DOCSLIB.ORG

(Cannabimimetics) in Serum, Hair, and Urine by Rapid and Sensitive HPLC Tandem Mass Spectrometry Screenings: Overview and Experience from Routine Testing

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(Cannabimimetics) in Serum, Hair, and Urine by Rapid and Sensitive HPLC Tandem Mass Spectrometry Screenings: Overview and Experience from Routine Testing DOI 10.1515/labmed-2012-0059 J Lab Med 2013; 37(4): 167–180 Drug Monitoring und Toxikologie/Drug Monitoring and Toxicology Redaktion: W. Steimer August Goebel , Marcus Boehm , Hartmut Kirchherr and W. Nikolaus K ü hn-Velten * Simultaneous identification and quantification of synthetic cannabinoids (cannabimimetics) in serum, hair, and urine by rapid and sensitive HPLC tandem mass spectrometry screenings: overview and experience from routine testing Simultane Identifizierung und Quantifizierung synthetischer Cannabinoide (Cannabimimetika) in Serum, Haar und Urin mittels schneller und sensitiver HPLC-Tandem- Massenspektrometrie-Screenings: Ü bersicht und Erfahrungen aus der Routineanalytik Abstract: Detection and quantification of synthetic can- Keywords: cannabimimetic; cannabinoid receptor nabinoids (synonym: cannabimimetics) used as a substi- agonist; designer drug; drug screening; LC-MS/MS; spice; tute for natural cannabis has been a real toxicological and synthetic cannabinoid; tandem-mass spectrometry. forensic issue since 2008. On the basis of a short overview of the pharmacological principle, chemical classification, Zusammenfassung: Der Nachweis und die Quantifizierung and legal situation in Germany, the development of sev- synthetischer Cannabinoide (Synonym: Cannabimime- eral analytical and screening approaches is presented. tika), die in Form von R ä uchermischungen als Cannabis- The paper further describes and validates a novel method ersatz in Gebrauch sind, ist seit 2008 ein aktuelles Thema for the simultaneous identification and quantification of der toxikologischen und forensischen Analytik. Auf der JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH- Grundlage einer kurzen Ü bersicht ü ber das pharma- 200, JWH-210, JWH-250, WIN48,098, WIN55,212-2, AM-694 kologische Prinzip, die chemische Klassifikation und die and CP47,497 by means of liquid chromatography-tandem gesetzliche Situation in Deutschland wird die Entwick- mass spectrometry (LC-MS/MS) in human serum and lung verschiedener Screeningmethoden dargestellt. Es hair using JWH-018-d11 and THC-d3 as internal stand- wird eine neue Methode zur simultanen Quantifizierung ards. Detection limits ranging from 0.018 to 0.192 ng/mL von JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH- for serum and from 0.140 to 0.820 pg/mg for hair, as well 200, JWH-210, JWH-250, WIN48,098, WIN55,212-2, AM-694 as very short retention times (up to 2.4 min), qualify this und CP47,497 in Serum und Haaren mittels Fl ü ssigchroma- method, which presently includes 11 further compounds tographie-Tandem-Massenspektrometrie (LC-MS/MS) mit on a semi-quantitative basis, for rapid screening. The same JWH-018-d11 und THC-d3 als internen Standards beschrie- method, using the deuterated 3-hydroxybutyl derivative of ben und validiert, die aufgrund der Nachweisgrenzen JWH-073, was applied for detection of 14 urinary metabo- von 0.018 bis 0.192 ng/mL im Serum und 0.140 bis 0.820 lites after enzymatic hydrolysis of conjugates. Observation pg/mg Haar sowie der besonders kurzen Retentionszeiten from routine analysis of 359 serum and 84 hair specimens (maximal 2,4 Minuten) als Screeningmethode geeignet reveals that concentrations of cannabimimetics in posi- ist. Die Methode inkludiert derzeit 11 weitere Substanzen tive samples may differ by factors of at least 400 and 3000 auf semiquantitativer Basis und ist nach enzymatischer with median values of 0.5 ng/mL and 9 pg/mg for serum Hydrolyse der Glucuronide unter Verwendung des deu- and hair, respectively. Conclusions regarding consump- terierten 3-Hydroxybutyl-Metaboliten von JWH-073 als tion behaviors and strategies to decipher metabolic routes internem Standard f ü r die Suche nach 14 Urinmetaboliten of these substances and possible implications are also verwendbar. Eine konsekutive Analytik der Routineana- discussed. lytik von 359 Serum- und 84 Haarproben ergibt, dass die 168 Goebel et al.: Simultaneous identification and quantification of synthetic cannabinoids gemessenen Konzentrationen in positiven Proben um or alterations in motor control [8 – 10] . Neuroprotective einen Faktor von 400 (Serum; Median 0.5 ng/mL) bzw. effects are currently discussed. Furthermore, receptor 3000 (Haare; Median 9 pg/mg) differieren k ö nnen. M ö gli- activation improves appetite and weight gain, so that it che R ü ckschl ü sse auf das Konsumverhalten und Ans ä tze can be expected that blockade of the CB1 receptor system zur Aufkl ä rung von Stoffwechselrouten und ihre Bedeu- leads to appetite loss. This has been successfully tried for tung werden abschlieβ end diskutiert. overweight patients with the drug rimonabant until 2008, although obese patients did not benefit from rimonabant Schl ü sselw ö rter: Cannabimimetika; Cannabinoid- treatment in terms of progression of carotid atherosclerosis Rezeptor-Agonisten; Designerdrogen; Drogenscree- [11] . By contrast, CB2 receptors are mainly associated with ning; LC-MS/MS; Spice; Synthetische Cannabinoide; different cells of the immune system and are expressed in Tandem-Massenspektrometrie. the cell membrane of B lymphocytes but mostly intracellu- larly in T cells and monocytes [12] . Their agonistic ligands exert anti-inflammatory and immunosuppressive activ- *Correspondence: Prof. Dr. W. Nikolaus K ü hn-Velten, Medizinisches ity via modulation of cytokine release. A recent approach Labor Bremen, Haferwende 12, 28357 Bremen, Germany, Tel.: + 49 421 2072107, Fax: + 49 421 20727107, integrating both receptor systems focuses on cannabi- E-Mail: [email protected] noid modulation of neuroinflammatory diseases [13] . As August Goebel, Marcus Boehm and Hartmut Kirchherr: could have been expected, a huge amount of non-natural Medizinisches Labor Bremen, Bremen, Germany cannabinoid receptor agonists (also known as cannabi- mimetics) were synthesized over the years in order to dif- ferentiate receptor systems by selectivities and potencies, Introduction to develop pain modulators, and, more recently, to find compounds with a potential to interact with the appetite Δ 9 -Tetrahydrocannabinol (THC), the pharmacological regulation network [3, 8] . principle of cannabis (marijuana), is the best-known The heterogeneous expression of CB receptors exogenous psychoactive cannabinoid with its effects enforces the presence of one or more endogenous physi- being known for many centuries. As a recreational drug, ological ligands. The search for candidate molecules THC is used in the form of chopped parts or pressed finally resulted in the identification of anandamide resin (hashish) of female plants [1] . For pharmaceutical (synonym: arachidonoyl ethanolamide) and related non- purposes, THC can be extracted by solvents from respec- classical derivatives of (poly)unsaturated fatty acids such tive plant material with the consequence that additional as 2-arachidonoylglycerol or oleamide [8, 14] . In addition psychoactive compounds are likewise present as in, for to receptor-mediated neuroprotective and immunosup- example, nabiximols which is used as supportive treat- pressive effects, anandamide may similarly act through ment of spasticity in patients suffering from multiple scle- modulation of ion channels, of vanilloid TRPV receptors, rosis [2] . By contrast, semi-synthetically produced THC is or of peroxisome proliferator-activated receptors, which used in certain countries as a pharmaceutical agent, such belong to the family of nuclear receptors [3, 8, 15] . From a as dronabinol for treatment of hyperemesis and appetite pharmacological point of view, the local impact on anan- loss for patients suffering from the AIDS wasting syn- damide synthesis and of anandamide degradation, which drome or side effects of chemotherapy [2, 3] . is predominantly catalyzed by fatty acid amide hydrolase The search for molecular transducers has led to the [16] , are promising approaches with regard to pain, appe- detection and cloning of two subtypes of cannabinoid tite, and immune cell modulation [8] . receptors, namely CB1 (with two subpopulations) and Cannabimimetics have been synthesized for several CB2 [3, 4] . Both are predominantly coupled to heterotri- years and have emerged on the market, which are offi- meric inhibitory G proteins with the consequence that cially marked “ not for human consumption ” , although, receptor activation results in diminished cAMP accu- not officially, designed as recreational hallucinogenic mulation, although the receptors express significant drugs and distributed in headshops or, predominantly, on intrinsic (or constitutive) activity due to rab-dependent internet platforms. These preparations are usually herbal endocytic cycling [5, 6] . The CB1 receptor predominates in mixtures to which one or more synthetic cannabimimetics the central nervous system where it mediates retrograde are added; one of the first brands was called “ Spice ” [17 – signaling at GABAergic and glutaminergic synapses [7] . 20] . Initially, the search of active components focused on It mediates psychoactive effects such as modulation of secondary plant ingredients such as salvinorin A before emotional control, impairment of cognition and memory, the principle became public [21] . The success of such Goebel et al.: Simultaneous identification and quantification of synthetic cannabinoids 169 preparations resulted, at least in part, from the fact that Makriyannis); (iv) aminoalkylindoles (subgroups consist it was initially possible to circumvent positive results of of naphthoylindoles, phenylacetylindoles, naphthylmeth- routine immunoassay-based
Load more

Recommended publications
  • The Role of Organic Small Molecules in Pain Management
    molecules Review The Role of Organic Small Molecules in Pain Management Sebastián A. Cuesta and Lorena Meneses * Laboratorio de Química Computacional, Facultad de Ciencias Exactas y Naturales, Escuela de Ciencias Químicas, Pontificia Universidad Católica del Ecuador, Av. 12 de Octubre 1076 Apartado, Quito 17-01-2184, Ecuador; [email protected] * Correspondence: [email protected]; Tel.: +593-2-2991700 (ext. 1854) Abstract: In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented. Keywords: anti-inflammatory drugs; QSAR; pain management; cyclooxygenase; multitarget drug; Citation: Cuesta, S.A.; Meneses, L. cannabinoid; neuropathic pain The Role of Organic Small Molecules in Pain Management.
    [Show full text]
  • N-Acyl-Dopamines: Novel Synthetic CB1 Cannabinoid-Receptor Ligands
    Biochem. J. (2000) 351, 817–824 (Printed in Great Britain) 817 N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo Tiziana BISOGNO*, Dominique MELCK*, Mikhail Yu. BOBROV†, Natalia M. GRETSKAYA†, Vladimir V. BEZUGLOV†, Luciano DE PETROCELLIS‡ and Vincenzo DI MARZO*1 *Istituto per la Chimica di Molecole di Interesse Biologico, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy, †Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, R. A. S., 16/10 Miklukho-Maklaya Str., 117871 Moscow GSP7, Russia, and ‡Istituto di Cibernetica, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy We reported previously that synthetic amides of polyunsaturated selectivity for the anandamide transporter over FAAH. AA-DA fatty acids with bioactive amines can result in substances that (0.1–10 µM) did not displace D1 and D2 dopamine-receptor interact with proteins of the endogenous cannabinoid system high-affinity ligands from rat brain membranes, thus suggesting (ECS). Here we synthesized a series of N-acyl-dopamines that this compound has little affinity for these receptors. AA-DA (NADAs) and studied their effects on the anandamide membrane was more potent and efficacious than anandamide as a CB" transporter, the anandamide amidohydrolase (fatty acid amide agonist, as assessed by measuring the stimulatory effect on intra- hydrolase, FAAH) and the two cannabinoid receptor subtypes, cellular Ca#+ mobilization in undifferentiated N18TG2 neuro- CB" and CB#. NADAs competitively inhibited FAAH from blastoma cells. This effect of AA-DA was counteracted by the l µ N18TG2 cells (IC&! 19–100 M), as well as the binding of the CB" antagonist SR141716A.
    [Show full text]
  • The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys
    The Journal of Neuroscience, May 11, 2011 • 31(19):7043–7048 • 7043 Brief Communications The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys Zuzana Justinova´,1,2 Sevil Yasar,3 Godfrey H. Redhi,1 and Steven R. Goldberg1 1Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, 2Maryland Psychiatric Research Centre, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21228, and 3Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224 Two endogenous ligands for cannabinoid CB1 receptors, anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain, and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. Here, we evaluated intravenously administered 2-AG for reinforcing effects in nonhuman primates. Squirrel monkeys that previously self-administered anandamide or nicotine under a fixed-ratio schedule with a 60 s timeout after each injection had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide range of doses. To assess involvement of CB1 receptors in the reinforcing effects of 2-AG, we pretreated monkeys with the cannabinoid CB1 receptor inverse agonist/antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide].
    [Show full text]
  • Pharmacy and Poisons (Third and Fourth Schedule Amendment) Order 2017
    Q UO N T FA R U T A F E BERMUDA PHARMACY AND POISONS (THIRD AND FOURTH SCHEDULE AMENDMENT) ORDER 2017 BR 111 / 2017 The Minister responsible for health, in exercise of the power conferred by section 48A(1) of the Pharmacy and Poisons Act 1979, makes the following Order: Citation 1 This Order may be cited as the Pharmacy and Poisons (Third and Fourth Schedule Amendment) Order 2017. Repeals and replaces the Third and Fourth Schedule of the Pharmacy and Poisons Act 1979 2 The Third and Fourth Schedules to the Pharmacy and Poisons Act 1979 are repealed and replaced with— “THIRD SCHEDULE (Sections 25(6); 27(1))) DRUGS OBTAINABLE ONLY ON PRESCRIPTION EXCEPT WHERE SPECIFIED IN THE FOURTH SCHEDULE (PART I AND PART II) Note: The following annotations used in this Schedule have the following meanings: md (maximum dose) i.e. the maximum quantity of the substance contained in the amount of a medicinal product which is recommended to be taken or administered at any one time. 1 PHARMACY AND POISONS (THIRD AND FOURTH SCHEDULE AMENDMENT) ORDER 2017 mdd (maximum daily dose) i.e. the maximum quantity of the substance that is contained in the amount of a medicinal product which is recommended to be taken or administered in any period of 24 hours. mg milligram ms (maximum strength) i.e. either or, if so specified, both of the following: (a) the maximum quantity of the substance by weight or volume that is contained in the dosage unit of a medicinal product; or (b) the maximum percentage of the substance contained in a medicinal product calculated in terms of w/w, w/v, v/w, or v/v, as appropriate.
    [Show full text]
  • Urine Drug Screening (UDS)
    Centre for Effective Practice Urine Drug Screening (UDS) Table 1: Why, who, and when? Why do UDS?1,2,3 Which patients should receive UDS? When should UDS be ordered?1 • Improve safety, encourage • Should be used routinely • At baseline (when receiving a new communication, and promote regardless of how well the patient or opioids or starting an opioid transparency of drug use patient is known to the trial) • Establish reliability of patient’s prescriber • At follow-up after initiation reported medication history • A universal approach will • Then annually or more frequently if high • Monitor adherence and detect help destigmatize testing risk or aberrant drug-related behaviours potential diversion • “I do this routinely for all of • Consider testing randomly to minimize my patients on opioids” potential for tampering Table 2: Immunoassay vs. broad spectrum (mass spec/chromatography)2,3 Immunoassay (IA) Gas Chromatography/Mass Spectrometry (GCMS) Liquid Chromatography/Tandem Mass Spectrometry (LC- MS/MS) Use Screening test Reserved for confirmatory testing (due to expense and Presumptive only; confirmatory testing needed for time required) significant decisions (e.g. legal/employment/forensic) Interpretation Does not differentiate between various opioids Differentiates: codeine, morphine, oxycodone, May not detect: hydromorphone, heroin • Semi-synthetic opioids (e.g. buprenorphine, More sensitive for semi-synthetic and synthetic opioids hydrocodone, hydromorphone, oxycodone, Sensitivity will depend on individual laboratory cut-off levorphanol)
    [Show full text]
  • The Cannabinoid WIN 55,212-2 Prevents Neuroendocrine Differentiation of Lncap Prostate Cancer Cells
    OPEN Prostate Cancer and Prostatic Diseases (2016) 19, 248–257 www.nature.com/pcan ORIGINAL ARTICLE The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells C Morell1, A Bort1, D Vara2, A Ramos-Torres1, N Rodríguez-Henche1 and I Díaz-Laviada1 BACKGROUND: Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells. METHODS: NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA. RESULTS: The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases.
