U.S. patent number 3,870,794 [Application Number 05/444,035] was granted by the patent office on 1975-03-11 for treatment of certain emotional disorders with nicotine compounds.
This patent grant is currently assigned to Foundation for Behavioral Research. Invention is credited to Grace S. Emley, Edward R. Hallin, Ronald R. Hutchinson, Nancy J. Murray.
United States Patent |
3,870,794 |
Hutchinson , et al. |
March 11, 1975 |
TREATMENT OF CERTAIN EMOTIONAL DISORDERS WITH NICOTINE
COMPOUNDS
Abstract
Nicotine and nicotine derivatives are employed in medicinal
treatment routines in a manner which produces unique and beneficial
changes in particular emotional disorders. Administration of the
compounds causes prompt and discrete reductions of anger,
hostility, irritability, and frustration. Simultaneously reactions
indicative of fear and anxiety are reduced without general sedation
effects. These excessive emotional states are rather supplanted by
improved focus upon and performance of necessary tasks. The
compounds can be administered in a variety of dosage forms and are
effective for the above-described purposes when administered in
amounts far less than toxic amounts.
Inventors: |
Hutchinson; Ronald R. (Augusta,
MI), Emley; Grace S. (Ross Township, Kalamazoo County,
MI), Hallin; Edward R. (Barry Township, Barry County,
MI), Murray; Nancy J. (Charlestown Township, Kalamazoo
County, MI) |
Assignee: |
Foundation for Behavioral
Research (Kalamazoo, MI)
|
Family
ID: |
23763223 |
Appl.
No.: |
05/444,035 |
Filed: |
February 20, 1974 |
Current U.S.
Class: |
514/343 |
Current CPC
Class: |
A61K
31/465 (20130101) |
Current International
Class: |
A61K
31/465 (20060101); A61l 027/00 () |
Field of
Search: |
;424/264 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3048520 |
August 1962 |
McKennis, Jr. et al. |
|
Other References
Merck Index, 7th Ed. (1960), p. 719..
|
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Woodhams, Blanchard and Flynn
Claims
The embodiments of the invention in which an exclusive property or
privilege is claimed are defined as follows:
1. A method of producing (A) reduction of anger, hostility,
irritability, frustration and the behavioral expression of these
emotions, without producing general depression, drowsiness or
sedation, or (B) reduction of fear, anxiety, nervousness and the
behavioral expression of these emotions, with the simultaneous
increase in focus upon and performance of necessary tasks, in
mammals requiring such treatment, which comprises administering to
such a mammal a unit dosage form of a therapeutic composition
containing an effective, non-toxic amount of nicotine,
pharmaceutically acceptable acid addition salt of nicotine,
nornicotine or cotinine, with a pharmaceutically acceptable
carrier, diluent or vehicle.
2. A method in accordance with claim 1, wherein the mammal is a
human and the effective amount is in the range of about 0.0002
mg/kg per hour to about 0.2 mg/kg per hour, administered daily in
divided doses.
3. A method in accordance with claim 2, wherein the mammal is a
human and the effective amount is in the range of 0.005 mg/kg per
hour to 0.05 mg/kg per hour.
4. A method in accordance with claim 1, wherein the mammal is a
human and the effective amount is in the range of about 0.001 mg/kg
to about 0.10 mg/kg administered in a single dosage.
5. A method according to claim 1 in which said salt is selected
from the group consisting of nicotine tartrate, nicotine
bitartrate, nicotine hydrochloride and nicotine sulfate.
6. A method according to claim 1, in which said composition is
administered orally.
7. A method according to claim 1, in which said composition is
administered parenterally.
8. A method according to claim 1, in which said composition is
administered by inhalation or insufflation.
Description
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to a new and useful medicinal treatment
effective in alleviating emotional states characterized by anger,
irritability, tension and concomitant fears and anxieties resulting
from stressful or frustrative living conditions. The treatment acts
to alter emotional balance and expression by two different
processes. Anger, hostility, irritability, frustration, and
feelings of tension are reduced but without general response
depression, drowsiness, or sedation. Simultaneously, reactions of
fear, anxiety, and nervousness are reduced and supplanted by
improved focus upon and performance of necessary tasks.
The successful treatment of emotional disorders by chemical means
has been hampered historically by the lack of objective laboratory
methods for quantitative assessment of specific emotional
processes. Previously available tests have relied upon gross visual
observations of humans and animals in either natural living
settings or special artificial social settings. The variability
inherent in such tests contributed greatly to the uncertainty of
the findings. During the past decade, precise, objective, and
efficient methods have been discovered for the measurement of
anger, hostility and aggressivity in both man and animals. The
techniques, now well established, allow the simultaneous
differential assessment of anger and aggressivity versus fear and
anxiety. The efficacy of the medicinal treatment according to this
invention has been verified by employing these precise testing
methods.
