DOCSLIB.ORG

Protocol for a Randomised Controlled Trial: Efficacy of Donepezil Against

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Protocol for a Randomised Controlled Trial: Efficacy of Donepezil Against BMJ Open: first published as 10.1136/bmjopen-2013-003533 on 25 September 2013. Downloaded from Open Access Protocol Protocol for a randomised controlled trial: efficacy of donepezil against psychosis in Parkinson’s disease (EDAP) Hideyuki Sawada, Tomoko Oeda To cite: Sawada H, Oeda T. ABSTRACT ARTICLE SUMMARY Protocol for a randomised Introduction: Psychosis, including hallucinations and controlled trial: efficacy of delusions, is one of the important non-motor problems donepezil against psychosis Strengths and limitations of this study in patients with Parkinson’s disease (PD) and is in Parkinson’s disease ▪ In previous randomised controlled trials for (EDAP). BMJ Open 2013;3: possibly associated with cholinergic neuronal psychosis the efficacy was investigated in patients e003533. doi:10.1136/ degeneration. The EDAP (Efficacy of Donepezil against who presented with psychosis and the primary bmjopen-2013-003533 Psychosis in PD) study will evaluate the efficacy of endpoint was improvement of psychotic symp- donepezil, a brain acetylcholine esterase inhibitor, for toms. By comparison, this study is designed to prevention of psychosis in PD. ▸ Prepublication history for evaluate the prophylactic effect in patients this paper is available online. Methods and analysis: Psychosis is assessed every without current psychosis. Because psychosis To view these files please 4 weeks using the Parkinson Psychosis Questionnaire may be overlooked and underestimated it is visit the journal online (PPQ) and patients with PD whose PPQ-B score assessed using a questionnaire, Parkinson (http://dx.doi.org/10.1136/ (hallucinations) and PPQ-C score (delusions) have Psychosis Questionnaire (PPQ) every 4 weeks. bmjopen-2013-003533). been zero for 8 weeks before enrolment are ▪ The strength of this study is its prospective randomised to two arms: patients receiving donepezil design using the preset definition of psychosis Received 3 July 2013 hydrochloride or patients receiving placebo. The using PPQ (hallucinations/illusion and delu- Accepted 30 August 2013 patients are then followed for 96 weeks. The primary sions). However, it could also be a limitation; outcome measure is the time to the event, defined as because other types of psychosis cannot be getting 2 points or more on the PPQ-B score or PPQ-C evaluated. http://bmjopen.bmj.com/ score, which is assessed using a survival time ▪ Another limitation is the sample size estimation. analysis. The hypothesis being tested is that donepezil Because there have never been any randomised prevents psychosis in patients with PD. Efficacy will be trials for the prevention of psychosis, previous tested statistically using the intention-to-treat analysis data for sample size estimation were insufficient. including a log-rank test or Cox proportional hazard To resolve this issue we estimated the sample size models. Secondary outcomes, such as changes of PPQ based on our previous retrospective cohort study. scores and Unified Parkinson’s Disease Rating Scale scores from baseline will be assessed. or postural reflex disturbance. These motor Ethics and dissemination: Ethics approval was on September 25, 2021 by guest. Protected copyright. symptoms are caused by the depletion of received from the Central Review Board of the National dopamine in the striatum. Dopamine Hospital Organization, Tokyo, Japan. The trial was declared and registered to the Pharmaceuticals and Medical Devices replacement therapy can improve motor dis- Agency(PMDA), Japan (No. 22-4018). All participants will turbances in PD. However, many patients receive a written informed consent that was approved by suffer from psychiatric symptoms, such as the Central Review. A completed written informed consent hallucinations and delusions, during their is required to enrol