DOCSLIB.ORG

PDF Download

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PDF Download CURRENT THERAPEUTIC RESEARCH VOL. 56, NO. 5, MAY 1995 EFFECTS OF CEREBRAL METABOLIC ENHANCERS ON BRAIN FUNCTION IN RODENTS KOICHIRO TAKAHASHI,l MINORU YAMAMOTO,’ MASANORI SUZUKI,’ YUKIKO OZAWA,’ TAKASHI YAMAGUCHI,l HIROFUMI ANDOH, AND KOUICHI ISHIKAWA2 ‘Department of Pharmacology, Clinical Pharmacology Research Laboratory, Yamunouchi Pharmaceutical Co. Ltd., and ‘Department of Pharmacology, School of Medicine, Nihon University, Tokyo, Japan AFWI’RACT The effects of cerebral metabolic enhancers (indeloxazine, bi- femelane, idebenone, and nicergoline) on reserpine-induced hypother- mia, the immobility period in forced swimming tests, and passive avoidance learning behavior were compared with the effects of ami- triptyline in rodents. Indeloxazine, bifemelane, and amitriptyline antagonized hypothermia in mice given reserpine. Indeloxaxine and amitriptyline decreased the immobility period in mice in the forced swimming test in a dose-dependent manner. The latency of step- through in the passive avoidance test in rats was prolonged by ad- ministration of indeloxazine but shortened by administration of amitriptyline. Neither idebenone nor nicergoline displayed any phar- macologic action in these tests. The results suggest that indeloxaxine possesses an antidepressant activity similar to that of amitriptyline but differs from amitriptyline in its anticholinergic properties and its ability to ameliorate impaired brain function such as that of learning behavior. In addition, indeloxazine exhibited broader effects on brain functions than either bifemelane, idebenone, or nicergoline. INTRODUCTION Cerebral metabolic enhancers (drugs that enhance energy metabolism) including brain glucose and ATP levels such as indeloxazine,1*2 bi- femelane, 3*4idebenone?6 and nicergoline,7>8 are currently used for the treatment of patients with various psychiatric symptoms. These symptoms include reduced spontaneity and emotional disturbance in patients with cerebral vascular disease. Clinical trials of these drugs for the treatment of depression in aged populations are now in progress. However, the antide- pressant actions of these drugs have not been compared under the same experimental conditions. The present study compared the effects of indel- oxaxine, bifemelane, idebenone, and nicergoline with those of amitripty- Address correspondence to: M. Yamamoto, Department of Pharmacology, Clinical Pharmacology Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., l-l-8, Azusawa, Itabashi-ku, Tokyo 174, Japan. Received forpublication on February 16,1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 478 oo11-393x196/~3.50 K. TAKAHASH ET AL.. line on reserpine-induced hypothermia, forced swimming, and passive avoidance learning behavior in rodents. Amitriptyline, a typical antide- pressant currently used for the treatment of depressed patients, was cho- sen as the positive control drug to evaluate the antidepressive activity of the other study drugs. MATERIALSANDMETHODS The experiments were carried out using male ICR strain mice (approxi- mately 30 g each) and male Wistar rats (approximately 300 g each). The animals were group-housed in cages under a l&hour light-dark cycle (lights turned on between 7:30 AM and 830 PM) with laboratory chow and water given ad libitum. Test drugs were administered orally to the mice 18 hours after the subcutaneous administration of reserpine (2 mg/kg). Rectal temperature was measured immediately before and at 60, 120, and 180 minutes after drug administration. Drugs Indeloxazine hydrochloride and amitriptyline hydrochloride, synthe- sized at Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan, were dis- solved in distilled water and administered orally. Bifemelane hydrochlo- ride, idebenone, and nicergoline, purchased commercially from Eisai, Tokyo, Japan, Takeda, Tokyo, Japan, and Tanabe Co. Ltd., Tokyo, Japan, respectively, were dissolved in 0.3% methylcellulose and administered orally. Distilled water and 0.3% methylcellulose were administered orally as vehicle control. Physostigmine sulfate (Tokyo Kasei Co. Ltd., Tokyo, Ja- pan), used as a positive control drug, was dissolved in saline solution. All drugs and vehicles were administered in a volume of 0.1 mLkg and 1 mL/kg to mice and rats, respectively. Forced Swimming-Induced Immobility in Mice The apparatus consisted of Plexiglass cylinders (24.5 cm x 6 cm x 18 cm; WW-3002, Ohara Co., Tokyo, Japan) with a waterwheel in the center. The waterwheel consisted of a Plexiglass shaft (5 cm long and 8 cm in diameter) on which 24 paddles (0.1 cm wide and 3.6 cm long) were attached at constant intervals. The waterwheel would move when application of a load greater than 5 g was applied to one of the paddles. The number of rotations of the waterwheel through an arc of 120” was counted via a photointerrupter attached to the shaft during the final 4 minutes of a 6-minute test. The tank contained water at a temperature of about 23 “C to a height of 12 cm; half of the paddles were resting in the water. 