Beta-carbolines and chemical dependence treatment 
Author Message
 Beta-carbolines and chemical dependence treatment

Utility
METHOD  OF  TREATING  CHEMICAL DEPENDENCY USING .BETA.-CARBOLINE
ALKALOIDS,
DERIVATIVES AND SALTS THEREOF

PATENT NO.:  5,591,738
ISSUED:      January 07, 1997 (19970107)
INVENTOR(s): Lotsof, Howard S., Staten Island, NY (New York), US (United
             States of America)
ASSIGNEE(s): NDA International, Inc, (A U.S. Company or Corporation),
             Staten Island, NY (New York), US (United States of America)
             [Assignee Code(s): 21291]
APPL. NO.:   8-322,490
FILED:       October 14, 1994 (19941014)
U.S. CLASS:  514-214 cross ref: 514-292; 514-810; 514-811; 514-812;
514-813
INTL CLASS:  [6] A61K 31-55; A61K 31-44
FIELD OF SEARCH: 514-214; 514-292; 514-810; 514-811; 514-812; 514-813

                             OTHER REFERENCES

Cappendijk, Susanne, et al; "The Inhibitory Effect of Norharman on
Morphine
Withdrawal  Syndrome  in  Rats: Comparison with Ibogaine", Behavi{*filter*}
Brain
Research,  Faculty  of  Medicine  and  Health  Sciences, Erasmus
University
Rotterdam, 3000 DR, Rotterdam, The Netherlands, Aug. 5, 1994, pp. 1-3.

Gunn,  J.  A.,  "Relations  Between  Chemical Constitution,
Pharmacological
actions,  and  Therapeutic  Uses,  in  the  Harmine Group of Alkaloids",
The
Pharmacological  Laboratory,  University  of  Oxford,  Mar.  14,  1935,
pp.
379-383, 395-396.

Slotkin,  Theodore A. and DiStefano, Victor; "A Model of Harmine
Metabolism
in  the  Rat",  The  Journal of Pharmacology and Experimental
Therapeutics,
Department  of  Pharmacology, University of Rochester, Rochester, New
York,
The Williams & Wilkins Co., vol. 174, No. 3, 1970, pp. 456-462.

Ho,  Beng  T.  et  al,  "Metabolism  of  Harmaline  in  Rats",
Biochemical
Pharmacology, vol. 20, pp. 1313-1319, Pergamon Press, 1971, Great Britain.

Slotkin,  Theodore  A. et al, "{*filter*} Levels and Urinary Excretion of
Harmine
and  its  Metabolites  in  Man  and  Rats",  The Journal of pharmacology
and
Experimental  Therapeutics,  1970, The William & Wilkins Co., vol. 173,
No.
1, pp. 26-30, USA.

Slotkin,  Theodore  and DiStefano, Victor, "Urinary Metabolites of Harmine
in   the  Rat  and  Their  Inhibition  of  Monoamine  Oxidase"
Biochemical
Pharmacology, vol. 19, pp. 125-131, Pergamon Press, 1970, Great Britain.

Zetler,  G.  et  al,  "Pharmacokinetic  in  the  Rat  of the
hallucinogenic
Alkaloids  Harmine  and  Harmaline", Naunyn-Schmiedeberg's Arch.
Pharmacol.
Springer-Verlag, 1974, pp. 285, 273-292.

Glick,  S.  D.,  et al, "Effects of iboga Alkaloids on Morphine and
{*filter*}
Self-Administration  in  Rats: Relationship to Tremorgenic Effects and to
Effects  on  Dopamine  Release  in  Nucleus  Accumbens and Striatum",
Brain
Research, Elsevier Science B. V., Jun. 7, 1994, pp. 14-22.

                                 ABSTRACT

A method of treating a chemical dependency disorder, an abuse syndrome or
a
combination   thereof   in   a   mammal  in  need  thereof,  which
entails
administering,  to a mammal in need thereof, an amount of a beta
-carboline
alkaloid,  hydrolyzable  derivative  thereof or
pharmaceutically-acceptable
salt  thereof  effective  to treat said chemical dependency disorder,
abuse
syndrome or a combination thereof in the mammal.

                       BACKGROUND OF THE INVENTION

  1. Field of the Invention

  The present invention relates to a method of treating chemical
dependency
using beta -carboline alkaloids, derivatives, and salts thereof.