in the study. Severe adverse events will long therapy process.12 be monitored by investigators and in cases where a severe In previous studies the efficacy of antidopa- adverse event was previously unreported, it will be minergic drugs, including clozapine,34olan- reported to the PMDA. zapine,5 quetiapine67and risperidone,8 was Clinical Trial Registration Number: UMIN000005403. investigated based on the possibility that psych- osis may be caused by excessive dopamine Clinical Research Center, replacement therapy. Although the efficacy of National Hospital of Utano, clozapine against psychosis without worsening Kyoto, Japan INTRODUCTION of motor symptoms of PD was established in Parkinson’s disease (PD) is a neurodegenerative the French Clozapine Parkinson Study4 and Correspondence to 4 Dr Hideyuki Sawada; disorder presenting with motor disturbances, the PSYCHOPLOS study, clozapine has a risk [email protected] including muscular rigidity, tremor, bradykinesia of granulocytopenia and requires careful Sawada H, Oeda T. BMJ Open 2013;3:e003533. doi:10.1136/bmjopen-2013-003533 1 BMJ Open: first published as 10.1136/bmjopen-2013-003533 on 25 September 2013. Downloaded from Open Access blood cell monitoring. Previous randomised clinical to demonstrate significant differences between active trials (RCTs) demonstrated that olanzapine improves drugs and placebo. Therefore, in this study, the main psychosis, but there were no significant differences in outcome measure is the prophylactic efficacy of donepe- improvement between the olanzapine groups and the zil and the efficacy will be analysed using a survival time placebo groups. In addition, olanzapine worsened analysis. motor symptoms in PD compared with placebo.5 Two Because psychosis may be overlooked and underesti- other RCTs demonstrated that quetiapine does not mated, it is assessed using Parkinson Psychosis worsen motor symptoms; however, its efficacy against Questionnaire (PPQ)22 given every 4 weeks. The PPQ psychosis was not superior to placebo.67A small-sized consists of four categorical dimensions: sleep disturb- RCT comparing risperidone and clozapine demonstrated ance, hallucinations/illusions, delusions and orienta- that risperidone improves psychosis as well as clozapine; tions. Eligible patients are those whose scores on the however, risperidone worsened motor symptoms.8 There PPQ-B (hallucinations/illusion) and PPQ-C (delu- have been no clinical trials regarding other antipsychotic sion) are zero at least for 8 weeks before enrolment drugs against psychosis in PD. Taken together antidopa- and the primary endpoint is the occurrence of psych- minergic drugs, except for clozapine, insufficiently osis that is defined as PPQ-B ≥2 or PPQ-C ≥2, because improve psychosis. the situations when PPQ-B or PPQ-C is ≥2canresult Cholinergic neurons of the basal forebrain play an in clinically harmful conditions. important role in cognitive function and disruption of To exclude patients with dementia with Lewy bodies the cholinergic system has been proposed in (DLB) and PD with dementia, patients with Minimental Alzheimer’s disease.910Previous reports demonstrated State Examination (MMSE) score less than 24 are that the cholinergic neurons are degenerated, as are excluded. The risk of psychosis is low in patients with an dopaminergic neurons in PD,11 suggesting the possibility H-Y stage of 2 or less and the evaluation of psychosis is that psychosis could be caused by cholinergic neuronal difficult in patients with H-Y stage of 5. Therefore, damage, but not by dopaminergic replacement therapy.12 patients with H-Y stage of 1−2 or 5 are excluded. The Previously we investigated the clinical risk factors for length of time to the occurrence of psychosis is com- psychosis in a retrospective cohort study (unpublished pared between participants who were prescribed placebo data). In this study, 334 patients with PD were followed and those who were prescribed donepezil. until the occurrence of psychosis in 24 months. PD