309A1 (en) 2000-10-06 2002-04-15 Bayer Aktiengesellschaft Regulation of human secretin receptor-like gpcr
AU2002218205A1 (en) 2000-10-06 2002-04-15 Bayer Aktiengesellschaft Human secretin receptor-like gpcr
US20040030100A1 (en) 2000-11-13 2004-02-12 Yonghong Xiao Regulation of human extracellular calcium- sensing g protein-coupled receptor
US20020155170A1 (en) 2000-11-30 2002-10-24 Walsh William John Nutrient supplements and methods for treating autism and for preventing the onset of autism
US20050019259A1 (en) 2001-05-16 2005-01-27 Ausubel Frederick M. Screening methods for pathogen virulence factors under low oxygen conditions
US8354438B2 (en) 2001-08-08 2013-01-15 Michael Chez Neurological functions
US7524824B2 (en) 2003-09-04 2009-04-28 Pacific Arrow Limited Composition comprising Xanthoceras sorbifolia extracts, compounds isolated from same, methods for preparing same and uses thereof
US7727561B2 (en) 2001-08-31 2010-06-01 Pacific Arrow Limited Composition comprising Xanthoceras sorbifolia extracts, compounds isolated from same, methods for preparing same and uses thereof
US20030220259A1 (en) 2001-12-21 2003-11-27 Robbert Benner Treatment of neurological disorders
US20080318871A1 (en) 2001-12-21 2008-12-25 Khan Nisar A Treatment of neurological disorders
GB0207362D0 (en) 2002-03-28 2002-05-08 Univ Liverpool Chemotherapy
US6724188B2 (en) 2002-03-29 2004-04-20 Wavbank, Inc. Apparatus and method for measuring molecular electromagnetic signals with a squid device and stochastic resonance to measure low-threshold signals
GB0208516D0 (en) 2002-04-15 2002-05-22 Univ Liverpool Chemotherapy
EP1511995A4 (en) 2002-04-19 2005-10-19 Wavbank Inc System and method for sample detection based on low-frequency spectral components
AU2003235199A1 (en) 2002-05-09 2003-11-11 Medigenes Nucleic acid probes for detection of non-viral organisms
AU2003242404A1 (en) 2002-06-13 2003-12-31 Hououdou Co., Ltd. Antibacterial agent and antibacterial composition
EP1538907A4 (en) 2002-07-02 2008-12-24 Southern Res Inst FTSZ INHIBITORS AND USES THEREOF
US20100210745A1 (en) 2002-09-09 2010-08-19 Reactive Surfaces, Ltd. Molecular Healing of Polymeric Materials, Coatings, Plastics, Elastomers, Composites, Laminates, Adhesives, and Sealants by Active Enzymes
US20100233146A1 (en) 2002-09-09 2010-09-16 Reactive Surfaces, Ltd. Coatings and Surface Treatments Having Active Enzymes and Peptides
US20040109853A1 (en) 2002-09-09 2004-06-10 Reactive Surfaces, Ltd. Biological active coating components, coatings, and coated surfaces
US20030143590A1 (en) 2002-11-18 2003-07-31 Shyam Ramakrishnan Regulation of human dopamine-like g protein- coupled receptor
US20030166600A1 (en) 2002-11-20 2003-09-04 Shyam Ramakrishnan Regulation of human isotocin-like g protein-coupled receptor
WO2004048936A2 (en) 2002-11-26 2004-06-10 University Of Utah Research Foundation Microporous materials, methods, and articles for localizing and quantifying analytes
US7597936B2 (en) 2002-11-26 2009-10-06 University Of Utah Research Foundation Method of producing a pigmented composite microporous material
US7771341B2 (en) 2003-01-22 2010-08-10 William Thomas Rogers Electromagnetic brain animation
BRPI0408099B1 (en) 2003-03-05 2014-04-08 Byocoat Entpr Inc Antimicrobial Solution and Process
US20040213738A1 (en) 2003-03-31 2004-10-28 Susan Croll-Kalish CIRL3-Like proteins, nucleic acids, and methods of modulating CIRL3-L-mediated activity
AU2003903317A0 (en) 2003-06-27 2003-07-10 Proteome Systems Intellectual Property Pty Ltd Method of isolating a protein
US8192733B2 (en) 2003-08-29 2012-06-05 Cobb & Associates Probiotic composition useful for dietary augmentation and/or combating disease states and adverse physiological conditions
US7759105B2 (en) 2003-08-29 2010-07-20 Cobb & Company, Llp Probiotic composition useful for dietary augmentation and/or combating disease states and adverse physiological conditions
US7749509B2 (en) 2003-08-29 2010-07-06 Cobb And Company, Llp Treatment of autism using probiotic composition
US20060177424A1 (en) 2003-08-29 2006-08-10 Cobb Mark L Treatment of disease states and adverse physiological conditions utilizing anti-fungal compositions
WO2005024416A1 (en) 2003-09-05 2005-03-17 Binghe Wang Water soluble boronic acid fluorescent reporter compounds and methods of use thereof
BRPI0414813A (en) 2003-09-26 2006-11-14 David R Whitlock method for the use of ammonia-oxidizing bacteria
