a6074458ex10_7.htm


    Exhibit
10.7


     

    
      


    

     

    
      


       

      
        	(19)	[EUROPEAN PATENT
      OFFICE LOGO]	
                [BAR
      CODE]

                 

                (11)                EP
      1 681 057 B1

              


      

       

       

       

    

     

    
       

       

    

     

     

     

     

    (12)                                      EUROPEAN PATENT
SPECIFICATION

     

    
      
        	
                (45)
      Date of publication and mention

              	
                (51)
      Int Cl.:

              	 
      
	
                of
      the grant of the patent:

              	
                A61K 31/485 (2006.01)

              	
                A61P 25/30 (2006.01)

              
	
                13.08.2008
      Bulletin 2008/33

              	
                A61P 3/04 (2006.01)

              	 
      


      

    

     

    (21) Application
number: 06396001.7

     

    (22) Date of
filing: 10.01.2006

     

    
      	
               

              (54)
      Use of naloxone for
      treating eating disorders

            


    

     

    Verwendung
von Naloxon zur Behandlung von Essstörungen 

     

    Utilisation
de Naloxone pour traiter les troubles alimentaires

     

     

      
        

      

    

    
      (84)
Designated Contracting States:

      AT
BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE
SI SK TR

       

      (30)
Priority: 10.01.2005 US
31534

       

      (43) Date
of publication of application: 19.07.2006 Bulletin
2006/29

       

      (73) Proprietor:
Sinclair, John D. 02550
Evitskog (FI)

       

      (72)
Inventor: Sinclair, John D.
02550 Evitskog (FI)

       

      (74) Representative:
Hovi, Simo Pekka Tapani et al
Seppo Laine Oy,

      Itämerenkatu
3 B

      00180
Helsinki (FI)

    

     

    
      (56)
References cited:

      EP-A-
0 790
058                                  US-B1-
6 569 449

       

      · FICHTER
M M: "DIE MEDIKAMENTOESE BEHANDLUNG VON ANOREXIA UND BULIMIA
NERVOSAEINEUEBERSICHTMEDICATIONFOR ANOREXIAAND BULIMIANERVOSA:A REVIEW"
NERVENARZT, SPRINGER VERLAG, BERLIN, DE, vol.64, no.1, 1993, pages21-35,
XP008016116 ISSN: 0028-2804

       

      · DREWNOWSKI
A ET AL: "Naloxone, an opiate blocker, reduces the consumption of sweet high-fat
foods in obese and lean female binge eaters" AMERICAN JOURNAL OF CLINICAL
NUTRITION 1995 UNITED STATES, vol. 61, no. 6, 1995, pages 1206-1212, XP002376723
ISSN: 0002-9165

       

      · "Drug
treatment for binge-eating disorders" JOURNAL OF THE AMERICAN DIETETIC
ASSOCIATION 1995 UNITED STATES, vol. 95, no. 11, 1995, page 1329, XP002376724
ISSN: 0002-8223

    

     

      
        

      

    

     

    Note:
Within nine months of the publication of the mention of the grant of the
European patent in the European Patent Bulletin, any person may give notice to
the European Patent Office of opposition to that patent, in accordance with the
Implementing Regulations. Notice of opposition shall not be deemed to have been
filed until the opposition fee has been paid. (Art. 99(1) European Patent
Convention).

    
    

     

     

    
      
        
        

      

      
        2

        
          

        

      

      
        
        

      

    

    EP
1 681 057 B1

     

     

    Description

     

    Background of the
Invention

     

    Field of the
Invention

     

    [0001] The present invention
relates to the treatment of eating disorders. In particular, the invention
relates to the use of naloxone in methods of eating disorder
ther­apy.

     

    Description of Related
Art

     

    [0002] Various eating
disorders, including binge eat­ing, bulimia, and stimulus-induced
over-eating, develop because the behaviors are reinforced by the opioidergic
system so often and so well that the person no longer can control the behavior.
Thus eating disorders resemble opiate addiction and alcoholism. Eating disorders
can-not, however, be treated effectively by continual daily ad-ministration of
opiate antagonists because normal healthy eating behavior is also reinforced by
the opioi­dergic system. Instead, a selective extinction method is needed
that weakens the eating disorder while strength­ening healthy eating.
Extinction sessions in which the eating disorder responses are emitted while an
opiate antagonist blocks reinforcement must be interspersed with learning
sessions in which healthy eating responses are made while free of antagonist. In
between extinction and learning sessions there must be a wash-out period in
which the antagonist is allowed to be eliminated from the body, and during which
neither problem eating nor healthy eating should occur. Consequently,
preparations with long-lasting antagonists such as naltrexone and nalmefene with
wash-out periods of a day or more are not suitable, but naloxone with a half
life of only about an hour is excellent. Naloxone cannot be taken orally.
In-stead it is administered transdermally or by nasal inha­lation. This
provides additional advantages with eating disorders: the purging with bulimia
does not affect the dosage; the gastrointestinal tract is not further disturbed
by the antagonist administration; and altering eating re­sponses does not
affect taking the medication.

     

    [0003] Opioid antagonists have
been patented for in­ducing anorexia (Smith, US Patent 4,217,353, 1980; US
Patent 4,477,457, 1984), and they also have been pat­ented for treating
anorexia (Huebner, US Patent 4,546,103, 1985). Both results are valid. The
antagonists can also reduce binge eating and also the purging asso­ciated
with bulimia, but normal eating, too. Narrowly lim­ited experiments have
found evidence for each of these effects. When put into long term practice,
however, the different effects counteract each other and cause
com­plications. For example, as Smith pointed out, the only clinical trial
using naloxone for anorexia was inconclusive because they coupled the treatment
with giving a hyper-caloric diet (Moore et al., 1981).

     

    [0004] Unfortunately, the
methods used and previously
proposed for the treatment of eating disorders are un­able to separate these
various actions. Consequently, the antagonists have produced mixed clinical
results, have not received FDA or equivalent European approval

     

    
      	
               
      

            	
              5 for
      use with eating disorders, and currently are not being used clinically for
      such purposes.

            


    

     

    [0005] In contrast, in the
field of alcoholism and drug addiction treatment, I proposed a method in which
the antagonists specifically remove the addictive behavior

     

    
      	
               
      

            	
              10
      (Sinclair, US Patent 4,882,335, Nov. 21, 1989; US Patent 5,587,381,
      Dec. 24, 1996; EP Patent 0 346 830 B1, May 11, 1995). Our double-blind
      placebo-controlled clinical trial has shown naltrexone is effective when
      used in ac-cord with this method but not when used
    otherwise

            


    

     

    
      	
               
      

            	
              15
      (Heinälä et al., 2001). Similar results have been obtained in
      nearly all trials (Sinclair, 2001). Naltrexone has been approved by the
      FDA for use in alcoholism treatment in 1995 and in Finland in 1996. Going
      one step further, I improved the method into a procedure of "selective
      ex-

            


    

     

    
      	
               
      

            	
              20
      tinction" that not only removes alcoholism and drug ad-diction but
      also enhances other competing behaviors (Sinclair, US Patent 5,587,381,
      1996; Sinclair et al., 1994; Sinclair, 2001). Especially in Finland where
      nal­trexone is widely used in this selective manner, it
      has

            


    

     

    
      	
               
      

            	
              25
      become a major factor in the treatment of alcoholism. [0006] Extinguished
      responses can be relearned; in-deed they are relearned more readily than
      they were learned the first time. Subjects can be advised after a given
      period of treatment to refrain henceforth from
  mak-

            


    

     

    
      	
               
      

            	
              30 ing
      the extinguished response ever again in order to avoid relearning, but
      they cannot avoid all responses reinforced through the opioidergic system.
      One solution, used in alcoholism treatment, is to continue taking
      antagonist in-definitely whenever there is a risk of drinking, or in
      this

            


    

     

    
      	
               
      

            	
              35 case
      of making the eating disorder response again. Al­ternatively,
      selective extinction can be used to "trim" of-fending responses that are
      beginning to arise again be-fore they become harmfully strong. Like
      finger-nails, the growth of responses is a useful natural process but
      can

            


    

     

    
      	
               
      

            	
              40
      become harmful when left uncontrolled. Thus individuals with a
      predilection for developing overly-strong respons­es might
      periodically review their current activities and then trim those responses
      that were beginning to get too strong -- as casually and almost as easily
      as we trim our nails.

            


    

    
       

      
        	
                 
      

              	
                45
      

                  [0007] Perhaps the
      greatest technological quest in this field since the discovery of the
      opioid antagonists has been for preparations that would cause the
      antagonists to remain in the body for longer periods of time.
      Naltrex-

                

              


      

       

    

    
      	
               
      

            	
              50 one
      and nalmefene have been preferred over naloxone not only because they can
      be taken orally but also be-cause of their much longer half-lives. Various
      slow-re­lease methods for naltrexone and nalmefene have been developed
      over the passed two decades to
provide

            


    

     

    
      	
               
      

            	
              55
      weeks or months of constant blockade. Alkermes Inc. has recently
      received FDA approval for Vivitrol, a long-acting, injectable formulation
      of naltrexone.

            


    

     

    
      
        
        

      

      
        3

        
          

        

      

      
        
        

      

    

    EP 1 681 057 B1

    
 

    Summary of the
Invention

     

    [0008] The present invention
relates to a new and al­ternative way of treating eating disorders based on
the use of naloxone.

     

    [0009] The above explained
quest, utilizing antago­nists having a prolonged action and activity in the
body, is consistent with the previously proposed methods for treating bulimia
and binge eating with opioid antagonists. Their imagined mechanisms of action
would work best if the antagonists were always present, thus eliminating
supposed problems of patient compliance.

     

    [0010] The present invention,
however, contemplates alternating periods when an opioid antagonist blocks the
opioid system (during which the eating disorder behav­iors are emitted) with
periods when the patient’s body is free of antagonist (during which normal
healthy eating behaviors are made).

     

    [0011] The present invention
is, therefore based on the use of naloxone for the preparation of pharmaceutical
compositions for methods of treating eating disorders in mammals, including
human beings.

     

    [0012] The method of treatment
preferred comprises "selective extinction". We have used a similar "selective
extinction" procedure extensively in treating alcoholism (Sinclair, 2001).
(Incidentally, there has been little prob­lem here with compliance.
Alcoholics have difficulty com­plying if you tell them to refrain from
drinking. They do not have a problem, however, with obeying the instruction to
take a pill always before drinking.)

     

    [0013] With alcoholics, we
include a wash-out period of about 48 hours for removal of the naltrexone.
During this time the patients should not drink alcohol and they also should not
engage in the alternative opioidergically­reinforced behaviors that we wish
to strengthen. This is not a problem with alcoholism or drug
addiction.

     

    [0014] In the case of eating
disorders, such long wash-out periods are not possible. For example, when
treating bulimia, the behavior we wish to extinguish is eating foods that
trigger bulimia. The alternative behavior we wish to strengthen is eating foods
that do not trigger bulimia. Ob­viously patients cannot be expected to avoid
both activ­ities, that is, to refrain from all eating, for a 48 hour
wash-out period. Nalmefene is removed even more slowly.

     

    [0015] Naloxone, however, has
a half-life of only 30 to 80 minutes in humans. A patient given naloxone on one
day would be free of it the following day.

     

    [0016] The present invention
contemplates the use of the opiate antagonist naloxone for the preparation of a
pharmaceutical composition for the treatment of eating disorders. In particular
the present invention provides for the use of naloxone (or a similar opiate
antagonist having a half-life of less than about 2 hours, preferably less than
90 minutes).

     

    [0017] In particular, the
present invention contem­plates the use of naloxone in the formulation of a
phar­maceutical composition used in a method based on se­lective
extinction.

     

    [0018] Particularly preferred
compositions are those which are suitable for transdermal or nasal
administration appropriate in a therapeutic method, utilizing the ability of
opiate antagonist to block positive reinforcement from

     

    
      	
               
      

            	
              5
      stimuli produced by highly-palatable foods, from purging, and from
      anorexic behavior in order to extinguish bulimia and other eating
      disorders while simultaneously strengthening normal healthy eating
      behaviors and the consumption of foods conducive to
  health.

            


    

     

    
      	
               
      

            	
              10
      [0019] The
      subject suffering from one of these overly-strong eating disorder
      responses makes the response repeatedly, in the presence of stimuli
      similar to those to which the response had been learned, while active
      quan­tities of naloxone are in his or her brain, thus
      eventually

            


    

     

    
      	
               
      

            	
              15
      extinguishing the response and removing the desire to make the
      response. These extinction sessions are sep­arated by "learning
      periods" when the subject is free of antagonist and can make other
      responses but not the problem response, in order to restore the strength
      of com-

            


    

     

    
      	
               
      

            	
              20
      peting responses. Thus the problem response is selec­tively
      extinguished.

            


    

     

    [0020] Considerable advantages
are obtained with the present invention.

     

    [0021] The lifetime prevalence
of bulimia is 2.8 % for

     

    
      	
               
      

            	
              25
      women, and 5.7 % of women will show bulimia-like syn­dromes
      (Kendler et al., 1992). The disorder was strongly influence by genetics,
      with a heritability coefficient of 55 %. Comorbidity was reported between
      bulimia and ano­rexia nervosa, alcoholism, panic disorder, generalized
      anxiety disorder, phobia, and major
depression.

            


    

     

    30 
[0022] In most cases the
subject will suffer from sev­eral related problem responses: e.g.,
overly-strong eat­ing responses for a dozen specific highly palatable food
items. Each will be extinguished separately. Further-

     

    
      	
               
      

            	
              35
      more, prior to extinguishing a particular response, the subject
      will not be allowed to make that response for at least a week. The
      resulting increased motivation to make the response after being deprived
      of the opportunity ("deprivation effect") will assure that the subject
      makes

            


    

     

    
      	
               
      

            	
              40 that
      response at the beginning of extinction and will in-crease the
      effectiveness of extinction.

            


    

     

    [0023] Depending upon the
severity and nature of the problem responses, provisions are made for using the
method within a treatment center, as an out-patient treatment, and as a
combination of the two.

     

    45


     

    Brief Description of the
Drawings

     

    [0024]

    50

    Figure 1a
shows selective extinction (interspersing periods when alcohol was drunk daily
following naloxone injection with periods when saccharin was drunk with no
injection) strongly reduced alcohol

    55          drinking,
while

     

    Figure 1b
depicts increasing saccharin drinking in the same animals relative to intakes by
control ani­mals injected with saline. Each data point is the
mean

     

    
      
        
        

      

      
        4

        
          

        

      

      
        
        

      

    

    


    


     

    5                           EP 1 681 057
B1                                               6

     

    of 1 to 4
days. The extremely low doses used from week 4 on have not previously been found
to be ef­fective. * p<0.05 relative to saline controls.

     

    Description of Preferred
Embodiments

     

    [0025] The present invention
involves taking the se­lective extinction method for separating the actions
of opioid antagonists on different behaviors and contem­plates applying it
to the treatment of eating disorders. Because the opioid antagonists
conventionally used in treating alcoholism are not suitable for treating eating
disorders, the present invention employs naloxone (or salts thereof) for use in
preparations that can be taken either transdermally or by nasal inhalation in a
manner suitable for selectively extinguishing eating disorders while reinforcing
healthy eating behaviors. In addition, several innovations are proposed to
optimize the method to the eating disorder field and which then differentiate
the method from all previously proposed treatments.

     

    [0026] The key for how to
separate the actions of the antagonists comes from an understanding of how the
antagonists act in the nervous system to produce bene­fits.

     

    [0027] There are two basic
processes through which long-term change is made in the organization of the
nerv­ous system as a result of experience: one causes learn­ing by
strengthening synapses; the other causes habit­uation and extinction by
weakening synapses (see Sin­clair, 1981). Experimental results also show
that the two occur under different circumstances and follow different rules.
Thus, extinction is not simply learning to do some-thing else but rather a
separate phenomenon. It also is distinct from forgetting; it is an active
process for remov­ing unsuccessful responses and requires the emission of
the response in the absence reinforcement.

     

    [0028] Our preclinical
experimental results had shown that alcohol drinking is a learned behavior
(Sinclair, 1974), and that opioid antagonists suppress alcohol drinking by
mechanism of extinction (Sinclair, U.S. Patent 4,882,335, Nov. 21, 1989;
Sinclair, 1990). Extinction weakens only those responses that are made while
re­inforcement is blocked. There the method I proposed for treating
alcoholism had the antagonist being adminis­tered just before the alcoholic
drank alcohol.

     

    [0029] Others in the field,
however, believed that opioid antagonists block the craving for alcohol caused
by an imbalance, either a deficiency in opioid receptor activity (Tractenberg
and Blum, 1987; Volpicelli et al., 1990) or having too much opioid receptor
activity (Reid and Hub-bell, 1922). According to these theories, the antagonists
would be effective if given during abstinence; they would block craving and the
onset of drinking.

     

    [0030] Our preclinical
experiments had shown that giv­ing opioid antagonists during abstinence not
only failed to reduce subsequent drinking, but actually tended to in-crease
subsequent drinking above control levels (Sinclair et al., 2003). The same
result was found in our dual clinical trial
(Heinola et al., 2001). Naltrexone was effective when paired with alcohol
drinking, but naltrexone tended to be worse than placebo when given during
abstinence. Similar results can be seen in the other clinical trials
(Sin-

     

    
      	
               
      

            	
              5
      clair, 2001). The latest published count had 41 clinical trials
      that obtained significant results from using opioid antagonists in a
      manner allowing extinction; 37 trials us­ing the antagonists in ways
      precluding extinction, how-ever, got negative results; only 4 trials had
      results con-

            


    

     

    
      	
               
      

            	
              10
      trary to this conclusion (Fantozzi and Sinclair, 2004). [0031] The mechanism
      causing the increase in alcohol drinking when antagonists are administered
      only during abstinence can be used to improve the efficacy of
      treat­ment. It can increase the strength of behaviors other
      than

            


    

     

    
      	
               
      

            	
              15
      alcohol drinking, of behaviors that can compete with drinking and
      help fill the vacuum as drinking is extin­guished. At the same time
      other behaviors that are rein-forced by endorphins are protected from
      extinction. One problem noted in some of the clinical alcohol trials is
      a

            


    

     

    
      	
               
      

            	
              20
      reduction in the patients’ interest in sweets or
      carbohy­drates, or in sex (Bohn et al. 1994; Balldin et al., 1997).
      This is probably caused by these behaviors being made while on naltrexone
      and thus, along with alcohol drinking, being partially extinguished.
      Naltrexone given to humans

            


    

     

    
      	
               
      

            	
              25
      reduces their preference for saccharin (Arbisi et al., 1999) [0032] The first step in
      our clinical use of selective ex­tinction in alcoholism treatment is
      to have patients make a list of behaviors they find pleasurable. The
      clinician identifies the behaviors on the list that are probably
      re-

            


    

     

    
      	
               
      

            	
              30
      inforced by the opioidergic system and advises the pa­tient to
      avoid engaging in these activities on the days when taking naltrexone and
      drinking. In the beginning of treatment, this is essentially every
      day.

            


    

     

    [0033] After the treatment has
reduced craving for al-

     

    
      	
               
      

            	
              35
      cohol, usually during the first month, the patient is advised to
      have a weekend, starting with Friday evening, with no naltrexone and
      drinking. Friday night and Saturday con­stitute a wash-out period for
      naltrexone to be removed from the body. On Sunday afternoon, the patient
      chooses

            


    

     

    
      	
               
      

            	
              40 some
      of the opioidergically-reinforced behaviors: eating a highly palatable
      meal, jogging, having sex, cuddling, cards, etc. As expected, patients
      usually report that the activities at this time are unusually
      enjoyable.

            


    

     

    [0034] The patients can return
to naltrexone and drink-

     

    
      	
               
      

            	
              45 ing
      on Monday. They are advised, however, to try the next week to have a
      longer period without naltrexone and drinking but with the alternative
      behaviors. A three-year follow-up showed that complying patients reported
      a maximum of 1.5 ± 0.4 (SEM)
      days per week (Sinclair et

            


    

     

    50 al.,
2000).

     

    [0035] The example included
here is a prior preclinical experiment
in which the alternative opioidergically-reinforced
behavior was saccharin drinking. Alcohol experienced rats
had continual access to food and water. Alcohol
solution was available for only an hour a day for 2 to 4 days.
On the next day or two, saccharin solution instead
was available. Naloxone (or saline for the control group) was
injected prior to the alcohol session. During

     

    
      
        
        

      

      
        5

        
          

        

      

      
        
        

      

    

    


    


     

    7                           EP 1 681 057
B1                                               8

     

    the first
three weeks when the naloxone doses were in the range previously found to be
effective, the alcohol drinking was practically abolished. Saccharin drinking in
the same animals was significantly increased.

     

    [0036] The opioidergic system
reinforces responses, not only when activated by an opiate or alcohol, but also
when certain types of stimuli are experienced. The stimuli cause a release of
opioids in the brain, reinforcing the responses that produced these stimuli.
Consequently, opioid antagonists have been shown in clinical trials to be
effective in treating compulsive gambling (Kim, US Patent 5,780,479, 1998; Kim
et al., 2001).

