STATUTORY DECLARATION
`
`I, Seema Rampersad ofThe British Library, 96 Euston Road, London NWl 2DB, United
`Kingdom, Legal designation the British Library Board ('the Library'), do solemnly and
`sincerely declare, that:
`
`l.
`
`I have access to and knowledge of the records and record keeping practices and
`procedures of the Library which relies to some extent on information collated by a third
`party. I have reviewed these records and record keeping practices, to prepare this
`declaration. Based on that review, the ordinary practices and procedures of the Library
`and to the best of my personal knowledge and belief, I make the following declaration.
`
`2. The Reading Rooms of the Library are open to any bona fide enquirer and any
`publication in the Library may be consulted in the Reading Rooms on request. Any
`organisation or individual may purchase photocopies of extracts from publications.
`
`On the 18th February 2002 the Library received a copy of the journal "Psychopharmacology
`(publisher Springer-Verlag) Volume 159, Number 4, February 2002 containing the article
`Depot Naltrexone: long-lasting antagonism of the effects of heroin in humans (Comer SD,
`Collins ED, Kleber HD, Nuwayser ES, Kerrigan JH, Fischman MW) on pages 351-360". It
`was to the best of my knowledge received intact and was assigned the Library Shelfmark:
`Document Supply 6946.546500. It was then catalogued on 18th February 2002 and then
`shelved on 18th February 2002 and would have been available for public use to the best of
`my knowledge and belief from that date. There is now produced to me and marked "A" a true
`and correct copy of the book cover, title page, content pages and copy of the article showing
`the Library receipt/cataloguing date stamp 18th February 2002 1
`•
`
`1 Each exhibit will have to be signed by the solicitor and will have to have the words below printed on it. The exhibit
`will then have to be signed and dated by the solicitor
`
`"This is the exhibit marked "A" referred to in the statutory declaration of
`signed the dh of April 2018
`before me
`Dolores Rice Notary Public"
`
`Seema Rampersad
`
`British Library Research Service
`Tel: +44 (0) 20 7412 7903 research@bl.uk
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`3. And I make this solemn declaration conscientiously believing the same to be true and by
`virtue of the provisions of the Statutory Declarations Act 1835.
`
`Signature~~,(_
`.S~MA- ti'["M I(:MfrP
`DECLARED at
`This 1 i"
`
`day of April
`
`in the year 201 8
`
`Date t1~' ~~ ~ J(
`
`Before me
`
`~&~ItA~
`Dolores Rice
`Notary Public
`
`3 Cedar Court
`6 Grosvenor Road
`Wanstead
`London
`Ell 2HQ
`
`Tel: 0208 530 3085
`
`British Library Research Service
`Tel: +44 (0) 20 7412 7903 research@bl.uk
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`18-FEB-2002 BSDS
`PSYCHOPHARMACOLOGY -BERLIN-
`
`BOSTON SPA
`LS23 7BQ
`
`.~
`
`6946.546500
`
`VOL 159 PART 4
`
`PB
`
`111
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`Psychopharmacology
`
`1 Aims and Scope
`
`Psychopharmacology is an international journal
`of research and scholarship, the aims of which are
`to cover the general area of elucidating mechanisms
`by which drugs affect behavior, both terms intended
`in the broadest sense. The scope of the Journal
`extends from clinical psychopharmacology (includ-
`ing trials), to experimental studies on the effects of
`drugs on cognition and behavior in humans and
`laboratory studies in experimental animals. The
`research methodologies (techniques covered)
`may range from neurochemical assays and electro-
`physiological recording to studies of functional
`neuroimaging, and the methods of experimental
`psychology and ethology, as well as clinical neuro-
`logy and psychiatry. The journal is particularly
`interested in articles that integrate these levels of
`analysis.
`
`2 Copyright
`
`Submission of a manuscript implies: that the
`work described has not been published before
`(except in form of an abstract or as part of a pub-
`lished lecture, review or thesis); that it is not under
`consideration for publication elsewhere; that its pub-
`lication has been approved by all co-authors, if any,
`as well as - tacitly or explicitly- by the responsible
`authorities at the institution where the work was
`carried out. Transfer of copyright to Springer-Verlag
`becomes effective if and when the article is accepted
`for publication. The copyright covers the exclusive
`right (for U.S. government employees: to the extent
`transferable) to reproduce and distribute the article,
`including reprints, translations, photographic
`reproductions, microform, electronic form (offline,
`online) or other reproductions of similar nature.