EP1697535A2 (en) 2003-11-14 2006-09-06 University of Utah Research Foundation Methods, articles, and compositions for identifying oligonucleotides
US20050238631A1 (en) 2003-12-04 2005-10-27 Steve Burwell Methods and compositions for preventing biofilm formation, reducing existing biofilms, and for reducing populations of bacteria
US7252957B2 (en) 2004-02-03 2007-08-07 Immunosciences Lab., Inc. Identification of etiology of autism
CA2558025A1 (en) 2004-03-04 2005-09-22 Vanderbilt University Cell-penetrating socs polypeptides that inhibit cytokine-induced signaling
WO2005086814A2 (en) 2004-03-09 2005-09-22 The Uab Research Foundation Methods and compositions related to regulation of cytokine production by glycogen synthase kinase 3 (gsk-3)
WO2005115478A2 (en) 2004-05-11 2005-12-08 The Regents Of The University Of California Methods and compositions for autism spectrum disorders
CA2566703A1 (en) 2004-05-11 2005-11-24 Vishwa Deep Dixit Methods of inhibiting proinflammatory cytokine expression using ghrelin
US9107864B2 (en) 2004-06-07 2015-08-18 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to treat cancers
US8501198B2 (en) 2004-06-07 2013-08-06 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to treat cancers
JP5070051B2 (en) 2004-06-07 2012-11-07 クー バイオロジックス インク． Bacterial composition for treating cancer
US8034359B2 (en) 2004-06-07 2011-10-11 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to cancers
US20050276806A1 (en) 2004-06-15 2005-12-15 Advanced Biotherapy, Inc. Treatment of autism
US8865749B2 (en) 2004-08-01 2014-10-21 Trevor Gordon Marshall Treatment and prevention of Th1 and ‘autoimmune’ diseases effected with antibiotics and/or angiotensin inhibition
US7880876B2 (en) 2004-10-21 2011-02-01 University Of Georgia Research Foundation, Inc. Methods of use for surface enhanced raman spectroscopy (SERS) systems for the detection of bacteria
US20080118913A1 (en) 2004-11-01 2008-05-22 Scott Michael M Genetic manipulation of brain serotonin using the pet-1 transcriptional control region
US20060115467A1 (en) 2004-12-01 2006-06-01 Pangborn Jon B Compositions and methods for the treatment of autism
US9095713B2 (en) 2004-12-21 2015-08-04 Allison M. Foster Methods and systems for treating autism by decreasing neural activity within the brain
AU2006215385B2 (en) 2005-02-17 2010-12-02 Integragen Uses of human autism susceptibility gene encoding a kinase
US7889334B2 (en) 2005-03-15 2011-02-15 University Of Georgia Research Foundation, Inc. Surface enhanced Raman spectroscopy (SERS) systems for the detection of bacteria and methods of use thereof
US8501463B2 (en) 2005-05-03 2013-08-06 Anaerobe Systems Anaerobic production of hydrogen and other chemical products
US20080058282A1 (en) 2005-08-30 2008-03-06 Fallon Joan M Use of lactulose in the treatment of autism
US7625704B2 (en) 2005-08-31 2009-12-01 Fred Hutchinson Cancer Research Center Methods and compositions for identifying bacteria associated with bacteria vaginosis
WO2007056463A2 (en) 2005-11-09 2007-05-18 Primera Biosystems, Inc. Multiplexed quantitative detection of pathogens
US20070135504A1 (en) 2005-12-11 2007-06-14 Marshall Trevor G Method of Treating and/or Preventing Inflammatory Diseases, including many Autoimmune and Neurological diseases, using drugs to modulate the VDR, and/or PPAR, and/or GCR and/or CB1 nuclear and GPCR receptors; in conjunction with antibiotics which target prokaryotic protein translation
WO2007095347A2 (en) 2006-02-13 2007-08-23 The Gov. Of The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Methods and compositions related to ghs-r antagonists
EP1870097A1 (en) 2006-06-15 2007-12-26 Newron Pharmaceuticals S.p.A. Alpha-aminoamide derivatives useful in the treatment of cognitive disorders
FR2902883B1 (en) 2006-06-22 2008-09-12 Nanectis Biotechnologies METHOD FOR DETECTING MICROORGANISM WITHIN A SAMPLE
US7575934B2 (en) 2006-07-07 2009-08-18 Nativis, Inc. Oriented magnetic particle-fluorescence detectable moiety compositions and methods of making and using the same
TW200819540A (en) 2006-07-11 2008-05-01 Genelux Corp Methods and compositions for detection of microorganisms and cells and treatment of diseases and disorders
US20120149872A1 (en) 2006-12-28 2012-06-14 Phillip Belgrader Channel-based purification device