     

    [0037] Opioidergic
reinforcement is well documented for food-related stimuli. On the basis of a
large body of data, Cooper and Kirkham (1990, p. 91) concluded that "ingested
items provide stimuli which lead to the release of endogenous opioidergic
peptides in the central nerv­ous system". The system does not appear to be
involved in the reinforcement from eventually obtaining calories, but rather
with that from the pleasant stimulation. For example, opiate antagonists reduce
sham feeding of su­crose, and they suppress the eating of chocolate-coated
cookies by rats, but not the intake of normal rat chow. Similarly in humans, the
antagonist nalmefene suppress-es intake of highly palatable foods but not that
of less pleasant tasting ones. Another general finding is that an­tagonists
suppress food consumption (and alcohol drink­ing) only in the later parts of
the first session or later parts of the first eating binge but not at the
beginning.

     

    [0038] Other workers in the
field interpret these results differently than I do. They suggest that
"endogenous opi­oids play a central role in the modulation of appetite"
(Jonas, 1990). The opioids released by food-related stim­uli block satiety
effects and make food stimuli continue to be pleasant even after caloric needs
have been satis­fied; thus the opioid release "contributes to the
mainte­nance of ingestional behavior" (Cooper and Kirkham, 1990) and is
"involved with processes associated with continuance of eating rather than
starting to eat" (Wild and Reid, 1990). In some people the opioid release is too
large or too long, and thus they do not stop eating (or alcohol drinking)
normally but rather have "out of control" binges. An opiate antagonist blocks
this opioid action; therefore, so long as the antagonist is present the
dura­tion of a binge is shortened. Similarly with alcohol drink­ing,
"antagonists at opioceptors [sic] would reduce the propensity to continue to
drink once drinking has begun" (Hubbell and Reid, 1990). Another interpretation
was made by Huebner (US Patent 4,546,103, 1985). He saw endorphins providing
satisfaction and pleasure from purging for bulimic patients and from anorexic
behavior. Blocking the opioid system with endorphins would re-move the reason
for patients making the behaviors, and thus help them to stop.

     

    [0039] Both of these
interpretations are best served by continual opioid blockade. If endorphins
cause normal eating to expand to a binge, then continual blockade would
continually prevent binges. Or if endorphins provide the
pleasure from purging, continual naltrexone would suppress purging at all times.
Therefore others have not proposed using only short periods of blockade
interspersed with periods when the opioid system was

    5 functional,
as is done with the present invention.

     

    [0040] I see the results not
as immediate effects of the opioids and the antagonists on appetite or satiety,
but rather as aftereffects produced by learning and extinc­tion. When a
highly palatable food is consumed, opioids

     

    
      	
               
      

            	
              10 are
      released and as a result, after consolidation, the re­sponse is
      stronger. In some people the responses are reinforced so often and so well
      that they become ex­tremely strong and cannot be controlled properly.
      When the response is emitted while an opiate antagonist
    blocks

            


    

     

    
      	
               
      

            	
              15 the
      reinforcement, the response is weakened. The effect can be seen even
      during the first session, not at the very beginning but reducing intake in
      the latter portions and thus terminating a binge earlier. The antagonists
      can re-duce purging if the behavior is emitted while
      reinforce-

            


    

     

    20 ment is
blocked because of extinction.

     

    [0041] Opiate antagonists have
been tested for eating disorders but the methods used were ones that would be
appropriate if the antagonists worked by directly increas­ing satiety or
reducing appetite. In particular, the subjects

     

    
      	
               
      

            	
              25 were
      kept continually on the antagonists in order to pre-vent all eating from
      getting out of control and turning into a binge. For example, Alger et al.
      (1990) gave patients suffering from binge eating initially 50 mg of the
      longer lasting antagonist, naltrexone, once daily, then twice
      dai-

            


    

     

    
      	
               
      

            	
              30 ly,
      and if that did not work, 3 times daily, apparently for the purpose of
      making sure the patient was never free of naltrexone. Although some
      patients seemed to benefit, over all the naltrexone treatment was not
      significantly better than placebo. Similarly, although some
      uncon-

            


    

     

    
      	
               
      

            	
              35
      trolled studies found benefits from naltrexone in the
      treat­ment of bulimia, the one placebo-controlled study did not
      (Jonas, 1990). A recent review of pharmacological treat­ments for
      binge eating does not include opioid antago­nists among the medicines
      for which there is clinical sup-

            


    

     

    40 port
(Carter et al., 2003).

     

    [0042] According to the
extinction hypothesis, keeping a person continually on the antagonist is not
optimal for treating eating disorders. In the case of binge eating, it weakens
not only the binge-eating response but also all

     

    
      	
               
      

            	
              45
      other emitted responses reinforced through the opioider­gic
      system. This makes the procedure less effective be-cause the probability
      of binge-eating is determined not by its absolute strength but rather by
      its strength relative to all competing responses. Of particular
      importance, eat-

            


    

     

    50 ing in a
healthy manner is also extinguished.

     

    [0043] As discussed above, the
present invention instead
employs the "selective extinction" procedure (Sinclair, US
Patent 5,587,381, 1996) which has the person take an
antagonist only before making the problem re 

    55 sponse but
free of the antagonist at times when the problem
response is not made. Thus extinction sessions, when
mainly the problem response is weakened, are interspersed
with "learning periods" when other competing

     

    
      
        
        

      

      
        6

        
          

        

      

      
        
        

      

    

    


    


     

    9                           EP 1 681 057
B1                                               10

     

    response
including healthy eating responses can regain their strength. In the treatment
of bulimia, only binge-eating of specific highly palatable food is weakened, but
other competing responses are not.

     

    [0044] Experimental support
comes from my studies with alcohol drinking: keeping rats continually on an
an­tagonist (large doses of naltrexone or nalmefene in the food)
significantly lowered alcohol drinking but did not reduce it as completely as
selective extinction produced by 1 hour sessions daily when alcohol and the
short-acting antagonist, naloxone, were present, as shown in the example
here.

     

    [0045] Support may also be
seen in the fact that the only blind, placebo-controlled experiment with humans
to obtain significant results involving binge eating and opioid antagonists was
an acute study in which naloxone significantly reduced the size of an eating
binge (Atkin-son, 1982).

     

    [0046] There are two other
advantages of selective ex­tinction. First, the continual presence of an
antagonist produces up-regulation of opioid receptors (Unterwald and Zukin,
1990; Parkes and Sinclair, 2000). Conse­quently, a problem response would
produce more rein­forcement after the end of antagonist treatment, than it
did before. Up-regulation should be attenuated with the selective extinction
procedure because the antagonist is present only for relatively short sessions
interspersed with antagonist-free periods.

     

    [0047] Second, although opiate
antagonists are con­sidered safe, there are side-effects, such as liver
toxicity with naltrexone, elevated cortisol levels, and possible
im­munosuppressive effects (Morgan and Kosten, 1990). These side-effects
should be greatly reduced or elimi­nated with only periodic administration
of the antagonist. The dysphoria sometimes reported with continual
admin­istration might also be caused by the general blocking of pleasure
from a wide range of activities, and should be less of a problem with selective
extinction where the per-son is free to enjoy opioidergic reinforcement from
other responses during the learning periods.

     

    [0048] Selective extinction
can be used for treating a variety of eating disorders. In addition to bulimia
and binge-eating, it could be used as a dieting aid. A contrib­uting factor
to obesity for many people is overly-strong eating responses and cravings for a
few highly palatable and high-energy foods: chocolate, cookies, peanut but-ter,
etc. Losing weight and then maintaining a normal weight would be possible after
these specific responses were removed by selective extinction. Similarly,
selective extinction could be used by people who are not neces­sarily
overweight but have to restrict their intake of a par­ticular substance
(e.g., sugar or sodium chloride) that can be identified with a specific stimulus
that activates the opioidergic system. (There is evidence that both sweet and
salty tastes are reinforcing through this system (Levine et al.,
1982).)

     

    [0049] The present invention
takes advantage of a re­lationship between opiate antagonists and a
phenomenon R. J.
Senter and I discovered called the "alcohol-deprivation effects" (Sinclair and
Senter, 1967). Taking alcohol away after prolonged prior experience gradually
over several days increases the desire for it. When it is

     

    
      	
               
      

            	
              5 first
      returned, intense drinking begins immediately, prob­ably accompanied
      by intensified pleasure and reinforce­ment. Deprivation effects also
      develop for saccharin and specific highly-palatable foods, as well as for
      many ha­bitual behaviors. Opiate antagonists have been found
      to

            


    

     

    
      	
               
      

            	
              10 be
      more effective in suppressing alcohol drinking after deprivation (Kornet
      et al., 1990). The probable reason is that extinction (unlike learning) is
      most effective with "massed trials", i.e., when the response is made over
      and over again, vigorously, without pausing (see
  Sinclair,

            


    

     

    
      	
               
      

            	
              15
      1981). Therefore, the extinction of specific eating re­sponses
      will generally be done after several days of dep­rivation of the
      specific food item. For example, if choco­late ice cream is listed by
      patients as a triggering food for bulimia, these patients will be told to
      abstain from

            


    

     

    
      	
               
      

            	
              20
      eating chocolate ice cream, plus ice cream in general and chocolate
      in general, for a week before taking an opioid antagonists and getting
      unlimited chocolate ice cream to eat and
purge.

            


    

     

    [0050] There is evidence
linking anorexia nervosa to

     

    
      	
               
      

            	
              25 the
      opioidergic system. First, it may develop from bulimia (Kassett and
      Gwirtsman, 1988). Second, there is some preliminary evidence from a small
      study showing for im­provement of anorexia nervosa from treatment with
      an opiate antagonist (Luby et al., 1987). Marrazzi and
  Luby

            


    

     

    
      	
               
      

            	
              30
      (1986) suggested that starvation causes the release of endorphins;
      anorexic patients starve themselves sup­posedly to get elation from
      their own opioids. I suspect the situation is somewhat more complicated.
      The specific anorexic behaviors may be reinforced by the opioid
      sys-

            


    

     

    
      	
               
      

            	
              35 tem,
      but a major factor contributing to the condition is the extinction of
      normal eating response. During the devel­opmental phase, the patients
      make all of the normal eat­ing responses: going to the table, taking
      the food, pushing it around with a fork, but then willfully withholding
      the

            


    

     

    
      	
               
      

            	
              40
      responses of tasting and swallowing the food. Thus the preliminary
      responses are made but do not get reinforce­ment from taste or from
      removal of hunger, and as a result are extinguished. In any case, it is
      clear that the solution is a strengthening of normal eating
      behaviors,

            


    

     

    
      	
               
      

            	
              45 and
      extinction of the responses maintaining anorexia. This should be
      accomplished by administering opioid an­tagonists while the patient is
      not eating, interspersed with antagonist-free periods when the patient
      does in fact eat a small amount of highly palatable
  food

            


    

     

    
      	
               
      

            	
              50
      [0051] The
      selective extinction method here for treat­ing eating disorders
      comprises selectively extinguishing the behaviors causing the disorder
      while strengthening normal health eating behaviors. It preferably
      comprises the steps of:

            


    

    55

    
      	
               
      

            	
              - repeatedly
      administering naloxone in a dosage suf­ficient to block the effects of
      opiate agonists to a sub­ject suffering from an eating disorder caused
      by one

            


    

     

    
      
        
        

      

      
        7

        
          

        

      

      
        
        

      

    

    


    


     

    11                           EP 1 681 057
B1                                               12

     

    or more
related problem responses;

     

    
      	
               
      

            	
              -
      while the amount of naloxone in the subject’s body is sufficient to block
      opiate effects, having the subject make one of the problem responses from
      which the subject suffers in the presence of stimuli similar to those to
      which it had been learned,

            


    

     

    
      	
               
      

            	
              -
      after the amount of naloxone is no longer sufficient to block opiate
      effects, having the subject make healthy eating responses to food items
      that do not trigger the problem responses;
and

            


    

     

    
      	
               
      

            	
              -
      continuing the steps of administration of naloxone and having one after
      another of the problem respons­es made, followed by having a
      naloxone-free period in which healthy eating occurs, until the problem
      re­sponses are extinguished.

