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US20020013270A1 - Method for treating a mental disorder - Google Patents

Method for treating a mental disorder Download PDF

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US20020013270A1
US20020013270A1 US09/866,033 US86603301A US2002013270A1 US 20020013270 A1 US20020013270 A1 US 20020013270A1 US 86603301 A US86603301 A US 86603301A US 2002013270 A1 US2002013270 A1 US 2002013270A1
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disorder
group
kit
antimicrobial
symptom
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Ellen Bolte
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Priority to US10/741,377 priority patent/US7307062B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the therapeutic treatment of mental disorders, and in particular to a new and useful method for treatment of mental disorders by administering an antimicrobial composition and/or administering a probiotic mixture to replenish gastrointestinal microbes.
  • the gastrointestinal tract is a highly complex ecosystem with as many as 300-400 bacterial species from 30 genera. Typical bacterial counts in the colon are 10 11-12 per gram of feces, and the bacterial composition of multiple specimens collected over time from single individuals appears to be quite stable. Competition for available nutrients and space limits bacterial growth in the colon and contributes to the delicate, yet relatively stable, balance of organisms. This balance is disrupted by the use of broad-spectrum antimicrobials. Large numbers of the intestinal population are killed by broad-spectrum antimicrobial use, substantially diminishing the colonization resistance of the host to deleterious microbes, such as gram-positive, spore-forming anaerobic bacteria. These bacteria are often ubiquitous in nature and are readily found in numerous environments.
  • Clostridium genus Approximately 10% of the organisms found in a human stool specimen belong to the Clostridium genus. When growth conditions become unfavorable, the bacteria produce spores that tolerate extreme conditions that the vegetative form of the bacteria cannot survive, such as those encountered during antimicrobial treatment.
  • the second line of evidence is from human and animal studies which have repeatedly demonstrated that intestinal colonization by opportunistic pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aerguinosa, Salmonella enteritidis, Shigella flexneri , and Vibrio cholerae . Intestinal colonization is greatly enhanced when protective intestinal microbiota are disrupted by broad-spectrum antimicrobials. In humans, the best-documented example of opportunistic colonization of the intestinal tract following antimicrobial use is that by Clostridium difficile , the causative agent of pseudomembranous colitis.
  • D-lactic acidosis Another relevant condition is d-lactic acidosis, in which associated neurological and psychiatric symptoms are well-documented.
  • D-lactic acidosis a complication of short bowel syndrome or intestinal bypass surgery for obesity, is a condition caused by a change in bacterial flora to an acid-tolerant, aciduric flora.
  • D-lactic acidosis creates a host of behavioral changes such as hostility, slurred speech, stupor, altered mental status, dizziness, asterixis, and ataxia. Treatment is with oral antimicrobials, resulting in rapid cessation of mental signs.
  • Certain clostridial species produce the most potent neurotoxins known to man. To date, researchers have identified seven serotypes of botulinum neurotoxin (BONT A to G) produced by at least four different clostridial species; C. botulinum, C. baratii, C. butyricum , and C. argentinense . Thus far, only C. tetani is known to produce tetanus neurotoxin (TeTX).
  • the structural genes for clostridial neurotoxin production are chromosomal (BONT type A, B, E, and F), plasmid-associated (TeTX and BONT-G), or bacteriophage-associated (BONT type C, D, and possibly F) DNA. Plasmids and bacteriophages are natural vehicles for the transfer of genetic material between bacteria, including the genes that control neurotoxin production. It is widely accepted and believed that additional clostridial species are capable of neurotoxin production.
  • tetanus neurotoxin can be transported to the central nervous system (CNS) via retrograde intra-axonal transport along the vagus nerve. Based on this finding, a clostridial neurotoxin, related to TeTX, elaborated by an organism that has colonized the intestinal tract, could gain access to the CNS via retrograde intra-axonal transport along afferent fibers of the vagus nerve. Once the toxin gained access to the CNS, cleavage of synaptic proteins would severely disrupt the delicate balance of neurotransmitters and cause behavioral symptoms indicative of mental illness, as evidenced by laboratory experiments in animals.
  • Behavioral symptoms have previously been associated with certain infectious diseases.
  • Specific examples of bacteria that may cause psychological symptoms are the causative agent of syphilis, Treponema pallidum , and the causative agent of Lyme disease, Borrelia burgdrferi .