US20080167198A1 (en) 2007-01-04 2008-07-10 Christopher Gerard Cooney Filter based detection system
WO2008084889A1 (en) 2007-01-08 2008-07-17 Medigenes Co., Ltd Dna chip for detection of staphylococcus aureus
WO2008084888A1 (en) 2007-01-08 2008-07-17 Medigenes Co., Ltd Dna chip for detection of escherichia coli
US7709213B2 (en) 2007-06-07 2010-05-04 Michael Chez Method for diagnosing a pervasive developmental disorder
US8653258B2 (en) 2007-06-08 2014-02-18 Georgia State University Research Foundation, Inc. Compositions for regulating or modulating quorum sensing in bacteria, methods of using the compounds, and methods of regulating or modulating quorum sensing in bacteria
TW200916113A (en) 2007-08-08 2009-04-16 Sod Conseils Rech Applic Method for inhibiting inflammation and pro-inflammatory cytokine/chemokine expression using a ghrelin analogue
US20090126514A1 (en) 2007-09-05 2009-05-21 Eric Gregory Burroughs Devices for collection and preparation of biological agents
US20100317677A1 (en) 2007-09-11 2010-12-16 Hassel Bret A Methods of Treating a Microbial Infection by Modulating RNase-L Expression and/or Activity
US20090112278A1 (en) 2007-10-30 2009-04-30 Neuropace, Inc. Systems, Methods and Devices for a Skull/Brain Interface
US8859230B2 (en) 2007-11-21 2014-10-14 Roskilde Universitet Polypeptides comprising an ice-binding activity
DK2268142T3 (en) 2007-11-27 2017-05-22 Algipharma As USING ALGINATED OLIGOMERS TO FIGHT BIOFILM
WO2009086204A2 (en) 2007-12-21 2009-07-09 Afraxis, Inc. Methods for treating neuropsychiatric conditions
US9783851B2 (en) 2008-02-20 2017-10-10 The Children's Hospital Of Philadelphia Genetic alterations associated with autism and the autistic phenotype and methods of use thereof for the diagnosis and treatment of autism
US20110183904A1 (en) 2008-04-10 2011-07-28 The Children's Mercy Hospital Methods and compositions for altering behavior associated with autism spectrum disorder
US9380784B2 (en) 2008-07-25 2016-07-05 Charles Derby Antimicrobial compositions and methods of use
EP2149613A1 (en) 2008-07-28 2010-02-03 Greenwood Genetic Center, Inc. Methods for determining dysregulation of methylation of brain expressed genes on the X chromosome to diagnose autism spectrum disorders
US20100087466A1 (en) 2008-09-03 2010-04-08 Michael Alan Sturgess Novel small molecule dnak inhibitors
WO2010062681A2 (en) 2008-10-30 2010-06-03 University Of South Florida Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism
US20120202700A1 (en) 2008-11-19 2012-08-09 Pierson Raymond M Sample preparation and detection method
EP2387611A4 (en) 2009-01-16 2012-08-15 Massachusetts Inst Technology DIAGNOSIS AND TREATMENT OF AUTISTICAL DISEASES
US20120004225A1 (en) 2009-01-22 2012-01-05 Neurotherapeutics Pharma, Inc. Bumetanide, furosemide, piretanide, azosemide, and torsemide analogs, compositions and methods of use
CN102325825B (en) 2009-02-18 2014-07-16 乔治亚大学研究基金公司 Photochemical cross-linkable polymers, methods of making photochemical cross-linkable polymers, and methods of using photochemical cross-linkable polymers
US20100215763A1 (en) 2009-02-20 2010-08-26 William John Martin Method of using the body's alternative cellular energy pigments (ACE-pigments) in the therapy of diseases
US10512769B2 (en) 2009-03-20 2019-12-24 Electrocore, Inc. Non-invasive magnetic or electrical nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development
US9056050B2 (en) 2009-04-13 2015-06-16 Curemark Llc Enzyme delivery systems and methods of preparation and use
EP2437784B8 (en) 2009-06-03 2013-12-11 Algipharma As Alginate oligomers for use in overcoming multidrug resistance in bacteria
CN102803956A (en) 2009-06-12 2012-11-28 纳内克蒂斯生物技术公司 Highly sensitive method for detection of viral HIV DNA remaining after antiretroviral therapy in AIDS patients
EP2443259A4 (en) * 2009-06-16 2012-10-10 Univ Columbia BIOMARKERS FOR AUTISM AND USES THEREOF
US9050276B2 (en) 2009-06-16 2015-06-09 The Trustees Of Columbia University In The City Of New York Autism-associated biomarkers and uses thereof
WO2011006158A2 (en) 2009-07-10 2011-01-13 University Of Maryland, Baltimore Targeting nad biosynthesis in bacterial pathogens
CA2768466C (en) 2009-07-22 2018-08-14 The Board Of Trustees Of The University Of Illinois Hdac inhibitors and therapeutic methods using the same
WO2011011094A1 (en) 2009-07-24 2011-01-27 Dowd Scot E Universal microbial diagnosis, detection, quantification, and specimen-targeted therapy