`
`All articles published in this journal are protect-
`ed by copyright, which covers the exclusive rights
`to reproduce and distribute the article (e.g., as off-
`prints), as well as all translation rights. No material
`published in this journal may be reproduced pho-
`tographically or stored on microfilm, in electronic
`data bases, video disks, etc., without first obtaining
`written permission from the publisher. The use of
`general descriptive names, trade names, trademarks,
`etc., in this publication, even if not specifically
`identified, does not imply that these names are not
`protected by the relevant laws and regulations.
`An author may make an article published by
`Springer-Verlag available on his/her personal home
`page, provided the source of the published article
`is cited and Springer-Verlag is mentioned as the
`copyright holder. Authors are requested to create a
`link to the published article in LINK, Springer's
`internet service. The link must be accon1.panicd by
`the following text: "The original publication is
`available on LINK at http://link.springer.de".
`While the advice and information in this journal
`is believed to be true and accurate at the date
`of its publication, neither the authors, the editors,
`nor the publisher can accept any legal responsibility
`for any errors or omissions that may be made.
`The publisher makes no warranty, express or implied,
`with respect to the material contained herein.
`Special regulations for photocopies in the USA:
`Photocopies may be made for personal or in-house
`use beyond the limitations stipulated under Section
`107 or 108 of U.S. Copyright Law, provided a fee is
`paid. All fees should be paid to the Copyright
`Clearance Center, Inc., 21 Congress Street, Salem,
`MA 01970, USA, stating the ISSN 0033-3158, the
`volume, and the first and last page numbers of
`
`each art~cle copied. The copyright owner's consent
`does not include copying for general distribution,
`promotion, new works, or resale. In these cases,
`specific written permission must first be obtained
`from the publisher.
`The Canada Institute for Scientific and Technical
`Information (CISTI) provides a comprehensive,
`world-wide document delivery service for all
`Springer-Verlag journals. For more information,
`or to place an order for a copyright -cleared
`Springer-Verlag document, please contact Client
`Assistant, Document Delivery, CISTI,
`Ottawa KIA oS2, Canada (Tel. +1-613-9939251;
`Fax +1-613-9528243; e-mail: cisti.docdel@nrc.ca).
`
`3 Suliscription information
`ISSN print edition.o033-3158
`ISSN electronic edition 1432-2072
`Volumes 159-164 (4 issues each) will appear
`in 2002.
`Psychopharmacology appears semi-monthly.
`It is published by Springer-Verlag Berlin,
`Heidelberger Platz 3, 14197 Berlin, Germany.
`Periodicals postage rates paid at New York,
`NY, and at additional mailing offices. Springer-
`Verlag New York Inc., 175 Fifth Avenue, New York,
`NY 10010, USA are our Mailing Agents.
`Postmaster send all address changes to:
`Psychopharmacology
`Springer-Verlag New York Inc.
`journal Fulfillment Services Dept.
`P.O. Box 2485, Secaucus, N) 07096-2485, USA
`11 North and South America
`Please ask for the appropriate price list in US $.
`Please mail orders and inquiries to:
`Springer-Verlag New York Inc.,
`journal Fulfillment, P.O. Box 2485,
`Secaucus, NJ 07096-2485, USA
`Tel. +r-8oo-SPRINGER (77746437) or +1-212-4601500
`Fax +1-201-3484505
`e-mail: journals@springer-ny.com
`11 All countries except North and South America
`Recommended annual subscription rate incl.
`basic LINK license: € 3450.00 (Prices are net-prices
`subject to local VAT) plus carriage charges:
`(Germany: € 53-5D, other countries: € 91.70). Single
`issue price available upon request.
`SAL delivery (surface airmail lifted) is mandatory
`to Japan, North & South East Asia, India, Australia
`and New Zealand. Customers should ask for the
`appropriate price list. Airmail delivery to all other
`countries is available upon request.