            


    

     

    [0052] Based on the above, the
invention comprises, i.a., the following preferred embodiments:

     

    In the
first, naloxone is used for the preparation of a pharmaceutical composition to
be Administered si­multaneously with the patient making eating disorder
responses but in a manner so that effective levels of naloxone are not present
in the body when the pa­tient makes healthy eating responses, and
continu­ing the alternating between extinction of eating dis­order
responses with naloxone and reinforcement of healthy eating behaviors until the
eating disorder re­sponses are weak enough to be controlled. Typically, in
the method, the patient makes said "healthy eating responses" a few hours,
preferably about 0.2 to 12 hours, in particular about 0.5 to 6 hours, typically
about 0.8 to 4 hours, after the first eating responses.

     

    In a
second embodiment, naloxone is used transder­mally and in a dose per day
amounting to about 0.001 mg to 50 mg.

     

    [0053] The present invention
provides a means, or de-vice, suitable for the rapid, easy and foolproof
transder­mal delivery of the opiate antagonist. The device is a package
containing a fixed dose of antagonist, a vehicle and a permeation enhancer to
assure rapid systemic de-livery of the antagonist. The package contemplated is a
container, such as a capsule, sachet, or squeeze tube, holding a fixed volume of
an ointment containing the an­tagonist, vehicle and enhancer. An important
consider­ation for the formulation that has not been mentioned previously is
the ease and rapidity of removing the transdermal composition and thus
terminating further naloxone administration.

     

    [0054] For the transdermal
administration, naloxone can be in the form of the acid, the base, or the salts
there-of. The concentrations of naloxone in the ointment can range from 1 mg/ml
up to or in excess of the solubility limit of the vehicle. Possible vehicles
include propylene glycol, isopropanol, ethanol, oleic acid,
N-methylpyrro­lidone, sesame oil, olive oil, wood alcohol ointments,
vaseline,
a triglyceride gel sold under the trade name Softisan 378, and the
like.

     

    [0055] Possible permeation
enhancers include satu­rated and unsaturated fatty acids and their esters,
alco-

     

    
      	
               
      

            	
              5 hols,
      acetates, monoglycerides, diethanolamides and N, N-dimethylamides, such as
      linolenic acid, linolenyl alco­hol, oleic acid, oleyl alcohol, stearic
      acid, stearyl alcohol, palmitic acid, palmityl alcohol, myristic acid,
      myristyl al­cohol, 1-dodecanol, 2-dodecanol, lauric acid,
      decanol,

            


    

     

    
      	
               
      

            	
              10
      capric acid, octanol, caprylic acid,
      1-dodecylazacy­cloheptan-2-one sold under the trade name Azone by
      Nelson Research and Development, ethyl caprylate, iso­propyl
      myristate, hexamethylene lauramide, hexameth­ylene palmitate, capryl
      alcohol, decyl methyl sulfoxide,

            


    

     

    
      	
               
      

            	
              15
      dimethyl sulfoxide, salicylic acid and derivatives,
      N,N-diethyl-m-toluamide, crotamiton, 1-substituted
      azacyclo­alkan-2-ones, polyethylene glycol manolaurate, and oth­er
      compounds compatible with the package and the an­tagonist, and having
      transdermal permeation activity. In

            


    

     

    
      	
               
      

            	
              20
      accord with patent EPA-0282156, corticosteroid or other agents to
      lessen skin irritation could also be included. A preferred vehicle is
      propylene glycol and a preferred en­hancer is linolenic acid (10
      %).

            


    

     

    [0056] Further details on
transdermal compositions 25 will
appear from US Patent No. 5,096,715.

     

    [0057] In a third embodiment,
naloxone is given by in­tranasal inhalation and the dose per day is 0.001 mg
to 50 mg.

     

    [0058] The intranasal
formulations can be formulated

     

    
      	
               
      

            	
              30 with
      naloxone in the form of the acid, the base, or the salts thereof together
      with a stabilizer and a surfactant. Among pharmaceutically acceptable
      surfactants the fol­lowing can be mentioned: Polyoxyethylene castor
      oil de­rivatives; mono-fatty acid esters of polyoxyethylene
      (20)

            


    

     

    
      	
               
      

            	
              35
      sorbitan and sorbitan esters (TWEEN 20 and TWEEN 80),
      polyoxyethylene monostearate (TWEEN 60), poly­oxyethylene (20)
      sorbitan monopalmitate (TWEEN 40), and polyoxyethylene 20 sorbitan
      monolaurate (TWEEN 20); polyglyceryl esters, and polyoxyethylated kernel
      oil.

            


    

     

    
      	
               
      

            	
              40
      Preferably, the surfactant will be between about 0.01 % and 10% by
      weight of the pharmaceutical composition. [0059] The
      pharmaceutically useful stabilizers include antioxidants, such as sodium
      sulfite and metabisulfite, sodium thiosulfate and formaldehyde,
      sulfoxylate, sulfur

            


    

     

    
      	
               
      

            	
              45
      dioxide, ascorbic acid, isoascorbic acid, thioglycerol,
      thi­oglycolic acid, cysteine hydrochloride, acetyl cysteine,
      hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated
      hydroxytoluene, butylated hydroxyanisole, al­pha-tocopherol and
      lecithin. The stabilizer will
preferably

            


    

     

    
      	
               
      

            	
              50 be
      present in a concentration of about 0.01% and 5% by weight of the
      intranasal composition.

            


    

     

    [0060] Naturally, the
compositions may contain other components, as well (e.g. chelating agents and
fluidizing agents).

     

    
      	
               
      

            	
              55
      [0061] Each
      of the above embodiments can be carried out by a method in which the dose
      of naloxone is started at a high level of 5 to 50 mg and then is
      progressively reduced over the days of
  treatment.

            


    

     

    


    


    
      
        
        

      

      
        8

        
          

        

      

      
        
        

      

    

     

    13                           EP 1 681 057
B1                                               14

     

    [0062] By the above
embodiments, various eating dis­orders, typically selected from the group
comprising, binge eating, bulimia, bulimia-like syndrome, anorexia nervosa, and
habitual over-eating stimulated by specific stimuli including certain foods,
situations, or moods, can be successfully treated.

     

    [0063] The method can also be
used in situations wherein the patient must lower intake of a particular class
of dietary substances including sodium chloride, sugars, cholesterols or
low-density cholesterols, and the re­sponses to be selectively extinguished
are the eating of particular foods with high amounts of these substances. [0064] It should be noted that
the method can be used with subjects diagnosed as suffering from maladaptive
overly-strong responses reinforced by stimulation-in­duced release of
opioids and resulting in eating disor­ders. It cannot be used for patients
for whom the opiate antagonist is contraindicated. In particularly, patients who
are physiologically dependent upon opiates must be excluded.

     

    [0065] Specific details for
the use of selective extinc­tion with each of the different varieties of
problem re­sponses are presented below. The initial steps, however, in each
case are similar. First, detailed information is ob­tained about the
patient’s responses: the particular re­sponses that cause the patient
problems, the situations in which they have typically been emitted, and
particularly the foods that trigger the behavior. Second, the patient is checked
for alcoholism, drug addiction, or other con­traindications. Third, if there
is any possibility of an active opiate addiction despite denials by the patient,
a small dose of opiate antagonist is administered under close medical
supervision.

     

    [0066] Naloxone is metabolized
so rapidly in the liver that all of it is removed during the first pass after
oral administration. Consequently, it usually is injected, as was the case in a
previous test for treating anorexia (Huebner, US Patent 4,546,103,
1985).

     

    [0067] Transdermal
administration of naloxone, how-ever, is much better suited for repeated
self-administra­tion. I previously proposed a transdermal devise for
ad-ministering a fixed dose of an opioid antagonist, including naloxone, for use
in alcoholism treatment (Sinclair, US Patent 5,096,715, 1992). Recent
experiments (Panchag­nula et al., 2001) have shown this devise with 33 %
pro­pylene glycol as the vehicle and ethanol as the permea­tion enhancer
is even more effective for transdermal de-livery of naloxone than I had
anticipated: "theoretically blood levels well above the therapeutic
concentration of naloxone can be achieved" with a transdermal patch of a
convenient size. An intranasal spray has also been shown suitable for rapid
administration of naloxone for the majority of subjects and could also be used,
probably in combination with transdermal administration (Loimer et al.,
1992).

     

    [0068] Avoiding the oral route
also has distinct advan­tages for selective extinction of eating disorders.
First, there is the problem that some of an orally administered medication
would be lost by purging, or not taken by an­orexic patients. Second,
troubles with the gastrointestinal tract are common complications with eating
disorders. Oral administration itself irritates the throat and it
directs

     

    
      	
               
      

            	
              5 the
      highest concentration of the medication to intestines where it interacts
      with opioidergically controlled motility. Third, the response of taking an
      oral medication is similar to the eating responses we are trying to alter
      with the treatment, thus adding a possible complication to the
      pro-

            


    

      10
cedure.

     

    Binge-eating and
bulimia

     

    [0069] Severe cases should be
handled initially in a

     

    
      	
               
      

            	
              15
      treatment center to assure compliance, to increase mo­tivation,
      to monitor health, and to provide counseling and training concerning
      correct eating habits. The information obtained includes a list of the
      patient’s "trigger foods", i.e., those highly palatable foods that
      precipitate binges,

            


    

     

    
      	
               
      

            	
              20 are
      frequently included in binges, are greatly craved, or give the patient
      intense pleasure when the first bite is eaten. A list is also prepared for
      the patient of "healthy foods", i.e., nutritious foods that do meet any of
      the above characteristics for trigger
foods.

