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`EXHIBIT R
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`I 1111111111111111 11111 111111111111111 IIIII IIIII IIIII IIIII 111111111111111111
`US005935975A
`[llJ Patent Number:
`[45] Date of Patent:
`
`United States Patent [19]
`Rose et al.
`
`5,935,975
`* Aug. 10, 1999
`
`[54] AGONIST-ANTAGONIST COMBINATION TO
`REDUCE THE USE OF NICOTINE AND
`OTHER DRUGS
`
`[75]
`
`[73]
`
`Inventors: Jed R. Rose, Venice; Edward D.
`Levin, Los Angeles, both of Calif.
`
`Assignee: Robert J. Schaap, Woodland Hills,
`Calif.; a part interest
`
`[ * l
`
`Notice:
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`[21]
`
`Appl. No.: 08/054,144
`
`[22]
`
`Filed:
`
`Apr. 30, 1993
`
`[63]
`
`[51]
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`
`Continuation of application No. 07/855,868, Mar. 23, 1992,
`Pat. No. 5,316,759, which is a continuation of application
`No. 07/231,092, Aug. 11, 1988, abandoned, which is a
`continuation-in-part of application No. 06/840,072, Mar. 17,
`1986, Pat. No. 4,846,199.
`Int. Cl.6
`.............................. A61K 31/44; A61K 9/70
`U.S. CI. .......................... 514/343; 424/449; 514/282;
`514/286; 514/561; 514/947; 514/660; 514/810;
`514/812; 514/813; 514/922
`Field of Search ..................... 424/10, 449; 514/660,
`514/810, 812, 813, 922, 947, 343, 282,
`561, 286
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2,981,641
`3,071,509
`3,980,766
`4,597,961
`4,783,456
`4,803,208
`4,846,199
`4,935,429
`5,075,341
`5,189,064
`5,219,858
`5,256,669
`5,266,574
`5,362,496
`5,385,903
`5,403,595
`5,512,578
`5,556,838
`5,565,455
`5,574,052
`
`4/1961 O'Neill ..................................... 131/17
`1/1963 O'Neill ..................................... 167/55
`9/1976 Shaw et al. ............................... 424/10
`7/1986 Etscorn ..................................... 424/28
`11/1988 Glassman ................................ 514/214
`2/1989 Pasternak .... ... .... ... ... ...... ... .... .. 514/282
`7 /1989 Rose ... ... ...... ... .... ... ... ...... ... .... .. 131/329
`6/1990 Dockis et al. . ... ... ...... .... ... ... ... 514/288
`12/1991 Mendelson et al. . ...... .... ... ... ... 514/282
`2/1993 Blum et al. ............................. 514/561
`6/1993 Parnell .. ...... ... .... ... ... ...... ... .... .. 514/264
`10/1993 Askanaz et al. .. ... ...... ... .... ... ... 514/282
`11/1993 Zagon et al. ............................ 514/282
`11/1994 Baker et al. ............................ 424/435
`1/1995 Steppuhn et al. . ... ...... .... ... ... ... 514/249
`4/1995 Kitchell et al. ......................... 424/501
`4/1996 Crain et al. .... ... ... ...... .... ... ... ... 514/282
`9/1996 Mayer et al. ............................. 514/25
`10/1996 Bjork et al. ............................. 514/252
`11/1996 Rose et al. .............................. 514/343
`
`OTHER PUBLICATIONS
`
`Involvement of Cholinergic Nicotine-like Receptors
`Kurt A Anderson, et al 1982 Acta Physiol Scand. llG(l).
`41-50 Abs.
`Behavioral Effects of Intraventricularly Administered Nico(cid:173)
`tine ... Victor J. DeNoble, et al., Psychopharmacologia,
`(Berlin) 77( 4), 317-21, 1982.
`Nicotine-catecholaminergic Interactions in Rat Brain: ...
`Kevin A. Roth, et al., Journal of Pharmacology EXP. THE
`221(2), 416-20, 198 abs.