  2. Description of the Background

  One  class  of  plant  indole alkaloids is the beta -carboline
alkaloids.
There are presently 64 known beta -carboline alkaloids dispersed
throughout
at  least  eight  plant  families.  Schultes,  R. E. et al., The Botany
and
Chemistry of Hallucinogens, C. C. Thomas, Springfield, Ill. All of the
beta
-carboline  alkaloids  share a three ring nucleus designated 4-carboline
by
Perkin  and Robinson. Organic Chemistry: An Advanced Treatise, Gilman
(John
Wiley  and  Sons,  1943).  The  first alkaloids of this class isolated
were
harmine and harmaline.

  Harmine was first isolated from Peganum harmala seeds by Fritsche in
1847
(Bestandtheile  der  samen  von Peganum harmala, Annalen 64:360-364),
while
harmaline  was  first  isolated  by Goegel in 1841 (In German, Isolation
of
Harmalol  &  Harmaline  form  Peganum  harmala,  Annalen  38:363 et seq.)
A
simplified  extraction method using acetic acid was published by
Hasenfratz
in  1927  (In  German,  Extraction  of  Harmine  and Harmaline from
Peganum
harmala,  Ann.  Chim.  Phys.  10(7):151).  Not until 1919, however, was
the
structure of harmaline established by Perkin and Robinson.

  Thereafter,  harmaline was first synthesized and its structure
elucidated
by  Manske  et  al.  (Manske RHF, Perkin, W. H., Robinson R, 1927, Part
IX.
Synthesis  of harmaline, Jour. Chem. Soc. London, 1-15). Other syntheses
of
harmine and harmaline were accomplished by Akabori & Saito (1930,
Synthesis
of  Harman  and  Harmine,  Bericht  63:2245-2249); Spath and Lederer
(1930,
Synthese  der  Harmala  alkaloids:  Harmalin,  Harmin,  und Harman,
Bericht
63:120-125);  and  Spencer  (1959, A synthesis of Harmaline, Canadian
Jour.
Chem. 37:1851-1858).

  One  of  the  earliest reviews of the physiological activity of
harmaline
was  that  of  Gunn,  who proposed that harmaline be used to treat
Malaria,
(1909,  Trans.  Royal  Soc.  Edinburgh  47:245f).  Similar  assertions
were
subsequently made for harmine in 1911 (Trans. Royal Soc. Edinburgh
48:83f).
In 1928, the efficacy of the harmala alkaloids to treat Parkinson's
disease
was  noted,  (1928, Uber ein neues auf das extrapyramidal-motorische
system
wirkendes alkaloid (Banisterine), Der Nervennarzt. 1:265-275).

  Later,  Chen  et al established the LD 50 for harmine in mice and
rabbits
and  further  determined  that  sodium  barbital  limited  toxicity
(1939,
Harmine,  the  Alkaloid of Caapi, Quart. Jour. Pharm. Pharmacol.
12:30-38).
This  paper additionally reviewed the pharmacology of known beta
-carboline
alkaloids.  Further  contributions  to  the  understanding  of  the
harmala
alkaloids   were   made   by  Gunn  et  1935.  Relations  between
Chemical
Constitution,  Pharmacological Actions, and Therapeutic Uses in the
Harmine
Group of Alkaloids; Arch. lnt'l. Pharmacodyn. Ther. 50:379-396).

  More  recently, it was demonstrated that harmaline is a monoamine
oxidase
inhibitor  (Udenfriend  S,  Witcop  B,  Redfield  B. G., Weissbach H,
1958,
Studies  with  reversible  inhibitors  of  monoamine oxidase: Harmaline
and
Related  Compounds,  Biochem. Pharmacol. 1:160-165). Lamarre et al.
defined
the   cerebellar   activity  of  harmaline  in  1971  (Lamarre  Y.  et
al,
Harmaline-Induced  Rhythmic  Activity  of  Cerebellar  and Lower Brain
Stem
Neurons,   Brain   Res.  32:246-250).  In  1973,  further  studies  of
the
physiological   effects  of  harmaline  were  provided.
(Harmaline-Induced
Rhythmic  Activity  of  Alpha  and Gamma Motoneurons in the Cat, Brain
Res.
63:430-434).