fi psychosis was signi cantly associated with the severity of Hypothesis to be examined in the study PD, PD duration and cognitive function. These data Psychosis may be caused by dysfunction of brain cholin- demonstrated that psychosis is associated with the severity ergic neurons. We examine the hypothesis that donepe- of the disease and cognitive function and the results are – zil prevents psychosis in patients with PD. http://bmjopen.bmj.com/ very consistent with previous reports.13 15 In addition, the influence of medications was analysed using a case- crossover study comparing medications at the endpoint METHODS AND ANALYSIS (occurrence of psychosis or end of the study) and those Study design for 1 or 3 months before the endpoint, and the analysis A multicentre, double-blinded, placebo-controlled, ran- showed that the use of anticholinergic drugs was a signifi- domised trial. A two arm study. cant risk factor for psychosis. In these results psychosis may have been caused by the degeneration of cholinergic Sites where the study is performed on September 25, 2021 by guest. Protected copyright. neurons and deterioration of cognitive function. Eight hospitals of the National Hospital Organization: Donepezil hydrochloride is an inhibitor of acetylcho- – Utano National Hospital, Hokkaido Medical Center, line esterase in brain neurons16 18 and activates choliner- 16 19 20 et al21 Sagamihara National Hospital, Shizuoka Institute of gic neurons. Manganelli have demonstrated, Epilepsy and Neurological Disorders, Kyoto Medical by using a neurophysiological technique, the short Center, Minami Kyoto Hospital, Toneyama National latency afferent inhibition, a functional involvement of Hospital and Nagasaki Kawatana Medical Center. central cholinergic
Load more

Recommended publications
  • Severe Organophosphate Poisoning with Delayed Cholinergic Crisis, Intermediate Syndrome and Organophosphate Induced Delayed Polyneuropathy on Succession
    Organophosphate Poisoning… Aklilu A 203 CASE REPORT SEVERE ORGANOPHOSPHATE POISONING WITH DELAYED CHOLINERGIC CRISIS, INTERMEDIATE SYNDROME AND ORGANOPHOSPHATE INDUCED DELAYED POLYNEUROPATHY ON SUCCESSION Aklilu Azazh ABSTRACT Organophosphate compounds are the organic derivatives of Phosphorous containing acids and their effect on neuromuscular junction and Autonomic Synapses is clinically important. After exposure these agents cause acute and sub acute manifestations depending on the type and severity of the agents like Acute Cholinergic Manifestations, Intermediate Syndrome with Nicotinic features and Delayed Central Nervous System Complications. The patient reported here had severe Organophosphate Poisoning with various rare complications on a succession. This is the first report of Organophosphates Poisoning complicated by Intermediate Syndrome and Organophosphate Induced Delayed Polyneuropathy in Ethiopia and it is reported to increase awareness of health care workers on these rare complications of a common problem. INTRODUCTION phosphorylated by the Phosphate end of Organophosphates; then the net result is Organophosphate compounds are the organic accumulation of excessive Acetyl Chlorine with derivatives of Phosphorous containing acids and resultant effect on Muscarinic, Nicotinic and their effect on Neuromuscular Junction and central nervous system (Figure 2). Autonomic synapses is clinically important. In the Neuromuscular Junction Acetylcholine is released Following classical OP poisoning, three well when a nerve impulse reaches
    [Show full text]
  • The National Drugs List