479 EFFECT OF INDELOWNE ON BRAIN FUNCTION Tests were conducted according to the method of Nomura et al.’ When a mouse was dropped into the water, it attempted to climb onto the wheel to escape from the water but could not do so due to rotation of the water- wheel. However, when the animal’s attempts to escape were finally aban- doned, the waterwheel would stop turning. The number of wheel rotations before the animal abandoned its attempts to escape were counted. Each mouse was placed in the water tank 1 hour after receiving a single oral (PO) administration of the drug. The number of rotations of the wheel was counted every 2 minutes for 6 minutes. The wheel counts during the final 4 minutes of the g-minute test for each mouse receiving the drug were compared with those of a control group of mice which had received distilled water and were exposed to a comparable situation. Passive Avoidance Learning in Rata Training was conducted according to the step-through procedure de- scribed by Jarvik and Kopp. lo The apparatus (Ohara Co.) consisted of two compartments (with clear plastic tops): an illuminated compartment (40 cm x 25 cm x 25 cm) containing a 60-watt lamp 25 cm above the top of the compartment (50 cm above the floor) and a dark compartment (25 cm x 15 cm x 25 cm). The two compartments were separated by a closed guillotine door (10 cm x 7 cm). Before training of passive avoidance learning, each rat underwent a single pretraining trial using the following procedure. The rat was placed in the illuminated compartment and the opaque guillotine door was raised 10 seconds later. After the rat entered the dark compartment, it was al- lowed to remain there for 10 seconds. In order to conduct the training, the rat was placed in the illuminated safe compartment. A door allowed the rat to enter the dark compartment, which contained a grid on the floor. Once the rat’s four paws were on the grid, a foot shock (60 V, 50 Hz) was deliv- ered to the floor grid for 2 seconds. The rat could escape the shock only by stepping back into the illuminated compartment. The rat was then re- turned to its home cage. The test trial was conducted 24 hours after the training session. The rat was again placed in the illuminated compartment of the same appa- ratus used in training, and the response latency before entering into the dark compartment was measured. The results were recorded as the aver- age step-through latency for each experimental group of animals. The rats were given a single po drug dose 60 minutes before the training session, in accordance with the methods of Yamamoto and Shimizu.” The step- through latency was measured both during the acquisition trial and the test trial (24 hours after the acquisition trial). The maximum observation period for monitoring behavior in this test was set at 10 minutes. 480 K. T- ET Al.. Values are expressed as the mean + SE. Results for reserpine- hypothermia, forced swimming-induced immobility, and passive avoid- ance learning behavior were analyzed using Student’s t test and Mann- Whitney U test, respectively. P < 0.05and P < 0.01 were considered significant. RESULTS Reaerpine-Induced Hypothermia in Mice Oral administration of indeloxaxine (1 and 3 mgkg), bifemelane (30 mg/kg po), and amitriptyline (1 and 3 mg/kg) antagonized the reserpine- induced hypothermia in a dose-dependent manner (Table I). In contrast, oral administration of idebenone (10 and 30 mg/kg) and nicergoline (1 to 10 mg/kg) exerted no effect on the reserpine-induced hypothermia. Forced Swimming-Induced Immobility in Mice Both indeloxaxine (50 mg/kg po) and amitriptyline (30 mg/kg po) in- creased the number of rotations by mice in a dose-dependent manner (Ta- Table I. Effects of indeloxazine, bifemelane, idebenone, nicergoline, and amitriptyline on reserpine-induced hypothermia in mice. Each value representa the mean for 6 to 7 mice. Temperature Change (2). Dose Tnatment (mo/lro 0W) 1 hour 2 hours 3houn Control f 0.7 f 0.4 ” 0.7 Control E : x.: 4.5 ” 0.6 Bifemelane 4:3 r 0:3 ;.; I ;.;$ 2:2 : 0’6 1.1 + 0:3 Control Nicergoline ?A I E 2:3 I 013 I!! i:3 f 0.4 1.6 2 0.6 Control 2.9 f 0.5 3.3 !?0.6 Amitriptyline ?: r :.;t 4.4 k 0.6 z.45 ;.;$ 3:9 z 0:7* 5.9 * 0.6$ . +f . * The difference in rectal temperature measured at l-hour intervals after treatment. The rectal temperature immediately before administration of the test drugs ran ed from 28.0 to 28.5 “C. Si nificantly different from the control group: tf < 0.0‘5 , SP c 0.01 (Student’s t test). Ni! = not done. 481 EFFECT OF INDELOXAZINB ON BRAIN FUNCTION ble II). However, bifemelane (10 to 100 mg/kg PO), idebenone (10 to 100 mg/kg PO), and nicergoline (1 to 30 mg/kg po) had little effect on this variable.