`Orders or claims can either be placed via a
`bookseller or sent directly to:
`Springer-Verlag, Customer Service journals,
`Haberstrasse 7, 69126 Heidelberg, Germany
`Tel. +49-6221-345240, Fax +49-6221-345229
`e-mail: subscriptions@springer.de
`Cancellations must be received by September 30
`to take effect at the end of the same year.
`Changes of address: Allow six weeks for all
`changes to become effective. All communications
`should include both old and new addresses
`(with postal codes) and should be accompanied
`by a mailing label from a recent issue. According
`to § 4 Sect. 3 of the German Postal Services Data
`Protection Regulations, if a subscriber's address
`changes, the German Federal Post Office can inform
`the publisher of the new address even if the sub-
`
`scriber has not submitted a formal application for
`mail to be forwarded. Subscribers not in agreement
`with this procedure may send a written complaint
`to Customer Service journals, Karin Tiks, within
`14 days of publication of this issue.
`Back volumes: Prices are available on request.
`Microform editions are available from:
`ProQuest. Further information available with
`http:/ /www.il.proquest.com/umi/.
`
`4 Electronic edition
`
`I
`
`An electronic edition of this journal is available
`via the LINK Internet Service at http://link.
`springer.de or at http://link.springer-ny.com.
`LINK Alert: Would you like to automatically
`receive via e-mail news of newly published articles
`listed in the journal's table of contents with direct
`links to the respective abstracts? Then take ad-
`vantage of our free LINK Alert service. To register
`and obtain further information, go to http:/ /link.
`springer.de/alert/ or http://link.springer-ny.com/
`alert/.
`Online First: Online First articles are published
`in electronic form weeks before distribution of
`the printed journal. An online publication date is
`published in each Online First article and its
`print version. Authors should be aware that after
`electronic publication they cannot withdraw an
`article or change its content. Any corrections
`have to be made in an Erratum which will be
`hyper linked to the article. Online First articles
`can be cited using their Digital Object Identifier
`(DOl), a unique and consistent identification
`code, included in both the print and the electronic
`versions.
`This journal is included .in the ADONIS service.
`In the ADONIS service copies of individual articles
`can be printed out from compact discs (CD-ROM)
`on demand. An explanatory leaflet giving further
`details of the scheme is available from the publisher
`on request.
`
`5 Responsible for advertisements
`
`Springer-Verlag, Edda Liickermann,
`Heidelberger Platz 3, 14197 Berlin, Germany
`Tel. +49-30-82787-5739; Fax +49-30-82787-5300
`e-mail: anzeigen@springer.de,
`Internet: www.wikom.springer.de
`
`6 Production
`Springer-Verlag, Marion Bludau-Wentz,
`journal Production Medicine,
`Postfach 10 52 So, 69042 Heidelberg, Germany
`Address for courier, express and registered mail:
`Tiergartenstrasse 17, 69121 Heidelberg, Germany
`Tel. +49-6221-4878325; Fax +49-6221-4878658
`e-mail: bludau@springer.de
`Typesetters and printers:
`Sturtz AG, Wiirzburg, Germany
`Springer-Verlag Berlin Heidelberg New York
`a member of BertelsmannSpringer
`Science+ Business Media GmbH
`http://www.springer.de
`Ownership and Copyright
`©Springer-Verlag Berlin Heidelberg 2002
`Printed in Germany
`
`A2
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`Psychopharmacology
`
`for North and South America
`
`for the rest of the world
`
`Clinical psychopharmacology
`
`Field editors J.H. Krystal, West Haven
