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  • Synaptic pruning starts at 6 years old Synaptic activity from 0-12 months peak point of synapse firing at 12 mos. Thought that misfiring happens during this time.
  • American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders, Fourth Edition, Text Revision. Retrieved from http://www.psychiatryonline.com.ez-proxy.brooklyn.cuny.edu:2048/copyrightBooks.aspx?resourceID=1
  • 16:06 – 17:44 or first minute… either one
  • Anything with chromosome 16 is from PBS video * Emerging Pharmacotherapies for Neurodevelopmental disorders. Wetmore DZ, Gamer CC.
  • Merlin, LR. Persistent Changes in Network Excitability Induced by Group I Metabotropic Glutamate Receptor Activation: Impact on Seizure Expression and Implications of Epileptogenic. SUNY Downstate Medical Center, Brooklyn, NY, USA
  • *Mark F. Bear, Kimberly M Huber, Stephen T. Warren, T he mGluR theory of fragile X mental retardation. HOW WILL YOU TARGET THE HIPPOCAMPUS?
  • Cambridge University Press 978-0-521-70463-2 - Pharmacology for Anesthesia and Intensive Care, Third Edition , Tom Peck, Sue Hill and Mark Williams (Excerpt). Specifically pgs 1-10, Cambridge, United Kingdom, Cambridge University Press, 2008   Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Detail Only Available(eng; includes abstract) By Strolin Benedetti M, Whomsley R, Baltes EL, Expert Opinion On Drug Metabolism & Toxicology [Expert Opin Drug Metab Toxicol], ISSN: 1742-5255, 2005 Oct; Vol. 1 (3), pp. 447-71; PMID: 16863455 BLOOD-BRAIN BARRIER DRUG TARGETING: THE FUTURE OF BRAIN DRUG DEVELOPMENT, William M. Pardridge , Molecular interventions, March 2003   vol. 3, no. 2 , 90-105. “ Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery”, Mohammad S. Alavijeh, Mansoor Chishty, M. Zeeshan Qaiser, and Alan M. Palmer, Neurotherapeutics: The Journal of the American Society for Experimental, 2005 October; 2(4): 554–571.
  • William A McKim, Drugs & Behavior: An Introduction to Behavioral Pharmacology 6 th Edition; Pearson Publishing, 2007
  • I’ve emailed an article that discusses how you can treat the fetus of pregnant rhesus monkey moms to make the babies be born with potential for autism. It doesn’t have to be exact, but you should try to come up with something closer to that design, such as inserting the protein, etc, and rather than getting your animal’s from the zoo, you can say they were naturally born and leave it at that. I also think your N is too large and not believable. Use 10 or 15 animals in each group. Also, I don’t recall seeing anything in here addressing tolerance (PK or PD). So will there be enzyme upregulation, requiring a higher dose before treatment terminates? It seems obvious that there is potential for long-term changes (that’s the goal, right?). Can you make it more clear what the possible negative aspects of this could be? There are glycine receptors located in the spinal cord, which play a role in reflexive behavior. HOW will you target only the glycine receptors that affect NMDArs in the hippocampus? You should be prepared to address this with something like “more studies are needed to determine the long term effects of Trazerpar on glycine receptors located in the spinal cord. Thus far, our studies are showing no changes in reflexive behavior in rhesus monkeys, but more long-term work needs to be done to confirm…”

Autism ppt Autism ppt Presentation Transcript

  • AutismPervasive DevelopmentalDisorderJacqueline, Zoga, Isabel, Anabelle
  • autism¹ Autism is a developmental disorder that appears in the first 3 years of life, and affects the brain’s normal development of social and communication skills.
  • autism Social skill impairments:  Fails to respond to his name  Poor eye contact  Appears not to hear you  Resist holding  Appears unaware of others’ feelings  Retreats into “own world”
  • autism Starts talking later than 2, other developmental delays by 30 months Loses previously acquired ability to say words* If does make request; does not make eye contact Speaks with abnormal tone or rhythm may be sing song voice or “robot” voice if does speak. If does speak- can’t start a conversation or keep one going May repeat words or phrases with no understanding of them
  • autism Behavior  Performs repetitive movement: rocking, spinning, hand flapping  Develops specific routines or rituals  Becomes very disturbed at the slightest change in routines  Moves constantly  May be fascinated by parts of an object: i.e. wheels of a toy car  May be unusually sensitive to light, sound, and touch, yet oblivious to pain
  • Diagnostic Criteria²
  • autism Doctor may recommend further developmental tests if:  Baby does not coo by 12 mos.  Does not gesture by 12 mos.  Does not say a single word by 16 mos.  Does not say two word phrases by 24 mos.  Loses previously acquired language or social skill by any age
  • autism In most cases normal development up to 1st year Then deficits in 3 areas of development  Social interaction  Language  Behavioro Some babies show symptoms before 12 mos.