Load more

Recommended publications
  • Table S1: Sensitivity, Specificity, PPV, NPV, and F1 Score of NLP Vs. ICD for Identification of Symptoms for (A) Biome Developm
    Table S1: Sensitivity, specificity, PPV, NPV, and F1 score of NLP vs. ICD for identification of symptoms for (A) BioMe development cohort; (B) BioMe validation cohort; (C) MIMIC-III; (D) 1 year of notes from patients in BioMe calculated using manual chart review. A) Fatigue Nausea and/or vomiting Anxiety Depression NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.99 (0.93- 0.59 (0.43- <0.00 0.25 (0.12- <0.00 <0.00 0.54 (0.33- Sensitivity 0.99 (0.9 – 1) 0.98 (0.88 -1) 0.3 (0.15-0.5) 0.85 (0.65-96) 0.02 1) 0.73) 1 0.42) 1 1 0.73) 0.57 (0.29- 0.9 (0.68- Specificity 0.89 (0.4-1) 0.75 (0.19-1) 0.68 0.97 (0.77-1) 0.03 0.98 (0.83-1) 0.22 0.81 (0.53-0.9) 0.96 (0.79-1) 0.06 0.82) 0.99) 0.99 (0.92- 0.86 (0.71- 0.94 (0.79- 0.79 (0.59- PPV 0.96 (0.82-1) 0.3 0.95 (0.66-1) 0.02 0.95 (0.66-1) 0.16 0.93 (0.68-1) 0.12 1) 0.95) 0.99) 0.92) 0.13 (0.03- <0.00 0.49 (0.33- <0.00 0.66 (0.48- NPV 0.89 (0.4-1) 0.007 0.94 (0.63-1) 0.34 (0.2-0.51) 0.97 (0.81-1) 0.86 (0.6-0.95) 0.04 0.35) 1 0.65) 1 0.81) <0.00 <0.00 <0.00 F1 Score 0.99 0.83 0.88 0.57 0.95 0.63 0.82 0.79 0.002 1 1 1 Itching Cramp Pain NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.98 (0.86- 0.24 (0.09- <0.00 0.09 (0.01- <0.00 0.52 (0.37- <0.00 Sensitivity 0.98 (0.85-1) 0.99 (0.93-1) 1) 0.45) 1 0.29) 1 0.66) 1 0.89 (0.72- 0.5 (0.37- Specificity 0.96 (0.8-1) 0.98 (0.86-1) 0.68 0.98 (0.88-1) 0.18 0.5 (0-1) 1 0.98) 0.66) 0.88 (0.69- PPV 0.96 (0.8-1) 0.8 (0.54-1) 0.32 0.8 (0.16-1) 0.22 0.99 (0.93-1) 0.98 (0.87-1) NA* 0.97) 0.98 (0.85- 0.57 (0.41- <0.00 0.58 (0.43- <0.00 NPV 0.98 (0.86-1) 0.5 (0-1) 0.02 (0-0.08) NA* 1) 0.72) 1 0.72) 1 <0.00 <0.00 <0.00 F1 Score 0.97 0.56 0.91 0.28 0.99 0.68 1 1 1 *Denotes 95% confidence intervals and P values that could not be calculated due to insufficient cells in 2x2 tables.