`
`Advisory editors B. Cohen, Belmont
`W.F. Gattaz, Sao Paulo
`M. Laruelle, New York
`C.J. McDougle, Indianapolis
`L.H. Price, Providence
`
`Human cognitive psychopharmacology
`
`Field editors H. de Wit, Chicago
`
`Advisory editors T. Roehrs, Detroit
`H. Weingartner, Washington DC
`
`Alcohol and substance abuse in humans
`
`Field editors H. de Wit, Chicago
`
`Advisory editors G. Bigelow, Baltimore
`S.S. O'Malley, New Haven
`K.A. Perkins, Pittsburgh
`
`Molecular neuropsychopharmacology
`
`Field editors D.R. Sibley, Bethesda
`
`Advisory editors
`
`I. Creese, Newark
`I. Kopin, Bethesda
`J.M. Perel, Pittsburgh
`B.L. Roth, Cleveland
`
`Behavioral pharmacology in laboratory animals
`
`Field editors K.A. Miczek, Medford
`
`Advisory editors J. Bergman, Belmont
`M.E. CmToll, Minneapolis
`C.L. Cunningham, Portland
`K.A. Grant, Winston-Salem
`S.G. Holtzman, Atlanta
`J. Stewart, Montreal
`
`Preclinical psychopharmacology
`
`Field editors M.A. Geyer, La Jolla
`
`Advisory editors C.W. Bradberry, West Haven
`J.N. Crawley, Bethesda
`G.F. Koob, San Diego
`I. Lucki, Philadelphia
`N.R. Swerdlow, La Jolla
`
`A4
`
`J. Gerlach, Roskilde
`P.J. Cowen, Oxford
`
`I. Anderson, Manchester
`P. Bech, Hiller0d
`0. Lingjaerde, Oslo
`E.S. Paykel, Cambridge
`
`D.M. Warburton, Reading
`
`I. Hindmarch, Guildford
`B.J. Sahakian, Cambridge
`J. Snel, Amsterdam
`
`D.M. Warburton, Reading
`
`I. Hindmarch, Guildford
`B.J. Sahaldan, Cambridge
`J. Snel, Amsterdam
`
`D. Hoyer, Basel
`
`J. Heykants, Beerse
`C.A. Marsden, Nottingham
`M.B.H. Youdim, Haifa
`
`T.W. Robbins, Cambridge
`
`A.R. Cools, Nijmegen
`B.J. Everitt, Cambridge
`M. Koch, Bremen
`W. Koek, Castres
`I.P. Stolerman, London
`M.-H. Thiebot, Paris
`
`A.R. Green, Loughborough
`
`G. DiChiara, Cagliari
`D.J. Heal, Nottingham
`H.J. Little, Durham
`M.J. Millan, Paris
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`Psychopharmacology
`
`Volume 159 Number 4 February 2002
`
`Original Investigations
`Kankaanpaa A, Meririnne E, Seppala T:
`5-HT 3 receptor antagonist MDL 72222 attenuates
`cocaine- and mazindol-, but not methylphenidate-
`induced neurochemical and behavioral effects
`in the rat 341
`Comer SD, Collins ED, Kleber HD, Nuwayser ES,
`Kerrigan JH, Fischman MW:
`Depot naltrexone: long-lasting antagonism
`of the effects of heroin in humans 351
`Collins SL, Kantak KM:
`Neuronal nitric oxide synthase inhibition decreases
`cocaine self-administration behavior in rats 361
`Blednov YA, Stoffel M, Cooper R, Wallace D, Mane N,
`Harris RA:
`Hyperactivity and dopamine D1 receptor activation
`in mice lacking girk2 channels 370
`Martin M, Ledent C, Parmentier M, Maldonado R,
`Valverde 0:
`Involvement of CBl cannabinoid receptors
`in emotional behaviour 379
`Winsauer PJ, McCann UD, Yuan J, Delatte MS,
`Stevenson MW, Ricaurte GA, Moerschbaecher JM:
`Effects of fenfluramine, m-CPP and triazolam
`on repeated-acquisition in squirrel monkeys before
`and after neurotoxic MDMA administration 388
`Evans SM, Haney M, Foltin RW:
`The effects of smoked cocaine during the follicular
`and luteal phases of the menstrual cycle in women
`397
`Karper PE, De La Rosa H, Newman ER, Krall CM,
`Nazarian A, McDougall SA, Crawford CA:
`Role of D1-like receptors in amphetamine-induced
`behavioral sensitization: a study using D1A receptor
`knockout mice 407
`
`Zhang M, Kelley AE:
`Intake of saccharin, salt, and ethanol solutions
`is increased by infusion of a mu opioid agonist
`into the nucleus accumbens 41 S
`Aravagiri M, Marder SR:
`Brain, plasma and tissue pharmacokinetics
`of risperidone and 9-hydroxyrisperidone
`after separate oral administration to rats 424