    [Show full text]
  • 208614788.Pdf
    0022-3565/02/3013-1020–1024$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 301, No. 3 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 0/986104 JPET 301:1020–1024, 2002 Printed in U.S.A. Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor AMY C. PORTER, JOHN-MICHAEL SAUER, MICHAEL D. KNIERMAN, GERALD W. BECKER, MICHAEL J. BERNA, JINGQI BAO, GEORGE G. NOMIKOS, PETRA CARTER, FRANK P. BYMASTER, ANDREA BAKER LEESE, and CHRISTIAN C. FELDER Lilly Research Laboratories, Neuroscience Division (A.C.P., G.G.N., P.C., F.P.B., A.B.L., C.C.F.), Drug Disposition (J.-M.S., M.J.B., J.B.), and Research Technologies and Proteins (M.D.K., G.W.B.), Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana Received December 19, 2001; accepted February 18, 2002 This article is available online at http://jpet.aspetjournals.org Downloaded from ABSTRACT The first endocannabinoid, anandamide, was discovered in rodhamine concentrations were 2- to 9-fold higher than anan- 1992. Since then, two other endocannabinoid agonists have damide. In contrast to previously described endocannabinoids, been identified, 2-arachidonyl glycerol and, more recently, no- virodhamine was a partial agonist with in vivo antagonist activ- ladin ether. Here, we report the identification and pharmaco- ity at the CB1 receptor. However, at the CB2 receptor, vi- 14 logical characterization of a novel endocannabinoid, vi- rodhamine acted as a full agonist. Transport of [ C]anandam- jpet.aspetjournals.org rodhamine, with antagonist properties at the CB1 cannabinoid ide by RBL-2H3 cells was inhibited by virodhamine.
    [Show full text]
  • D30c5a005c7b549217479d4cbb
    RESEARCH ARTICLE Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial Jose M. Trigo1, Alexandra Soliman1, Lena C. Quilty2,3, Benedikt Fischer3,4,5,6, JuÈrgen Rehm3,4,5,7,8, Peter Selby3,9,10, Allan J. Barnes11¤a, Marilyn A. Huestis11¤b, Tony P. George3,9,12, David L. Streiner3,13, Gregory Staios1, Bernard Le Foll1,9* a1111111111 a1111111111 1 Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada, 2 Campbell Family Mental Health Research a1111111111 Institute, CAMH, Toronto, Canada, 3 Department of Psychiatry, University of Toronto, Toronto, Canada, a1111111111 4 Institute of Medical Science, University of Toronto, Faculty of Medicine, Toronto, Canada, 5 Institute for a1111111111 Mental Health Policy Research, CAMH, Toronto, Canada, 6 Centre for Applied Research in Mental Health & Addiction, Faculty of Health Sciences, Simon Fraser University, Vancouver, Canada, 7 Addiction Policy, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada, 8 Institute of Clinical Psychology and Psychotherapy & Center of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische UniversitaÈt Dresden, Dresden, Germany, 9 Addictions Division, CAMH, Toronto, Canada, 10 Department of Family and Community Medicine, University of Toronto, Toronto, Canada, 11 Chemistry and Drug OPEN ACCESS Metabolism, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, United Citation: Trigo JM, Soliman A, Quilty LC, Fischer B, States of America, 12 Division of Brain and Therapeutics, CAMH, Toronto, Canada, 13 Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, Canada Rehm J, Selby P, et al.
    [Show full text]
  • Beneficial Changes in Rat Vascular Endocannabinoid System In
    International Journal of Molecular Sciences Article Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597 Marta Baranowska-Kuczko 1,2,* , Hanna Kozłowska 1, Monika Kloza 1, Ewa Harasim-Symbor 3, Michał Biernacki 4 , Irena Kasacka 5 and Barbara Malinowska 1 1 Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland; [email protected] (H.K.); [email protected] (M.K.); [email protected] (B.M.) 2 Department of Clinical Pharmacy, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland 3 Department of Physiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] 4 Department of Analytical Chemistry, Medical University of Białystok, ul. Mickiewicza 2D, 15-222 Białystok, Poland; [email protected] 5 Department of Histology and Cytophysiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] * Correspondence: [email protected]; Tel./Fax: +48-85-74-856-99 Citation: Baranowska-Kuczko, M.; Abstract: Our study aimed to examine the effects of hypertension and the chronic administration of Kozłowska, H.; Kloza, M.; the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabi- Harasim-Symbor, E.; Biernacki, M.; noid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small Kasacka, I.; Malinowska, B. Beneficial mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats Changes in Rat Vascular (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days).