    [Show full text]
  • Inline-Supplementary-Material-1.Pdf
    Appendix 1: STOPP/START criteria version 2 applied to the TRUST dataset Physiological system Criteria Criteria included Number (%) (The relevant () criteria for each participant were applied to the dataset and recorded in of Microsoft Office Excel ® (2013)) criteria included out of total criteria STOPP criteria Indication of medication A1. Any drug prescribed without an evidence-based clinical indication. X 1/3 (33.3) A2. Any drug prescribed beyond the recommended duration, where treatment duration is X well defined. A3. Any duplicate drug class prescription e.g. two concurrent NSAIDs, SSRIs, loop diuretics, ACE inhibitors, anticoagulants (optimisation of monotherapy within a single drug class should be observed prior to considering a new agent). Cardiovascular system B1. Digoxin for heart failure with preserved systolic ventricular function (no clear evidence X 7/13 (53.8) of benefit). B2. Verapamil or diltiazem with NYHA Class III or IV heart failure (may worsen heart failure). B3. Beta-blocker in combination with verapamil or diltiazem (risk of heart block). B4. Beta blocker with symptomatic bradycardia (< 50/min), type II heart block or complete heart block (risk of profound hypotension, asystole). B5. Amiodarone as first-line antiarrhythmic therapy in supraventricular tachyarrhythmias X (higher risk of side-effects than beta-blockers, digoxin, verapamil or diltiazem). B6. Loop diuretic as first-line treatment for hypertension (safer, more effective alternatives available). B7. Loop diuretic for dependent ankle oedema without clinical, biochemical evidence or radiological evidence of heart failure, liver failure, nephrotic syndrome or renal failure (leg elevation and /or compression hosiery usually more appropriate). B8. Thiazide diuretic with current significant hypokalaemia (i.e.
    [Show full text]
  • Local Product Document Pfizer Venezuela, S.A
    LOCAL PRODUCT DOCUMENT PFIZER VENEZUELA, S.A. 1. MEDICINAL PRODUCT BRAND NAME ® SERMION 2. CUALITATIVE AND CUANTITATIVE COMPOSITION Every coated tablet contains 10 and 30 mg of Nicergoline. 3. PHARMACEUTICAL FORM Coated tablets. 4. CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS 1. Cerebrovascular insufficiency of senile source. 2. Peripheral Vasodilator. 3. Treatment of Senile dementia from light to medium level of vascular type and Alzheimer. 4.2 DOSAGE 1. 30 mg/day and Cerebrovascular insufficiency of senile source. 2. 30 mg twice per day, as Peripheral Vasodilator and on treatment of Senile dementia from light to medium level of vascular type and Alzheimer. 4.3 CONTRAINDICATIONS Hypersensitivity to Nicergoline. 4.4 WARNINGS AND PRECAUTIONS Nicergoline, as other adrenergic blocking agents, may significantly reduce blood pressure (arterial hypotension) in some patients. Likewise, as other sympatholytic agents, it has been associated to different degrees of sexual impotence and libido reduction. Do not administer this product if pregnant, if pregnancy is suspected or during breast-feeding. 4.5 ADVERSE EFFECTS Drowsiness, cephalea, tiredness, constipation, pyrosis, vomiting, diarrhea, facial flushing, sexual impotence and libido reduction, uric acid and L.H increment. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacokinetics Properties A) Onset and Duration - Benign prostatic hypertrophy, intramuscular: 2 hours. - Two hours after a single 4-mg intramuscular injection, average peak and mean urinary flow rates increased by 50% and 77%, respectively. B) Drug Concentration Levels - ORAL: 1 to 1.5 hours. - Maximal blood levels are reached 1 to 1.5 hours after oral dosing. - The mean maximum plasma concentrations after daily administration of a 30-mg film-coated tablet and a 30-mg effervescent tablet solution are 88 ng/mL and 41 ng/mL, respectively).
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Non-Antibiotics, Efflux Pumps and Drug Resistance of Gram-Negative Rods
    Polish Journal of Microbiology MINIREVIEW 2018, Vol. 67, No 2, 129–135 DOI: 10.21307/pjm-2018-017 Non-antibiotics, Efflux Pumps and Drug Resistance of Gram-negative Rods AGNIESZKA EWA LAUDY* Department of Pharmaceutical Microbiology, Medical University of Warsaw, Warsaw, Poland Submitted 24 March 2018, revised 29 March 2018, accepted 04 April 2018 Abstract Non-antibiotic medicinal products consist of drugs with diverse activity against bacteria. Many non-antibiotics demonstrate direct anti- bacterial activity against Gram-positive cocci. The activity observed against Gram-negative rods is much lower and non-antibiotics primarily from the following groups: non-steroidal anti-inflammatory drugs, cardiovascular and antidepressant medicinal products demonstrate this activity. It has been shown that the low activity of some non-antibiotics or the absence of activity against Gram-negative rods is related, among other things, to the extrusion of these compounds from bacterial cells by multi-drug resistance efflux pumps. Substrates for the resistance-nodulation-division efflux systems include the following non-antibiotics: salicylate, diclofenac, ibuprofen, mefenamic acid, naproxen, amitriptyline, alendronate sodium, nicergoline, and ticlopidine. In addition, interactions between non-antibiotics and multi-drug resistance efflux pumps have been observed. It has also been revealed that depending on the concentration, salicylate induces expression of multi-drug resistance efflux pumps in Escherichia coli, Salmonella enterica subsp. enterica serotype Typhimurium, and Burkholderia cenoce­ pacia. However, salicylate does not affect the expression of the resistance-nodulation-division efflux systems Stenotrophomonasin maltophilia and Acinetobacter baumannii. Most importantly, there were no effects of medicinal products containing some non-antibiotic active substances, except salicylate, as substrates of multi-drug resistance efflux pumps, on the induction of Gram-negative rod resistance to quinolones.