`Attenburrow M-J, Odontiadis J, Murray BJ, Cowen PJ,
`Franklin M:
`Chromium treatment decreases the sensitivity
`of 5-HT2A receptors 432
`Pone KCF, Beckett SRG, Topham lA, Swettenham J,
`Ball M, Maddocks L:
`Long-term changes in social interaction and reward
`following repeated MDMA administration
`to adolescent rats without accompanying serotonergic
`neurotoxicity 437
`Case Report
`Kasper S:
`Managing reboxetine-associated urinary hesitancy
`in a patient with major depressive disorder:
`a case study 445
`
`On line e ditio n in LINK- http:/1/ink.springet~de
`
`Indexed in I abstracted by Current Contents, Psychological Abstracts,
`Psyc INFO, Index Medicus and in EM BASE
`
`Printed on acid-free paper
`
`~Springer
`
`A5
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`Psychopharmacology (2002) 159:35 1-360
`DOl 10.1007 ls002 130 I 00909
`
`Sandra D. Comer · Eric D. Collins
`Herbert D. Kleber · Elie S. Nuwayser
`James H. Kerrigan · Marian W. Fischman
`Depot naltrexone: long-lasting antagonism of the effects
`of heroin in humans
`
`Received: 28 November 2000 I Accepted: 2 August 2001 I Published online: 1 November 2001
`© Springer-Verlag 2001
`
`Abstract Rationale: Naltrexone, an opioid antagonist, is
`currently approved as a treatment for heroin dependence.
`However, naltrexone is generally not well accepted by
`patients, and medication non-compliance is a difficult
`obstacle to treatment. A sustained-release form of nal-
`trexone may improve compliance. Objective: The pres-
`ent study was designed to evaluate the time course, safe-
`ty, and effectiveness of a depot formulation of naltrexone
`(Depotrex®). Methods: Twelve heroin-dependent indi-
`viduals participated in an 8- week inpa tient study. After a
`!-week detoxification period, six participants received
`192 mg naltrexone base and six participants received
`384 mg naltrexone base. For safety, the low dose of de-
`pot naltrexone was tested before the high dose. The ef-
`fects of heroin (0, 6.25, 12.5, 18.75, 25 mg, IV) were
`evaluated for the next 6 weeks. One dose of heroin was
`tested per day on Mondays through Fridays, and the en-
`tire dose range was tested each week. Active heroin dos-
`es were administered in ascending order during the
`week, while placebo could be administered on any day.
`Subjective, performance, and physiological effects were
`measured both before and after heroin administration.
`The hypothese s were that depot naltrexone would antag-
`onize the effects of heroin, and that the high dose of de-
`pot naltrexone would produce a more effective and lon-
`ger-lasting antagonism than the low dose. Results: The
`low and high doses of depot naltrexone antagonized her-
`oin-induced subjective ratings for 3 and 5 weeks, respec-
`tively. Plasma levels of naltrexone remained above
`1 ng/ml for approximately 3 and 4 weeks after adminis-
`tration of 192 mg and 384 mg naltreX:one. Other than the
`initial discomfort associated with the injection of depot
`
`S.D. Comer (181) · E.D. Collins · H.D. Kleber· M.W. Fischman
`Division on Substance Abuse,
`New York State Psychiatric Institute and Department of Psychiatry,
`College of Physicians and Surgeons of Columbia University,
`1051 Riverside Drive, Unit 120, New York, NY 10032, USA
`e-mail: sdc I O@columbia.edu
`Tel.: +1-212-5435981, Fax: +1 -212-5435991
`E.S . Nuwayser · J.H. KetTigan
`Biotek Inc., 21-C Olympia Avenue, Woburn, MA 01801 , USA
`
`naltrexone, there were no untoward side-effects. Conclu-
`sions: These results suggest that this depot formulation
`of naltrexone provides a safe, effective, long-lasting an-
`tagonism of the effects of heroin.
`
`Keywords Heroin · Human · Naltrexone · Opioid ·
`Subjective effect · Sustained-release · Depotrex
`
`Introduction
`
`Naltrexone, an orally effective opioid antagonist, was
`approved in 1984 by the Food and Drug Administration
`as a maintenance medication for the treatment of heroin
`dependence. Naltrexone potently antagonizes the effects
`of opioid agonists, while producing no agonist effects of
`its own (Jaffe and Martin 1990). Tolerance does not de-
`velop to naltrexone's antagonist effects and the drug has
`few side effects, even after chronic administration of
`over 1 year (Kleber et al. 1985). Because of its ability to
`antagonize the effects of mu opioid agonists, its long du-
`ration of action, and its favorable pharmacokinetic and
`metabolic characteristics (Martin et al. 1966, 1973 ), nal-
`trexone initially held great promise as a treatment for
`opioid dependence. The early rationale for using a pure
`antagonist was that once the individual was maintained
`on naltrexone, subsequent attempts to self-administer the
`illicit opioid would not produce euphoria (Wikler 1965;
`Martinet a!. 1966) and the user would eventually discon-
`tinue opioid use altogether.
`Although the use of naltrexone as a maintenance ther-
`apy for opioid abuse can be effective (Martinet al. 1973;
`O'Brien eta!. 1975; Judson et al. 1981), it has been used
`most successfully with only a select subpopulation of
`highly motivated individuals. Because of the problems
`with medication non-compliance, naltrexone therapy has
`not lived up to its initial promise. This may be in part be-
`cause opioid users are accustomed to self-administering
`potent reinforcers, and, by contrast, the complete ab-
`sence of opioid-induced reinforcing effects may be unac-
`ceptable. Another factor that may contribute to noncom-
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`352
`Table 1 Participant demo-
`graphics. Numbers in parenthe-
`ses represent+ 1 SEM
`
`192 mg naltrexone
`
`384 mg naltrexone
`
`Age (average; years)
`Years of heroin use (average)
`Amount spent for heroin (average; $/day)
`Tobacco cigarette use (range; no. per day)
`Cocaine use (range; occasions/week)
`Amphetamine use (range; occasions/week)
`Marijuana use (range; occasions/week)
`Alcohol use (range; occasions/week)
`Sedative use (range; occasions/week)
`
`33.8 (2.5)
`10.7 (2.5)
`$39 (4)
`8-20
`0-1
`0-1
`0-1
`0-1
`0-1
`
`29.2 (3.2)
`9.1 (3.5)
`$55 (12)
`10-20
`0-3
`0
`0-3
`0-3
`0-1
`
`pliance is that, unlike methadone, discontinuation of nal-
`trexone maintenance has no adverse consequences (e.g.
`withdrawal effects). Furthermore, naltrexone itself may
`induce adverse neuropsychiatric and gastrointestinal ef-
`fects, such as dysphoria, nausea, and abdominal pain
`(Hollister et al. 1981; Crowley et al. 1985; Oncken et al.
`2001).
`Sustained-release forms of naltrexone could increase
`compliance and ultimately improve treatment effective-
`ness (Martin and Sandquist 1974; Abrahams and Ronel
`1975; Chiang et al. 1985a, 1985b). Chiang et al. (1985a,
`1985b), for example, administered biodegradable beads
`containing a dose of 63 mg naltrexone to normal, healthy
`volunteers. Following an initial burst of release, this for-
`mulation yielded relatively constant plasma levels of nal-
`trexone (0.3-0.5 ng/ml) for up to 1 month. However,
`when these investigators administered challenge doses of
`morphine (15 mg IM), the results were variable. In some
`participants, morphine was completely ineffective, while
`in others, morphine-like effects were observed. In addi-
`tion, three of the five participants who completed the
`study developed tissue inflammation near the site of
`bead implantation (Chiang et al. 1985b). Although the
`adverse tissue reaction and the variable antagonist effec-
`tiveness of the naltrexone beads limited its clinical utili-
`ty, the rationale behind the development of a sustained-
`release form of naltrexone was sound.
`A new depot formulation of naltrexone (Depotrex®)
`has been developed that provides a stable, long-lasting
`elevation in plasma naltrexone levels with either no or
`minimal side-effects (Heishman et al. 1994; Alim et al.
`1995; Kranzler et al. 1998). In an early tolerability study,
`Alim and colleagues (1995) reported blockade of the
`physiological and subjective effects of 10 mg intrave-
`nous (IV) morphine in cocaine-dependent participants
`who received 206 mg depot naltrexone; side-effects as-
`sociated with naltrexone were minimal in these partici-
`pants. Kranzler and colleagues (1998) further showed
`that 206 mg depot naltrexone significantly reduced the
`percentage of heavy drinking days in alcoholics. Adverse
`effects reported after depot naltrexone were comparable
`to those reported after oral naltrexone administration.