`Cardivascular Response in Central Administration of Cho(cid:173)
`linergic Drugs ... In Ho Kim, 1981, Ulhakpu Nonmunzip,
`34(4) 669-79. Abs.
`Interanimal Olfactory aes in Operant Drng Discrimination
`Procedure K. Extanoc, ct al., Psychopharmacology (Berlin)
`1981, 73(4), 363-71 abs.
`
`(List continued on next page.)
`
`Primary Examiner----Chhaya D. Sayala
`Attorney, Agent, or Firm-Robert J. Schaap
`
`[57]
`
`ABSTRACT
`
`A method of treating and reducing a drug dependency such
`as a nicotine dependency is provided. The method comprises
`initially administering to a subject a drug, such as nicotine
`or an agonist of the drug in an amount which would
`normally provide the desired pharmacologic effects and at
`least partially satiate the needs for the drug by a user. The
`method also comprises administering to the subject an
`antagonist to the drug or an agonist in an amount sufficient
`to at least partially block the pharmacologic effects of the
`drug or an agonist while there is a substantial amount of the
`drug or an agonist present in the system of the user. In one
`embodiment of the invention, the drng and the antagonist are
`administered substantially simultaneously so as to occupy a
`substantial portion of the receptors of the user for that drug
`thereby blocking or attenuating the effects of any further
`intake of the drug or an agonist thereof. In another
`embodiment, the drug or an agonist is first administered and
`the antagonist is self-administered by a subject in a manner
`which mimics the use of the drug thereby counter(cid:173)
`conditioning the drug user to the stimuli associated with the
`normal administration of the drug. The invention further
`provides a method of therapeutically treating psychophysi(cid:173)
`ologic diseases and disorders involving neuronal dysregu(cid:173)
`lation. The method additionally provides a pharmacologic
`composition for the treatment and reduction of drug depen(cid:173)
`dence and which relies upon a combination of an agonist and
`an antagonist.
`
`35 Claims, 2 Drawing Sheets
`
`RJREDVA 001651236
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`

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`5,935,975
`Page 2
`
`O1HER PUBLICATIONS
`
`Suppressive Effects of Intraperitoneal and Intraventricular
`Injections . . Robert J. Waldhillig Pharmacology, Bio(cid:173)
`chemical Behavior, 12(4), 619-23, 1980 abs.
`Nicotine-like Behavioral Effect After Small Doses of
`Mecamylamine P. Driscoll, Psychopharmacologia, 46(1),
`119-21 (1976) abs.
`Gawin, FH. Chronic Neuropharmacology of Cocaine: Jr. of
`Clin. Psychiatry, 49:2 (Feb. 1988), p. 11-16.
`Goeders, NE et al. Cortical Dopaminergic Involvement ...
`Science, 221 (Aug. 1983) p. 773-775.
`Harris, LS. Central Neuropunoral Systems, Fed Proceed .,
`20:1 (Jan-Feb 1970), p. 28-32.
`Harris, L. et al: Protection Againts Disipropyfluorophos(cid:173)
`phate Intox., Arch. of Pharm. 1984 327:64---69.
`Krystal J., et al. The Intermittent Antagonist Paradigm:
`Problems of Drug Depend. 1989, p. 45.
`Judson, BA, et al. Uses of Naloxone, Research On The
`Treatment . .. Of The Art. 1983, Chap. 1. p. 1-12.
`Meyer, RE, et al. A Behavioral Paradigm, Arch. of General
`Psych., 33 (Mar. 1976) p. 371-377.
`Suzuki, T. et al., Life Sciences, vol. 42(26), pp. 2729-2737
`1988.
`Comparitive Toxicity For Mice ... , P. Driscoll. Praeven(cid:173)
`timedizin 17 (4), 211-213 1972 abstract.
`Changes In Body Temperature ... , G. H. Hall, Br. Jr. of
`Pharmacology (1972) 44, 634--641.
