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Novel Neuroprotective Compunds for Use in Parkinson's Disease
Novel neuroprotective compounds for use in Parkinson’s disease A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Ahmed Shubbar December, 2013 Thesis written by Ahmed Shubbar B.S., University of Kufa, 2009 M.S., Kent State University, 2013 Approved by ______________________Werner Geldenhuys ____, Chair, Master’s Thesis Committee __________________________,Altaf Darvesh Member, Master’s Thesis Committee __________________________,Richard Carroll Member, Master’s Thesis Committee ___Eric_______________________ Mintz , Director, School of Biomedical Sciences ___Janis_______________________ Crowther , Dean, College of Arts and Sciences ii Table of Contents List of figures…………………………………………………………………………………..v List of tables……………………………………………………………………………………vi Acknowledgments.…………………………………………………………………………….vii Chapter 1: Introduction ..................................................................................... 1 1.1 Parkinson’s disease .............................................................................................. 1 1.2 Monoamine Oxidases ........................................................................................... 3 1.3 Monoamine Oxidase-B structure ........................................................................... 8 1.4 Structural differences between MAO-B and MAO-A .............................................13 1.5 Mechanism of oxidative deamination catalyzed by Monoamine Oxidases ............15 1 .6 Neuroprotective effects -
(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. -
PSP: Some Answers
PSP: Some Answers Lawrence I. Golbe, MD Professor of Neurology, Rutgers Robert Wood Johnson Medical School Director of Clinical Affairs and Scientific Advisory Board Chairman, CurePSP October 2017 What is Progressive Supranuclear Palsy (PSP)? Of the approximately five to seven of every 100,000 people in Canada with progressive supranuclear palsy (PSP), few, if any, had ever heard of the disease before their diagnosis. In fact, most patients with PSP report that their family doctors knew nothing about it until a neurologist made the diagnosis. As of now, three of every four people with a diagnosis of PSP could have been diagnosed earlier, if their doctor had suspected it and performed the appropriate examination. However, it is appearing in medical journals more and more often, which will help doctors become familiar with PSP. This pamphlet should help patients and their families do the same. Why has no one heard of PSP? PSP is rare: no one even realized it existed until 1963, when several patients were first described at a national neurology research convention and the disease was given its name. In retrospect, at least 12 cases of PSP had appeared in the medical literature between 1909 and 1962, but because of its resemblance to Parkinson’s, it wasn’t recognized as a distinct disease. The brain under the microscope is almost identical to that of “post-encephalitic parkinsonism,” a common condition in the early 20th century but now nearly extinct, which also made for erroneous diagnoses during that era. Although PSP is slightly more common than the well-known amyotrophic lateral sclerosis (called ALS, or Lou Gehrig’s disease in the U.S. -
Carbidopa and Levodopa | Memorial Sloan Kettering Cancer Center
PATIENT & CAREGIVER EDUCATION Carbidopa and Levodopa This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider. Brand Names: US Duopa; Rytary; Sinemet; Sinemet CR [DSC] Brand Names: Canada AA-Levocarb CR; APO-Levocarb; APO-Levocarb 100/25; APO-Levocarb 250/25; DOM-Levo-Carbidopa; Duodopa; MINT-Levocarb; PMS-Levocarb CR; Pro-Lecarb; PRO-Levocarb-100/25 [DSC]; Sinemet 100/25; Sinemet 250/25; Sinemet CR 200/50 [DSC]; Sinemet CR [DSC]; TEVA-Levocarbidopa What is this drug used for? It is used to treat Parkinson’s disease. It is used to treat signs like Parkinson’s disease caused by other health problems. It may be given to you for other reasons. Talk with the doctor. What do I need to tell my doctor BEFORE I take this drug? If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had. If you have any of these health problems: Glaucoma, a skin lump or growth, or a history of skin cancer. Carbidopa and Levodopa 1/10 If you are taking any of these drugs: Reserpine or tetrabenazine. If you are taking any of these drugs: Linezolid or methylene blue. If you have taken certain drugs for depression or Parkinson’s disease in the last 14 days. This includes isocarboxazid, phenelzine, tranylcypromine, selegiline, or rasagiline. Very high blood pressure may happen. -
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. -
Compositions for Continuous Administration of Dopa