    ^ ^ ^ ^ ^[ ^ The National Drugs List Of Syrian Arab Republic Sexth Edition 2006 ! " # "$ % &'() " # * +$, -. / & 0 /+12 3 4" 5 "$ . "$ 67"5,) 0 " /! !2 4? @ % 88 9 3: " # "$ ;+<=2 – G# H H2 I) – 6( – 65 : A B C "5 : , D )* . J!* HK"3 H"$ T ) 4 B K<) +$ LMA N O 3 4P<B &Q / RS ) H< C4VH /430 / 1988 V W* < C A GQ ") 4V / 1000 / C4VH /820 / 2001 V XX K<# C ,V /500 / 1992 V "!X V /946 / 2004 V Z < C V /914 / 2003 V ) < ] +$, [2 / ,) @# @ S%Q2 J"= [ &<\ @ +$ LMA 1 O \ . S X '( ^ & M_ `AB @ &' 3 4" + @ V= 4 )\ " : N " # "$ 6 ) G" 3Q + a C G /<"B d3: C K7 e , fM 4 Q b"$ " < $\ c"7: 5) G . HHH3Q J # Hg ' V"h 6< G* H5 !" # $%" & $' ,* ( )* + 2 ا اوا ادو +% 5 j 2 i1 6 B J' 6<X " 6"[ i2 "$ "< * i3 10 6 i4 11 6! ^ i5 13 6<X "!# * i6 15 7 G!, 6 - k 24"$d dl ?K V *4V h 63[46 ' i8 19 Adl 20 "( 2 i9 20 G Q) 6 i10 20 a 6 m[, 6 i11 21 ?K V $n i12 21 "% * i13 23 b+ 6 i14 23 oe C * i15 24 !, 2 6\ i16 25 C V pq * i17 26 ( S 6) 1, ++ &"r i19 3 +% 27 G 6 ""% i19 28 ^ Ks 2 i20 31 % Ks 2 i21 32 s * i22 35 " " * i23 37 "$ * i24 38 6" i25 39 V t h Gu* v!* 2 i26 39 ( 2 i27 40 B w< Ks 2 i28 40 d C &"r i29 42 "' 6 i30 42 " * i31 42 ":< * i32 5 ./ 0" -33 4 : ANAESTHETICS $ 1 2 -1 :GENERAL ANAESTHETICS AND OXYGEN 4 $1 2 2- ATRACURIUM BESYLATE DROPERIDOL ETHER FENTANYL HALOTHANE ISOFLURANE KETAMINE HCL NITROUS OXIDE OXYGEN PROPOFOL REMIFENTANIL SEVOFLURANE SUFENTANIL THIOPENTAL :LOCAL ANAESTHETICS !67$1 2 -5 AMYLEINE HCL=AMYLOCAINE ARTICAINE BENZOCAINE BUPIVACAINE CINCHOCAINE LIDOCAINE MEPIVACAINE OXETHAZAINE PRAMOXINE PRILOCAINE PREOPERATIVE MEDICATION & SEDATION FOR 9*: ;< " 2 -8 : : SHORT -TERM PROCEDURES ATROPINE DIAZEPAM INJ.
    [Show full text]
  • Upregulation of Peroxisome Proliferator-Activated Receptor-Α And
    Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer Chih-Yang Wang, Ying-Jui Chao, Yi-Ling Chen, Tzu-Wen Wang, Nam Nhut Phan, Hui-Ping Hsu, Yan-Shen Shan, Ming-Derg Lai 1 Supplementary Table 1. Demographics and clinical outcomes of five patients with ampullary cancer Time of Tumor Time to Age Differentia survival/ Sex Staging size Morphology Recurrence recurrence Condition (years) tion expired (cm) (months) (months) T2N0, 51 F 211 Polypoid Unknown No -- Survived 193 stage Ib T2N0, 2.41.5 58 F Mixed Good Yes 14 Expired 17 stage Ib 0.6 T3N0, 4.53.5 68 M Polypoid Good No -- Survived 162 stage IIA 1.2 T3N0, 66 M 110.8 Ulcerative Good Yes 64 Expired 227 stage IIA T3N0, 60 M 21.81 Mixed Moderate Yes 5.6 Expired 16.7 stage IIA 2 Supplementary Table 2. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of an ampullary cancer microarray using the Database for Annotation, Visualization and Integrated Discovery (DAVID). This table contains only pathways with p values that ranged 0.0001~0.05. KEGG Pathway p value Genes Pentose and 1.50E-04 UGT1A6, CRYL1, UGT1A8, AKR1B1, UGT2B11, UGT2A3, glucuronate UGT2B10, UGT2B7, XYLB interconversions Drug metabolism 1.63E-04 CYP3A4, XDH, UGT1A6, CYP3A5, CES2, CYP3A7, UGT1A8, NAT2, UGT2B11, DPYD, UGT2A3, UGT2B10, UGT2B7 Maturity-onset 2.43E-04 HNF1A, HNF4A, SLC2A2, PKLR, NEUROD1, HNF4G, diabetes of the PDX1, NR5A2, NKX2-2 young Starch and sucrose 6.03E-04 GBA3, UGT1A6, G6PC, UGT1A8, ENPP3, MGAM, SI, metabolism
    [Show full text]
  • Muscarinic Acetylcholine Receptor
    mAChR Muscarinic acetylcholine receptor mAChRs (muscarinic acetylcholine receptors) are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certainneurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibersin the parasympathetic nervous system. mAChRs are named as such because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpineand scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists. Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. www.MedChemExpress.com 1 mAChR Inhibitors & Modulators (+)-Cevimeline hydrochloride hemihydrate (-)-Cevimeline hydrochloride hemihydrate Cat. No.: HY-76772A Cat. No.: HY-76772B Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic receptor agonist, is a candidate therapeutic drug for receptor agonist, is a candidate therapeutic drug for xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR The general pharmacol. properties of this drug on the The general pharmacol. properties of this drug on the gastrointestinal, urinary, and reproductive systems and other… gastrointestinal, urinary, and reproductive systems and other… Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg 1 mg, 5 mg AC260584 Aclidinium Bromide Cat. No.: HY-100336 (LAS 34273; LAS-W 330) Cat.