`Temperature Responses In The Rat ... , J. Baird et al,.
`European Jr. of Pharmacology 21 (1973) 203-211.
`
`Cardiovascular Responses ... , British Jr. Pharmac. (1973)
`47, 196-205. W.J. Long ct al.
`Effects Of Nicotine On Self-Stimulation, Pradhan, et al., Jr.
`of Pharmacology and Experimental Therapeutics 1971, vol.
`176, No. 1. p. 229-243.
`Titration of Oral nicotine Intake ... , S.D. Glick, et al.
`Nature, v. 233, 207-208, 1971.
`Nicotine Self-Administration ... , H.M. Hanson, et al., Ch.
`7.
`Norman A. Krasnegor, NIDA Research Monograph 23, Jan.
`1979. p. 70-9.
`Influencing Cigarette Smoking ... , I.P. Stolerman, et. al.,
`Psychopharmacologia (Berl.) 28-247-249 (1973).
`Effects
`of Mecamylamine On Human Cigarette
`Smoking ... , Nemeth-Coslett, et al., Psycho Pharmacology
`(1986) 88:420-425.
`Could Nicotine Antagonists Be Used ... , by I.P. Stolerman,
`Br. Jr. of Addiction (1986) 81, 47-53.
`Mecamylamine Pretreatment ... , C.S. Pomerleau, et. al.,
`Psycho Pharmacology (1987) 91:391-393.
`Clinical Evaluation ofMecamylamine ... , F.S. Tennant, Jr.,
`et al., NIDA Research Monograph, 49 (1984). 239-246.
`Withdrawal From Nicotine Dependence ... , F.S. Tennant,
`Jr., et al., NIDA Research Monograph, 55 (1985). p.
`291-297.
`Rose, J.E., et al., "Pharm Biochem. & Behavior," vol. 41 #1,
`Jan. 1992, p. 219-226.
`
`RJREDVA 001651237
`
`

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`Case 1:20-cv-00393-LO-TCB Document 690-8 Filed 06/02/21 Page 4 of 16 PageID# 16070
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`U.S. Patent
`
`Aug. 10, 1999
`
`Sheet 1 of 2
`
`5,935,975
`
`tt,1&m~~~~
`FIG!
`
`s O 2'-f z
`
`L/2.
`
`~15.2
`
`FIG .Y
`
`Jb
`
`F/5 .. 5
`
`RJREDVA 001651238
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`Case 1:20-cv-00393-LO-TCB Document 690-8 Filed 06/02/21 Page 5 of 16 PageID# 16071
`
`U.S. Patent
`
`Aug. 10, 1999
`
`Sheet 2 of 2
`
`5,935,975
`
`NORMAL CONDITIONING OF SMOKERS
`30-r-----------,
`
`FIG.Ei
`
`Tr ME C MINUTES)
`
`t:: NICOTINE
`
`INTAKE
`
`60
`
`rlG.7
`
`ELEVATED
`BASEUNE
`~FROM
`NICOTINE
`SKIN PATCH
`
`t = MECAMYLAMINE
`
`INTAKE
`
`TIME
`
`(MINUTES)
`
`RJREDVA_001651239
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`Case 1:20-cv-00393-LO-TCB Document 690-8 Filed 06/02/21 Page 6 of 16 PageID# 16072
`
`5,935,975
`
`1
`AGONIST-ANTAGONIST COMBINATION TO
`REDUCE THE USE OF NICOTINE AND
`OTHER DRUGS
`
`RELATED APPLICATIONS
`This application is a continuation of U.S. patent applica(cid:173)
`tion Ser. No. 07/855,868, filed Mar. 23, 1992, now U.S. Pat.
`No. 5,316,759 dated May 31, 1994, which is a continuation
`of U.S. patent application Ser. No. 07/231,092, filed Aug. 11,
`1988, now abandoned and which is a continuation-in-part of
`U.S. patent application Ser. No. 06/840,072, filed Mar. 17,
`1986, now U.S. Pat. No. 4,846,199 dated Jul. 11, 1989.