(19) TZZ ¥ _T (11) EP 2 432 454 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/08 (2006.01) A61K 9/10 (2006.01) 01.03.2017 Bulletin 2017/09 A61K 31/198 (2006.01) A61P 25/16 (2006.01) (21) Application number: 10725880.8 (86) International application number: PCT/IL2010/000400 (22) Date of filing: 17.05.2010 (87) International publication number: WO 2010/134074 (25.11.2010 Gazette 2010/47) (54) COMPOSITIONS FOR CONTINUOUS ADMINISTRATION OF DOPA DECARBOXYLASE INHIBITORS ZUSAMMENSETZUNGEN FÜR DIE KONTINUIERLICHE VERABREICHUNG VON DOPA-DECARBOXYLASEHEMMERN COMPOSITIONS POUR ADMINISTRATION CONTINUE D’UN INHIBITEUR DE LA DOPA-DÉCARBOXYLASE (84) Designated Contracting States: (74) Representative: ABG Patentes, S.L. et al AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Avenida de Burgos, 16D GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Edificio Euromor PL PT RO SE SI SK SM TR 28036 Madrid (ES) (30) Priority: 19.05.2009 US 179511 P (56) References cited: WO-A1-2006/006929 US-A- 4 409 233 (43) Date of publication of application: 28.03.2012 Bulletin 2012/13 • NYHOLM D: "Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations (73) Proprietor: Neuroderm Ltd and dyskinesias in advanced Parkinson’s 74036 Ness Ziona (IL) disease" EXPERT REVIEW OF NEUROTHERAPEUTICS, FUTURE DRUGS, (72) Inventors: LONDON, GB LNKD- • YACOBY-ZEEVI, Oron DOI:10.1586/14737175.6.10.1403, vol. 6, no. 10, 1 60946 Bitsaron (IL) January 2006 (2006-01-01), pages 1403-1411, •NEMAS,Mara XP008082627 ISSN: 1473-7175 70700 Gedera (IL) Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. -
Oral Systemic Therapy Pharmacy Toolkit
Oral Systemic Therapy Pharmacy Toolkit PROCARBAZINE INSTRUCTIONS FOR THE PHARMACIST Prescription • All orders should be written on a pre-printed order; if not, compare prescription to standard regimens in the Systemic Therapy Manual to confirm the dosing and instructions o The order must be signed by BOTH the prescriber (at the bottom) AND at least one other oncology health professional (nurse or hospital pharmacist) who has verified the order o Measure the patient’s height (cm) and weight (Kg), then recalculate body surface area (BSA) • The prescription may not be refilled (unless specifically ordered by the oncologist) and it may not be filled as a continuing care prescription o If the prescriber has written for refills, do not dispense until the oncology team authorizes the refill; Blood work must be checked for each cycle. • Always check for drug-drug interactions, especially before the first cycle, as described below. Consult the Drug Interactions section (page 4), and consider an online drug interactions checking program. • Check with patient for any other medications filled at a different pharmacy Handling and Dispensing • When handling this drug, disposable gloves should be worn at all times by any woman of child-bearing potential. Counting trays and other equipment directly exposed to the drug should be cleaned with a sodium hypochlorite (bleach) solution (or soap and water), followed by rinsing with copious amounts of water (wear gloves). Do not open capsules in an open air environment and risk inhalation of powder. • ALWAYS affix the auxiliary label to identify this medication as “Cancer Chemotherapy”- this is an important warning label for other health professionals caring for the patient. -
Parkinson's Disease Fact Sheet
Parkinson’s Disease Fact Sheet About Parkinson’s Disease Parkinson’s disease is a progressive, incurable neurological disorder associated with a loss of dopamine-generating cells in the brain. It is primarily associated with progressive loss of motor control, but it results in a complex array of symptoms, including many non-motor symptoms. Parkinson’s impacts an estimated one million people in the United States. Critical Clinical Care Considerations • To avoid serious side effects, Parkinson’s patients need their medications on time, every time — do not skip or postpone doses. • Write down the exact times of day medications are to be administered so that doses are given on the same schedule the patient follows at home. • Do not substitute Parkinson’s medications or stop levodopa therapy abruptly. • Resume medications immediately following procedures, unless vomiting or severely incapacitated. • If an antipsychotic is necessary, use pimavanserin (Nuplazid), quetiapine (Seroquel) or clozapine (Clozaril). • Be alert for symptoms of dysphagia (trouble swallowing) and risk of pneumonia. • Ambulate as soon as medically safe. Patients may require assistance. Common Symptoms of Parkinson’s Disease Motor Non-Motor • Shaking or tremor at rest • Depression • Bradykinesia or freezing (being stuck • Anxiety in place when attempting to walk) • Constipation • Low voice volume or muffled speech • Cognitive decline and dementia • Lack of facial expression • Impulse control disorders • Stiffness or rigidity of the arms, legs • Orthostatic hypotension or -
S41467-019-09610-2.Pdf
Corrected: Author correction ARTICLE https://doi.org/10.1038/s41467-019-09610-2 OPEN Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids Christopher J. Vavricka1, Takanobu Yoshida1, Yuki Kuriya1, Shunsuke Takahashi 1, Teppei Ogawa2, Fumie Ono3, Kazuko Agari1, Hiromasa Kiyota4, Jianyong Li5, Jun Ishii 1, Kenji Tsuge1, Hiromichi Minami6, Michihiro Araki1,3, Tomohisa Hasunuma1,7 & Akihiko Kondo 1,7,8 1234567890():,; Previous studies have utilized monoamine oxidase (MAO) and L-3,4-dihydroxyphenylalanine decarboxylase (DDC) for microbe-based production of tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) precursor to opioid analgesics. In the current study, a phylogenetically distinct Bombyx mori 3,4-dihydroxyphenylacetaldehyde synthase (DHPAAS) is identified to bypass MAO and DDC for direct production of 3,4-dihydrox- yphenylacetaldehyde (DHPAA) from L-3,4-dihydroxyphenylalanine (L-DOPA). Structure- based enzyme engineering of DHPAAS results in bifunctional switching between aldehyde synthase and decarboxylase activities. Output of dopamine and DHPAA products is fine- tuned by engineered DHPAAS variants with Phe79Tyr, Tyr80Phe and Asn192His catalytic substitutions. Balance of dopamine and DHPAA products enables improved THP biosynthesis via a symmetrical pathway in Escherichia coli. Rationally engineered insect DHPAAS produces (R,S)-THP in a single enzyme system directly from L-DOPA both in vitro and in vivo, at higher yields than that of the wild-type enzyme. However, DHPAAS-mediated downstream BIA production requires further improvement. 1 Graduate School of Science, Technology and Innovation, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan. 2 Mitsui Knowledge Industry Co., Ltd. (MKI), 2-3-33 Nakanoshima, Kita-ku, Osaka 530-0005, Japan. -