    [Show full text]
  • 4 Supplementary File
    Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation.
    [Show full text]
  • WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (74) Agents: GILL JENNINGS & EVERY LLP et al; The A61P 25/28 (2006.01) A61K 31/194 (2006.01) Broadgate Tower, 20 Primrose Street, London EC2A 2ES A61P 25/16 (2006.01) A61K 31/205 (2006.01) (GB). A23L 1/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB20 15/05 1898 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 29 June 2015 (29.06.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 141 1570.3 30 June 2014 (30.06.2014) GB TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 1412414.3 11 July 2014 ( 11.07.2014) GB (84) Designated States (unless otherwise indicated, for every (71) Applicant: MITOCHONDRIAL SUBSTRATE INVEN¬ kind of regional protection available): ARIPO (BW, GH, TION LIMITED [GB/GB]; 39 Glasslyn Road, London GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, N8 8RJ (GB).
    [Show full text]
  • Safety of Nicergoline As an Agent for Management of Cognitive Function Disorders
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 610103, 6 pages http://dx.doi.org/10.1155/2014/610103 Review Article Safety of Nicergoline as an Agent for Management of Cognitive Function Disorders Bernd Saletu, Amit Garg, and Ahsan Shoeb Section of Sleep Research and Pharmacopsychiatry, Department of Psychiatry, Medical University of Vienna, Waehringer Guertel, 1090 Vienna, Austria Correspondence should be addressed to Amit Garg; [email protected] Received 13 March 2014; Revised 4 August 2014; Accepted 12 August 2014; Published 28 August 2014 Academic Editor: Rui Liu Copyright © 2014 Bernd Saletu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer’s disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency’s (EMEA’s) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms.
    [Show full text]
  • Gps' Drug Treatment for Depression by Patients' Educational Level
    RESEARCH GPs’ drug treatment for depression by patients’ educational level: registry- based study Anneli Borge Hansen, MD1,2*, Valborg Baste, MSc. Statistics, PhD1, Oystein Hetlevik, MD, PhD1,2, Inger Haukenes, MSc. Philosophy, PhD1,2, Tone Smith- Sivertsen, MD, PhD1,3, Sabine Ruths, MD, PhD1,2 1Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway; 2Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 3Division of Psychiatry, Haukeland University Hospital, Bergen, Norway Abstract Background: Antidepressant drugs are often prescribed in general practice. Evidence is conflicting on how patient education influences antidepressant treatment. Aim: To investigate the association between educational attainment and drug treatment in adult patients with a new depression diagnosis, and to what extent sex and age influence the association. Design & setting: A nationwide registry- based cohort study was undertaken in Norway from 2014– 2016. Method: The study comprised all residents of Norway born before 1996 and alive in 2015. Information was obtained on all new depression diagnoses in general practice in 2015 (primary care database) and data on all dispensed depression medication (Norwegian Prescription Database [NorPD]) 12 months after the date of diagnosis. Independent variables were education, sex, and age. Associations with drug treatment were estimated using a Cox proportional hazard model and performed separately for sex. *For correspondence: ahan@ Results: Out of 49 967 patients with new depression (61.6% women), 15 678 were dispensed drugs norceresearch. no (30.4% women, 33.0% men). Highly educated women were less likely to receive medication (hazard ratio [HR] = 0.93; 95% confidence interval [CI] = 0.88 to 0.98) than women with low education.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Pharmaceutical Appendix to the Harmonized Tariff Schedule
    Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research Date Submitted by the 27-Jun-2019 Author: Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department
    [Show full text]