`
`GOVERNMENT RIGHTS
`This invention was made with the support of the Veterans
`Administration of the United States government. The gov(cid:173)
`ernment has certain rights in this invention.
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates in general to certain new and useful
`improvements in methods and compositions for treating and
`reducing drug dependency and for therapeutically treating
`psychophysiologic diseases and disorders involving neu(cid:173)
`ronal dysregulation and more particularly, to methods and 25
`compositions of the type stated which rely upon the admin(cid:173)
`istration of a combination of a drug or an agonist and an
`antagonist thereof to the drug.
`2. Brief Description of the Prior Art
`The substantial use of drugs and particularly, the wide(cid:173)
`spread abuse of drugs has led to increased incidence of
`health problems and has even largely contributed to signifi(cid:173)
`cant increases in crime. It has been well established that the
`intake of the drug nicotine through tobacco smoking has
`resulted in various adverse health conditions. While the use
`of drugs, such as nicotine, do not necessarily lead to
`increased incidence of crime, use of this drug and similar
`related drugs does present significant health problems.
`While the use of other addictive drugs including con- 40
`trolled substances such as various narcotics, e.g., heroin and
`cocaine, also can result in adverse health conditions, these
`more serious drug uses have a significant social impact in
`that they give rise to a substantial increase in numerous types
`of criminal activity. Various governmental agencies have 45
`expended substantial sums of money in attempting to eradi(cid:173)
`cate or at least reduce the incidence of crime, but without
`much success. Accordingly, in recent years, there has been
`an increased emphasis on attempting to treat and reduce
`drug dependency.
`The use of drugs is also involved in the treatment of
`various psychophysiologic disorders, and particularly psy(cid:173)
`chiatric disorders involving dysregulation of a neurotrans(cid:173)
`mitter. In addition, certain diseases involving imbalances of
`the autonomic nervous system are treated by administration 55
`of certain drugs. Here again, these drugs may have serious
`side effects in that while they may attenuate a certain
`disorder, they exacerbate other disorders. Further, many of
`the drugs used to treat these disorders can produce depen(cid:173)
`dence as for example a dependence on diazepam, as for 60
`example, that composition offered under the trademark
`VALIUM. Therefore, the subject receiving the agonist
`thereof and the antagonist while finding some release from
`the disorder or disease, may become severely addicted to the
`drug which is used.
`In general, two approaches have been used in the phar(cid:173)
`macologic treatment of drug dependence. The first approach
`
`2
`is often described as the "substitution approach" and pro(cid:173)
`vides an alternative drug which is designed to theoretically
`allow the user to withdraw from the habitually abused drug
`without suffering the aversive symptoms normally associ-
`5 ated with a withdrawal from a drug. As a simple example,
`methadone is often administered to heroin addicts in the
`treatment of heroin addiction. It was anticipated and initially
`believed that a substitution of methadone for heroin, for
`example, would lead to the eventual cessation of all drug use
`10 after a weaning period in which the dose of the substituted
`drug was gradually reduced.
`This first approach to drug dependency has met a very low
`rate of success. It has been found that the substitution of one
`drug for another docs not typically wean the subjects from
`15 all drugs. In fact, it has been found in many cases that the
`drug users will store the substituted drug, such as the
`methadone, and continue to use the more addictive drug,
`heroin or morphine, and only use the stored substitute,
`methadone, when the heroin or morphine is not readily
`20 available. Thus, this first approach to reduced drug depen(cid:173)
`dency has met with very little success.
`There have also been various proposed treatments for the
`administration of nicotine ( the putative addictive substance
`in tobacco smoking) as a replacement for tobacco smoking.
`One of the most successful approaches which have been
`used to date in reducing the incidence of tobacco smoking
`relies upon nicotine containing chewing gum. The use of this
`type of gum suffers from several problems, including not
`only the bad taste and destruction of dental appliances, but
`30 the gastrointestinal upset which results therefrom and which
`also reduces compliance. Moreover, the nicotine containing
`chewing gums do not satisfy that craving which most
`smokers experience for the distinct sensations in the throat
`and chest elicited by the nicotine in smoke. Over the course
`35 of many years of tobacco smoking, these particular sensa(cid:173)
`tions have become an important part of and conditioned with
`the habit of smoking and help maintain tobacco smoke
`dependency.
`There have also been several proposals for administering
`nicotine through various aerosol sprays. However, the aero(cid:173)
`sol sprays are designed to supply that amount of nicotine
`which would have been acquired by a user through the
`normal channel of tobacco smoking. The sprays result in
`severe respiratory tract irritation. There is no available
`means to provide the nicotine either by means of an oral or
`nasal spray and attenuate the severe irritating effects of the
`nicotine.
`The second known general approach which has been used
`so in the pharmacologic treatment of drug dependence involves
`the blocking of the reinforcing effects of the abused drug. It
`is theorized that by reducing the motivation of the user, there
`would be a reduced incidence of self-administration of a
`drug by the user. As a simple example, naltrexone is pres(cid:173)
`ently used to block the reinforcing effects of heroin and
`mecamylamine has been used to block the reinforcing
`effects of nicotine. This latter approach has not been found
`to be effective in that the intense withdrawal symptoms
`suffered by the user encourage compensating use of the
`addictive drug and thereby reduce compliance with the
`treatment unless a sufficient period of abstinence has elapsed
`so that the individnal's nervous system is accustomed to the
`absence of the abused drug. The administration of an antago(cid:173)
`nist alone also creates a dysphoric state which encourages
`65 relapse and return to the abused drug.
`Each of the aforementioned approaches have only been
`used experimentally. Moreover the individual antagonist
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`5,935,975
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`3
`approach and the individual agonist approach have each
`been found to be relatively ineffective. The second approach
`has been ineffective due to the fact that there are significant
`withdrawal or other adverse symptoms. This causes the drug
`abuser to return to his original drug habit in order to avoid 5
`the pain and discomfort associated with the withdrawal.
`Thus, this latter approach to reduce drug dependency has
`also met with little success.
`Heretofore, no one has attempted to combine the sus(cid:173)
`tained administration of a drug agonist and an antagonist to 10
`that drug in a therapeutic treatment. It would appear that the
`administration of an agonist and its antagonist would accom(cid:173)
`plish little, since the antagonist would effectively cancel out
`the effects of the agonist with a result that the combination
`would be equivalent to giving nothing at all.
`
`4
`eases and disorders involving neuronal dysregulation by a
`simultaneous administration of a drug or an agonist of the
`drug and an antagonist to the drug.
`The term "agonist" is used in a broad sense and includes
`the drug of interest. Thus, for example, in this case, nicotine
`is an agonist and heroin is an agonist. Methadone is merely
`another agonist for heroin since it provides effects similar to
`that of heroin. 11ms the term "agonist" as used herein, unless
`otherwise specified, will include the drug itself.
`The method in a broad sense, comprises initially admin-
`istering to a subject a drug or an agonist of this drug in an
`amount which would normally provide the desired pharma(cid:173)
`cologic effects. Moreover, the amount of the drug applied
`would at least partially satiate the needs for the drug by the
`15 user. The method also involves administering to a subject an
`antagonist to the drug or its other agonist in an amount
`sufficient to at least partially block the pharmacologic effects
`of the drug or an agonist thereof while there is a substantial
`systemic amount of the drug or its agonist present.
`The method of the present invention involves two general
`approaches to the treatment of drug dependency and to the
`therapeutic treatment of the above described psychophysi(cid:173)
`ologic diseases and disorders which involve use of drugs. In
`the first approach, there is a treatment for the dependency on
`the drug by saturating a substantial portion of the known
`receptors for that drug with a combination of the drug or its
`other agonist and an antagonist to that drug or such other
`agonist. In this case, the agonist or drug is administered in
`an amount to which the subject is generally dependent upon
`that drug to thereby satisfy a demand for the drug. The
`antagonist is generally simultaneously administered to the
`same subject in an amount to attenuate the pharmacologic
`effects of the drug or an agonist thereof. In this case, the drug
`or its agonist and the antagonist are preferably present in
`such an amount that more receptors of the drug are occupied
`by the drug and the antagonist than could safely be occupied
`by the drug alone or the antagonist alone. Moreover, a lesser
`number of the receptors are left available to respond to the
`drug thereby insulating the user from the reinforcing effects
`of the drug and at the same time minimizing adverse
`symptoms associated with the antagonist. With the use of the
`current agonist-antagonist therapy one can attenuate the
`fluctuations of a neural system while keeping the absolute
`level of activation constant. In other words, one can attenu(cid:173)
`ate the impact of an abused drug without causing a with(cid:173)
`drawal syndrome and one can decrease the pathologically
`wide fluctuations in neural activity with adverse side effects
`associated with giving only an agonist, such as barbiturates
`for epilepsy, or an antagonist, such as a dopamine antagonist
`for schizophrenia.
`In this case, purpose of the invention is to saturate the
`receptors of the drug to thereby insulate the individual from
`the reinforcing effects of the drug. In the case of nicotine, the
`55 individual would be administered both nicotine and an
`antagonist to nicotine, such as mecamylamine. In the case of
`other drugs such as heroin, or its agonist, methadone, the
`antagonist naltrexone would be administered.
`In accordance with this aspect of the invention, the drug
`60 may be present in an amount which would otherwise be
`toxic in the absence of the antagonist but the toxicity is offset
`by the presence of the antagonist. The drug should prefer(cid:173)
`ably be administered in a sufficiently high dose to occupy a
`sufficient number of the receptors and thereby substantially
`65 reduce a subject's demand for the drug.
`In one preferred embodiment, both the drug, or its agonist,
`and the antagonist may be administered by means of a
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`OBJECTS OF THE INVENTION
`
`It is, therefore, one of the primary objects of the present
`invention to provide a method of reducing the dependency
`on drugs by utilizing a combination of an agonist and an
`antagonist.
`It is another object of the present invention to provide a
`method of the type stated for reducing drug dependency by
`simultaneously administering a drug or an agonist of that
`drug along with an antagonist to that drug and thereby
`occupy a substantial number of the receptors of a subject
`available to that drug or its agonist.
`It is a further object of the present invention to provide a
`method of the type stated which enables administering an
`agonist and antagonist without causing an over-activity or
`under-activity of the receptor for the agonist thereby avoid(cid:173)
`ing dangerous side effects which would occur if the agonist
`or antagonist were given alone in the same dosages.
`It is a another salient object of the present invention to
`provide a method of the type stated in which a drug or
`another agonist of that drug is administered to an individual
`to provide a certain systemic level and an antagonist is
`self-administered by the individual which causes a reduction
`in the satisfaction associated with the intake of the drug or
`an agonist thereof.
`It is also an object of the present invention to provide a
`method for treating psychophysiologic disorders and dis(cid:173)
`eases involving neuronal dysregulation by the simultaneous
`application of an agonist and an antagonist in relative
`amounts so that substantial portions are present in the
`bloodstream in the patient having the disorder or disease.
`It is an additional object of the present invention to
`provide a novel composition of a drug or an agonist of that
`drug and an antagonist to that drug.