Parkinson's and Diet
MICHAELJFOX.ORG Parkinson’s and Diet: Overview No one specific diet is recommended for with aging and Parkinson’s disease. A diet everyone with Parkinson’s disease (PD). Still, high in antioxidants may therefore help to what you eat may impact how well your offset oxidative stress, although proof is medication works and can help some of the lacking at this time. non-motor symptoms that are associated with PD. For general health and well-being, doctors encourage people with Parkinson’s SHOPPING LIST FOR FOODS to follow a balanced diet, which includes whole grains, healthy fats (in foods like nuts, CONTAINING ANTIOXIDANTS avocado and olive oil) and antioxidants. Vegetables: artichokes, okra, kale, bell peppers, potatoes Antioxidants are molecules that clear out Fruits: berries, pears, apples, grapes free radicals — substances that are potentially toxic to cells. Free radicals are Legumes: kidney beans, edamame, lentils formed in the body from normal metabolism, Nuts: pecans, walnuts, hazelnuts but are increased by exposure to environmental Dark chocolate toxins, such as cigarette smoke and air Red wine (in moderation), coffee, tea pollution. Free radicals contribute to a condition called oxidative stress, which is associated The Michael J. Fox Foundation for Parkinson's Research | A Practical Guide on Parkinson’s Disease and Diet 2 Diet and Parkinson’s Medications Parkinson’s and Constipation If you take certain Parkinson’s medications, dietary adjust- Constipation is, unfortunately, common among people with ments may help the drugs work more effectively or avoid side Parkinson’s disease. Not only is this non-motor symptom effects. uncomfortable, it can interfere with medication absorption Carbidopa/levodopa — contained in Sinemet, Sinemet CR, and effectiveness. -
Opicapone for the Management of End-Of-Dose Motor Fluctuations in Patients with Parkinson’S Disease Treated with L-DOPA
Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson’s disease treated with L-DOPA Andrew J. Lees MD1, Joaquim Ferreira MD2, Olivier Rascol MD3, Heinz Reichmann MD,4 Fabrizio Stocchi MD,5 Eduardo Tolosa MD,6 Werner Poewe MD7 1. University College London, Reta Lila Weston Institute, London, UK 2. Hospital de Santa Maria, Centro de Estudos Egas Moniz, Lisbon, Portugal 3. Departments of Clinical Pharmacology and Neurosciences, Clinical Investigation Center CIC 1436, NS-Park/FCRIN network and NeuroToul COEN Center, INSERM, Toulouse University Hospital and Toulouse3 University, Toulouse, France 4. Department of Neurology, Technische Universitaet Dresden, Dresden, Germany 5. Institute of Neurology, IRCCS San Raffaele Pisana, Rome, Italy 6. Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS, Universitat de Barcelona, Spain. 7. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Corresponding author Professor Andrew Lees University College London, Reta Lila Weston Institute, 1 Wakefield Street London WC1N 1PJ London, UK Email: [email protected] Direct telephone: + 44 20 7xxxxxxx Fax: +44 20 7xxxxxxx 1 Joaquim Ferreira [email protected] Olivier Rascol [email protected] Eduardo Tolosa [email protected] Fabrizio Stocchi [email protected] Heinz Reichmann [email protected] Werner Poewe [email protected] 2 Summary Introduction: Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L- DOPA therapy. Areas covered: In this review, we describe the preclinical and clinical development of opicapone. -
ZELAPAR™ (Selegiline Hydrochloride) Orally Disintegrating Tablets
ZELAPAR™ (selegiline hydrochloride) orally disintegrating tablets DESCRIPTION ZELAPARTM Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenthylamine. Selegiline hydrochloride is described chemically as: (-)-(R)-N, α-dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is: Its empirical formula is C13H17N·HCl, representing a molecular weight of 223.75. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water, chloroform, and methanol. ZELAPARTM Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, citric acid, yellow iron oxide, and grapefruit flavor. CLINICAL PHARMACOLOGY The mechanisms accounting for selegiline’s beneficial adjunctive action in the treatment of Parkinson’s disease are not fully understood. Inhibition of monoamine oxidase type B (MAO-B) activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity. Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a suicide substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme’s essential flavin adenine dinucleotide (FAD) cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose.