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Medical Review Officer Manual
Department of Health and Human Services Substance Abuse and Mental Health Services Administration Center for Substance Abuse Prevention Medical Review Officer Manual for Federal Agency Workplace Drug Testing Programs EFFECTIVE OCTOBER 1, 2010 Note: This manual applies to Federal agency drug testing programs that come under Executive Order 12564 dated September 15, 1986, section 503 of Public Law 100-71, 5 U.S.C. section 7301 note dated July 11, 1987, and the Department of Health and Human Services Mandatory Guidelines for Federal Workplace Drug Testing Programs (73 FR 71858) dated November 25, 2008 (effective October 1, 2010). This manual does not apply to specimens submitted for testing under U.S. Department of Transportation (DOT) Procedures for Transportation Workplace Drug and Alcohol Testing Programs (49 CFR Part 40). The current version of this manual and other information including MRO Case Studies are available on the Drug Testing page under Medical Review Officer (MRO) Resources on the SAMHSA website: http://www.workplace.samhsa.gov Previous Versions of this Manual are Obsolete 3 Table of Contents Chapter 1. The Medical Review Officer (MRO)........................................................................... 6 Chapter 2. The Federal Drug Testing Custody and Control Form ................................................ 7 Chapter 3. Urine Drug Testing ...................................................................................................... 9 A. Federal Workplace Drug Testing Overview.................................................................. -
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Hydrochloride (M0896)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride Product Number M 0896 Store at Room Temperature Product Description References 1. The Merck Index, 12th ed., Entry# 6376. Molecular Formula: C12H15N • HCl 2. Przedborski, S., et al., The parkinsonian toxin Molecular Weight: 209.7 MPTP: action and mechanism. Restor. Neurol. CAS Number: 23007-85-4 Neurosci., 16(2), 135-142 (2000). Synonym: MPTP • HCl 3. Adams, J. D., Jr., et al., Parkinson's disease - redox mechanisms. Curr. Med. Chem., 8(7), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 809-814 (2001). is a piperidine derivative and dopaminergic neurotoxin 4. Ziering, A., et al., Piperidine Derivatives. Part III. that has been used in neurological research. MPTP is 4-Arylpiperidines. J. Org. Chem., 12, 894-903 metabolized to 1-methyl-4-phenylpyridine (MPP+), (1947). which in turn can cause free radical production in vivo 5. Schmidle, C. J., and Mansfield, R. C, The and lead to oxidative stress. Thus MPP+ is generally aminomethylation of olefins. IV. The formation of acknowledged as the active metabolite derived from 1-alkyl-4-aryl-1,2,3,6-tetrahydropyridines. J. Am. MPTP.2,3 The synthesis of MPTP has been Chem. Soc., 78, 425-428 (1956). reported.4,5 6. Davis, G. C., et al., Chronic Parkinsonism secondary to intravenous injection of meperidine MPTP is widely utilized in in vivo research studies as a analogues. Psychiatry Res., 1, 249-254 (1979). model for Parkinsonism.6-11 A mouse investigation of 7. Burns, R. S., et al., A primate model of MPTP treatment has indicated a possible role for parkinsonism: selective destruction of cyclooxygenase 2 (COX-2) in Parkinsonian dopaminergic neurons in the pars compacta of the neurodegeneration.12 A review describes the substantia nigra by N-methyl-4-phenyl-1,2,3,6- application of MPTP studies to programmed cell death tetrahydropyridine. -
Mechanistic Comparison Between MPTP and Rotenone Neurotoxicity in Mice T ⁎ Sunil Bhurtel, Nikita Katila, Sunil Srivastav, Sabita Neupane, Dong-Young Choi
Neurotoxicology 71 (2019) 113–121 Contents lists available at ScienceDirect Neurotoxicology journal homepage: www.elsevier.com/locate/neuro Full Length Article Mechanistic comparison between MPTP and rotenone neurotoxicity in mice T ⁎ Sunil Bhurtel, Nikita Katila, Sunil Srivastav, Sabita Neupane, Dong-Young Choi Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea ARTICLE INFO ABSTRACT Keywords: Animal models for Parkinson’s disease (PD) are very useful in understanding the pathogenesis of PD and MPTP screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone Rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of ’ Parkinson s disease mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In Neurotrophic factors this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. -
Dexmethylphenidate Hydrochloride Extended-Release Capsules These
DEXMETHYLPHENIDATE HYDROCHLORIDE- dexmethylphenidate hydrochloride capsule, extended release Granules Pharmaceuticals Inc. ---------- HIGHLIGHTS OF PRESCRIBING INFORMATION Dexmethylphenidate hydrochloride extended-release capsules These highlights do not include all the information needed to use DEXMETHYLPHENIDATE HYDROCHLORIDE EXTENDED-RELEASE CAPSULES safely and effectively. See full prescribing information for DEXMETHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE CAPSULES. DEXMETHYLPHENIDATE HYDROCHLORIDE extended-release capsules, for oral use, CII Initial U.S. Approval: 2005 WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. • CNS stimulants, including dexmethylphenidate hydrochloride extended-release, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence( 5.1, 9.2, 9.3). • Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy ( 5.1, 9.2). INDICATIONS AND USAGE Dexmethylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) ( 1) DOSAGE AND ADMINISTRATION • Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2) • Patients currently on methylphenidate: Dexmethylphenidate hydrochloride extended-release dosage is half the current total daily dosage of methylphenidate -
Ecstasy: the Clinical, Pharmacological and Neurotoxicological Effects of the Drug Mdma Topics in the Neurosciences
ECSTASY: THE CLINICAL, PHARMACOLOGICAL AND NEUROTOXICOLOGICAL EFFECTS OF THE DRUG MDMA TOPICS IN THE NEUROSCIENCES Other books in the series: Rahamimoff, Rami and Katz, Sir Bernard, eds.: Calcium, Neuronal Function and Transmitter Release. ISBN 0-89838-791-4. Fredrickson, Robert C.A., ed.: Neuroregulation of Autonomic, Endocrine and Immune Systems. ISBN 0-89838-800-7. Giuditta, A., et al., eds.: Role of RNA and DNA in Brain Function. ISBN 0-89838-814-7. Stober, T., et al.,: Central Nervous System Control of the Heart. ISBN 0-89838-820-l. Kelly J., et al., eds.: Polyneuropathies Associated with Plasma Cell Dyscrasias. ISBN 0-89838-884-8. Galjaard, H. et al., eds.: Early Detection and Management of Cerebral Palsy. ISBN 0-89838-890-2. Ferrendelli, J., et al., eds.: Neurobiology of Amino Acids, Pep tides and Trophic Factors. ISBN 0-89838-360-9. ECSTASY: THE CLINICAL, PHARMACOLOGICAL AND NEUROTOXICOLOGICAL EFFECTS OF THE DRUGMDMA Edited by STEPHEN J. PEROUTKA Stanford University Medical Center ~. KLUWER ACADEMIC PUBLISHERS "BOSTON IDORDRECHT ILONDON Distributors for North America: Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA for all other countries: Kluwer Academic Publishers Group, Distribution Centre, Post Office Box 322, 3300 AH Dordrecht, The Netherlands Library of Congress Cataloging-in-Publication Data Ecstasy: the clinical, pharmacological, and neurotoxicological effects of the drug MDMA / edited by Stephen]. Peroutka. p. cm. - (Topics in the neurosciences; TNSC9) Includes bibliographies and index. ISBN- 13:978- I -4612-8799-5 e-ISBN-13:978- I -4613-1485-1 DOl: 10.1007/978-1-4613-1485-1 1. MDMA (Drug) 2. -
Inhibits Dyskinesia Expression and Normalizes Motor Activity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Primates
The Journal of Neuroscience, October 8, 2003 • 23(27):9107–9115 • 9107 Behavioral/Systems/Cognitive 3,4-Methylenedioxymethamphetamine (Ecstasy) Inhibits Dyskinesia Expression and Normalizes Motor Activity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Primates Mahmoud M. Iravani, Michael J. Jackson, Mikko Kuoppama¨ki, Lance A. Smith, and Peter Jenner Neurodegenerative Disease Research Centre, Guy’s, King’s, and St. Thomas’ School of Biomedical Sciences, King’s College, London SE1 1UL, United Kingdom Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] was shown to prolong the action of L-3,4-dihydroxyphenylalanine (L-DOPA) while suppressing dyskinesia in a single patient with Parkinson’s disease (PD). The clinical basis of this effect of MDMA is unknown but may relate to its actions on either dopaminergic or serotoninergic systems in brain. In normal, drug-naive common marmosets, MDMA administration suppressed motor activity and exploratory behavior. In 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated, L-DOPA-primedcommonmarmosets,MDMAtransientlyrelievedmotordisability but over a period of 60 min worsened motor symptoms. When given in conjunction with L-DOPA, however, MDMA markedly decreased dyskinesia by reducing chorea and to a lesser extent dystonia and decreased locomotor activity to the level observed in normal animals. MDMA similarly alleviated dyskinesia induced by the selective dopamine D2/3 agonist pramipexole. The actions of MDMA appeared to be mediated through 5-HT mechanisms because its effects were fully blocked by the selective serotonin reuptake inhibitor fluvoxamine. Furthermore,theeffectofMDMAon L-DOPA-inducedmotoractivityanddyskinesiawaspartiallyinhibitedby5-HT1a/bantagonists.The ability of MDMA to inhibit dyskinesia results from its broad spectrum of action on 5-HT systems. -