  • the association of certain gastrointestinal illnesses with neurological and psychological symptoms is also recognized, as in d-lactic acidosis. In spite of the recognized association between bacteria and neurological and psychological symptoms in certain conditions, the possibility that the vast majority of mental illnesses symptoms are caused by a bacterial infection of the intestinal tract is a paradigm shift.
  • the present invention provides a method of treating an individual exhibiting at least one symptom of a mental disorder, in particular the method comprises administering to the individual an antimicrobial composition in an amount effective to inhibit or eliminate the at least one symptom of the disorder.
  • disruption of the flora within the gastrointestinal tract or poorly developed flora within the gastrointestinal tract of young infants and subsequent pathogenic microbial proliferation in one or more regions of the gastrointestinal tract can mediate a variety of disruptions of neurological functions.
  • Toxins, in particular neurotoxins, produced by one or more species of the proliferating microbes mediate these neurological disruptions.
  • a treatment goal is to create an environment that does not favor the growth of the neurotoxigenic organism(s).
  • Antimicrobials such as vancomycin, metronidazole, bacitracin, teicoplanin, ramoplanin, and fusidic acid have been studied for the treatment of C. difficile colitis. When treatment with a single agent failed to result in a remission of symptoms, the use of two antimicrobial agents with different modes of action were used. Particular combinations appear to be synergistic.
  • the present invention including antibacterial therapy directed to the proliferating microbial species, results in improved mental function through inhibition or elimination of the proliferating species. Furthermore, recurrence of the mental symptoms can be limited or potentially prevented by repopulation of the gastrointestinal tract by normal human gut flora, known as competitive replacement therapy or “probiotic therapy”. In all likelihood, the mental syndromes themselves can be prevented or limited in the first place by appropriate probiotic therapy following administration of broad-spectrum antimicrobial.
  • the pathogenic proliferation of microbes in the gut can at least partially cause deleterious mental symptoms and syndromes of many disorders, including at least some forms of Attention Deficit/Hyperactivity Disorder (ADHD), Autistic Disorder, Childhood Disintegrative Disorder, Conduct Disorder, Oppositional Defiant Disorder, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), Anxiety Disorder, Mood Disorders including Major Depressive Disorders, Bipolar Disorder (I and II), Psychotic Disorders including Shizophreniform, Schizoaffective Disorder, Schizophrenia (all types), and Psychotic Disorder Not Otherwise Specified.
  • ADHD Attention Deficit/Hyperactivity Disorder
  • Autistic Disorder Autistic Disorder
  • Childhood Disintegrative Disorder Conduct Disorder
  • Oppositional Defiant Disorder Pervasive Developmental Disorder-Not Otherwise Specified
  • Anxiety Disorder Mood Disorders including Major Depressive Disorders, Bipolar Disorder (I and II), Psychotic Disorders including Shizophreniform, Schizoaffective Disorder, Schiz
  • an antimicrobial selected as a therapy for any of the above disorders will have one or more of the following properties:
  • bactericidal activity Preferably bactericidal activity
  • Drugs that have one or more of the above characteristics may be utilized for antimicrobial therapy in treating mental disorders with a gut flora etiology.
  • the different modes of action by which antimicrobial agents either kill or inhibit bacterial organisms are elaborated below.
  • the following examples are provided only for the purposes of illustrating the different classes of antibiotics, categorized by their modes of action, and are not intended to limit the scope of the present invention.
  • the bacterial cell wall is composed of a macromolecular network called peptidoglycan, present either alone or in combination with other substances.
  • peptidoglycan a macromolecular network
  • certain antibacterial agents prevent the synthesis of intact peptidoglycan.
  • the cell wall is greatly weakened and results in lysis of the cell. Table 1 below provides a partial listing of these inhibitors.
  • Cephalosporins Cephalexin, cefpodoxime proxetil, cefoperazone, cefotaxime, ceftazidime, crftriaxone, moxalactam, loracarbef, cephradine, cefprozil, cefadroxil, cephalothin, RU 59863 Glycopeptides vancomycin, teicoplanin, teicoplanin A2 complex, ristocetin, aglycone Glycolipodepsipep- Ramoplanin tide Polypeptide Bacitracin
  • Antibacterial agents in this group can act on the 30S or the 50S portion of the procaryotic ribosome and block protein synthesis.
  • the bacterial cell cannot produce the proteins it requires as a result of the antibiotic's action, cell death occurs.
  • protein synthesis can be disrupted by inhibiting the binding of tRNA on the 30S or 50S ribosomal subunit, interfering with attachment of tRNA to the mRNA-ribosome complex and thus blocking the growth of the polypeptide chain, or altering the shape of the 30S subunit of the ribosome to result in the incorrect deciphering of genetic code on the mRNA.
  • Table 2 below provides a partial listing of the inhibitors of protein synthesis.
  • These antibacterial agents can be effective due to their action on DNA or RNA synthesis. While the modes of action of the agents in this group may vary, all affect the synthesis of nucleic acids. Particular modes of action include; binding to one subunit of DNA-dependent RNA polymerase and preventing initiation of transcription, inhibiting the activity of DNA gyrase from participating in the coiling and nicking of DNA to form superhelices during replication and transcription, or causing DNA mutations due to a cytotoxic effect. Table 3 below provides a partial listing of the inhibitors of nucleic acid synthesis.
  • Antimicrobial agents that inhibit the synthesis of essential metabolites may compete with microorganisms for required substrate.
  • PABA para-aminobenzoic acid
  • the enzyme that normally converts PABA to folic acid combines with the drug instead, thereby preventing folic acid synthesis.
  • Table 4 below provides a partial listing of the inhibitors of essential metabolites. TABLE 4 Inhibitors of Synthesis of Essential Metabolites Class Specific Examples Sulfonamides Sulfamethoxazole 2,4-diaminopyrimidine Trimethoprim
  • the probiotic therapy of the present invention is preferably administered as a mixture of a large number of species that are normal, benign inhabitants of the gut, and more preferably in the general proportion in which they are found in healthy humans.
  • a bacterial mixture containing the species Clostridium innocuum, Clostridium ramosum, Bacteroides ovatus, Bacteroides vulgatus, Bacteroides thetaiotamicron, Clostridium bifermentans, Peptostreptococcus productus, Streptococcus faecalis , and two strains of Escherichia coli can be successfully used for the treatment of chronic, relapsing C. difficile colitis.
  • a suitable probiotic mixture is composed of species described as the most prevalent species and in the proportion found normally in the colon. Dosage, measured by colony forming units (cfu) of each bacterium, is preferably at least the number found in the mean count/gram, and is supplied to the patient daily or twice daily for a period of time until it is determined that the bacteria have become established.
  • the formulation can be provided as active cells or spores. It can be provided in an enterically coated form, such as for active cells, to protect sensitive cells from the gastric environment.
  • a preferred therapy involves temporary elimination or suppression of the patient's flora with the use of antimicrobial agents and introduction of a new, non-pathogenic flora that consist of a number of bacteria normally found in the bowel that convey colonization resistance. This therapy is used to prevent regrowth or re-implantation of populations of the offending bacteria.
  • regressive-onset autistic children have demonstrated success using the present invention.
  • Significant improvement in the symptoms of children with regressive-onset autism has been demonstrated by providing antimicrobials directed toward intestinal bacteria.
  • the terms “regressive-onset,” “delayed-onset” or “late-onset” indicate an autistic syndrome that appears in a child generally between 12 and 18 months old who had previously undergone normal development. Symptoms of this syndrome include the loss of language, social, and play skills, and onset of autistic characteristics such as self-stimulation behaviors and the avoidance of eye contact.
  • a Developmental Profile provided descriptive developmental levels to contrast with developmental age. Although the mean chronological age of the children was 59.4 ⁇ 12.7 months, the mean developmental age for the domains of communication, socialization, and self-help, 23.0 months ⁇ 13.0, 25.6 months ⁇ 12.9, and 34.4 ⁇ 12.4, respectively, are evidence of their significant developmental delay.
  • the Childhood Autism Rating Scale (CARS) was also administered. Based upon CARS diagnostic categories, six children met the criteria for severe autism, two for moderate autism, and three for mild autism.
  • the antimicrobial dose of vancomycin was 500 mg/day given orally as a liquid (500 mg/6 ml), divided 2 ml t.i.d. for eight weeks. This was followed by four weeks of oral treatment with a probiotic mixture of Lactobacillus acidophilus, L. bulgaricus , and Bifidobacterium bifidum (40 ⁇ 10 9 cfu/ml).
