DOCSLIB.ORG

Basic Concepts in Medicinal Chemistry, 2Nd Edition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

APP ANSWERS TO CHAPTER QUESTIONS CHAPTER 2 STRUCTURE ANALYSIS CHECKPOINT Checkpoint Drug 1: Venetoclax 1. Answers provided in table below. Functional Group Name Contribution to Water and/or Lipid Solubility A Halogen (chlorine atom) Lipid Solubility B Alicyclic ring, alkyl ring, cycloalkane Lipid Solubility C Tertiary amine (piperazine) Water Solubility D Heterocyclic ring system (pyrrolopyridine) Hydrocarbons: Lipid Solubility Nitrogen atoms: Water Solubility E Aromatic ring; phenyl ring; aromatic hydrocarbon Lipid Solubility F Sulfonamide Water Solubility G Secondary aromatic amine/aniline Water Solubility H Ether Hydrocarbons: Lipid Solubility Oxygen atom: Water Solubility 2. The sulfonamide and tertiary amine will be primarily ionized in most physiological environments and can participate in ion-dipole interactions (as the ion) with water. In the event that they are unionized, they could participate in hydrogen bonding interactions with water. The nitrogen atoms of the heterocyclic ring system, as well as the secondary aromatic amine, and the oxygen atom of the ether will not be appreciably ionized, but can participate in hydrogen bonding interactions with water. Thus, all of these functional groups contribute to the water solubility of venetoclax. The halogen as well as the hydrocarbon chains and rings are not able to ionize or form hydrogen bonds with water and thus contribute to the lipid solubility of venetoclax. 477 Unauthenticated | Downloaded 09/29/21 10:36 AM UTC 478 BASIC CONCEPTS IN MEDICINAL CHEMISTRY 3. Answers provided in table below. Electron Donating or Withdrawing Resonance or Induction A Electron Withdrawing Induction B Both Donates electrons into the aromatic ring through resonance. Withdraws electrons from adjacent methylene groups through induction. C Electron Donating Resonance D Electron Withdrawing Induction (from aromatic ring) Resonance (from ionized sulfonamide) E Electron Withdrawing Resonance Checkpoint Drug 2: Elamipretide 1. Answers provided in the grid below. Character: Function: Name of Functional Group Hydrophobic, Hydrophilic, or both Contribute to Solubility or Absorption A Guanidine Hydrophobic (R) Absorption (R) Hydrophilic (H2NCNHNH) Solubility (H2NCNHNH) B Primary amine Hydrophobic (R) Absorption (R) Hydrophilic (NH2) Solubility (NH2) C Amide Hydrophobic (R) Absorption (R) Hydrophilic (C=ONH2) Solubility (C=ONH2) D Aromatic hydrocarbon; Hydrophobic (R) Absorption (R) aromatic ring; phenyl ring E Phenol Hydrophobic (R) Absorption (R) Hydrophilic (OH) Solubility (OH) R = carbon scaffolding 2. Part A: Every amino acid has an amine (basic), a unique side chain, and a carboxylic acid (acidic). As building blocks of proteins, the amine and carboxylic acid of adjacent amino acids are linked to form an amide or peptide linkage (neutral). Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and carboxylic acid of adjacent amino acids are linked to form a peptide bond (amide = neutral). The easiest way to read these kinds of molecules is to look for the pattern “amine-side chain-carbonyl” (representing one amino acid) and to completely ignore the fact that the amine and adjacent carboxylic acid are really an amide. In the diagram below, the “amine-side chain-carbonyl” pattern for the first two amino acids/amino acid derivatives is shown. Unauthenticated | Downloaded 09/29/21 10:36 AM UTC 32 New Structures: Pages 3, 4, 10, 12, 14, 21, 22 (2 instances), 45, 46, 47, 48 (2 instances), 75, 77, 78 (2 instances), 79, 82, 84, 85, 86 (2 instances), 87, 93 (2 instances), 94, 95, 96 (all structures of this page), 97, 107 (2 instances) 6 Revised Structures: Pages 6, 15, 51, 52, 58, 59 1 New/Replacement Structure: Page 91 Every structure in Chapter 10 (Pages 108-151) is new. Answers to Chapter Questions CHAPTER 2 Checkpoint Drug 2: Elamipretide APPENDIX: ANSWERS TO CHAPTER QUESTIONS 479 Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and H2N NH NH2 N H carbonyl side chain amine O O H H N N H N N NH 2 H 2 side chainO amine O carbonyl H3C CH3 OH Using this pattern, the first amino acid in the sequence is the amino acid arginine, the second amino acid is a derivative of tyrosine, the third amino acid is lysine, and the fourth amino acid is phenylalanine. Pa rt CPart: The C: portions The portions of the of moleculethe molecule that that represent represent arginine, arginine, lysine, lysine, and and phenylalanine have phenylalanine have been boxed. arginine lysine phenylalanine Part D: The second amino acid is a derivative of tyrosine. REVIEW QUESTIONS 3. Part A: Functional groups are identified in the structure shown below. amidine thioether guanidine H UnauthenticatedN | Downloaded 09/29/21 10:36 AM UTC NH2 N S H N H N N 2 S SO2NH2 aromatic heterocycle (1.3 thiazole) 480 BASIC CONCEPTS IN MEDICINAL CHEMISTRY 3. Answers provided in the grid below. Amino Acid Side Chain Amino Acid Side Evaluation: Amino Acid Side Chain Chain Evaluation: Name of Amino Acid or Hydrophobic, Hydrophilic, Evaluation: Nucleophilic, Amino Acid Derivative or Both Acidic, Basic, Neutral Electrophilic, NA 1 Arginine Hydrophilic (NHC=NHNH2) Basic NA Hydrophobic (R) 2 Tyrosine derivative Hydrophilic (OH) Acidic Nucleophilic Hydrophobic (R) 3 Lysine Hydrophilic (NH2) Basic Nucleophilic Hydrophobic (R) 4 Phenylalanine Hydrophobic Neutral NA R = carbon scaffolding. REVIEW QUESTIONS 1. Answers provided in the grid below. Box Functional Group Name A Guanidine B Secondary amine C Cycloalkane (cyclopropane) D Carboxylic acid E Amide F Sulfonamide G Aromatic hydrocarbon (or aromatic ring) 2. Answers provided in the grid below. Box Functional Group Name A Ketone B Cycloalkene (cyclohexadiene) C Secondary alcohol D Aliphatic halogen E Ester F Cycloalkane Unauthenticated | Downloaded 09/29/21 10:36 AM UTC Part C: The portions of the molecule that represent arginine, lysine, and phenylalanine have arginine lysine phenylalanine REVIEW QUESTIONS APPENDIX: ANSWERS TO CHAPTER QUESTIONS 481 3. Part A: Functional groups are identified in the structure shown below. 3. Part A: Functional groups are identified in the structure shown below. amidine thioether guanidine H N NH2 N S H N H N N 2 S SO2NH2 aromatic heterocycle (1.3 thiazole) Part B: The aromatic heterocycle (1,3 thiazole) and the sulfonamide are both electron withdrawing groups and will significantly decrease the magnitude of the pK values for both the guanidine and amidine. The experimentally measured pK a a values for the guanidine and the amidine are in the range of 6.7–6.9. Part C: The amidine is not protonated at physiological pH because the sulfonamide is an electron withdrawing group and will pull (or withdraw) electrons from the amidine through induction. This will decrease the ability of the amidine to attract protons (H+); therefore, its basicity will decrease. The experimentally measured pKa values for famotidine are all in the range of 6.7 and 6.9. The amidine, guanidine, and aromatic heterocycle are all basic in character. At pH = 7.4, the pH > pKa for these functional groups and, therefore, the basic functional groups are predominantly unionized in this pH environment. 4. Part A: Answers provided in the grid below. Contribution to Water Name of Three Oxygen Hydrophilic Solubility Containing Functional and/or and/or Hydrogen Bond Acceptor, Groups Hydrophobic Lipid Solubility Donor, Both, or Neither Primary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) and donor Secondary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) and donor Ether Hydrophilic (O) Water solubility (O) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) R = carbon scaffolding. Part B: The primary and secondary alcohols, as well as the ethers, all have hydrophilic character. The alcohols (primary and secondary) are able to interact with water as both hydrogen bond acceptor and donors, which means that they make a sizable contribution to the water solubility of lactulose. The ethers are able to interact with water as a hydrogen bond acceptor only and, therefore, make somewhat less of a contribution to water solubility as compared to the alcohols. Unauthenticated | Downloaded 09/29/21 10:36 AM UTC &'UXJZDWHULQWHUDFWLRQVGLSROHGLSROHLQWHUDFWLRQ 1RWH:KHQDSSURSULDWHEHVXUHWRGUDZLQWKHFRUUHFWDUURZDQGSDUWLDOFKDUJHV + 2 2 482 BASIC CONCEPTS IN MEDICINAL CHEMISTRY + 2 + 2 2+ 2 Part C: The primary and secondary alcohols,+ 2 as2 well as the ethers all have hydrophilic character. The alcohols (primary 2+and secondary) are able to interact with water as both hydrogen bond acceptors and donors, which means that they will be able to attract and interact with water. The2+ ethers are able to interact with water as a hydrogen bond acceptor only and, therefore,2+ make somewhat less of a contribution to the drug’s ability to attract and interact with water. /DFWXORVH One mechanism to relieve constipation is to (Q increaseXORVH the water content of the stool so as to make it easier to eliminate. Lactulose achieves this by attracting and interacting with water with its seven OH groups and two ethers. $QVZHU Part D: Answer provided in figure below. :DWHU +\GURJHQERQG GRQRU 'UXJ +\GURJHQERQG DFFHSWRU δ+ δ− :DWHU +\GURJHQERQG DFFHSWRU 'LSROHGLSROH − δ 'UXJ +\GURJHQERQG δ+ GRQRU 5. Part A: Answers provided in the grid below. Contribution to Water Solubility and/or Name of Functional Group Hydrophilic and/or Hydrophobic Lipid Solubility Aromatic
Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas Et Al