Selegiline) in Monkeys*
Intravenous self-administration studies with /-deprenyl (selegiline) in monkeys* /-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, /-methamphetamine, the major metabolite of /-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with /-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administra- tion of either cocaine or /-methamphetamine. Thus /-deprenyl did not appear to have cocaine- or meth- amphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that de- spite long-term use of /-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. /-Deprenyl has recently been suggested as a potential med- ication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to pro- duce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely. (CLIN PHARMACOL THER 1994;56:774-80.) Gail D. Winger, PhD,a Sevil Yasar, MD,b'd'e S. Steven Negus, PhD,a and Steven R. Goldberg, pIli/i d'e Ann Arbor, Mich., and Baltimore, Md. From the 'Department of Pharmacology, University of Michigan /-Deprenyl (selegiline) has been known for several -
Designer-Drugs-China-White-And-MPTP.Pdf
Selected Papers of William L. White www.williamwhitepapers.com Collected papers, interviews, video presentations, photos, and archival documents on the history of addiction treatment and recovery in America. Citation: White, W. (2014). Designer drugs, China white, and the story of MPTP. Posted at www.williamwhitepapers.com Designer Drugs, China White, and the Story of MPTP William L. White Emeritus Senior Research Consultant Chestnut Health Systems [email protected] NOTE: The original 1,000+ page manuscript for Slaying the Dragon: The History of Addiction Treatment and Recovery in America had to be cut by more than half before its first publication in 1998. This is an edited excerpt that was deleted from the original manuscript. "Designer drugs"--a term coined by The modern story of designer drugs pharmacologist Gary Henderson, of the begins in 1976 with Barry, a bright, twenty- University of California--represent efforts by three-year-old college student from chemists to alter the molecular structure of a Bethesda, Maryland. Barry created an psychoactive drug to change the drug analogue of meperidine (Demerol)--MPPP, identity while maintaining or intensifying the that was not legally controlled as a way to original drug's psychoactive properties. avoid contact with the illicit drug market. He Designer drugs are often analogues-- continued to synthesize and use MPPP for chemical cousins--of the drugs they’re six months without incident. In the summer modeled after and may have effects and of 1976, he made a new batch of MPPP but risks quite different than these original through a mistake in the synthesis procedure substances. -
Signaling Plays an Important Role in MPTP-Induced Neuronal Death
Cell Death and Differentiation (2016) 23, 542–552 & 2016 Macmillan Publishers Limited All rights reserved 1350-9047/16 www.nature.com/cdd c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death RWu1,2, H Chen1,3,JMa1,2,QHe1,2, Q Huang4, Q Liu5, M Li*,4 and Z Yuan*,1,2,3 Oxidative stress is a major cause of sporadic Parkinson’s disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Abl- mediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl–p38α signaling may represent a therapeutic target for PD. Cell Death and Differentiation (2016) 23, 542–552; doi:10.1038/cdd.2015.135; published online 30 October 2015 Parkinson’s disease (PD), the second most common neuro- cell signaling activities, including growth factor signaling, cell degenerative disorder, -
Recommended Methods for the Identification and Analysis Of