  • AB was the product of a full-term uncomplicated pregnancy. Development of language, social and play skills proceeded normally until 19 months of age. At that time AB lost expressive and receptive language skills, play skills, self-help skills and his social behavior deteriorated substantially. Immediately prior to the regression, AB had received five 10-day courses of broad-spectrum antimicrobial agents and was taking a “daily maintenance dose” of trimethoprim/sulfamethoxazole as prophylactic therapy. Severe diarrhea, attributed to the antimicrobial therapy, did not improve when the medication was discontinued. He developed abdominal extension, his stools appeared abnormal (foamy, bulky), with undigested food frequently present.
  • AB was treated with a probiotic fecal enema in an effort to recolonize his bowel with beneficial organisms.
  • Donor stool for the fecal enema was obtained from AB's healthy 7-year-old sibling.
  • Whole-bowel irrigation with a polyethylene glycol solution (GoLytelyTM) was used to prepare the bowel prior to the introduction of fifty grams of donor stool suspended in 500 ml of saline.
  • the probiotic fecal enema was repeated.
  • Weakening of the bacterial cell wall by the polypeptide bacitracin may increase the nitroimidizole metronidazole absorption by anaerobic bacteria, thus resulting in potentially synergistic activity. Also, by combining the use of metronidazole and bacitracin, risk of developing antimicrobial resistance may be reduced.
  • AB was forming short sentences 3-4 word without prompting.
  • AB made such dramatic gains in academics and language that district personnel changed the school placement to a learning-disabled classroom at the local public school.
  • AB had previously attended class at a private school for children with severe disabilities.
  • antimicrobial therapy was discontinued and probiotic treatment with Lactobacillus GG was initiated.
  • Lactobacillus GG was selected on the basis of its purported efficacy in the treatment of other gastrointestinal illnesses.
  • a severe deterioration in behavior occurred within two weeks (while AB was taking the probiotic agent).
  • Stereotyped movements, aggressive behavior and an irritable disposition were prominent.
  • Gains in expressive language were retained. Cognitive gains appeared intact, although testing was difficult due to the child's inability to concentrate and uncooperative disposition.
  • a bacterial mixture was prepared from fresh stool that was collected from AB's healthy sibling.
  • Ten grams of stool was mixed into 500 ml of fluid.
  • the fluid consisted of a mixture of 250 ml of water and 250 ml of no-fat milk, and was preheated to 99° F.
  • the mixture was strained and administered via nasogastric tubing into the stomach for passage throughout the small bowel.
  • 20 grams of stool was mixed into another 500 ml of the fluid mixture and given as a retention enema. This treatment resulted in significant and ongoing gains in social development.
  • CC was a fourteen year old male whose symptoms were consistent with major depressive disorder, obsessive compulsive disorder, and atypical psychosis. Standard anti-psychotic medications were unsuccessful in treating the symptoms. CC also had severe gastrointestinal symptoms and was subsequently diagnosed with Crohn's disease. CC began treatment with prednisone and mesalamine, a standard therapy for Crohn's disease. Treatment with metronidazole (250 mg t.i.d.) was ordered simultaneously and continued for six weeks. CC showed a rapid improvement in attitude, mood and rebounded academically. Behavior problems were absent. A subsequent deterioration in behavior was first noted two months following the discontinuance of the metronidazole.
  • CC experienced an acute psychiatric relapse and was admitted to the hospital.
  • a colonoscopy confirmed active lesions in the right colon consistent with Crohn's disease.
  • Treatment with prednisone and mesalamine was initiated for his Crohn's disease, with the prednisone later tapered to 20 mg/day after several months.
  • his subtle gastrointestinal symptoms resolved, his psychotic features failed to improve despite further trials of anti-psychotic agents.
  • Three months after the psychiatric relapse a second course of metronidazole (500 mg t.i.d. for 30 days) was initiated. Within three weeks, a dramatic improvement in his psychiatric symptoms was again noted, and by five weeks he was off all anti-psychotic medication.
  • CC was able to return to high school and completed his junior year with high honors.
  • Diagnosis Attention deficit/hyperactivity disorder (at age 7), Major depressive disorder (at age 13), Bipolar (at age 14).