`With the above and other objects in view, our invention
`resides in the novel features of form and arrangement and
`combination of steps in the method and in the components
`forming part of the composition as hereinafter described.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention relates in general terms to a method
`of treating and reducing drug dependency. Any of a number
`of known drug dependencies can be treated in accordance
`with the method of the invention including for example,
`dependency on nicotine, heroin ( or morphine),
`benzodiazepines, cocaine, and the like. The invention in a
`broad aspect relies upon a combination of an administration
`of a drug or another agonist of the drug and an antagonist to
`the drug. The present invention also provides a unique
`method of therapeutically treating psychophysiologic dis-
`
`RJREDVA 001651241
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`transdermal patch, as hereinafter described in more detail.
`The drug or its agonist and for that matter the antagonist,
`may be administered by other means such as oral
`administration, intravenous administration etc. In order to
`wean the person from the use of the drug, both the drug, or 5
`its agonist, and the antagonist may be reduced in selected
`amounts over a period of time.
`The use of this approach is effective in that the user will
`receive little or no satisfaction from taking additional
`amounts of the drug inasmuch as a very substantial portion 10
`of the receptors for that drug are already occupied by the
`initial dose of the drug and the initial dose of the antagonist
`to the drug.
`The second general approach used in the administration of
`the agonist and an antagonist involves an inverse condition- 15
`ing to the stimuli associated with the taking of the abused
`drug. In this case, the method involves administering to a
`subject a drug or an agonist of the drug in an amount which
`would achieve a systemic level of the drug to which the
`subject was previously accustomed. This approach to the 20
`method also involves the self-administration of an antago(cid:173)
`nist to the drug or its agonist, but only at selected intervals.
`Moreover, the antagonist is preferably administered in a
`form similar to the administration of the abused drug, as
`hereinafter described.
`While this approach does increase the saturation of the
`receptors for the drug by the presence of the drug and the
`antagonist, it more importantly causes a reduction of the
`enjoyable effects associated with the taking of the drug. The
`subject is administered a certain amount of the drug or an 30
`agonist thereof to provide a desired systemic level. The
`administration of the antagonist is preferably in a form with
`sensory cues which mimics or closely simulates the form in
`which the user was accustomed to taking the drug, as
`aforesaid. Thus, by taking the drug in this form, there is an 35
`inverse conditioning or counter-conditioning of the stimuli
`associated with the taking of the drug.
`As a simple example of this latter approach in treating and
`reducing drug dependency, the dependency on nicotine
`could be reduced by providing a desired systemic level of 40
`nicotine through a transdermal patch or other means. The
`antagonist, such as mecamylamine, could be incorporated
`into a smoking device, such as a simulated cigarette which
`provides many if not most of the sensory cues in normal
`tobacco smoking. In this way, when the user took a puff from 45
`the simulated cigarette, instead of receiving nicotine, he
`would receive an antagonist, namely the mecamylamine,
`thereby further depriving the user of the pharmacologic
`effects of nicotine to which he or she was previously
`accustomed. The usual conditioning is that smoking is 50
`associated with increased nicotine stimulation and pleasur(cid:173)
`able effects. However, in this case, smoking and its attendant
`sensory cues would be associated with decreased nicotine
`stimulation and the unpleasant effects of withdrawal when(cid:173)
`ever the user smoked.
`It can be observed that one important factor in each of the
`above identified approaches to the method of the present
`invention is that there is generally a sustained level of the
`agonist in a user's bloodstream. When using the first
`approach, there would generally be a sustained level of both 60
`the agonist and the antagonist since they are generally
`simultaneously administered. In the second approach, there
`would at least be the sustained level of the agonist and the
`user would self-administer the antagonist at the will of the
`user. Thus, there would be peaks in the amount of the 65
`antagonist in the bloodstream of the user of the second
`approach.
`
`6
`Preferably, in both approaches to the method of the
`invention, the agonist is administered by a route which is
`different than that employed in the actual use of the drug.