            


    

     

    
      	
               
      

            	
              25
      [0070] The
      patient is kept initially on diet specifically excluding a particular
      trigger food and foods with similar characteristics for a week prior to
      treatment. (In the afore-mentioned example, if the trigger is chocolate
      ice cream, the patient avoids not only chocolate ice cream but
      all

            


    

     

    
      	
               
      

            	
              30 ice
      cream and all chocolate.) Naloxone is then adminis­tered, perhaps
      first by nasal spray and then transdermal­ly, and then while active
      quantities are present in the system, the patient is presented with the
      trigger food and encouraged to have an eating binge of it. If possible,
      the

            


    

     

    
      	
               
      

            	
              35
      situation in which the food is eaten should be similar to that in
      which the patient usually has had eating binges. The response set should
      also be similar; e.g., if the pa­tient typically has purged after an
      eating binge previously, purging should occur also in the extinction
      session. No

            


    

     

    40 healthy
foods should be available.

     

    The
duration of an extinction session should match the patient’s previous binging
behavior. If binging normally continued for several days, the same should occur
in treatment, with additional transdermal administrations of

     

    45 naloxone
being given as needed.

     

    [0071] At the end of the
extinction session, the transdermal administration is stopped and the skin area
involved is washed thoroughly.

     

    [0072] The extinction session
is followed the next day 50 by a
"learning period" of one day or more when no antagonist
is given and only healthy foods are available. Not only
are trigger foods not available, but also all stimuli related to
them; the patient should not see them or smell them, nor
should they be discussed in counseling. The 

    55 safe foods
can be restricted to meal times, but the patient can eat as
much as desired then: no attempt at dieting should
occur during the learning periods. Learning of alternative
behaviors can be encouraged, but care should

     

    
      
        
        

      

      
        9

        
          

        

      

      
        
        

      

    

    


    


     

    15                           EP 1 681 057
B1                                               16

     

    be used
with regard to responses reinforced through the opioid system. For example,
greater than normal intake of alcohol should not be allowed.

     

    [0073] In subsequent
extinction sessions, the patient binges on other trigger foods that have not
been included in the previous sessions. In severe case being handled at a
clinical center, treatment continues until binge eating with most of the
patient’s trigger foods has been extin­guished and the person has gained
greater control over his or her eating habits. Thereafter, an out-patient mode
of selective extinction treatment can be used. The subject is given take-home
doses of the opiate antagonist and told to take one whenever there is a high
probability that unsafe foods will be eaten in the next few hours. The
instructions state that the patients should go ahead and have an eating binge if
they feel like it, but only after taking naloxone. Under no circumstance should
they binge without taking the antagonist. The antagonist should not be taken
otherwise, i.e., when the patient thinks there is little chance of eating
trigger foods.

     

    Dietary aid for
stimulus-bound overeating

     

    [0074] An out-patient mode of
selective extinction is used for patients with less severe eating problems and
high motivation and ability for compliance. It can be used with subjects who are
obese or only moderately over-weight whose weight problem is not due to
glandular anomalies but rather is caused by eating more than more than caloric
needs in response to specific stimuli. The stimuli can be specific
highly-palatable ("trigger") food items, situations, or moods. Examples of
trigger food items would be chocolate, mayonnaise, peanut butter, potato chips,
cream, butter, and cheese. Examples of trigger situations are watching
television, fast food and other restaurants, parties, holidays, and "midnight
snack" excursions. Examples of moods are premenstrual syn­drome (PMS),
post-traumatic stress (PTS), anxiety in an­ticipation of a stress situation,
and celebration euphoria. [0075] The procedure is the
same as that with binge-eating and bulimia except the subject is not kept in a
treatment center but rather conducts his or her own ex­tinction sessions in
the outside world. The subject is given clear, precise instructions (similar to
those specified above for binge eating and bulimia) on how to extinguish the
problem eating responses (e.g., 1. create a list of trigger stimuli, 2. choose
one, 3. refrain from it for one week, 4. arrange for the trigger stimulus to be
present, 5. self-administer naloxone, 6. what to do during inter­vening
"learning periods" when the antagonist is not tak­en and the trigger stimuli
are avoided as much as possi­ble.

     

    Dietary aid for limiting
intake of specific substances (sug­ar, salt,
etc.)

     

    [0076] Selective extinction
can be used for people who are not necessarily overweight but must reduce their
intake of a
particular substance that is closely associated with a distinct stimulus that
causes opioid release. 

     

    [0077] One example is with
people who need to reduce their intake of sodium chloride. Sodium chloride is
closely

     

    
      	
               
      

            	
              5
      associated with salty tastes, and there is evidence show­ing
      that a salty taste produces reinforcement through the opioidergic system
      (Levine et al., 1982). The person is given a series of extinction sessions
      on naloxone and learning periods off of the antagonist. During the
      extinc-

            


    

     

    
      	
               
      

            	
              10 tion
      sessions a variety of salty-tasting foods are eaten. If necessary, the
      salty taste could be produced by a salt substitute, but sodium chloride
      should be used if there is no medical danger from short-term intake of the
      sub-stance. During the learning sessions, salty-tasting
    foods

            


    

     

    
      	
               
      

            	
              15 are
      omitted from the diet completely. The responses of eating salty foods are
      thus selectively extinguished, while the responses of eating non-salty
      foods are not weak­ened and may be enhanced. This will reduce the
      desire for salty foods and make it easier for the person to
      stay

            


    

     

    20 on a
low salt diet.

     

    [0078] A similar procedure
could be used with people who need to restrict their intake of sugars. Sweet
foods are eaten during the extinction sessions and non-sweet ones during the
learning periods. The sweet taste could

     

    
      	
               
      

            	
              25 be
      produced with artificial sweeteners, but sugar should be used if there is
      no medical danger from such limited
intake.

            


    

     

    [0079] The method also can be
used with people who need to restrict their intake of cholesterols or
specifically

     

    
      	
               
      

            	
              30
      low-density cholesterols. Although there probably is no specific
      taste stimuli associated with cholesterols, they tend to be present in
      highest amounts in particular highly-palatable foods. Consequently, during
      the extinction ses­sions the person eats these particular foods and
      during

            


    

     

    
      	
               
      

            	
              35 the
      learning session the person eats foods with low amounts of cholesterol or
      low-density cholesterols. [0080] This procedure
      could be used either in a treat­ment center or on an out-patient basis
      depending upon the person’s ability to comply and the severity of the
      ail-

            


    

    40 ment
requiring the dietary limitations.

     

    Anorexia
nervosa

     

    [0081] The patient is kept
continually on a transdermal

    
      	
               
      

            	
              45 opiate
      antagonist for a period (probably 2 days or more) while intravenous
      nutrients are supplied. Naltrexone or nalmefene could be used initially
      but naloxone should be used in the last
day.

            


    

     

    [0082] Antagonist
administration is then abruptly ter-

    
      	
               
      

            	
              50
      minated. During the next day (a learning period when the system is
      free of active levels of antagonist), the patient is given small portions
      of a variety of highly-palatable foods and strongly encouraged to eat at
      least a small amount. The rebound supersensitivity of the opioid
      sys-

            


    

     

    
      	
               
      

            	
              55 tem
      should help to reinforce the eating responses that are
    made.

            


    

     

    [0083] The next day the
patient is placed again on the antagonists and fed intravenously. The pattern of
extinc-

     

    
      
        
        

      

      
        10

        
          

        

      

      
        
        

      

    

    


    


     

    17                           EP 1 681 057
B1                                               18

     

    tion
sessions and learning periods continues. New high­ly-palatable foods are
introduced on each antagonist-free day, with at least a week between duplication
of the same food item in order to allow deprivation effects to increase the
reinforcement. After the first sessions, in-creasing attention is paid to
providing a well-rounded, nutritious variety of highly-palatable foods.
Pharmaco­logical potentiation of the opioidergic response, e.g., with
moderate amounts of alcohol, can be employed.

     

    [0084] During extinction
session days on the antago­nist, the patient is encouraged to make the most
common responses from his or her own list of previously-learned competing
anorexic responses (e.g., vigorous exercise) that are probably reinforced
through the opioid system. In most cases, the aim should be weakening these
re­sponses only to a normal level.

     

    EXAMPLE

     

    [0085] Selective extinction:
weakening of one behavior and at the same time strengthening another. Selective
extinction is produced by pairing the response we want to decrease (alcohol
drinking by rats in this example) with an opioid antagonist and pairing the
response we want to become more powerful (saccharin drinking here) with times
when the antagonist is not in the body.

     

    [0086] The example
demonstrates that selective ex­tinction can be produced with naloxone (i.e.,
the antag­onist best suited for treating eating disorders.) It also shows
that selective extinction works with eating behav­iors like saccharin
drinking that are normally reinforced by the flavor causing endorphins to be
released.

     

    Methods

     

    [0087] Male Wistar rats (n=26)
were individually housed with daily access to 10 % ethanol, with food and water
always present. After 2 months prior experience, the rats were switched to
having 2-4 alcohol-access days interspersed with 1 or 2 days when saccharin
solution (1 g/l) was available for 1 hr. The rats were then divided into 2
matched groups, one always receiving a subcutaneous dose of naloxone prior to
alcohol access and a control group receiving a similar injection of saline prior
to alcohol access. No injections were made prior to saccharin ac­cess. In
addition, the naloxone dose was progressively reduced from 10.000 to 0.005
mg/kg.

     

    Results

     

    [0088] The naloxone injections
significantly reduced alcohol drinking in comparison with both the alcohol
in-take by the controls and in comparison with their own prior levels (see Fig.
la). The alcohol drinking continued to be significantly reduced for 8 weeks;
many of these weeks involved doses far lower than previously found to be
effective. Alcohol drinking was reduced to nearly zero for most rats for 6
weeks. The suppression of drinking of alcohol
drinking appears greater than in previous exper­iments in which both alcohol
drinking and antagonist ad-ministration occurred every day and specifically
greater than in studies aimed at maintaining a continual presence

     

    
      	
               
      

            	
              5 of
      the antagonist by using longer lasting naltrexone or nalmefene and mixing
      them with the food.

            


    

     

    [0089] In contrast to the
sharp reduction in alcohol drinking, saccharin drinking was consistently higher
in the naloxone treated rats than in the controls and signif-

     

    
      	
               
      

            	
              10
      icantly so during the first three weeks when doses of naloxone
      previously shown to be effective were used (see Fig.
  1b).

            


    

     

    References

     

    15

    [0090]

     

    "Naloxone
in the Treatment of Anorexia Nervosa: Effect on Weight Gain and Lipolysis" R.
Moore, I.H

     

    
      	
              20

            	
              Mills,
      A. Forster, Journal of the Royal Society of Med­icine 1981, 74,
      129-31.