Insofar as we are aware, no prior scientifically based disclosure
regarding the benefits of nicotine upon emotional processes,
behavioral expression, or performance has occurred. The long
standing practice in numerous cultures through many hundreds of
years of using tobacco products containing nicotine is well known.
Nicotine or nicotine related substances have previously been
employed or proposed for employment as a treatment for colic (U.S.
Pat. No. 101,145), tobacco substitute (U.S. Pat. Nos. 904,521 and
2,981,641), insecticide and parasiticide (U.S. Pat. No. 2,175,980),
muscle relaxant (U.S. Pat. No. 3,048,520), snake repellent (U.S.
Pat. No. 3,069,314), antihistamine potentiator (U.S. Pat. No.
3,126,319), swine food additive (U.S. Pat. No. 3,252,802) and skin
care agent (U.S. Pat. No. 2,437,561).
SUMMARY OF THE INVENTION
This invention is based on the unexpected discovery that the
administration of very small quantities of nicotine or nicotine
derivatives to mammals, including human beings, produces in the
subject treated immediate and substantial reductions in anger or
aggressivity and improved task performance, without general
response sedation or reduction.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a new and useful medicinal treatment
effective in reducing emotional states characterized by anger,
irritability, tension and concomitant fears and anxieties resulting
from stressful or frustrative living conditions. The treatment acts
to alter the emotional balance and expression of the subject
treated by two different processes. Anger, hostility, irritability,
frustration, and feelings of tension are reduced but without
general response depression, drowsiness, or sedation.
Simultaneously, reactions of fear, anxiety, and nervousness are
reduced and supplanted by improved focus upon and performance of
necessary tasks.
Specifically the treatment involves the administration to a mammal,
especially human beings, in a pharmaceutically acceptable dosage
form, of a therapeutically effective amount of nicotine or its
pharmacologically acceptable acid addition salts, especially
nicotine tartrate, nicotine bitartrate, nicotine hydrochloride and
nicotine sulfate, or a metabolite of nicotine, especially
nornicotine or cotinine (available from K & K Laboratories,
Plainview, N.Y.). The drug can be administered in any of several
forms and dosages suitable to maximum convenience and desired
effect. Administration can be (1) oral -- in the form of powder,
capsules, tablet, pill, elixir, syrup, lozenge, or chewable mastic.
Representative compositions for oral dosage forms are:
Preparation 1A - Capsule - Two piece gelatin capsules containing 5
mg of essential active ingredient are prepared as follows: Nicotine
tartrate 5 mg Lactose U.S.P. 195 mg
These ingredients are powdered and mixed together and filled into
gelatin capsules.
Preparation 1B - Syrup - A teaspoon (10 cc) of syrup containing 5
mg of essential active ingredient is prepared as follows:
Nicotine tartrate 5 mg Wild Cherry Syrup 10 cc
The nicotine tartrate is stirred, with wild cherry syrup until
uniformly distributed.
(2) inhalation of insufflation from an atomizer, inhaler or
insufflator. A representative composition of this dosage form is as
follows:
Preparation 2A - Inhalation and insufflation devices can be used as
the means of administering the drug. The constituents described in
Example 1A can be used in these devices.
(3) parenteral administration via standard hypodermic
procedures.
A representative composition of this dosage form is as follows:
Preparation 3A - Parenteral - Each injection (2cc) contains 2 mg of
essential active ingredients is prepared as follows:
Nicotine tartrate 2 mg Normal Saline for injection 2 cc
The nicotine tartrate is dissolved in the normal saline for
subcutaneous injections.
Pharmaceutical preparations can be designed to provide delayed
and/or prolonged release of effective agent in accordance with
conventional practice. Buffering by conventional pharmaceutical
buffering agents can be useful to facilitate drug uptake and
minimization of tissue irritation.
Thus, the process of the present invention is accomplished by oral
inhalation, insufflation and parenteral administration of
pharmaceutical compositions for administration to humans and
animals in unit dosage forms, such as tablets, capsules, pills,
powders, granules, sterile parenteral solutions or suspensions, and
oral solutions or suspensions containing suitable quantities of
nicotine or its pharmacologically acceptable acid addition salts or
metabolites.