`Although this formulation of depot naltrexone appears to
`be safe and effective in treating alcohol dependence, it
`has not yet been tested with heroin. The purpose of the
`current study was 1) to determine whether the new for-
`mulation of depot naltrexone will antagonize the effects
`
`of heroin at doses comparable to those used on the
`streets today, and 2) to assess the duration of antagonist
`effect of 192 mg and 384 mg depot naltrexone. The hy-
`pothesis was that depot naltrexone would dose-depen-
`dently antagonize the effects of heroin.
`
`Materials and methods
`Participants
`Fifteen heroin-dependent men, who were not seeking treatment for
`their drug use, began the 8-week protocol. Three participants left
`the study prior to depot naltrexone administration: one was dis-
`charged for aggressive behavior toward the staff, and two left for
`personal reasons. Twelve participants (eight non-Hispanic Cauca-
`sian, three Hispanic, and one African American) completed the
`study: six received 192 mg depot naltrexone, and six received
`384 mg depot naltrexone (Table 1). The low dose of depot naltrex-
`one was tested in the first six participants. The groups did not dif-
`fer in age, years of heroin use, and amount of money spent on her-
`oin per day. All participants had experience using heroin IV. One
`participant in the low-dose group and two in the high-dose group
`preferred to use heroin intranasally; all other participants preferred
`to use heroin IV. All participants were dependent on heroin at the
`start of the study, as verified by a naloxone challenge test (Wang
`1974).
`After an initial telephone interview, eligible participants com-
`pleted detailed questionnaires on drug use, general health and
`medical history, and a medical and psychological evaluation in the
`laboratory. An electrocardiogram and Mantoux test or chest X-ray
`were also performed. Routine laboratory analyses included a
`blood chemistry panel, thyroid function test, syphilis and hepatitis
`(A, B, and C) screening, and urinalysis. Urine drug toxicologies
`(opioids, cocaine, benzodiazepines, cannabinoids, and ampheta-
`mines) were also performed using a radiative energy attenuation
`and fluorescence polarization immunoassay system (ADx System;
`Abbott Laboratories, Abbott Park, Ill., USA). Participants were
`told that they would be detoxified from heroin during the first
`week of the study, that they would receive one of two doses ot a
`depot formulation of naltrexone, and that a range of IV heroin
`doses would be tested each week for the 6 weeks following depot
`naltrexone administration.
`Participants were excluded from the study if they were seeking
`drug treatment, dependent on alcohol or illicit drugs other than
`opioids, or had a major Axis I psychiatric diagnosis other than
`opioid dependence. Those who had recent histories of violence 01
`who were on parole/probation were excluded from the study. Par-
`ticipants were required to be physically healthy, and fully able tc
`perform all study procedures. Although both men and women
`were screened for the study, none of the women met the eligibility
`requirements. Prior to admission, participants completed a training
`session, during which the study procedures were explained tc
`them in detail. Volunteers were paid $25 per inpatient day and ar
`additional $25 per day bonus if they completed the study. Partici·
`pants signed consent forms describing the aims of the study, anc
`
`AMN1010
`IPR of Patent No. 7,919,499
`
`

`

`the potential risks and benefits of participation. Free HIV testing
`and education were offered, and during the last week of the study,
`participants were offered referrals for treatment. This study was
`approved by the Institutional Review Board of the New York State
`Psychiatric Institute (NYSPI).
`
`Apparatus
`
`During experimental sessions, participants were seated in a room
`equipped with Macintosh computers. All computer activities, vital
`signs and behaviors were continuously monitored by the experi-
`menters in an adjacent control room via a continuous on-line com-
`puter network, video cameras, and vital signs monitors (cardiovas-
`cular function was measured using a Sentry II Vital Signs Monitor,
`NBS Medical, Costa Mesa, Calif., USA; arterial oxygen saturation
`was measured using a pulse oximeter Model 400, Palco Laborato-
`ries, Santa Cruz, Calif., USA). Communication between the staff
`and participants was kept to a minimum during experimental ses-
`sions.