US20120237994A1 (en) 2009-08-12 2012-09-20 University Of Georia Research Foundation, Inc. Biochars, methods of using biochars, methods of making biochars and reactors
US8383360B2 (en) 2009-08-14 2013-02-26 The Regents Of The University Of California Methods of diagnosing and treating autism
US20110037976A1 (en) 2009-08-17 2011-02-17 Yiping Zhao Flexible surface enhanced raman spectroscopy (sers) substrates, methods of making, and methods of use
TWI463990B (en) 2009-09-21 2014-12-11 Ferring Bv Oxytocin receptor agonists
EP2486143A1 (en) 2009-10-05 2012-08-15 AAK Patent B.V. Methods for diagnosing irritable bowel syndrome
US7973065B2 (en) 2009-10-07 2011-07-05 Shaw Intellectual Properties Holding, Inc. Antimicrobial compounds
JP2013507394A (en) 2009-10-09 2013-03-04 プロセラ インコーポレイテッド Compositions and methods comprising Pediococcus for reducing at least one symptom associated with an autism spectrum disorder in a human diagnosed with an autism spectrum disorder
PT2493471T (en) 2009-10-26 2020-01-09 Borody Thomas J Novel enteric combination therapy
US20130004477A1 (en) 2009-10-26 2013-01-03 Zhe Lu Methods for Treating Inflammation and Oxidative Stress Related Diseases
GB2475226A (en) 2009-11-03 2011-05-18 Genetic Analysis As Universal Prokaryote 16S ribosome PCR primer pair
TW201121570A (en) 2009-11-12 2011-07-01 Genentech Inc A method of promoting dendritic spine density
SI2523661T1 (en) 2010-01-15 2017-09-29 Inserm (Institut National De La Sante Et De La Recherche Medicale) Nkcc inhibitors for the treatment of autism
GB201001602D0 (en) 2010-02-01 2010-03-17 Cytovation As Oligopeptidic compounds and uses therof
EP2544688B1 (en) 2010-03-02 2016-09-07 President and Fellows of Harvard College Methods and compositions for treatment of angelman syndrome
WO2011139649A2 (en) 2010-04-26 2011-11-10 University Of Georgia Research Foundation, Inc. Synthesis and application reactive antimicrobial copolymers for textile fibers
US9714481B2 (en) 2010-04-28 2017-07-25 The University Of Georgia Research Foundation, Inc Photochemical cross-linkable polymers, methods of making photochemical cross-linkable polymers, methods of using photochemical cross-linkable polymers, and methods of making articles containing photochemical cross-linkable polymers
JP6034782B2 (en) 2010-05-25 2016-11-30 ザ・リージェンツ・オブ・ザ・ユニバーシティー・オブ・カリフォルニアＴｈｅ Ｒｅｇｅｎｔｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｃａｌｉｆｏｒｎｉａ BAMBAM: Simultaneous comparative analysis of high-throughput sequencing data
US9707207B2 (en) 2010-05-26 2017-07-18 The United States Of America As Represented By The Department Of Veterans Affairs Method for diagnosing, preventing, and treating neurological diseases
ES2971415T3 (en) 2010-07-26 2024-06-05 Qu Biologics Inc Immunogenic anti-inflammatory compositions
US8980279B2 (en) 2010-07-26 2015-03-17 Qu Biologics Personalized site-specific immunomodulation
JP5960717B2 (en) 2010-12-16 2016-08-02 オーティズム バイオテック リミテッド Biomarkers and their use in the diagnosis and treatment of autism
DK2667715T3 (en) 2011-01-27 2017-10-23 Neuren Pharmaceuticals Ltd TREATMENT OF AUTISM SPECTRUM DISORDERS USING GLYCYL-L-2-METHYLPROLYL-L-GLUTAMIC ACID
CA2825599C (en) 2011-02-01 2021-07-13 The Board Of Trustees Of The University Of Illinois 4-methyl-n-hydroxybenzamide compounds as histone deacetylase (hdac) inhibitors
US20120244601A1 (en) 2011-03-22 2012-09-27 Bertozzi Carolyn R Riboswitch based inducible gene expression platform
WO2012159023A2 (en) 2011-05-19 2012-11-22 Virginia Commonwealth University Gut microflora as biomarkers for the prognosis of cirrhosis and brain dysfunction
US20140171339A1 (en) 2011-06-06 2014-06-19 The University Of North Carolina At Chapel Hill Methods and kits for detecting adenomas, colorectal cancer, and uses thereof
EP2532733B1 (en) 2011-06-06 2015-01-14 Commissariat à l'Énergie Atomique et aux Énergies Alternatives A method for enhancing the fermentative poteltial and growth rate of microorganisms under anaerobiosis
US20130005806A1 (en) 2011-06-17 2013-01-03 Beaudet Arthur L Analysis of tmlhe and carnitine biosynthesis for autism diagnosis
US9442092B2 (en) 2011-06-20 2016-09-13 Kerry Lane Methods for treatment of autism
US20140315992A1 (en) 2011-07-07 2014-10-23 The Children's Hospital Of Philadelphia Genetic Alterations Associated with Autism and the Autistic Phenotype and Methods of Use Thereof for the Diagnosis and Treatment of Autism