            


    

     

    "Targeted
Use of Naltrexone Without Prior Detoxifi­cation in the Treatment of Alcohol
Dependence: A Factorial Double-Blind Placebo-Controlled Trial." P

     

    
      	
               
      

            	
              25
      Heinälä, H. Alho, K. Kiianmaa, J. Lönnqvist, K. Kuop­pasalmi,
      and J.D. Sinclair, Journal of Clinical Psy­chopharmacology, 2001. 21,
      287-292.

            


    

     

    "Evidence
about the Use of Naltrexone and for Dif­ferent Ways of Using It in the
Treatment of Alcohol-

     

    
      	
              30

            	
              ism"
      J. D. Sinclair, Alcohol and Alcoholism 2001,36,
  2-10.

            


    

     

    "The Rest
Principle: A Neurophysiological Theory of Behavior" J. D. Sinclair, Lawrence
Erlbaum Associ­ates, Hillsdale, NJ, 1981.

     

    
      	
              35

            	
              "Rats
      Learning to Work for Alcohol" J. D. Sinclair, Nature 1974, 249,
      590-592.

            


    

     

    "Drugs to
Decrease Alcohol Drinking", J.D.Sinclair, Annals of Medicine, 1990, 22,
357-362.

     

    "Alcohol
and Opioid Peptides: Neuropharmacologi-

     

    
      	
               
      

            	
              40 cal
      Rational for Physical Craving of Alcohol" M.C. Tractenberg, and K. Blum.
      American Journal of Drug and Alcohol Abuse 1987,13,
    365-372.

            


    

     

    "Naltrexone
and the Treatment of Alcohol Depend­ence" J.R. Volpicelli, C.P.O’Brien,
A.I.Alterman, and

     

    
      	
               
      

            	
              45 M.
      Hayashida, In Opioids, Bulimia, and Alcohol Abuse & Alcoholism,
      L.D.Reid, ed. Springer-Verlag, New York, 1990, pp
  195-214.

            


    

     

    "Opioids
Modulate Rats’ Propensities to Take Alco­holic Beverages" L. D. Reid, and C.
L. Hubbell, in

     

    
      	
               
      

            	
              50 Novel
      Pharmacological Interventions for Alcoholism. C.A. Naranjo and E.M.
      Sellers (eds) New York: Springer-Verlag,
  pp.121-134,1992

            


    

     

    "Uso
Efficace del Naltrexone: Ciò Che Non è Stato Detto a Medici e Pazienti"
(Effective use of naltrex-

     

    
      	
               
      

            	
              55 one:
      What doctors and patients have not been told) D. Sinclair, F. Fantozzi,
      and J. Yanai, The Italian Journal of the Addictions, 2003,
      41,15-21.

            


    

     

    "La
Ricaduta Nell’Alcol: un Concetto Vincente, Ma

     

    


    


    
      
        
        

      

      
        11

        
          

        

      

      
        
        

      

    

     

    19                           EP 1 681 057
B1                                               20

     

    in Via di
Estinzione?" F. Fantozzi, and D. Sinclair, Personalit Dipendenze 2004,10,
219-243. "Naltrexone and Brief Counselling to Reduce Heavy Drinking" M. J. Bohn,
H.R. Kranzler, D. Beazoglou, and B.A. Staehler, The American Journal on
Addic­tions 1994, 3, 91-99.

     

    "A
Randomized 6 Month Double-Blind Placebo-Con­trolled Study of Naltrexone and
Coping Skills Edu­cation Programme" J. Balldin, M. Berglund, S. Borg, M.
Månsson, P. Berndtsen, J. Franck, L. Gustafsson, J. Halldin, C. Hollstedt, L-H.
Nilsson, and G. Stolt, Alcohol and Alcoholism 1997, 32, 325.

     

    "The
Effect of Naltrexone on Taste Detection and Recognition Threshold" P.A. Arbisi,
C.J. Billington, A.S. Levine, Appetite 1999, 32, 241-249. "Long-Term Follow Up
of Continued Naltrexone Treatment" J. D. Sinclair, K. Sinclair, and H. Alho,
Alcoholism: Clinical and Experimental Research 2000, 24, suppl.
182A.

     

    "Double-Blind
Naltrexone and Placebo Comparison Study in The Treatment of Pathological
Gambling" S. W. Kim, J. E. Grant, D. E. Adson, and Y. C. Shin, Biological
Psychiatry 2001, 49:914-921.

     

    "Basic
Mechanisms of Opioids’ Effects on Eating and Drinking", S.J. Cooper and T.C.
Kirkham, in Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D. Reid, ed.
Springer-Verlag, New York, 1990, 91-110.

     

    "Naltrexone
and Bulimia: Initial Observations", J.M. Jonas, in Opioids, Bulimia, and Alcohol
Abuse & Al­coholism, L.D. Reid, ed., Springer-Verlag, New York, 1990,
123-130.

     

    "Obesity,
Anorexia Nervosa, and Bulimia: A General Overview", K.D. Wild and L.D. Reid,in
Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D. Reid, ed.,
Springer-Verlag, New York, 1990, 3-21.

     

    "Opioids
Modulate Rats’ Intake of Alcoholic Bever-ages", C.L. Hubbell and L.D. Reid, in
Opioids, Bulim­ia, and Alcohol Abuse & Alcoholism, L.D. Reid, ed.,
Springer-Verlag, New York, 1990, 145-174.

     

    "Using
Drugs to Manage Binge-Eating among Obese and Normal Weight Patients", S.A.Alger,
M.J.Schwalberg, J.M. Bigaoutte, L.J. Howard, and L.D. Reid, in: Opioids,
Bulimia, and Alcohol Abuse & Alcoholism, L.D.Reid, ed., Springer-Verlag, New
York, 1990, 131-142.

     

    "Pharmacologic
Treatment Of Binge Eating Disor­der" W.P. Carter, J.I. Hudson, J.K. Lalonde,
L. Pindy­ck, S.L. McElroy, and H.G. Pope Jr., International Journal of
Eating Disorders 2003, 34, Suppl:S74-88. "Naloxone Decreases Food Intake in
Obese Hu-mans", R. L. Atkinson, Journal of Clinical Endocrinol­ogy and
Metabolism, 1982, 55, 196-198.

     

    "The
Endogenous Opioidergic Systems" E.M.Unter­wald and R.S.Zukin, in, Opioids,
Bulimia, and Alco­hol Abuse & Alcoholism, L.D. Reid, ed.,
Springer-Verlag, New York, 1990, 49-72.

     

    "Reduction
of Alcohol Drinking and Upregulation of Opioid Receptors by Oral Naltrexone in
AA Rats" J.H. Parkes
and J.D.Sinclair. Alcohol, 2000, 21, 215-221.

     

    "Potential
Toxicities of High Doses of Naltrexone in Patients with Appetitive Disorders",
C.J. Morgan and

     

    
      	
               
      

            	
              5 T.R.
      Kosten, in Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D.
      Reid, ed. Springer-Verlag, New York, 1990,
  261-273.

            


    

     

    "Flavor
Enhances the Antidipsogenic Effect of Naloxone", A. S. Levine, S. S. Murray, J.
Kneip, M.

     

    
      	
              10

            	
              Grace
      and J. E. Morley, Physiology and Behavior, 1982, 28,
  23-25.

            


    

     

    "Increased
preference for ethanol in rats following alcohol deprivation", J.D. Sinclair,
and R.J.Senter, Psychonomic Science 1967, 8, 11-12.

     

    
      	
               
      

            	
              15 "The
      Effect of Naltrexone on Alcohol Consumption after Alcohol Deprivation in
      Rhesus Monkeys", M. Kornet, C. Goosen, and J.M. Van Ree, Abstracts of the
      XXth Nordic Meeting on Biological Alcohol Re-search, Espoo, Finland, May
      13-15, 1990, abstract

            


    

     

    20           20

     

    "Pattern
of Onset of Bulimic Symptoms in Anorexia Nervosa", J.A. Kassett, H.E. Gwirtsman,
W.H. Kaye, H.A. Brandt, and D.C. Jimerson, American Journal of Psychiatry, 1988,
145, 1287-1288.

     

    
      	
               
      

            	
              25
      "Case Reports: Treatment of Chronic Anorexia Ner­vosa with
      Opiate Blockade", E.D. Luby, M.A. Mar­razzi, and J. Kinzie, Journal of
      Clinical Psychophar­macolgy, 1987, 7,
52-53.

            


    

     

    "An
Auto-Addiction Opioid Model of Chronic Anorex-

     

    
      	
               
      

            	
              30 ia
      Nervosa", M.A. Marrazzi and E.D. Luby, Interna­tional Journal of
      Eating Disorders, 1986, 5, 191-208. "Transdermal Delivery of Naloxone:
      Effect of Water, Propylene Glycol, Ethanol and Their Binary
      Combi­nations on Permeation Through Rat Skin" R.
  Pan-

            


    

     

    
      	
               
      

            	
              35
      chagnula, P.S. Salve, N.S. Thomas, A.K. Jain, and P. Ramarao,
      International Journal of Pharmacology 2001, 219,
  95-105.

            


    

     

    "Nasal
Administration of Naloxone is as Effective as the Intravenous Route in Opiate
Addicts" N. Loimer,

     

    
      	
              40

            	
              P.
      Hofmann, and H.R. Chaudhry, International Jour­nal of Addictions,
      1994, 29, 819-827.

            


    

     

    "The
Genetic Epidemiology of Bulimia Nervosa" K.S. Kendler, C. MacLean, M. Neale, R.
Kessler, A. Heath, and L. Eaves, American Journal of Psychia-

     

    45           try,
1991,148, 1627-1637.

     

    "Selective
Extinction of Alcohol Drinking in Rats with Decreasing Doses of Opioid
Antagonists" J.D. Sin­clair, L. Vilamo, and B. Jakobson. Alcoholism:
Clin­ical and Experimental Research 1994, 18, 489.

     

    50

     

    Claims

     

    1. Use of naloxone for the
preparation of a pharmaceu-

     

    
      	
               
      

            	
              55
      tical composition for treating eating disorders by a method based
      on selective extinction comprising the
steps:

            


    

     

    
      
        
        

      

      
        12

        
          

        

      

      
        
        

      

    

    


    


     

    21                            EP 1 681 057
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    - identification of the
specific responses in the patient’s eating behavior that are unhealthy or
otherwise inappropriate,

    -
administering the pharmaceutical composition containing naloxone just before the
patient 5
makes these unhealthy responses,

    - having
the patient make healthy eating re­sponses only when the effective levels of
naloxone are no longer present in the body, and

    - having
the patient to alternate between making 10 unhealthy
eating responses when effective lev­els of naloxone are present and making
healthy eating responses when effective levels of naloxone are not present, so
long as the patient

    still
wants to make the unhealthy eating respons­ 15
es.