    [Show full text]
  • The In¯Uence of Medication on Erectile Function
    International Journal of Impotence Research (1997) 9, 17±26 ß 1997 Stockton Press All rights reserved 0955-9930/97 $12.00 The in¯uence of medication on erectile function W Meinhardt1, RF Kropman2, P Vermeij3, AAB Lycklama aÁ Nijeholt4 and J Zwartendijk4 1Department of Urology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; 2Department of Urology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands; 3Pharmacy; and 4Department of Urology, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands Keywords: impotence; side-effect; antipsychotic; antihypertensive; physiology; erectile function Introduction stopped their antihypertensive treatment over a ®ve year period, because of side-effects on sexual function.5 In the drug registration procedures sexual Several physiological mechanisms are involved in function is not a major issue. This means that erectile function. A negative in¯uence of prescrip- knowledge of the problem is mainly dependent on tion-drugs on these mechanisms will not always case reports and the lists from side effect registries.6±8 come to the attention of the clinician, whereas a Another way of looking at the problem is drug causing priapism will rarely escape the atten- combining available data on mechanisms of action tion. of drugs with the knowledge of the physiological When erectile function is in¯uenced in a negative mechanisms involved in erectile function. The way compensation may occur. For example, age- advantage of this approach is that remedies may related penile sensory disorders may be compen- evolve from it. sated for by extra stimulation.1 Diminished in¯ux of In this paper we will discuss the subject in the blood will lead to a slower onset of the erection, but following order: may be accepted.
    [Show full text]
  • Classification of Medicinal Drugs and Driving: Co-Ordination and Synthesis Report
    Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Due date of deliverable: 21.07.2011 Actual submission date: 21.07.2011 Revision date: 21.07.2011 Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UVA Revision 0.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public PP Restricted to other programme participants (including the Commission x Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) DRUID 6th Framework Programme Deliverable D.4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Page 1 of 243 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Authors Trinidad Gómez-Talegón, Inmaculada Fierro, M. Carmen Del Río, F. Javier Álvarez (UVa, University of Valladolid, Spain) Partners - Silvia Ravera, Susana Monteiro, Han de Gier (RUGPha, University of Groningen, the Netherlands) - Gertrude Van der Linden, Sara-Ann Legrand, Kristof Pil, Alain Verstraete (UGent, Ghent University, Belgium) - Michel Mallaret, Charles Mercier-Guyon, Isabelle Mercier-Guyon (UGren, University of Grenoble, Centre Regional de Pharmacovigilance, France) - Katerina Touliou (CERT-HIT, Centre for Research and Technology Hellas, Greece) - Michael Hei βing (BASt, Bundesanstalt für Straßenwesen, Germany).
    [Show full text]
  • The Role of Serotonin in Memory: Interactions with Neurotransmitters and Downstream Signaling
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bushehr University of Medical Sciences Repository Exp Brain Res (2014) 232:723–738 DOI 10.1007/s00221-013-3818-4 REVIEW The role of serotonin in memory: interactions with neurotransmitters and downstream signaling Mohammad Seyedabadi · Gohar Fakhfouri · Vahid Ramezani · Shahram Ejtemaei Mehr · Reza Rahimian Received: 28 April 2013 / Accepted: 20 December 2013 / Published online: 16 January 2014 © Springer-Verlag Berlin Heidelberg 2014 Abstract Serotonin, or 5-hydroxytryptamine (5-HT), is there has been an alteration in the density of serotonergic found to be involved in many physiological or pathophysi- receptors in aging and Alzheimer’s disease, and serotonin ological processes including cognitive function. Seven dis- modulators are found to alter the process of amyloidogen- tinct receptors (5-HT1–7), each with several subpopulations, esis and exert cognitive-enhancing properties. Here, we dis- have been identified for serotonin, which are different in cuss the serotonin-induced modulation of various systems terms of localization and downstream signaling. Because involved in mnesic function including cholinergic, dopa- of the development of selective agonists and antagonists minergic, GABAergic, glutamatergic transmissions as well for these receptors as well as transgenic animal models as amyloidogenesis and intracellular pathways. of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has Keywords Serotonin · Memory · Signaling pathways improved in recent years. A large body of evidence indi- cates the interplay between serotonergic transmission and Abbreviations other neurotransmitters including acetylcholine, dopamine, 2PSDT Two-platform spatial discrimination task γ-aminobutyric acid (GABA) and glutamate, in the neu- 3xTg-AD Triple-transgenic mouse model of Alzheimer’s robiological control of learning and memory.