    [Show full text]
  • Anandamide-Mediated CB1/CB2 Receptor-Independent NO Production in Rabbit Aortic Endothelial Cells
    JPET Fast Forward. Published on March 22, 2007 as DOI: 10.1124/jpet.106.117549 JPET FastThis article Forward. has not beenPublished copyedited on and Marchformatted. 22, The 2007 final version as DOI:10.1124/jpet.106.117549 may differ from this version. JPET # 117549 Anandamide-mediated CB1/CB2 receptor-independent NO production in rabbit aortic endothelial cells LaTronya McCollum, Allyn C. Howlett and Somnath Mukhopadhyay1 Neuroscience of Drug Abuse Research Program Julius. L. Chambers Biomedical/Biotechnology Research Institute North Carolina Central University, Durham, NC 27707 Downloaded from jpet.aspetjournals.org at ASPET Journals on September 30, 2021 1 Copyright 2007 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on March 22, 2007 as DOI: 10.1124/jpet.106.117549 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 117549 Running title: Novel Anandamide receptor mediated eNOS activation 1Corresponding author Somnath Mukhopadhyay, Ph.D. Neuroscience of Drug Abuse Research Program J. L. Chambers Biomedical/Biotechnology Research Institute North Carolina Central University Downloaded from 700 George Street, Durham, NC 27707 Ph # (919) 530-7762 FAX (919) 530-7760 jpet.aspetjournals.org [email protected] Abbreviations used are: Abn-CBD, abnormal cannabidiol; DAF-DA, 4-amino-5- methylamino-2',7'-difluorofluorescein diacetate; ECL, enhanced chemiluminescence; eNOS, at ASPET Journals on September 30, 2021 endothelial NO synthase; MAPK, mitogen-activated protein kinase; PCR, polymerase chain reaction; PKA, cyclic AMP-dependent protein kinase; PI3-kinase, phosphatidylinositol 3-kinase; PVDF, polyvinylidene difluoride; PTX, pertussis toxin; RAEC, rabbit aortic endothelial cells; RT-PCR, reverse transcription-polymerase chain reaction; SDS-PAGE, sodium dodecyl sulfate- polyacrylamide gel electrophoresis.
    [Show full text]
  • Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After D9-Tetrahydrocannabinol and Anandamide Administration
    Neuropsychopharmacology (2010) 35, 1775–1787 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org FAAHÀ/À Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation after D9-Tetrahydrocannabinol and Anandamide Administration 1 1 1 2 1 Katherine W Falenski , Andrew J Thorpe , Joel E Schlosburg , Benjamin F Cravatt , Rehab A Abdullah , 1 1 1 1 Tricia H Smith , Dana E Selley , Aron H Lichtman and Laura J Sim-Selley* 1Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA; 2 The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA 9 Repeated administration of D -tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB1 cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAHÀ/À mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose–effect curves for antinociception, catalepsy, and hypothermia than in AEA dose–effect curves. Subchronic THC significantly attenuated agonist- 35 3 stimulated [ S]GTPgS binding in brain
    [Show full text]
  • Nabiximols for the Treatment of Cannabis Dependence a Randomized Clinical Trial
    Research JAMA Internal Medicine | Original Investigation Nabiximols for the Treatment of Cannabis Dependence A Randomized Clinical Trial Nicholas Lintzeris, MBBS, PhD; Anjali Bhardwaj, PhD; Llewellyn Mills, PhD; Adrian Dunlop, MBBS, PhD; Jan Copeland, PhD; Iain McGregor, PhD; Raimondo Bruno, PhD; Jessica Gugusheff, PhD; Nghi Phung, MBBS, PhD; Mark Montebello, PhD; Therese Chan, BPharm; Adrienne Kirby, BSc(Hons); Michelle Hall, GradCertHlthSc; Meryem Jefferies, PhD; Jennifer Luksza, PhD; Marian Shanahan, PhD; Richard Kevin, PhD; David Allsop, PhD; for the Agonist Replacement for Cannabis Dependence (ARCD) study group Supplemental content IMPORTANCE There are no effective medications for treating dependence on cannabis. OBJECTIVE To examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence. DESIGN, SETTING, AND PARTICIPANTS This parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week, multisite outpatient study recruited participants from February 3, 2016, to June 14, 2017, at 4 outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18 to 64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Results for primary efficacy measures and all secondary outcomes were obtained using a modified intention-to-treat data set. INTERVENTIONS Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses—up to 32 sprays daily (tetrahydrocannabinol, 86.4 mg, and cannabidiol, 80 mg), dispensed weekly.
    [Show full text]