`Thus, in the case of nicotine, administration of an agonist
`would occur by means of a transdermal patch or a route
`other than by way of smoking. In the case of the heroin,
`methadone would likely be used because it has a longer
`acting effect than heroin, but would be administered by a
`route different than the user employed for the administration
`of heroin. Thus, if the user self-administered heroin through
`a hypodermic needle, the methadone would be administered
`orally or by means other than a hypodermic needle. In this
`way, there will not be any reinforcement of the original
`response obtained by the common method of using the drug.
`In both approaches, it can also be observed that there is
`essentially no self-administration of the agonist alone. In
`other words, the agonist may be self-administered in com(cid:173)
`bination with the antagonist as for example, a composition
`in the form of a pill or tablet. Otherwise, the agonist would
`generally always be administered in a therapy, as for
`example, in a treatment center, or the like. The antagonist
`could be self-administered, as described above.
`The present invention is also highly effective in the
`treatment of various psychophysologic disorders and dis(cid:173)
`eases involving neuronal dysfunction, as described above.
`25 The invention utilizing both the agonist and the antagonist is
`effective in treating disorders involving dysregulation of a
`neurotransmitter as for example, in manic depression and
`schizophrenia and epilepsy. Imbalances of the autonomic
`nervous system can also be treated by the concurrent
`agonist-antagonist administration, as well. In particular,
`sympathetic nervous system disorders e.g. hypertension
`could also be treated by this approach with the adrenergic
`agonist-antagonist combinations.
`The present invention also provides a unique composition
`of both an agonist and an antagonist. The composition is
`novel and unobvious in view of the fact that one would not
`normally attempt to combine an agonist and an antagonist
`for the reasons described above. Moreover, it is important to
`have a single composition which may be in tablet or pill
`form, for example, or which may be administered through a
`transdermal patch. In this way, the user who is typically an
`abuser of a drug or an agonist of that drug will not be able
`to separate the desired portion of the composition, namely
`the drug or agonist from the antagonist. When the user takes
`the composition, the user will receive both the drug or its
`agonist and the antagonist to the drug.
`This invention possesses many other advantages and has
`other purposes which will be made more clearly apparent
`from a consideration of the forms in which it may be
`embodied. They will now be described in more detail for
`purposes of illustrating the general principles of the
`invention, but it is to be understood that such detailed
`description is not to be taken in a limiting sense.
`BRIEF DESCRIPTION OF THE DRAWINGS
`Having thus described the invention in general terms,
`reference will now be made to the accompanying drawings
`(two sheets) in which:
`FIG. 1 is a schematic vertical sectional view of a trans(cid:173)
`dermal patch for the transdermal administration of an ago(cid:173)
`nist or an antagonist;
`FIG. 2 is a vertical sectional view of an apparatus capable
`of being used for inhaling an aerosol of an agonist or an
`antagonist;
`FIG. 3 is a schematic side elevational view, partially
`broken away and in section, and showing a modified form of
`apparatus for inhaling an aerosol of an agonist or an antago(cid:173)
`nist;
`
`55
`
`RJREDVA 001651242
`
`

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`Case 1:20-cv-00393-LO-TCB Document 690-8 Filed 06/02/21 Page 9 of 16 PageID# 16075
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`5,935,975
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`7
`FIG. 4 is a schematic side elevational view, partially
`broken away and in section, and showing another modified
`form of apparatus for inhaling an aerosol of an agonist or an
`antagonist;
`FIG. 5 is an enlarged fragmentary sectional view showing
`a delivery tube forming part of the apparatus of FIG. 4;
`FIG. 6 is a graph showing a normal conditioning of a
`smoker with nicotine receptor activation as a function of
`time; and
`FIG. 7 is a graph showing an inverse conditioning of
`smokers with nicotine receptor activation as a function of
`time.
`
`5
`
`8
`In this way, the user will not suffer a severe withdrawal
`symptom which would otherwise occur with the presense of
`a large amount of the antagonist and a very small amount of
`the agonist. In like manner, the user will not be able to obtain
`the pharmacologic effects to which he or she was normally
`accustomed if there is not an excess of the agonist