    [Show full text]
  • Nicotine and Neurotransmitters
    Module 2 —Legal Doesn’t Mean Harmless Overview Overview Summary This module focuses on how two drugs, nicotine and alcohol, change the functioning of the brain and body. Both drugs are widely used in the community, and for adults, using them is legal. Nonetheless, both alcohol and nicotine can have a strong impact on the functioning of the brain. Each can cause a number of negative effects on the body and brain, ranging from mild symptoms to addiction. The goal of this module is to help students understand that, although nicotine and alcohol are legal for adults, they are not harmless substances. Students will learn about how nicotine and alcohol change or disrupt the process of neurotransmission. Students will explore information on the short- and long- term effects of these two drugs, and also learn why these drugs are illegal for children and teens. Through the media, students are exposed to a great deal of information about alcohol and tobacco, much of which is misleading or scientifically inaccurate. This module will provide information on what researchers have learned about how nicotine and alcohol change the brain, and the resulting implications for safety and health. Learning Objectives At the end of this module: • Students can explain how nicotine disrupts neurotransmission. • Students can explain how alcohol use may harm the brain and the body. • Students understand how alcohol can intensify the effect of other drugs. • Students can define addiction and understand its basis in the brain. • Students draw conclusions about why our society regulates the use of nicotine and alcohol for young people.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness Et Al
    USOO6264,917B1 (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness et al. (45) Date of Patent: Jul. 24, 2001 (54) TARGETED ULTRASOUND CONTRAST 5,733,572 3/1998 Unger et al.. AGENTS 5,780,010 7/1998 Lanza et al. 5,846,517 12/1998 Unger .................................. 424/9.52 (75) Inventors: Jo Klaveness; Pál Rongved; Dagfinn 5,849,727 12/1998 Porter et al. ......................... 514/156 Lovhaug, all of Oslo (NO) 5,910,300 6/1999 Tournier et al. .................... 424/9.34 FOREIGN PATENT DOCUMENTS (73) Assignee: Nycomed Imaging AS, Oslo (NO) 2 145 SOS 4/1994 (CA). (*) Notice: Subject to any disclaimer, the term of this 19 626 530 1/1998 (DE). patent is extended or adjusted under 35 O 727 225 8/1996 (EP). U.S.C. 154(b) by 0 days. WO91/15244 10/1991 (WO). WO 93/20802 10/1993 (WO). WO 94/07539 4/1994 (WO). (21) Appl. No.: 08/958,993 WO 94/28873 12/1994 (WO). WO 94/28874 12/1994 (WO). (22) Filed: Oct. 28, 1997 WO95/03356 2/1995 (WO). WO95/03357 2/1995 (WO). Related U.S. Application Data WO95/07072 3/1995 (WO). (60) Provisional application No. 60/049.264, filed on Jun. 7, WO95/15118 6/1995 (WO). 1997, provisional application No. 60/049,265, filed on Jun. WO 96/39149 12/1996 (WO). 7, 1997, and provisional application No. 60/049.268, filed WO 96/40277 12/1996 (WO). on Jun. 7, 1997. WO 96/40285 12/1996 (WO). (30) Foreign Application Priority Data WO 96/41647 12/1996 (WO).