US20140298494A1 (en) 2011-07-25 2014-10-02 Beth Israel Deaconess Medical Center, Inc. Animal model of autism
US9439421B2 (en) 2011-08-04 2016-09-13 University Of Georgia Research Foundation, Inc. Permanent attachment of ammonium and guanidine-based antimicrobials to surfaces containing -OH functionality
DE102011110945A1 (en) 2011-08-15 2013-02-21 Evonik Degussa Gmbh Biotechnological synthesis of organic compounds with alkIL gene product
DE102011110946A1 (en) 2011-08-15 2016-01-21 Evonik Degussa Gmbh Biotechnological synthesis of omega-functionalized carboxylic acids and carboxylic acid esters from simple carbon sources
US9775855B2 (en) 2011-09-14 2017-10-03 Thomas J. Lewis Compositions comprising macrolide and tetracycline and their uses
EP2756071B1 (en) 2011-09-14 2017-12-20 University Of Guelph Media supplements and methods to culture human gastrointestinal anaerobic microorganisms
DK2766483T3 (en) 2011-10-10 2022-04-19 Hospital For Sick Children PROCEDURES AND COMPOSITIONS FOR SCREENING AND TREATING DEVELOPMENTAL DISORDERS
CA2852999A1 (en) 2011-10-14 2013-04-18 University Of Georgia Research Foundation, Inc. Photochemical cross-linkable polymers, methods of making photochemical cross-linkable polymers, methods of using photochemical cross-linkable polymers, and methods of making articles containing photochemical cross-linkable polymers
CA2851617A1 (en) 2011-10-14 2013-04-18 University Of Georgia Research Foundation, Inc. Synthesis and application reactive antimicrobial copolymers for textile fibers
US9491946B2 (en) 2011-11-01 2016-11-15 University Of Central Florida Research Foundation, Inc. Ag loaded silica nanoparticle/nanogel formulation, methods of making, and methods of use
US20130108702A1 (en) 2011-11-01 2013-05-02 Swadeshmukul Santra Copper/silica nanoparticles, methods of making, and methods of use
US8810789B2 (en) 2011-11-07 2014-08-19 University Of Georgia Research Foundation, Inc. Thin layer chromatography-surfaced enhanced Raman spectroscopy chips and methods of use
US8962662B2 (en) 2011-11-15 2015-02-24 Byocoat Enterprises, Inc. Antimicrobial compositions and methods of use thereof
US20120128683A1 (en) 2011-11-22 2012-05-24 Shantha Totada R Autism treatment
US20130183680A1 (en) 2011-12-22 2013-07-18 Quest Diagnostics Investments Incorporated Assays and methods for the diagnosis of post-streptococcal disorders
US9133525B2 (en) 2012-01-26 2015-09-15 Luc Montagnier Detection of DNA sequences as risk factors for HIV infection
DK2812452T3 (en) 2012-02-09 2020-06-29 Population Bio Inc METHODS AND COMPOSITIONS FOR SCREENING AND TREATING DEVELOPMENT DISORDERS
WO2013130953A2 (en) 2012-03-01 2013-09-06 The Trustees Of Columbia University In The City Of New York Autism-associated biomarkers and uses thereof
EP2639308A1 (en) 2012-03-12 2013-09-18 Evonik Industries AG Enzymatic omega-oxidation and -amination of fatty acids
WO2013139861A1 (en) 2012-03-20 2013-09-26 Luc Montagnier Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
US8906918B1 (en) 2012-03-23 2014-12-09 University Of South Florida (A Florida Non-Profit Corporation) Compositions, methods of use, and methods of treatment
US10280168B2 (en) 2012-03-30 2019-05-07 Agency For Science, Technology And Research Bicyclic heteroaryl derivatives as MNK1 and MNK2 modulators and uses thereof
US20130280724A1 (en) 2012-04-11 2013-10-24 Nestec Sa Methods for diagnosing impending diarrhea
US20130296430A1 (en) 2012-05-03 2013-11-07 Antonio Hardan Compositions and methods for treating autism and autism spectrum disorder
US20130317006A1 (en) 2012-05-24 2013-11-28 Amy Yasko Use of polymorphisms for identifying individuals at risk of developing autism
US20140336181A1 (en) 2012-05-24 2014-11-13 Amy Yasko Use of polymorphisms for identifying individuals at risk of developing autism
US9719144B2 (en) 2012-05-25 2017-08-01 Arizona Board Of Regents Microbiome markers and therapies for autism spectrum disorders
WO2014007606A1 (en) 2012-07-05 2014-01-09 N.V. Nutricia Product for use in the prophylactic or therapeutic treatment of a negative emotion or introvert behaviour
US8987246B2 (en) 2012-07-18 2015-03-24 The Johns Hopkins University Methods for treatment of autism spectrum disorder
EA201590175A1 (en) 2012-07-26 2015-06-30 Дзе Реджентс Оф Дзе Юниверсити Оф Калифорния SCREENING, DIAGNOSTICS AND FORECASTING OF AUTISM AND OTHER DEVELOPMENTAL DISABILITIES