    US 20130253 056A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas et al. (43) Pub. Date: Sep. 26, 2013 (54) CONTINUOUS ADMINISTRATION OF (60) Provisional application No. 61/179,511, filed on May LEVODOPA AND/OR DOPA 19, 2009. DECARBOXYLASE INHIBITORS AND COMPOSITIONS FOR SAME Publication Classification (71) Applicant: NEURODERM, LTD., Ness-Ziona (IL) (51) Int. Cl. A63L/216 (2006.01) (72) Inventors: Mara Nemas, Gedera (IL); Oron (52) U.S. Cl. Yacoby-Zeevi, Moshav Bitsaron (IL) CPC .................................... A6 IK3I/216 (2013.01) USPC .......................................................... 514/538 (73) Assignee: Neuroderm, Ltd., Ness-Ziona (IL) (57) ABSTRACT (21) Appl. No.: 13/796,232 Disclosed herein are for example, liquid aqueous composi (22) Filed: Mar 12, 2013 tions that include for example an ester or salt of levodopa, or an ester or salt of carbidopa, and methods for treating neuro Related U.S. Application Data logical or movement diseases or disorders such as restless leg (63) Continuation-in-part of application No. 12/961,534, syndrome, Parkinson's disease, secondary parkinsonism, filed on Dec. 7, 2010, which is a continuation of appli Huntington's disease, Parkinson's like syndrome, PSP. MSA, cation No. 12/836,130, filed on Jul. 14, 2010, now Pat. ALS, Shy-Drager syndrome, dystonia, and conditions result No. 7,863.336, which is a continuation of application ing from brain injury including carbon monoxide or manga No. 12/781,357, filed on May 17, 2010, now Pat. No. nese intoxication, using Substantially continuous administra 8,193,243. tion of levodopa and/or carbidopa or ester and/or salt thereof.
  • Parkinson Disease-Associated Cognitive Impairment

    Parkinson Disease-Associated Cognitive Impairment

    PRIMER Parkinson disease-associated cognitive impairment Dag Aarsland 1,2 ✉ , Lucia Batzu 3, Glenda M. Halliday 4, Gert J. Geurtsen 5, Clive Ballard 6, K. Ray Chaudhuri 3 and Daniel Weintraub7,8 Abstract | Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment. Parkinson disease (PD) is the most common movement The full spectrum of cognitive impairment occurs in disorder and the second most common neurodegenera­ individuals with PD, from subjective cognitive decline tive disorder after Alzheimer disease (AD).
  • Azilect, INN-Rasagiline