  • Other diagnoses for which DSM-IV criteria are met include: Conduct Disorder
  • S.H. was the product of a full-term uncomplicated pregnancy. Childhood development was normal until 18 months of age. At that time, S.H. developed chronic ear infections. S.H. was repeatedly treated with broad-spectrum antimicrobials and twice had surgery for the placement of ear tubes. She began speech therapy at 4 and a half years old. Early history is also notable for diarrhea, vomiting, body aches, hypersensitivity to sound, and insomnia. At 7 years old, she was diagnosed with attention deficit/hyperactivity disorder and counseling was undertaken. At 10 years of age, S.H. began to threaten suicide. At 13 years of age, S.H. became obsessive and was diagnosed with Major Depressive Disorder and prescribed paroxetine. Six months later, the diagnosis was changed to Bipolar II Disorder and S.H. was admitted to a treatment facility. Treatment with gabapentin was initiated and she was subsequently released.
  • DSM-IV Diagnosis autistic disorder
  • CM was born prematurely at 28 weeks gestation weighing 2 pounds, 10 ounces. He remained hospitalized for 80 days and suffered from significant medical complications due to his premature birth. CM has been diagnosed with spastic quadriplegia with moderately impaired neuromotor and cognitive functioning. He has severe delays in fine and gross motor skills. Also, severe delays in receptive and expressive language, consistent with his premature birth.
  • CM was making progress before developmental and behavioral regression occurred. CM had started to say words such as ma, dada, baba, up. CM lost expressive language skills and began to exhibit numerous negative behaviors consistent with an autistic spectrum disorder. Specific behaviors include irritability and temper tantrums, odd meaningless movements, and odd meaningless vocalizations. CM also exhibited difficulty in social situations and showed little interest in playing with peers or forming relationships with his peers.
  • CM had frequent ear infections and was placed on a six-month “maintenance dose” of trimethoprim/sulfamethoxazole as prophylactic therapy. In spite of the placement of tympanostomy tubes at 18 months of age, CM continued to develop recurrent and persistent otis media untila second set of tubes were inserted approximately six months later.
  • CM now 5 years old, was treated with clarithromycin. According to parental report, CM became more cooperative and was much calmer. CM was happier and showed more interest in things going on around him. Head banging and tantrums stopped.
  • DSM-IV diagnosis Childhood Disintegrative Disorder
  • N.D. was the product of a full term uncomplicated pregnancy. He met all the major developmental milestones within normal age limits and began using his first words when he was 17 months old. Shortly after N.D.'s third birthday, he began to show abnormal behavior patterns: temper tantrums, self-injury, aggression towards others, oppositional, and echolalia, just to name a few. After seeing many specialists throughout the year, he was finally diagnosed with autism January 2000, shortly after his fourth birthday.
  • N.D. was treated with metronidazole (standard dosage for his age/weight,) for 17 days, followed by Lactobacillus Acidophilus GG, (Culturelle), 20 billion cells per day.
  • Table 7 summarizes N.D.'s experience during metronidazole therapy and the resultant behavior deterioration shortly after discontinuation.
  • K.H. is the product of a normal, healthy pregnancy. By 15 months of age, K.H. was beginning two word combinations, enjoyed playing with his brother and demonstrated joint attention skills. In all respects, development appeared to be completely normal. K.H. experienced an unexplainable regression in behavior and language development. By 20 months of age, K.H. could no longer speak a single word and by 24 months of age he lost receptive language skills, eye contact and play skills. He experienced difficulty sleeping at night and experienced “night terrors.”
  • K.H. currently 10 years old, is non-verbal, extremely hyperactive, with widely varying mood states. K.H. has had reoccurring ear infections since the age of 18 months. Most recently, when K.H. experiences an ear infection, he is prescribed either cefpodoxime proxetil, a cephalosporin, and/or an amoxicillin with a beta-lactamase inhibitor, such as clavulanate potassium. K.H. experiences positive improvement in his autistic symptoms when taking these antimicrobials. Noted improvements include, calmness, improved sleep patterns, and the use of more signs for communication. As soon as K.H.'s antibiotics were finished, K.H. became more hyper, more easily aggitated, and more aggressive.

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US09/866,033 US20020013270A1 (en) 2000-06-05 2001-05-25 Method for treating a mental disorder
US10/741,377 US7307062B2 (en) 2000-06-05 2003-12-19 Method for treating a mental disorder

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US20971200P 2000-06-05 2000-06-05
US21481300P 2000-06-28 2000-06-28
US24058200P 2000-10-16 2000-10-16
US09/866,033 US20020013270A1 (en) 2000-06-05 2001-05-25 Method for treating a mental disorder

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