  Even  more  recently,  Singh  et  al  ascertained  neurotransmission
and
neurohormonal  effects  of  harmaline.  Further,  harmaline, as a
monoamine
oxidase  inhibitor,  was  shown to have an effect upon the concentration
of
dopamine  and  serotonin  in  the  striatum  of  the  cat  with and
without
unilateral  brainstem  lesions,  Canad. J. Physiol. Pharmacol.
45:897-904).
However, the opposite effects of harmaline on serotonin and on dopamine
and
its  metabolites, homovanillic acid and norepinephrine, in the brain of
the
cat,  has also been noted, Canad. J. Physiol. Pharmacol. 46:585-589).
Klein
&  Rowe studied the relationship of harmine, melatonin and serotonin
(1970,
Pineal   gland  in  organ  culture:  Harmine  Inhibition  of
Serotonin-C14
Oxidation  is  Accompanied by Stimulation of Melatonin-C14 Production,
Mol.
Pharmacol.6:164171).  Given and Longenecker evaluated binding of harmine
to
human   platelets  (1983,  Tetrahydroisoquinolines  and  beta
-carbolines:
specific binding to human platelet alpha 2-receptors in vitro, Res.
Commun.
Chem. Pathol. Pharmacol. 41(2):349-352).

    Clarification   of  the  relationship  of  the  harmala  alkaloids
and
benzodiazepine   receptors  were  presented  by  Robertson  et  al.
(1981,
Interactions   of   beta  -carbolines  with  the  Benzodiazepine
Receptor,
Structure  Activity  Relationships,  Eur.  J.  Pharmacol.  76:281)  and
by
Rommelspacher  et al. (1981, Benzodiazepine Antagonism by Harmine and
Other
beta -carbolines In Vitro and In Vivo, Eur. J. Pharmacol. 70:409).

  The  effects  of  harmaline  in  psychotherapy were evaluated by
Naranjo.
(1969,  Psychotherapeutic  possibilities  of  new  fantasy-enhancing
{*filter*},
Clin.  Toxicol. 2(2):209-224). See also The Healing Journey (1975,
124-173,
Harmaline and the collective unconscious, Pantheon Books, N.Y.).

  Finally,  a  review  of  the field and the development of harmine from
an
historical  and  medical  perspective  is provided by Sanchez-Ramos.
(1991,
Banesterine    and    Parkinson's   Disease,   Clinical  
Neuropharmacology
14(5):391-401).

  Thus,   to  date,  harmine  and  harmaline  have  been  used  largely
in
physiological,   particularly   neurological,   laboratory
investigations.
However, little attention has been given to clinical uses thereof.

  At  the  same time, chemical dependencies continue unabated among all
age
groups,  with  neither  young  nor  old  persons being immune from
chemical
dependency  disorders,  abuse syndromes or combinations thereof.
Presently,
relatively  "benign"  {*filter*}, such as methadone, are administered to
persons
as  a  substitute for {*filter*}, such as {*filter*}. However, this approach is
only
intended  to  minimize  the adverse effects of drug withdrawal and does
not
reduce  the  underlying craving for the drug. Generally, efforts to date
to
combat  drug  abuse have focused on minimizing withdrawal symptoms.
Little,
or nothing, has been done to minimize craving for {*filter*}ive substances.

  Accordingly,  it  would  be  quite desirable if a compound or
composition
were  known  which,  upon  administration, afforded a reduced craving for
a
substance  which causes chemical dependency disorders, abuse syndromes or
a
combination thereof in mammals.

                        SUMMARY OF THE INVENTION

  Accordingly, it is an object of the present invention to provide a
method
for reducing craving for chemically-{*filter*}ing substances in mammals.

  Additionally, it is also an object of the present invention is to
provide
a  method  of  treating  chemical  dependency disorders, abuse syndromes
or
combinations thereof in mammals.

  It   is,   further,  an  object  of  the  present  invention  to
provide
pharmaceutical  compositions  for  treating  chemical dependency
disorders,
abuse syndromes or conditions thereof in mammals.

  The  above  objects  and  others  are  provided  by  a method of
treating
chemical dependency disorders, abuse syndromes or a combinations thereof
in
a  mammal,  which  entails  administering  an  effective  amount  of a
beta
-carboline alkaloid, hydrolyzable derivative or
pharmaceutically-acceptable
salt thereof to a mammal in need thereof.



Wed, 29 Sep 1999 03:00:00 GMT
 
 [ 1 post ] 

 Relevant Pages 

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