  • autism  Thisvideo gives some insight on what a child with Autism looks like:  http://www.youtube.com/watch?v=bG0vko7GHDQ ³
  • Drug treatment SSRIs and antipsychotic medication  Prozac, Zoloft, Lustral, Celexa (SSRIs)  Haldol, Risperdal, Abilify* (antipsychotics)4 *Abilify is also used as an anti depressant
  • autismEpidemiology- conflicting statisticsoThe Autism And Developmental Disabilities Network(ADDM) estimates the prevalence of autism spectrumdisorder in the US to be 2-7 cases per 1,000o“however there have not been any definitive studiesto date providing an accurate estimate of theprevalence of the overall population”5oRuns in family: if 1 child in the family has it the chancesare 1 in 5 for another to have it vs. 1 in 150 in familieswith no autism6oThe ADDM estimates the prevalence of autismspectrum disorders to be 1 in 110 among 8 year oldoMore prevalent among boys7
  • autism Genetic component:8  Studies included DNA from family members with at least 2 autistic children compared with DNA of family members with autism
  • autism Findings:9  Chromosomes 16 had a “chunk” missing which may have included 25 genes in the family with autism
  • autism • Chromosome 5- there is a “mysterious gene” next to SEM 5A9 • SEM 5A is a gene involved in neuro-circuitry8 • It is thought that since this “mystery” gene is so close to SEMA 5A it too is involved in neural circuit • This mystery gene was present in 10% of the families with autism10
  • Rational Even though there are no studies indicating the specific cause of autism, there are studies that show excessive glutamate causes excessive excitatory action followed by long term depression of the neuron.11 A major study done by LR Merlin of SUNY Downstate Medical , here in Brooklyn showed activation of group mGluR elicits depolarization of hippocampal neurons. 11
  • Rational
  • Pharmacodynamics Our drug is partially agonizing a glycine receptor, which in turn decreases the firing of NMDA receptors. 12 Being that NMDA is a glutamate receptor we are in turn decreasing NMDA excitation. The focus of our drug activity will take place in the hippocampus. 13
  • Pharmacodynamics
  • TRAZERPAR™
  • Drug Names Chemical Name: 7-{4-[-(2,3- aminoethanoic acid)piperazin-1- yl]butoxy}-3,4-dihydroquinolin-2(1H)-one Generic Name: Glyparatic Acid Trade Name: TRAZERPAR™
  • Trazerpar Will not aim at altering one aspect of behavior in a child with autism Will target the receptor site to decrease glutamate firing so that the neural circuitry will be developed normally thus the symptoms of autism will not be allowed to be expressed TRAZERPAR will be replacing all other drugs because it will take preventative measures.
  • Target Population Individual (babies) who tested positive for “missing chunk” in chromosome 16 and/or had presence of “mysterious gene” located next to gene SEMA 5A. 12 months (no later than 18 months) Babies that would be given the genetic test would be those who had a family history of 2 more individuals w/ autism Babies who showed under 18 months old deficiency (or disappearance of) following skills:  Not making eye contact  Not responding to name  Appears not to hear you  Does not coo by 12 mos.  Does not gesture by 12 mos.  Does not say single word by 16 mos.
  • Pharmacokinetics Route of administration: Oral (drug in the form of a fine powder) Can be administered via the child’s formula, food, (except grapefruit juice or anything containing grapefruit), etc. Absorption: Will occur in the intestines. Considering TRAZEPAR™ has a pKa of 5, the intestines would be the best place for absorption since it has a pH of 5.5-7, making our drug more unionized and lipid soluble in this environment.14
  • Pharmacokinetics
  • Pharmacokinetics Metabolism: First-Pass Metabolism  Once TRAZEPAR™ is absorbed by the intestines and then blood, it will go through first-pass metabolism by the liver.  Why: An infant is born with a certain amount of cytochrome P450 enzymes, which enables the liver to act as an agent for the metabolism of drugs. This will ensure at a higher rate that the infant will be able to successfully metabolize TRAZEPAR™. 15
  • Pharmacokinetics Distribution: To the CNS, Pass the Blood Brain Barrier via Active Transport Why: TRAZEPAR™ is partially agonizing a glycine site, which in turn is decreasing conductance from a glutamate receptor Active transport is needed here because glycine is an amino acid, and typically most drugs targeting a site which is an amino acid requires a certain amount of energy used at that site, thus requiring active transport as the mechanism for the distribution of TRAZEPAR™.16
  • Pharmacokinetics Excretion: The drug will be changed into an inactive metabolite by the liver, and excreted by the kidneys through the urine.17
  • Autism in Rhesus Monkeys  Rhesus Monkeys from the San Diego Zoo -Treatment Group (TG) 18 “Autism induced” rhesus monkeys were given Trazerpar -Comparison Group (CG) 18 “Non-Autistic” rhesus monkeys were given a saline solution  Results - TG: 13 (75%) rhesus monkeys showed normal social and behavior skills - CG: The rhesus monkeys failed to show an improvement in social and behavior skills
  • Dose Response Curves ED 50 TD 50 LD 50
  • Possible Side Effects  Dizziness  Lightheadedness  Sedation  Excessive sleepiness More Harmful Side Effects Include:  Tremors  seizures
  • SummaryTrazerpar Does not aim to alter a single behavioral or cognitiveaspect of Autism.Overall Our drug will target the receptor site in order to decreaseglutamate firing, which in turn will allow for normal developmentof neural circuitry. Thus, the symptoms associated with Autism will not beallowed to develop in the first place.