For oral administration, either solid or fluid unit dosage forms
can be prepared. For preparing solid compositions such as tablets,
the principal active ingredient is mixed with conventional
ingredients such as talc, magnesium stearate, dicalcium phosphate,
magnesium aluminum silicate, calcium sulfate, starch, lactose,
acacia, methylcellulose, and functionally similar materials as
pharmaceutical diluents or carriers. The tablets can be coated or
otherwise compounded to provide a dosage form affording the
advantage of prolonged or delayed action or predetermined
successive action of the enclosed medication. For example, the
tablet can comprise an inner dosage and an outer dosage component,
the latter being in the form of an envelope over the former. The
two components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings such materials including a number of polymeric acids or
mixture of polymeric acids with such materials as shellac, cetyl
alcohol, cellulose acetate phthalate, styrene maleic acid copolymer
and the like. Wafers are prepared in the same manner as tablets,
differing only in shape and the inclusion of sucrose or other
sweetener and flavor. In their simplest embodiment, capsules, like
tablets, are prepared by mixing the compound of the formulation
with an inert pharmaceutical diluent and filling the mixture into a
hard gelatin capsule of appropriate size. In another embodiment,
capsules are prepared by filling hard gelatin capsules with
polymeric acid coated beads containing the compound of the formula
1. Soft gelatin capsules are prepared by machine encapsulation of a
slurry of the nicotine compound with an acceptable vegetable oil,
light liquid petrolatum or other inert oil.
Fluid unit dosage forms for oral administration such as syrups,
elixirs, and suspensions can be prepared. The water-soluble forms
of the nicotine compounds 1 can be dissolved in an aqueous vehicle
together with sugar, aromatic flavoring agents and preservatives to
form a syrup. An elixir is prepared by using a hydroalcoholic
(ethanol) vehicle with suitable sweeteners such as sucrose together
with an aromatic flavoring agent. Suspensions can be prepared of
the insoluble forms with a syrup vehicle with the aid of a
suspending agent such as acacia, tragacanth, methylcellulose and
the like.
For parenteral administration, fluid unit dosage forms are prepared
utilizing a nicotine compound and a sterile vehicle, water being
preferred. The compound, depending on the form and concentration
used, can be either suspended or dissolved in the vehicle. In
preparing solutions, a water-soluble form of the nicotine compound
can be dissolved in water for injection and filter sterilized
before filling into a suitable vial or ampul and sealing.
Advantageously, adjuvants such as a local anesthetic, preservative
and buffering agents can be dissolved in the vehicle. To enhance
the stability, the composition can be frozen after filling into the
vial and the water removed under vacuum. The dry lyophilized powder
is then sealed in the vial and an accompanying vial of water for
injection is supplied to reconstitute the powder prior to use.
Parenteral suspensions are prepared in substantially the same
manner except that the compound is suspended in the vehicle instead
of being dissolved and sterilization cannot be accomplished by
filtration. The compound can be sterilized by exposure to ethylene
oxide before suspending in the sterile vehicle.
The term "unit dosage form" as used in the specification and claims
refers to physically discrete units suitable as unitary dosages for
human subjects and animals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
diluent, carrier or vehicle. The specifications for the novel unit
dosage forms of this invention are dictated by and directly
dependent on (a) the unique characteristics of the active material
and the particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such an active
material for therapeutic use in humans and animals. Examples of
suitable unit dosage forms in accord with this invention are
tablets, capsules, pills, troches, suppositories, powder packets,
granules, wafers, cachets, teaspoonfuls, tablespoonfuls,
dropperfuls, ampuls, vials, segregated multiples of any of the
foregoing, and other forms as herein described.
Nicotine, its pharmacologically acceptable acid addition salts and
metabolites thereof when administered in the dosage amounts
specified in this application are not toxic to a normal human
adults. The drug is rapidly metabolized by the body to relatively
inactive, low toxicity substances and is excreted. Tolerance can
develop following repeated usage.
The dosage of the nicotine compound for treatment depends on the
route and frequency of administration; the age, weight and
condition of the patient; and the severity of the particular
emotional condition to be treated. Therapeutically effective
dosages appropriate for clinically sufficient results can vary from
0.0002 to 0.2 mg/kg per hour, preferably from 0.005 to 0.05 mg/kg
per hour, especially about 0.0125 mg/kg per hour. For continuous
(chronic) treatment the nicotine compound can be administered in
appropriately sized dosages 3 or 4 times a day so as to supply, in
total, the indicated amount of compound per day. For intermittent
or occasional treatment, as the need arises, the individual acute
dosage (single dosage) needed to promptly produce the described
effects will, in most cases for adult humans, lie in the 0.001 -
0.10 mg/kg range. Preferred unit dosage forms contain about 0.07
mg/kg for oral administration, 0.02 mg/kg for subcutaneous
administration and 0.002 mg/kg for intravenous administration. The
initial dosage can suitably be one-half these amounts and the
optimal dose for achieving the desired results can be determined by
successive trials of ascending or descending dosage strength.