US20150232927A1 (en) 2012-08-15 2015-08-20 James M. Sikela Evaulation of duf1220 copy number and methods of using the same
RU2015111258A (en) 2012-08-29 2016-10-20 Саликс Фармасьютикалз, ИНК. LABORATIVE COMPOSITIONS AND METHODS OF TREATMENT OF CONSTIPATION AND RELATED GASTROINTESTINAL DISEASES AND CONDITION
EP2890808A4 (en) 2012-08-29 2016-09-28 California Inst Of Techn DIAGNOSIS AND TREATMENT OF AUTISM SPECTRUM DISORDER
US10233495B2 (en) 2012-09-27 2019-03-19 The Hospital For Sick Children Methods and compositions for screening and treating developmental disorders
AU2013333882B2 (en) 2012-10-17 2019-05-16 Enterome Gene signatures of inflammatory disorders that relate to the liver
US20140112985A1 (en) 2012-10-22 2014-04-24 Polonez Therapeutics Llc Method of prevention and treatment of clostridium difficile infection
EP2730655A1 (en) 2012-11-12 2014-05-14 Evonik Industries AG Process for converting a carboxylic acid ester employing BioH-deficient cells
WO2014075745A1 (en) 2012-11-19 2014-05-22 Université Catholique de Louvain Use of akkermansia for treating metabolic disorders
US8906668B2 (en) 2012-11-23 2014-12-09 Seres Health, Inc. Synergistic bacterial compositions and methods of production and use thereof
ES2786193T3 (en) 2012-12-12 2020-10-09 Broad Inst Inc Genetic engineering and optimization of improved enzyme systems, methods, and compositions for sequence manipulation
SG11201504523UA (en) 2012-12-12 2015-07-30 Broad Inst Inc Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
EP2746397A1 (en) 2012-12-21 2014-06-25 Evonik Industries AG Production of omega amino fatty acids
EP2746400A1 (en) 2012-12-21 2014-06-25 Evonik Industries AG Preparation of amines and diamines from a carboxylic acid or dicarboxylic acid or a monoester thereof
PT2935312T (en) 2012-12-21 2018-10-26 Hoffmann La Roche Peptides as oxytocin agonists
AU2014207618A1 (en) 2013-01-16 2015-08-06 Emory University Cas9-nucleic acid complexes and uses related thereto
CA2898015A1 (en) 2013-01-17 2014-07-24 F. Hoffmann-La Roche Ag Oxytocin receptor agonists for the treatment of cns diseases
WO2014120994A1 (en) 2013-01-31 2014-08-07 The Johns Hopkins University Rufinamide and derivatives and their use in modulating the gating process of human voltage-gated sodium channels
EP3587558A3 (en) 2013-02-04 2020-03-04 Seres Therapeutics, Inc. Methods of populating a gastrointestinal tract
WO2014121304A1 (en) 2013-02-04 2014-08-07 Seres Health, Inc. Compositions and methods
US10279012B2 (en) 2013-03-11 2019-05-07 Healthpartners Research & Education Methods of treating and preventing social communication disorder in patients by intranasal administration of insulin
EP2969012A4 (en) 2013-03-12 2016-09-14 Univ Yale COMPOSITIONS AND METHODS FOR IDENTIFYING MICROBES RELATED TO SECRETORY ANTIBODIES
US9402925B2 (en) 2013-03-12 2016-08-02 The Board Of Trustees Of The Leland Stanford Junio Probes and methods of imaging a bacterial infection
EP2971127B1 (en) 2013-03-14 2018-02-28 University Of Ottawa Methods for the diagnosis and treatment of inflammatory bowel disease
US20160040215A1 (en) 2013-03-14 2016-02-11 Seres Therapeutics, Inc. Methods for Pathogen Detection and Enrichment from Materials and Compositions
WO2014152432A2 (en) 2013-03-15 2014-09-25 The General Hospital Corporation Rna-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci
US20160030391A1 (en) 2013-03-15 2016-02-04 The Johns Hopkins University Methods and compositions for improving cognitive function
GB201312713D0 (en) 2013-03-22 2013-08-28 Weaver Connie M Uses of soluble corn fibre for increasing colonic bacteria populations and increasing mineral absorption
KR102396328B1 (en) 2013-04-17 2022-05-10 세이지 테라퓨틱스, 인크. 19-nor c3,3-disubstituted c21-n-pyrazolyl steroids and methods of use thereof
US9725481B2 (en) 2013-04-17 2017-08-08 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof
US20160068563A1 (en) 2013-04-17 2016-03-10 Boyd L. Harrison 19-nor neuroactive steroids and methods of use thereof
HUE051403T2 (en) 2013-04-17 2021-03-01 Sage Therapeutics Inc 19-nor neuroactive steroids for methods of treatment
AU2014253749B2 (en) 2013-04-19 2018-09-20 California Institute Of Technology Parallelized sample handling
BR112015027699B1 (en) 2013-05-01 2021-11-30 Neoculi Pty Ltd USE OF ROBENIDINE OR A THERAPEUTICLY ACCEPTABLE SALT THEREOF, ANTIBACTERIAL PHARMACEUTICAL COMPOSITION AND MEDICAL DEVICE