  • References1. Kerig, Patricia, and Charles Wenar. Developmental Psychopathology. 5th ed. McGraw Hill Higher Education, 2006. Print.2. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders, Fourth Edition, Text Revision. Retrieved from http:// www.psychiatryonline.com.ez-proxy.brooklyn.cuny.edu:2048/copyrightBooks.aspx?resourceID=13. "YouTube - Children and Autism." YouTube - Broadcast Yourself. Web. 07 April 2011. http:// www.youtube.com/watch?v=bG0vko7GHDQ4. "NIMH · Autism Spectrum Disorders (Pervasive Developmental Disorders)." NIMH · Home. Web. 07 Apr. 2011. http:// www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml5. Autism Genes. Nova Science Now, Hosted by: Neil de Grasse Tyson. Exec. Producer Samuel Fine, Exec. Editor Neil de Grasse Tyson. Episode 2, PBS 2009.6. Autism Genes. Nova Science Now, Hosted by: Neil de Grasse Tyson. Exec. Producer Samuel Fine, Exec. Editor Neil de Grasse Tyson. Episode 2, PBS 2009.7. Autism Genes. Nova Science Now, Hosted by: Neil de Grasse Tyson. Exec. Producer Samuel Fine, Exec. Editor Neil de Grasse Tyson. Episode 2, PBS 2009.8. (same as above)9. (same as above)10. Westmore, D. Z., and C. C. Gamer. "Emerging Pharmacotherapies for Neurodevelopmental Disorders." PubMed. 31 Sept. 2010. Web. 13 Apr. 2011. http:// www.ncbi.nlm.nih.gov/pubmed/2081425611. Merlin, LR. Persistent Changes in Network Excitability Induced by Group I Metabotropic Glutamate Receptor Activation: Impact on Seizure Expression and Implications of Epileptogenic. SUNY Downstate Medical Center, Brooklyn, NY, USA (accessed through SUNY downstate website).12. Bear, Mark F., Kimberly M. Huber, and Stephen T. Warner. "The MGluR Theory of Fragile X Mental Retardation." NIH. 24 July 2004. Web. 13 Apr. 2011. http:// www.ncbi.nlm.nih.gov/pubmed/1521973513. (same as 12)
  • References Cont’d14. a. Cambridge University Press 978-0-521-70463-2 - Pharmacology for Anesthesia andIntensive Care, Third Edition , Tom Peck, Sue Hill and Mark Williams (Excerpt). Specificallypgs 1-10, Cambridge, United Kingdom, Cambridge University Press, 2008b. “Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and CentralNervous System Drug Discovery”, Mohammad S. Alavijeh, Mansoor Chishty, M. ZeeshanQaiser, and Alan M. Palmer, Neurotherapeutics: The Journal of the American Society forExperimental, 2005 October; 2(4): 554–571.c. McKim, William A. Drugs and Behavior: an Introduction to Behavioral Pharmacology.6th ed. Upper Saddle River, NJ: Pearson Education, 2007. Print.15. Differences in absorption, distribution, metabolism and excretion of xenobioticsbetween the pediatric and adult populations. Detail Only Available(eng; includesabstract) By Strolin Benedetti M, Whomsley R, Baltes EL, Expert Opinion On DrugMetabolism & Toxicology [Expert Opin Drug Metab Toxicol], ISSN: 1742-5255, 2005 Oct;Vol. 1 (3), pp. 447-71; PMID: 16863455Blood-brain Barrier Drug Targeting: The Future Of Brain Drug Development, William M.Pardridge, Molecular interventions, March 2003 vol. 3, no. 2 , 90-105.16-17 (same as above)
  • Other References1. Autism-Pub Med: http://www.ncbi.nih.gov?pubmedhealth/pmh0002494/2. Autism- Mayo Clinic: http://mayoclinic.com/health/autism/ds00348/DSection=symptims3. For Figure 1: http:// www.cnsspectrums.com/aspx/article_pf.aspx?articleid=10894. For Figure 2: http:// www.cnsspectrums.com/userdocs/articleimages/70/Stahl_BigFig_4.jpg5. For information on abilify:6. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000221/ Disclaimer: These were additional websites we looked at to get better knowledge or images