    Azilect, INN-Rasagiline

    SCIENTIFIC DISCUSSION 1. Introduction AZILECT is indicated for the treatment of idiopathic Parkinson’s disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations. Rasagiline is administered orally, at a dose of 1 mg once daily with or without levodopa. Parkinson’s disease is a common neurodegenerative disorder typified by loss of dopaminergic neurones from the basal ganglia, and by a characteristic clinical syndrome with cardinal physical signs of resting tremor, bradikinesia and rigidity. The main treatment aims at alleviating symptoms through a balance of anti-cholinergic and dopaminergic drugs. Parkinson’s disease (PD) treatment is complex due to the progressive nature of the disease, and the array of motor and non-motor features combined with early and late side effects associated with therapeutic interventions. Rasagiline is a chemical inhibitor of the enzyme monoamine oxidase (MAO) type B which has a major role in the inactivation of biogenic and diet-derived amines in the central nervous system. MAO has two isozymes (types A and B) and type B is responsible for metabolising dopamine in the central nervous system; as dopamine deficiency is the main contributing factor to the clinical manifestations of Parkinson’s disease, inhibition of MAO-B should tend to restore dopamine levels towards normal values and this improve the condition. Rasagiline was developed for the symptomatic treatment of Parkinson’s disease both as monotherapy in early disease and as adjunct therapy to levodopa + aminoacids decarboxylase inhibitor (LD + ADI) in patients with motor fluctuations. 2. Quality Introduction Drug Substance • Composition AZILECT contains rasagiline mesylate as the active substance.
  • 3 Drugs That May Cause Delirium Or Problem Behaviors CARD 03 19 12 JUSTIFIED.Pub

    3 Drugs That May Cause Delirium Or Problem Behaviors CARD 03 19 12 JUSTIFIED.Pub

    Drugs that May Cause Delirium or Problem Behaviors Drugs that May Cause Delirium or Problem Behaviors This reference card lists common and especially problemac drugs that may Ancholinergics—all drugs on this side of the card. May impair cognion cause delirium or contribute to problem behaviors in people with demena. and cause psychosis. Drugs available over‐the‐counter marked with * This does not always mean the drugs should not be used, and not all such drugs are listed. If a paent develops delirium or has new problem Tricyclic Andepressants Bladder Anspasmodics behaviors, a careful review of all medicaons is recommended. Amitriptyline – Elavil Darifenacin – Enablex Be especially mindful of new medicaons. Clomipramine – Anafranil Flavoxate – Urispas Desipramine – Norpramin Anconvulsants Psychiatric Oxybutynin – Ditropan Doxepin – Sinequan Solifenacin – VESIcare All can cause delirium, e.g. All psychiatric medicaons should be Imipramine – Tofranil Tolterodine – Detrol Carbamazepine – Tegretol reviewed as possible causes, as Nortriptyline – Aventyl, Pamelor Gabapenn – Neuronn effects are unpredictable. Trospium – Sanctura Anhistamines / Allergy / Leveracetam – Keppra Notable offenders include: Insomnia / Sleep Valproic acid – Depakote Benzodiazepines e.g. Cough & Cold Medicines *Diphenhydramine – Sominex, ‐Alprazolam – Xanax *Azelasne – Astepro Pain Tylenol‐PM, others ‐Clonazepam – Klonopin *Brompheniramine – Bromax, All opiates can cause delirium if dose *Doxylamine – Unisom, Medi‐Sleep ‐Lorazepam – Avan Bromfed, Lodrane is too high or
  • Drug-Induced Movement Disorders