RU2666540C2 (en) 2013-05-01 2018-09-11 Неокули Пти Лтд Compounds and methods of treating infections
WO2014201037A2 (en) 2013-06-10 2014-12-18 New York University Methods for manipulating immune responses by altering microbiota
JP6738729B2 (en) 2013-06-17 2020-08-12 ザ・ブロード・インスティテュート・インコーポレイテッド Delivery, engineering and optimization of systems, methods and compositions for targeting and modeling postmitotic cell diseases and disorders
CA2915795C (en) 2013-06-17 2021-07-13 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components
US10011850B2 (en) 2013-06-21 2018-07-03 The General Hospital Corporation Using RNA-guided FokI Nucleases (RFNs) to increase specificity for RNA-Guided Genome Editing
WO2014209412A1 (en) 2013-06-29 2014-12-31 Viva Pharmaceutical, Inc. N-acetyl l-cysteine chelates and methods for making and using the same
US20150037285A1 (en) 2013-07-03 2015-02-05 New York University Methods for efficient transfer of viable and bioactive microbiota
CN105407728A (en) 2013-07-21 2016-03-16 霍勒拜欧姆公司 Methods and systems for microbiome characterization, monitoring and treatment
US9781936B2 (en) 2013-10-09 2017-10-10 University Of Central Florida Research Foundation, Inc. Compositions, methods of making a composition, and methods of use
US20150224164A1 (en) 2013-11-26 2015-08-13 Neuren Pharmaceuticals Limited Treatment of autism spectrum disorders using glycyl-l-2-methylprolyl-l-glumatic acid
US9752175B2 (en) 2014-01-06 2017-09-05 The Trustees Of Princeton University Systems and methods to detect biofilm streamer growth and their uses
CA2936809A1 (en) 2014-01-14 2015-07-23 Children's Hospital Medical Center Compositions comprising ketamine for treating an autism spectrum disorder
US9215877B2 (en) 2014-02-05 2015-12-22 University Of Central Florida Research Foundation, Inc. Compositions including a vacancy-engineered(VE)-ZnO nanocomposite, methods of making a composition , method of using a composition
US20160002620A1 (en) 2014-07-03 2016-01-07 Luc Montagnier Method for digital transduction of dna in living cells
WO2016065075A1 (en) 2014-10-21 2016-04-28 uBiome, Inc. Method and system for microbiome-derived diagnostics and therapeutics
CA2966357A1 (en) 2014-10-30 2016-05-06 California Institute Of Technology Compositions and methods comprising bacteria for improving behavior in neurodevelopmental disorders
US10124025B2 (en) 2014-10-30 2018-11-13 California Institute Of Technology Compositions and methods comprising bacteria for improving behavior in neurodevelopmental disorders
KR20170086492A (en) 2014-10-30 2017-07-26 캘리포니아 인스티튜트 오브 테크놀로지 Compositions and methods comprising bacteria for improving behavior in neurodevelopmental disorders
KR20160057500A (en) 2014-11-05 2016-05-24 아카데미아 시니카 Pharmaceutical composition containing clioquinol for treating autism spectrum disorders
US20160151366A1 (en) 2014-11-17 2016-06-02 Vanderbilt University Compositions and Methods for Treating Autism Spectrum Disorders
MA41020A (en) 2014-11-25 2017-10-03 Evelo Biosciences Inc PROBIOTIC AND PREBIOTIC COMPOSITIONS, AND THEIR METHODS OF USE FOR MODULATION OF THE MICROBIOME

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001093904A1 (en) * 2000-06-05 2001-12-13 The United States Of America As Represented By The Department Of Veterans Affairs Method of treating gastrointestinal diseases associated with species of genus clostridium
WO2007068831A2 (en) 2005-12-14 2007-06-21 Luc Montagnier Method for characterising a biologically active biochemical element by analysing low frequency electromagnetic signals
US20100069399A1 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceutical, Inc. Arylpiperazine modulators of d2 receptors, 5-ht1a receptors, and/or 5-ht2a receptors
US20120024701A1 (en) 2010-06-24 2012-02-02 Luc Montagnier General procedure for the identification of dna sequences generating electromagnetic signals in biological fluids and tissues

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
ADRIEN JL; ROSSIGNOL-DELETANG N; MARTINEAU J; COUTURIER G; BARTHELEMY C: "Regulation of cognitive activity and early communication development in young autistic, mentally retarded, and young normal children", DEV PSYCHOBIOL, vol. 39, 2001, pages 124 - 136
BLANC R; ADRIEN JL; ROUX S; BARTHELEMY C: "Dysregulation of pretend play and communication development in children with autism", AUTISM, vol. 9, 2005, pages 229 - 245