     

    
      	
              2. Use
      according to claim 1, wherein the eating disorder is selected from the
      group comprising binge eating, bulimia, bulimia-like syndrome, anorexia
      nervosa, and habitual over-eating stimulated by specific stim­uli
      including certain foods, situations, or moods.

               

              3. Use
      of naloxone for the preparation of a pharmaceu­tical composition for
      improving compliance among patients who must lower intake of a particular
      class of restricted food including dietary substances such as sodium
      chloride, sugars, cholesterols or low-den­sity cholesterols by a
      method based on selective ex­tinction comprising the
      steps:

            


    

     

    20

     

    25

     

    30

     

    -
administering the pharmaceutical composition containing naloxone just before the
patients eats the restricted food,

    - having
the patient eat other non-restneted food 35 only when
the effective levels of naloxone are no longer present in the body,

    - having
the patient alternate between occasion-ally eating the restricted food when the
effective levels of naloxone are present and eating non- 40 restricted
food when effective levels of naloxone are not present, so long as the patient
still wants to eat the restricted food.

    -
Identifizieren der spezifischen Reaktionen im Essverhalten des Patienten, welche
ungesund oder anderweitig ungünstig sind,

    
      	
              Patentansprüche

              1. Verwendung von
      Naloxon zur Herstellung eines Arz­neimittels zur Behandlung von
      Essstörungen durch ein Verfahren beruhend auf selektiver Löschung,
      umfassend die Schritte:

            


    

     

    -
Verabreichen des Arzneimittels enthaltend Na­loxon kurz bevor der Patient
diese ungesunden Reaktionen ausführt,

    - den
Patienten dazu bringen, die gesunden Essreaktionen nur dann auszuführen, wenn
die wirksamen Spiegel von Naloxon nicht länger im Körper vorherrschen,
und

    - den
Patienten dazu bringen, zwischen dem Ausführen von ungesunden Essreaktionen,
wenn wirksame Spiegel von Naloxon vorherr­schen, und dem Ausführen von
gesunden Ess­reaktionen, wenn wirksame Spiegel von Nalo­xon nicht
vorherrschen, zu wechseln, so lange der Patient die ungesunden Essreaktionen
im­mer noch ausführen will.

     

    
      	
               

              4. The
      use according to any of claims 1 to 3, wherein 45 naloxone
      is given transdermally and the dose per day is 0.001 mg to 50
      mg.

               

              5. The
      use according to any of claims 1 to 3, wherein naloxone is given by
      intranasal inhalation and the 50 dose
      per day is 0.001 mg to 50 mg.

               

              6. The
      use in accordance with any of the preceding claims, wherein the dose of
      naloxone is started at a high level of 5 to 50 mg and then is
      progressively 55
      reduced over the days of treatment.

               

            


    

    
      	
              2. Verwendung
      nach Anspruch 1, wobei die Essstö­rung ausgewählt ist aus Binge
      Eating, Bulimie, buli­mieähnlichem Syndrom, Anorexia nervosa und
      ge­wohnheitsmäßigem Über-Essen stimuliert durch spezifische Stimuli
      einschließlich bestimmter Nah­rungsmittel, Situationen oder
      Gemütszustände.

               

              3. Verwendung
      von Naloxon zur Herstellung eines Arz­neimittels zur Verbesserung der
      Therapietreue unter Patienten, welche die Aufnahme von einer
      bestimm­ten Klasse an begrenzten Nahrungsmitteln herab­setzen
      müssen, einschließlich Diätsubstanzen wie Natriumchlorid, Zucker,
      Cholesterine oder LDL­Cholesterine, durch ein Verfahren beruhend auf
      se­lektiver Löschung umfassend die
Schritte:

            


    

     

    -
Verabreichen des Arzneimittels enthaltend Na­loxon kurz bevor der Patient
das begrenzte Nah­rungsmittel isst,

     

    - den
Patienten dazu bringen, andere, nicht-be­grenzte Nahrungsmittel nur dann zu
essen, wenn die wirksamen Spiegel von Naloxon nicht länger im Körper
vorherrschen, und

     

    - den
Patienten dazu bringen, zwischen dem ge­legentlichen Essen des begrenzten
Nahrungs­mittels, wenn wirksame Spiegel von Naloxon vorherrschen, und dem
Essen von nicht-be­grenzten Nahrungsmitteln, wenn wirksame Spiegel von
Naloxon nicht vorherrschen, zu wechseln, so lange der Patient das begrenzte
Nahrungsmittel immer noch essen will.

     

    
      
        
        

      

      
        13

        
          

        

      

      
        
        

      

    

    


    


     

    23                           EP 1 681 057
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              4.  

            	
              Verwendung
      gemäß einem der Ansprüche 1 bis 3, wobei Naloxon transdermal verabreicht
      wird und die Tagesdosis 0,001 mg bis 50 mg
  beträgt.

            


    

     

    
      5

       

    

    
      	
              5.  

            	
              Verwendung
      gemäß einem der Ansprüche 1 bis 3, wobei Naloxon durch intranasale
      Inhalation verab­reicht wird und die Tagesdosis 0,001 mg bis 50 mg
      beträgt.

            


    

     

    
      	
              6.  

            	
              Verwendung
      gemäß einem der vorangegangenen 10
      Ansprüche, wobei die Dosis an Naloxon bei einem hohen Spiegel von 5
      bis 50 mg gestartet und dann allmählich über die Tage der Behandlung
      reduziert wird.

            


    

     

    


    -
administrer la composition pharmaceutique contenant la naloxone juste avant que
le patient n’ait ces réponses morbides,

    - faire
que le patient ait des réponses alimen­taires saines seulement lorsque les
taux effica­ces de naloxone ne sont plus présents dans le corps,
et

    - faire
que le patient alterne entre manger occa­sionnellement des aliments
interdits lorsque les taux efficaces de naloxone sont présents et manger des
aliments non interdits lorsque les taux efficaces de naloxone ne sont plus
pré­sents, tant que le patient veut encore manger les aliments
interdits.

    


     

    15

    


     

    Revendications

     

    
      	
              1.  

            	
              Utilisation
      de naloxone pour la préparation d’une composition pharmaceutique pour le
      traitement de troubles alimentaires par un procédé basé sur une extinction
      sélective comprenant les étapes de
:

            


    

     

    -
identifier les réponses spécifiques dans le com­portement alimentaire d’un
patient qui sont mor­bides, ou inappropriées,

     

    -
administrer la composition pharmaceutique contenant la naloxone juste avant que
le patient n’ait ces réponses morbides,

     

    - faire
que le patient ait des réponses alimen­taires saines seulement lorsque les
taux effica­ces de naloxone ne sont plus présents dans le corps,
et

     

    - faire
que le patient alterne entre les réponses alimentaires morbides lorsque les taux
efficaces de naloxone sont présents et des réponses ali­mentaires saines
lorsque les taux efficaces de naloxone ne sont plus présents, tant que le
pa­tient veut encore avoir des réponses alimen­taires
morbides.

     

    
      	
              2.  

            	
              Utilisation
      selon la revendication 1, dans laquelle le trouble alimentaire est choisi
      dans le groupe com­prenant l’hyperphagie boulimique, la boulimie, un
      syndrome similaire à la boulimie, l’anorexie mentale, et l’hyperphagie
      ordinaire stimulée par des stimulus spécifiques incluant certain(e)s
      aliments, situations, ou humeurs.

            


    

     

    
      	
              3.  

            	
              Utilisation
      de naloxone pour la préparation d’une composition pharmaceutique pour
      améliorer l’obser­vance des patients qui doivent réduire la
      consom­mation d’une classe particulière d’aliments interdits incluant
      des substances alimentaires telles que le chlorure de sodium, les sucres,
      les cholestérols ou les cholestérols de basse densité par un procédé basé
      sur l’extinction sélective comprenant les étapes de
  :

            


    

    


    
      	
              4.  

            	
              Utilisation
      selon l’une quelconque des revendica­tions 1 à 3, dans laquelle la
      naloxone est administrée par voie transdermique et la dose quotidienne est
      de 0,001 mg à 50 mg.

            


    

     

    20

    
      	
              5.  

            	
              Utilisation
      selon l’une quelconque des revendica­tions 1 à 3, dans laquelle la
      naloxone est administrée par inhalation intranasale et la dose quotidienne
      est de 0,001 mg à 50 mg.

            


    

     

    25

    
      	
              6.  

            	
              Utilisation
      selon l’une quelconque des revendica­tions précédentes, dans laquelle
      la dose de naloxo­ne est initiée à un taux élevé de 5 à 50 mg puis est
      progressivement réduite pendant le
traitement.

            


    

     

    30

     

    35

     

    40

     

    45

     

    50

     

    55

    
      
        
        

      

      
        14

        
          

        

      

      
        
        

      

    

     

    EP 1 681 057
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        15

        
          

        

      

      
        
        

      

    

     

    EP 1 681 057 B1

     

    REFERENCES
CITED IN THE DESCRIPTION

     

    This
list of references cited by the applicant is for the reader’s convenience only. It
does not form part of the
European patent document.
Even though great care has been taken in compiling the references, errors or
omissions cannot be excluded and the EPO disclaims all liability in this
regard.