    Drug-Induced Movement Disorders

    Medical Management of Early PD Samer D. Tabbal, M.D. May 2016 Associate Professor of Neurology Director of The Parkinson Disease & Other Movement Disorders Program Mobile: +961 70 65 89 85 email: [email protected] Conflict of Interest Statement No drug company pays me any money Outline So, you diagnosed Parkinson disease .Natural history of the disease .When to start drug therapy? .Which drug to use first for symptomatic treatment? ● Levodopa vs dopamine agonist vs MAOI Natural History of Parkinson Disease Before levodopa: Death within 10 years After levodopa: . “Honeymoon” period (~ 5-7 years) . Motor (ON/OFF) fluctuations & dyskinesias: ● Drug therapy effective initially ● Surgical intervention by 10-15 years - Deep brain stimulation (DBS) therapy Motor Response Dyskinesia 5-7 yrs >10 yrs Dyskinesia ON state ON state OFF state OFF state time time Several days Several hours 1-2 hour Natural History of Parkinson Disease Prominent gait impairment and autonomic symptoms by 20-25 years (Merola 2011) Behavioral changes before or with motor symptoms: . Sleep disorders . Depression . Anxiety . Hallucinations, paranoid delusions Dementia at anytime during the illness . When prominent or early: diffuse Lewy body disease Symptoms of Parkinson Disease Motor Symptoms Sensory Symptoms Mental Symptoms: . Cognitive and psychiatric Autonomic Symptoms Presenting Symptoms of Parkinson Disease Mood disorders: depression and lack of motivation Sleep disorders: “acting out dreams” and nightmares Early motor symptoms: Typically Unilateral . Rest tremor: chin, arms or legs or “inner tremor” . Bradykinesia: focal and generalized slowness . Rigidity: “muscle stiffness or ache” Also: (usually no early postural instability) . Facial masking with hypophonia: “does not smile anymore” or “looks unhappy all the time” .
  • Treatment Options for Motor and Non-Motor Symptoms of Parkinson’S Disease

    Treatment Options for Motor and Non-Motor Symptoms of Parkinson’S Disease

    biomolecules Review Treatment Options for Motor and Non-Motor Symptoms of Parkinson’s Disease Frank C. Church Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] Abstract: Parkinson’s disease (PD) usually presents in older adults and typically has both motor and non-motor dysfunctions. PD is a progressive neurodegenerative disorder resulting from dopamin- ergic neuronal cell loss in the mid-brain substantia nigra pars compacta region. Outlined here is an integrative medicine and health strategy that highlights five treatment options for people with Parkinson’s (PwP): rehabilitate, therapy, restorative, maintenance, and surgery. Rehabilitating begins following the diagnosis and throughout any additional treatment processes, especially vis-à-vis consulting with physical, occupational, and/or speech pathology therapist(s). Therapy uses daily administration of either the dopamine precursor levodopa (with carbidopa) or a dopamine ago- nist, compounds that preserve residual dopamine, and other specific motor/non-motor-related compounds. Restorative uses strenuous aerobic exercise programs that can be neuroprotective. Maintenance uses complementary and alternative medicine substances that potentially support and protect the brain microenvironment. Finally, surgery, including deep brain stimulation, is pursued when PwP fail to respond positively to other treatment options. There is currently no cure for PD. In conclusion, the best strategy for treating PD is to hope to slow disorder progression and strive to achieve stability with neuroprotection. The ultimate goal of any management program is to improve the quality-of-life for a person with Parkinson’s disease.
  • Re-Submission Rasagiline 1Mg Tablet (Azilectò) (No

    Re-Submission Rasagiline 1Mg Tablet (Azilectò) (No

    Scottish Medicines Consortium Re-Submission rasagiline 1mg tablet (AzilectÒ) (No. 255/06) Lundbeck Ltd / Teva Pharmaceuticals Ltd 10 November 2006 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a resubmission rasagiline (AzilectÒ) is not recommended within NHS Scotland for the treatment of idiopathic Parkinson’s disease as adjunct therapy (with levodopa) in patients with end of dose fluctuations. Rasagiline reduces off-time in patients with Parkinson’s disease and end of dose fluctuations on levodopa, similar to reductions shown with the less effective of two currently marketed catechol-O-methyl transferase inhibitors. The economic case has not been demonstrated. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium 1 Indication Treatment of idiopathic Parkinson’s disease as adjunct therapy (with levodopa) in patients with end of dose fluctuations. Dosing information 1mg once daily Product availability date 4th July 2005 Summary of evidence on comparative efficacy Rasagiline is an irreversible inhibitor of the monoamine oxidase-B (MAO-B) enzyme. One effect of this enzyme inhibition is an increase in extracellular dopamine levels in the striatum, with subsequently increased dopaminergic activity. This is thought to be the mechanism of action of rasagiline in Parkinson’s disease (PD). Two double-blind trials recruited 687 and 472 adults, aged >30 years, with idiopathic PD defined by the presence of two cardinal signs (resting tremor, bradykinesia or rigidity) who experienced motor fluctuations for at least 1 hour per day (excluding morning akinesia) in the first study and for at least 2.5 hours per day in the second study, with a Hoehn and Yahr score <5 in the off-state.
  • Guideline for Preoperative Medication Management