    [Show full text]
  • Neurochemical Mechanisms Underlying Alcohol Withdrawal
    Neurochemical Mechanisms Underlying Alcohol Withdrawal John Littleton, MD, Ph.D. More than 50 years ago, C.K. Himmelsbach first suggested that physiological mechanisms responsible for maintaining a stable state of equilibrium (i.e., homeostasis) in the patient’s body and brain are responsible for drug tolerance and the drug withdrawal syndrome. In the latter case, he suggested that the absence of the drug leaves these same homeostatic mechanisms exposed, leading to the withdrawal syndrome. This theory provides the framework for a majority of neurochemical investigations of the adaptations that occur in alcohol dependence and how these adaptations may precipitate withdrawal. This article examines the Himmelsbach theory and its application to alcohol withdrawal; reviews the animal models being used to study withdrawal; and looks at the postulated neuroadaptations in three systems—the gamma-aminobutyric acid (GABA) neurotransmitter system, the glutamate neurotransmitter system, and the calcium channel system that regulates various processes inside neurons. The role of these neuroadaptations in withdrawal and the clinical implications of this research also are considered. KEY WORDS: AOD withdrawal syndrome; neurochemistry; biochemical mechanism; AOD tolerance; brain; homeostasis; biological AOD dependence; biological AOD use; disorder theory; biological adaptation; animal model; GABA receptors; glutamate receptors; calcium channel; proteins; detoxification; brain damage; disease severity; AODD (alcohol and other drug dependence) relapse; literature review uring the past 25 years research- science models used to study with- of the reasons why advances in basic ers have made rapid progress drawal neurochemistry as well as a research have not yet been translated Din understanding the chemi- reluctance on the part of clinicians to into therapeutic gains and suggests cal activities that occur in the nervous consider new treatments.
    [Show full text]
  • Two Types of Muscarinic Response to Acetylcholine in Mammalian Cortical Neurons (Clngulate/M Current/Cholinergic/Pirenzepine) DAVID A
    Proc. Nail. Acad. Sci. USA Vol. 82, pp. 6344-6348, September 1985 Neurobiology Two types of muscarinic response to acetylcholine in mammalian cortical neurons (clngulate/M current/cholinergic/pirenzepine) DAVID A. MCCORMICK AND DAVID A. PRINCE Department of Neurology, Room C338, Stanford University School of Medicine, Stanford, CA 94305 Communicated by Richard F. Thompson, May 22, 1985 ABSTRACT Applications of acetylcholine (AcCho) to py- The cerebral cortex contains nicotinic as well as several ramidal cells of guinea pig cingulate cortical slices maintained subtypes of muscarinic AcCho receptors (20-23). Previous in vitro result in a short latency inhibition, followed by a reports suggest that cholinergic slow excitation is mediated prolonged increase in excitability. Cholinergic inhibition is by receptors possessing muscarinic characteristics, while mediated through the rapid excitation of interneurons that cholinergic inhibition may be due to activation of receptors utilize the inhibitory neurotransmitter y-aminobutyric acid that have both nicotinic and muscarinic properties (5, 24). (GABA). This rapid excitation of interneurons is. associated The recent characterization of receptor antagonists (e.g., with a membrane depolarization and a decrease in neuronal pirenzepine) and agonists (e.g., pilocarpine) that are relative- input resistance. In contrast, AcCho-induced excitation of ly specific for subtypes ofmuscarinic receptors (21, 22) raises pyramidal cells is due to a direct action that produces a the question of whether different types of cholinergic re- voltage-dependent increase in input resistance. In the experi- sponses demonstrated physiologically within the central ments reported here, we investigated the possibility that these nervous system might be due to activation of different two responses are mediated by different subclasses of cholin- subclasses of muscarinic receptors, as appears to be the case ergic receptors.
    [Show full text]
  • Drug Class Review Ophthalmic Cholinergic Agonists
    Drug Class Review Ophthalmic Cholinergic Agonists 52:40.20 Miotics Acetylcholine (Miochol-E) Carbachol (Isopto Carbachol; Miostat) Pilocarpine (Isopto Carpine; Pilopine HS) Final Report November 2015 Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist Gary Oderda, PharmD, MPH, Professor University of Utah College of Pharmacy Copyright © 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved. Table of Contents Executive Summary ......................................................................................................................... 3 Introduction .................................................................................................................................... 4 Table 1. Glaucoma Therapies ................................................................................................. 5 Table 2. Summary of Agents .................................................................................................. 6 Disease Overview ........................................................................................................................ 8 Table 3. Summary of Current Glaucoma Clinical Practice Guidelines ................................... 9 Pharmacology ............................................................................................................................... 10 Methods .......................................................................................................................................
    [Show full text]