     

    Patent
documents cited in the description

     

    
      
        
          	
                  · US
      4217353 A [0003]

                	
                  · • US 5587381 A [0005] [0005]
      [0043]

                
	
                  · US
      4477457 A [0003]

                	
                  · • EP 0346830 B1 [0005]

                
	
                  · US
      4546103 A [0003] [0038]
      [0066]

                	
                  · • US 5780479 A [0036]

                
	
                  · US
      4882335 A [0005]
      [0028]

                   

                	
                  · • US 5096715 A [0056]
      [0067]

                   

                


        

      

    

     

    Non-patent
literature cited in the description

     

    
      	
              ·  

            	
              R. MOORE ; I.H MILLS ; A.
      FORSTER. Naloxone in the Treatment of Anorexia Nervosa: Effect on
      Weight Gain and Lipolysis. Journal of the Royal Society
      of Medicine, 1981, vol. 74, 129-31 [0090]

            


    

     

    
      	
              ·  

            	
              P HEINÄLÄ ; H. ALHO ; K.
      KIIANMAA ; J. LÖNNQVIST ; K. KUOPPASALMI ; J.D. SIN­CLAIR.
      Targeted Use of Naltrexone Without Prior Detoxification in the
      Treatment of Alcohol Depend­ence: A Factorial Double-Blind
      Placebo-Controlled Trial. Journal of Clinical
      Psychopharmacology,
      2001, vol. 21, 287-292 [0090]

            


    

     

    
      	
              ·  

            	
              J. D. SINCLAIR. Evidence
      about the Use of Naltrex­one and for Different Ways of Using It in the
      Treatment of Alcoholism. Alcohol and Alcoholism,
      2001, vol. 36, 2-10 [0090]

            


    

     

    
      	
              ·  

            	
              J. D. SINCLAIR. The Rest
      Principle: A Neurophysi­ological Theory of Behavior. Lawrence Erlbaum
      As­sociates, 1981 [0090]

            


    

     

    
      	
              ·  

            	
              J. D. SINCLAIR. Rats
      Learning to Work for Alcohol. Nature, 1974, vol. 249,
      590-592 [0090]

            


    

     

    
      	
              ·  

            	
              J.D.SINCLAIR. Drugs to
      Decrease Alcohol Drinking. Annals of Medicine,
      1990, vol. 22, 357-362 [0090]

            


    

     

    
      	
              ·  

            	
              M.C. TRACTENBERG ; K. BLUM.
      Alcohol and Opi­oid Peptides: Neuropharmacological Rational for
      Physical Craving of Alcohol. American Journal
      of Drug and
      Alcohol Abuse, 1987, vol. 13, 365-372 [0090]

            


    

     

    
      	
              ·  

            	
              Naltrexone
      and the Treatment of Alcohol Depend­ence. J.R. VOLPICELLI ; C.P.O’BRIEN ;
      A.I.ALTERMAN ; M. HAYASHIDA. Opioids, Bulim­ia, and Alcohol
      Abuse & Alcoholism. Springer-Verlag, 1990, 195-214 [0090]

            


    

     

    
      	
              ·  

            	
              Opioids
      Modulate Rats’ Propensities to Take Alco­holic Beverages. Novel
      Pharmacological Interven­tions for Alcoholism. Springer-Verlag, 1992,
      121-134 [0090]

            


    

     

    
      	
              ·  

            	
              Uso
      Efficace del Naltrexone: Ciò Che Non è Stato Detto a Medici e Pazienti.
      D. SINCLAIR ; F. FANTOZZI
      ; J. YANAI. The Italian Journal of the Ad­dictions. 2003, vol.
      41, 15-21 [0090]

            


    

     

    


     

    
      	
              ·  

            	
              F. FANTOZZI ; D. SINCLAIR.
      La Ricaduta Nell’Alcol: un Concetto Vincente, Ma in Via di
      Estinzione. Per­sonalit Dipendenze,
      2004, vol. 10, 219-243 [0090]

            


    

     

    
      	
              ·  

            	
              M. J. BOHN ; H.R. KRANZLER ; D.
      BEAZOGLOU ; B.A.
      STAEHLER. Naltrexone and Brief Counselling to Reduce Heavy
      Drinking. The American
      Journal on
      Addictions,
      1994, vol. 3, 91-99 [0090]

            


    

     

    
      	
              ·  

            	
              J. BALLDIN ; M. BERGLUND ; S.
      BORG ; M. MÅNSSON ; P. BERNDTSEN ; J. FRANCK ; L. GUSTAFSSON ; J. HALLDIN
      ; C. HOLLSTEDT ; L-H. NILSSON. A Randomized 6 Month
      Dou­ble-Blind Placebo-Controlled Study of Naltrexone and Coping Skills
      Education Programme. Alcohol and Alcoholism,
      1997, vol. 32, 325 [0090]

            


    

     

    
      	
              ·  

            	
              P.A. ARBISI ; C.J. BILLINGTON ;
      A.S. LEVINE. The Effect of Naltrexone on Taste Detection and
      Rec­ognition Threshold. Appetite, 1999, vol.
      32, 241-249 [0090]

            


    

     

    
      	
              ·  

            	
              J. D. SINCLAIR ; K. SINCLAIR ;
      H. ALHO. Long-Term Follow Up of Continued Naltrexone
      Treat­ment. Alcoholism: Clinical and
      Experimental Re-search, 2000, vol. 24 (182A [0090]

            


    

     

    
      	
              ·  

            	
              S. W. KIM ; J. E. GRANT ; D. E.
      ADSON ; Y. C. SHIN. Double-Blind Naltrexone and Placebo
      Com­parison Study in The Treatment of Pathological Gam­bling.
      Biological Psychiatry,
      2001, vol. 49, 914-921 [0090]

            


    

     

    
      	
              ·  

            	
              S.J. COOPER ; T.C. KIRKHAM.
      Basic Mechanisms of Opioids’ Effects on Eating and Drinking. Opioids, Bulimia, and Alcohol Abuse
      & Alcoholism, 1990, 91-110 [0090]

            


    

     

    
      	
              ·  

            	
              Naltrexone
      and Bulimia: Initial Observations. J.M. JONAS. Opioids,
      Bulimia, and Alcohol Abuse & Al­coholism. Springer-Verlag, 1990,
      123-130 [0090]

            


    

     

    
      	
              ·  

            	
              Obesity,
      Anorexia Nervosa, and Bulimia: A General Overview. K.D. WILD ; L.D. REID.
      Opioids, Bulimia, and Alcohol Abuse & Alcoholism.
      Springer-Verlag, 1990, 3-21 [0090]

            


    

     

     

    
      
        
        

      

      
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    EP 1 681 057 B1

    
 

    
      	
              ·  

            	
              Opioids
      Modulate Rats’ Intake of Alcoholic Beverag­es. C.L. HUBBELL ; L.D. REID.
      Opioids, Bulimia, and Alcohol Abuse & Alcoholism.
      Springer-Verlag, 1990, 145-174 [0090]

            


    

     

    
      	
              ·  

            	
              Using
      Drugs to Manage Binge-Eating among Obese and Normal Weight Patients. S.A.ALGER ; M.J.SCHWALBERG ;
      J.M. BIGAOUTTE ; L.J. HOWARD ; L.D. REID.
      Opioids, Bulimia, and Alcohol Abuse & Alcoholism.
      Springer-Verlag, 1990, 131-142 [0090]

            


    

     

    
      	
              ·  

            	
              Pharmacologic
      Treatment Of Binge Eating Disorder. W.P. CARTER ; J.I. HUDSON ;
      J.K. LALONDE ; L. PINDYCK ; S.L. MCELROY ; H.G.
      POPE JR. Inter-national Journal of Eating Disorders. 2003, vol. 34,
      S74-88 [0090]

            


    

     

    
      	
              ·  

            	
              R. L. ATKINSON. Naloxone
      Decreases Food Intake in Obese Humans. Journal of Clinical
      Endocrinology and
      Metabolism, 1982, vol. 55, 196-198 [0090]

            


    

     

    
      	
              ·  

            	
              The
      Endogenous Opioidergic Systems. E.M.UNTERWALD ; R.S.ZUKIN.
      Opioids, Bulimia, and Alcohol Abuse & Alcoholism.
      Springer-Verlag, 1990, 49-72 [0090]

            


    

     

    
      	
              ·  

            	
              J. H. PARKES ; J.D.SINCLAIR.
      Reduction of Alco­hol Drinking and Upregulation of Opioid
      Receptors by Oral Naltrexone in AA Rats. Alcohol, 2000, vol. 21,
      215-221 [0090]

            


    

     

    
      	
              ·  

            	
              Potential
      Toxicities of High Doses of Naltrexone in Patients with Appetitive
      Disorders. C.J. MORGAN ;
      T.R. KOSTEN. Opioids, Bulimia, and Alcohol Abuse & Alcoholism.
      Springer-Verlag, 1990, 261-273 [0090]

            


    

     

    
      	
              ·  

            	
              A. S. LEVINE ; S. S. MURRAY ;
      J. KNEIP ; M. GRACE ; J. E. MORLEY. Flavor Enhances the
      An­tidipsogenic Effect of Naloxone. Physiology and Be­havior,
      1982, vol. 28, 23-25 [0090]

            


    

     

    
      	
              ·  

            	
              J.D. SINCLAIR ; R.J.SENTER.
      Increased prefer­ence for ethanol in rats following alcohol
      deprivation. Psychonomic
      Science, 1967, vol. 8, 11-12 [0090]

            


    

     

    
      	
                
      ·

            	
              M. KORNET ; C. GOOSEN ; J.M.
      VAN REE. The Effect of Naltrexone on Alcohol Consumption after
      Alcohol Deprivation in Rhesus Monkeys. Abstracts of the XXth Nordic
      Meeting on Biological Alcohol Re-search, 13 May 1990 [0090]

            


    

     

    
      	
              ·  

            	
              J.A. KASSETT ; H.E. GWIRTSMAN ;
      W.H. KAYE ; H.A. BRANDT ; D.C. JIMERSON. Pattern of Onset of
      Bulimic Symptoms in Anorexia Nervosa. American Journal of Psychiatry,
      1988, vol. 145, 1287-1288 [0090]

            


    

     

    
      	
              ·  

            	
              E.D. LUBY ; M.A. MARRAZZI ; J.
      KINZIE. Case Re-ports: Treatment of Chronic Anorexia Nervosa with
      Opiate Blockade. Journal
      of Clinical Psychopharma­colgy, 1987, vol. 7, 52-53 [0090]

            


    

     

    
      	
              ·  

            	
              M.A. MARRAZZI ; E.D. LUBY.
      An Auto-Addiction Opioid Model of Chronic Anorexia Nervosa. Interna­tional
      Journal
      of Eating
      Disorders, 1986, vol. 5, 191-208 [0090]

            


    

     

    
      	
              ·  

            	
              R. PANCHAGNULA ; P.S. SALVE ;
      N.S. THOMAS ; A.K.
      JAIN ; P. RAMARAO. Transdermal Delivery of Naloxone: Effect of
      Water, Propylene Gly­col, Ethanol and Their Binary Combinations on
      Per­meation Through Rat Skin. International Journal of
      Pharmacology,
      2001, vol. 219, 95-105 [0090]

            


    

     

    
      	
              ·  

            	
              N. LOIMER ; P. HOFMANN ; H.R.
      CHAUDHRY. Na­sal Administration of Naloxone is as Effective as
      the Intravenous Route in Opiate Addicts. International Journal of
      Addictions, 1994, vol. 29, 819-827 [0090]

            


    

     

    
      	
              ·  

            	
              K.S. KENDLER ; C. MACLEAN ; M.
      NEALE ; R. KESSLER
      ; A. HEATH ; L. EAVES. The Genetic Ep­idemiology of Bulimia
      Nervosa. American
      Journal
      of Psychiatry,
      1991, vol. 148, 1627-1637 [0090]

            


    

     

    
      	
              ·  

            	
              J.D. SINCLAIR ; L. VILAMO ; B.
      JAKOBSON. Se­lective Extinction of Alcohol Drinking in Rats
      with De-creasing Doses of Opioid Antagonists. Alcoholism: Clinical and
      Experimental Research, 1994, vol. 18, 489 [0090]

            


    

     

     

    
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