    Guideline for Preoperative Medication Management

    Guideline: Preoperative Medication Management Guideline for Preoperative Medication Management Purpose of Guideline: To provide guidance to physicians, advanced practice providers (APPs), pharmacists, and nurses regarding medication management in the preoperative setting. Background: Appropriate perioperative medication management is essential to ensure positive surgical outcomes and prevent medication misadventures.1 Results from a prospective analysis of 1,025 patients admitted to a general surgical unit concluded that patients on at least one medication for a chronic disease are 2.7 times more likely to experience surgical complications compared with those not taking any medications. As the aging population requires more medication use and the availability of various nonprescription medications continues to increase, so does the risk of polypharmacy and the need for perioperative medication guidance.2 There are no well-designed trials to support evidence-based recommendations for perioperative medication management; however, general principles and best practice approaches are available. General considerations for perioperative medication management include a thorough medication history, understanding of the medication pharmacokinetics and potential for withdrawal symptoms, understanding the risks associated with the surgical procedure and the risks of medication discontinuation based on the intended indication. Clinical judgement must be exercised, especially if medication pharmacokinetics are not predictable or there are significant risks associated with inappropriate medication withdrawal (eg, tolerance) or continuation (eg, postsurgical infection).2 Clinical Assessment: Prior to instructing the patient on preoperative medication management, completion of a thorough medication history is recommended – including all information on prescription medications, over-the-counter medications, “as needed” medications, vitamins, supplements, and herbal medications. Allergies should also be verified and documented.
  • Safinamide for Parkinson's Disease

    Safinamide for Parkinson's Disease

    Bedfordshire and Luton Joint Prescribing Committee (JPC) 18 September 2019 Review Date September 2022 Bulletin 277: Safinamide for Parkinson’s Disease JPC Recommendation: A Formulary application for Safinamide for the treatment of Parkinson’s Disease was considered at the September 2019 JPC meeting. Following discussion, the Committee decided not to support the Formulary application for safinamide. The main concerns were the lack of head to head trials with appropriate comparators, safety issues (e.g. retinopathy) and cost/cost-effectiveness. Bedfordshire CCG Luton CCG Page 1 of 15 New Medicine Review Bulletin Safinamide for the treatment of Parkinson’s disease Medicine Safinamide (Xadago®) for the treatment of Parkinson’s disease Document status Final Date of last revision 03/09/2019, minor update 05/11/19 Proposed Sector of Primary and Secondary Care prescribing Introduction Introduction Summary Key The Luton & Dunstable Hospital has requested the addition of safinamide for the points treatment of Parkinson’s disease (in accordance with the marketing authorisation Evidence level for safinamide and NICE Clinical Guideline 71 – Parkinson’s Disease in Adults) to be added the Joint Bedfordshire and Luton Formulary. This review outlines the key evidence of efficacy, safety and cost for safinamide and is mainly based on NICE Evidence Summary – Parkinson’s disease with motor fluctuations: safinamide, published 21 February 2019. Key Points:- The summary of product characteristics (SPC) states that safinamide (Xadago: Profile Pharma) is a highly selective and reversible MAO-B inhibitor. This differs from rasagiline and selegiline which are selective and irreversible MAO-B inhibitors (European Public Assessment Report [EPAR]: Xadago). Several other mechanisms of action of safinamide have been identified by in-vitro data, including sodium channel inhibition and reducing excessive glutamate release.
  • Part I: Synthesis of Functionalized Bile Acids Towards The