BOURGERON T: "A synaptic trek to autism", CURR OPIN NEUROBIOL, vol. 19, 2009, pages 231 - 234
BOURREAU Y.; ROUX S.; GOMOT M.; BONNET-BRILHAULT F.; BARTHELEMY C.: "Validation of the repetitive and restricted behaviour scale in autism spectrum disorders", EUROPEAN CHILD AND ADOLESCENT PSYCHIATRY, vol. 18, no. 11, November 2009 (2009-11-01), pages 675 - 682, XP019762626, DOI: doi:10.1007/s00787-009-0028-5
CORNELIA BRENDEL ET AL: "Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model", JOURNAL OF MOLECULAR MEDICINE, SPRINGER, BERLIN, DE, vol. 89, no. 4, 1 December 2010 (2010-12-01), pages 389 - 398, XP019889972, ISSN: 1432-1440, DOI: 10.1007/S00109-010-0704-4 *
HOOPER, D.; RUBINSTEIN, E.: "Quinolone Antimicrobial Agents, Vd Edition", 2004, AMERICAN SOCIETY OF MICROBIOLOGY PRESS
KANNER L.: "Autistic disturbances of affective contact", NERVOUS CHILD, vol. 2, 1943, pages 217 - 50
LEVY SE; HYMAN SL: "Novel treatments for autistic spectrum disorders", MENT RETARD DEV DISABIL RES REV, vol. 11, 2005, pages 131 - 142
LEVY SE; HYMAN SL: "Pediatric assessment of the child with developmental delay", PEDIATR CLIN NORTH AM, vol. 40, 1993, pages 465 - 477
PATTERSON PH: "Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness", CURR OPIN NEUROBIOL, vol. 12, 2002, pages 115 - 118
PERSICO AM; BOURGERON T: "Searching for ways out of the autism maze: genetic, epigenetic and environmental clues", TRENDS NEUROSCI, vol. 29, 2006, pages 349 - 358, XP025031254, DOI: doi:10.1016/j.tins.2006.05.010
ZHANEL, G. G., DRUGS, vol. 61, no. 4, 2001, pages 443 - 98

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10039777B2 (en) 2012-03-20 2018-08-07 Neuro-Lm Sas Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
WO2018235082A1 (en) * 2017-06-20 2018-12-27 Ben Noon Alon Compositions comprising an anti-inflammatory drug and a dicer activator for use in the treatment of neuronal diseases
US10980780B2 (en) 2017-06-20 2021-04-20 Neurosense Therapeutics Ltd. Methods and compositions of anti-inflammatory drug and dicer activator for treatment of neuronal diseases
AU2018287021B2 (en) * 2017-06-20 2021-09-02 Neurosense Therapeutics Ltd. Compositions comprising an anti-inflammatory drug and a dicer activator for use in the treatment of neuronal diseases

Also Published As

Publication number Publication date
US10039777B2 (en) 2018-08-07
US20190134073A1 (en) 2019-05-09
US20170035792A1 (en) 2017-02-09

Similar Documents

Publication Publication Date Title
US10039777B2 (en) Methods and pharmaceutical compositions of the treatment of autistic syndrome disorders
CN103356612B (en) Pharmaceutical combination comprising an antibacterial agent and an active substance selected from thymol and carvacrol
EP3876712B1 (en) Screening methods for treatments of intraocular diseases or disorders
CA2818100C (en) Compounds and their use
EP3886852B1 (en) Octyl gallate and esters thereof of for use in the treatment and prevention of age-related macular degeneration caused by bacillus megaterium
AU2009285632A1 (en) Compositions and methods of treatment comprising ceftaroline
EP3762376B1 (en) Diphenyl substituted thiophene-2-amide derivatives and pharmaceutical compositions thereof useful as antimicrobial
CA2835907A1 (en) Compositions comprising antibacterial agent and tazobactam
US10736937B2 (en) Methods and pharmaceutical compositions for the treatment of bacterial superinfections post-influenza
AU2016322012A1 (en) Antibiotic therapy
WO2020021035A1 (en) Use of antibiotics for the treatment of immunoglobulin a nephropathy
US20190321324A1 (en) Quaternary amine antibiotic therapeutics
JP6178224B2 (en) Combined anti-methicillin-resistant Staphylococcus aureus drug and β-lactam antibiotic antibacterial activity enhancer
US20210369675A1 (en) Antimicrobial drug methods of use &amp; therapeutic compositions
AU2014200107B2 (en) Compositions and methods of treatment comprising ceftaroline
EP3075733A1 (en) Novel heterocyclic compounds and their use in preventing or treating bacterial infections
WO2018193369A1 (en) Antibacterial compositions

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13711041

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 14386215

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13711041

Country of ref document: EP

Kind code of ref document: A1