`
`Detoxification procedures
`
`Participants were admitted into the hospital, and detoxified during
`the first week after admission. Buprenorphine (8 mg sublingual
`tablet; National Institute on Drug Abuse, Rockville, Md., USA)
`was administered on the first 1-2 days after admission. Two days
`after the last buprenorphine dose, oral naltrexone (DuPont
`Pharma, Wilmington, Del., USA) was administered for 3 con-
`secutive days (25, 50, and 50 mg per day) to ensure that partici-
`pants were willing and able to tolerate its effects. Clonidine HCl
`(0.2 mg PO, every 6 h; Boehringer Ingelheim Pharmaceuticals,
`Inc., Ridgefield, Conn., USA), ketorolac tromethamine (30 mg
`IM, every 6 h; Roche Laboratories, Nutley, N.J., USA), prochlor-
`perazine (10 mg PO or IM, every 8 h; SmithKline Beecham Con-
`sumer Healthcare, Pittsburgh, Penn., USA) and clonazepam (2 mg
`PO, every 8 h; Roche Laboratories) were available, as needed,
`during the detoxification week. Thereafter, trazodone (50-100 mg
`PO, at bedtime; Warner Chilcott, Morris Plains, N.J., USA) was
`available if participants reported having trouble sleeping. Depot
`naltrexone was administered on a Monday morning, 2 days after
`the last oral naltrexone dose.
`
`General procedures
`
`The effects of IV heroin (placebo, 6.25, 12.5, 18.75, and 25 mg)
`were evaluated each week for 6 weeks following depot naltrexone
`administration. The entire dose range was tested each week, and
`one dose of heroin was tested each day on weekdays. For safety,
`active heroin doses were administered in ascending order within
`each week, with the exception that the day of placebo injection
`was varied across weeks. On the day that depot naltrexone was ad-
`ministered, placebo was tested during the experimental session.
`
`Experimental sessions
`
`During all sessions, participants completed computerized tasks
`and subjective-effects questionnaires. Heart rate and blood pres-
`sure were measured every 2 min, and blood oxygen saturation
`was monitored continuously with a pulse oximeter and recorded
`every minute during experimental sessions. Participants received
`breakfast between 0800 and 0900 and lunch between 1230 and
`1330 hours. Experimental sessions occurred between 0930 and
`1130 hours. Participants were not allowed to smoke tobacco ciga-
`rettes during experimental sessions.
`Physiologic, subjective and performance effects were mea-
`sured both before and after drug administration (see descriptions
`below). Heroin or placebo was administered only if vital signs
`were within safe limits (Sp02 >93%). A photograph was taken of
`the right pupil before and 4, 10, 20, 40 and 60 min after drug ad-
`
`353
`
`ministration. The subjective-effects battery (see description be-
`low) was administered before and 4, 40 and 90 min after drug ad-
`ministration. The performance battery (see description below) was
`administered before and 10 and 60 min after drug administration.
`The Subjective Opioid Withdrawal Scale was administered before
`drug administration. The Drug Effects Questionnaire was adminis-
`tered 90 min after drug administration.
`
`Subjective measures
`
`Four questionnaires were used to assess subjective effects
`throughout the experimental sessions. The first questionnaire was
`a 26-item visual analog scale (VAS) designed to assess subjective
`and physiological effects (modified from Foltin and Fischman
`1995). The first 18 lines were labeled with adjectives describing
`mood states (e.g., "I feel...:" "high") and four additional lines, la-
`beled with questions about the dose just received (i.e. "I liked the
`dose," "For this dose, I would pay"). Participants also indicated,
`by making a mark along a 100 mm line, how much they "wanted"
`each of the following drugs: heroin, cocaine, alcohol, and tobacco.
`Participants rated each item on the VAS from "Not at all" (0 mm)
`to "Extremely" (100 mm), except for the "For this dose, I would
`pay" question, which ranged between $0 (0 mm) to $20 (100 mm).
`The second questionnaire was a 13-item opioid symptom checklist
`consisting of true/false questions designed to measure opioid ef-
`fects (e.g. "My skin is itchy," etc.; Fraser et al. 196