Vienna International Centre, P.O. Box 500, 1400 Vienna, Austria Tel: (+43-1) 26060-0, Fax: (+43-1) 26060-5866, www.unodc.org RECOMMENDED METHODS FOR THE IDENTIFICATION AND ANALYSIS OF AMPHETAMINE, METHAMPHETAMINE AND THEIR RING-SUBSTITUTED ANALOGUES IN SEIZED MATERIALS (revised and updated) MANUAL FOR USE BY NATIONAL DRUG TESTING LABORATORIES Laboratory and Scientific Section United Nations Office on Drugs and Crime Vienna RECOMMENDED METHODS FOR THE IDENTIFICATION AND ANALYSIS OF AMPHETAMINE, METHAMPHETAMINE AND THEIR RING-SUBSTITUTED ANALOGUES IN SEIZED MATERIALS (revised and updated) MANUAL FOR USE BY NATIONAL DRUG TESTING LABORATORIES UNITED NATIONS New York, 2006 Note Mention of company names and commercial products does not imply the endorse- ment of the United Nations. This publication has not been formally edited. ST/NAR/34 UNITED NATIONS PUBLICATION Sales No. E.06.XI.1 ISBN 92-1-148208-9 Acknowledgements UNODC’s Laboratory and Scientific Section wishes to express its thanks to the experts who participated in the Consultative Meeting on “The Review of Methods for the Identification and Analysis of Amphetamine-type Stimulants (ATS) and Their Ring-substituted Analogues in Seized Material” for their contribution to the contents of this manual. Ms. Rosa Alis Rodríguez, Laboratorio de Drogas y Sanidad de Baleares, Palma de Mallorca, Spain Dr. Hans Bergkvist, SKL—National Laboratory of Forensic Science, Linköping, Sweden Ms. Warank Boonchuay, Division of Narcotics Analysis, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand Dr. Rainer Dahlenburg, Bundeskriminalamt/KT34, Wiesbaden, Germany Mr. Adrian V. Kemmenoe, The Forensic Science Service, Birmingham Laboratory, Birmingham, United Kingdom Dr. Tohru Kishi, National Research Institute of Police Science, Chiba, Japan Dr. -
Reduced Vesicular Storage of Dopamine Causes Progressive Nigrostriatal Neurodegeneration
8138 • The Journal of Neuroscience, July 25, 2007 • 27(30):8138–8148 Neurobiology of Disease Reduced Vesicular Storage of Dopamine Causes Progressive Nigrostriatal Neurodegeneration W. Michael Caudle,1,2 Jason R. Richardson,1,2,3 Min Z. Wang,1,2 Tonya N. Taylor,1,2 Thomas S. Guillot,1,2 Alison L. McCormack,4 Rebecca E. Colebrooke,5 Donato A. Di Monte,4 Piers C. Emson,5 and Gary W. Miller1,2 1Center for Neurodegenerative Disease, 2Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, 3Department of Environmental and Occupational Medicine, University of Medicine and Dentistry-New Jersey/Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, 4The Parkinson’s Institute, Sunnyvale, California 94089, and 5The Babraham Institute, Neurobiology Programme, Babraham, Cambridge CB2 4AT, United Kingdom The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express ϳ5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts to L-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosinehydroxylase.Furthermore,weobservedanincreasein␣-synucleinimmunoreactivityandaccumulationandneurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, ␣-synuclein accumulation, and an L-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson’s disease. -
Serotonin Syndrome How to Avoid, Identify, &
Serotonin syndrome How to avoid, identify, & As the list of serotonergic agents grows, recognizing hyperthermic states and potentially dangerous drug combinations is critical to our patients’ safety. 14 Current VOL. 2, NO. 5 / MAY 2003 p SYCHIATRY Current p SYCHIATRY treat dangerous drug interactions Harvey Sternbach, MD Clinical professor of psychiatry UCLA Neuropsychiatric Institute Los Angeles, CA romptly identifying serotonin syn- drome and acting decisively can keep side effects at the mild end of the spec- Ptrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents. This article presents the latest evidence on how to: • reduce the risk of serotonin syndrome • recognize its symptoms • and treat patients with mild to life- threatening symptoms. WHAT IS SEROTONIN SYNDROME? Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behav- ioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic in- teractions between drugs that increase serotonin activity.1,2 continued VOL. 2, NO. 5 / MAY 2003 15 Serotonin Table 1 activity or reduced ability to How to recognize serotonin syndrome secrete endothelium-derived nitric oxide may diminish the System Clinical signs and symptoms ability to metabolize serotonin.2 Autonomic Diaphoresis, hyperthermia, hypertension, tachycardia, pupillary dilatation, nausea, POTENTIALLY DANGEROUS diarrhea, shivering COMBINATIONS Neuromotor Hyperreflexia, myoclonus, restlessness, MAOIs. Serotonin syndrome tremor, incoordination, rigidity, clonus, has been reported as a result of teeth chattering, trismus, seizures interactions between MAOIs— Cognitive-behavioral Confusion, agitation, anxiety, hypomania, including selegiline and insomnia, hallucinations, headache reversible MAO-A inhibitors (RIMAs)—and various sero- tonergic compounds.