    Part I: Synthesis of Functionalized Bile Acids Towards The

    PART I: SYNTHESIS OF FUNCTIONALIZED BILE ACIDS TOWARDS THE CONSTRUCTION OF STEROIDAL MACROCYCLES. PART II: EVALUATION AND EXPANSION OF A MODULAR CARD GAME FOR TEACHING ORGANIC CHEMISTRY A DISSERTATION IN Chemistry and Pharmaceutical Sciences Presented to the Faculty of the University of Missouri-Kansas City in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY by CHRISTOPHER ANTON KNUDTSON B.S., Saint Louis University 2004 M.S., Kansas University 2011 Kansas City, Missouri 2019 © 2019 CHRISTOPHER ANTON KNUDTSON ALL RIGHTS RESERVED PART I: SYNTHESIS OF FUNCTIONALIZED BILE ACIDS TOWARDS THE CONSTRUCTION OF STEROIDAL MACROCYCLES. PART II: EVALUATION AND EXPANSION OF A MODULAR CARD GAME FOR TEACHING ORGANIC CHEMISTRY Christopher A. Knudtson, Candidate for the Doctor of Philosophy Degree University of Missouri-Kansas City, 2019 ABSTRACT In Part I, the synthesis of chenodeoxychoic acid (CDCA) derivatives towards the construction of unique chemical architectures are reported. Building on previously described methods, CDCA based macrocycles with inner cavities have been synthesized and characterized. Attempts toward oxa-Michael coupling of CDCA monomers to form sulfonate ester linked dimmers is described. CDCA was also functionalized with terminal alkynes (pentynyl, hexynyl, and heptynyl) and aryl iodide and cyclized to from the respective macrocycles. These have been coupled together via oxygen-free Sonogashira reaction conditions to form large barrel-like steroidal architectures. These structures were investigated by 1H NMR, 13 C NMR spectroscopy, and HR-MS, and MALDI-TOF spectroscopy. In part II a game to teach organic chemistry, ChemKarta was evaluated as a teaching tool. Analysis of an undergraduate class’s impressions of the game showed that Chemkarta was an easy to learn and enjoyable game, but the amount of information in the game could be overwhelming for some students.
  • Summary Review

    Summary Review

    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022075Orig1s000 SUMMARY REVIEW Summary Review Date 08/27/2019 Gerald Podskalny, DO, MPHS From Eric Bastings, MD Billy Dunn, MD Subject Summary Review NDA/BLA # and Supplement# NDA 22075 Applicant K vowa Kirin, Inc. Date of Submission 07/27/2019 PDUFA Goal Date 08/27/2019 Proprietary Name Nourianz Established or Proper Name Istrndefvlline Dosa2e Form(s) Oral tablets Adjunctive treatment to levodopa/carbidopa in patients Applicant Proposed with Parkinson's disease (PD) experiencing "off ' Indication(s)/Population(s) episodes Applicant Proposed Dosing 20 mg or 40 mg taken orally, once daily Re2imen(s) Recommendation on Regulatory Approval Action Recommended Adjunctive treatment to levodopa/carbidopa in patients Indication(s)/Population(s) (if with Parkinson's disease (PD) experiencing "off ' applicable) episodes Recommended Dosing 20 mg or 40 mg taken orally, once daily Re2imen(s) (if applicable) 1 Reference ID: 4483Q!tS 1. Benefit-Risk Assessment Benefit-Risk Assessment Framework Benefit-Risk Integrated Assessment Kyowa Kirin, Inc., submitted a 505(b)(1) NDA for istradefylline (Nourianz), proposed for adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. PD is a neurodegenerative disorder that is caused by progressive loss of dopaminergic neurons in the basal ganglia. The typical age of onset is around 60 years, with men more frequently affected than women. PD causes progressive motor symptoms, including bradykinesia, rigidity, and resting tremor. Although effective treatments are available, the disease causes progressive disability. As PD advances, patients develop motor fluctuations (e.g., “off” periods and dyskinesia) and non-motor complications.
  • Identification of Novel Monoamine Oxidase B Inhibitors from Ligand Based Virtual Screening

    Identification of Novel Monoamine Oxidase B Inhibitors from Ligand Based Virtual Screening

    Identification of novel monoamine oxidase B inhibitors from ligand based virtual screening A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Mohammed Alaasam August, 2014 Thesis written by Mohammed Alaasam B.S., University of Baghdad, 2007 M.S., Kent State University, 2014 Approved by Werner Geldenhuys , Chair, Master’s Thesis Committee Richard Carroll , Member, Master’s Thesis Committee Prabodh Sadana , Member, Master’s Thesis Committee Eric Mintz , Director, School of Biomedical Sciences James Blank , Dean, College of Arts and Sciences ii Table of Contents List of figure ...................................................................................................................... vi List of tables ..................................................................................................................... xiii Acknowledgments............................................................................................................ xiv Chapter one: Introduction ............................................................................................... 1 1.1.Parkinson's disease ....................................................................................................... 1 1.2.Monoamine oxidase enzymes ....................................................................................... 7 1.3.Structures of MAO enzymes ....................................................................................... 12 1.4.Three dimentiona