The duration and periodicity of treatment will necessarily depend
upon the nature and chronicity of stressful living conditions.
Optimally the drug therapy regimen will be used as an adjunct to
other social and psychiatric efforts toward more stress-free living
routines.
EXAMPLE 1
Three squirrel monkeys (Saimiri sciureus) served as subjects. In
the test apparatus the subjects were partially restrained from the
waist down. Painful electric shocks delivered to the tail of the
test subject produced subsequent biting attack upon a pneumatic
hose suspended in front of the animal (Hutchinson, R. R., et al.,
J. exp. Anal. Behav., 1966, 9, 233-237). Prior to shock delivery
the subjects engaged in motor performances of lever pressing and
chain pulling (Hutchinson, R.R., et al., J. exp. Anal. Behav.,
1971, 15, 141-166). d-Amphetamine in doses from 0.06 - 0.5 mg/kg
increased both responses. Morphine in doses from 0.06 - 2.0 mg/kg
reduced both responses. Administration of nicotine in doses from
0.04 - 0.8 mg/kg caused a progressive dose dependent reduction in
biting attack reactions but left the other motor responses (lever
response) substantially unaffected or actually increased. This
differential effect of nicotine upon aggression and attack
responses, in relation to motor responses is similar to the
reported effects of chlorpromazine, a major tranquilizer. The test
data is presented in the following table. The data given shows
increases (+) and decreases (-) in the number of the indicated
responses, in comparison to the responses of the same test subjects
tested previously without administration of the compounds
(controls). This shows the effect of acute administration of a
single dosage.
TABLE 1
__________________________________________________________________________
DOSAGE (mg/kg) d-Amphetamine Chlorpromazine .06 .12 .25 .5 .06 .12
.25 .5 1.0 2.0
__________________________________________________________________________
Lever Response +5 +12 +30 +60 +20 +25 +50 +5 +10 -8 Change Bite
Response -25 +180 +400 +600.sup.+ -10 -20 -100 -110 -150 -150
Change Morphine Nicotine .06 .12 .25 .5 1.0 2.0 .04 .16 .32 .64 .8
__________________________________________________________________________
Lever Response -7 -20 -10 -35 -50 -45 +5 +10 +5 +20 +8 Change Bite
Response -5 -25 -35 -100 -150 -190 -45 +25 -75 -125 -45 Change
__________________________________________________________________________
These effects are statistically significant.
Wilcoxon Signed Ranks Test ______________________________________
Lever Bite ______________________________________ d-amphetamine
p<.02 p<.01 chlorpromazine p<.05 p<.01 morphine
p<.01 p<.01 nicotine p<.02 p<.05
______________________________________
EXAMPLE 2
Four squirrel monkey (Saimiri sciureus) subjects ingested various
concentrations of nicotine in their drinking water continuously for
several weeks. Nicotine dosage was altered in a counterbalanced
design. Daily one hour tests of aggressivity and other motor
responses, as described in Example 1, produced for all subjects a
progressive, dose dependent, reduction in attack responses
immediately after shock, while over a portion of the dosage range
pre-shock responses were elevated or unaffected. This shows the
effect of a chronic administration of nicotine over an extended
time period.
TABLE 2
__________________________________________________________________________
NICOTINE DOSAGE mg/kg/day
__________________________________________________________________________
.002 .005 .01 .03 .06 .1 .2
__________________________________________________________________________
Difference pre-shock +57 +4 +41 +30 -77 -35 -30 responses from
post-shock +53 +3 -28 -51 -25 -56 -30 Controls responses
__________________________________________________________________________
EXAMPLE 3
Four volunteer adult male human subjects were tested in 30 minute
daily sessions in which a repetitive intense pure tone (110
decibel, 3,000 hertz) was delivered for 2 seconds each 3 minutes
and their jaw contractions (masseter muscle) were recorded. This
loud noise caused jaw clenching immediately after the tone
delivery. The values recorded on 2 days prior to nicotine
administration are set forth in the column entitled "Before
Nicotine Administration." On two subsequent days 5 milligrams of
nicotine in 5 ounces of water was administered 15 minutes before
the test. All subjects showed marked reductions in jaw contractions
produced by the tone while other motor responses were left
unaffected. These values are shown in the column entitled "During
Nicotine Administration." On the following day, nicotine was not
administered and the test was repeated. The values for this test
are shown in the column entitled "After Nicotine Administration."
The data for "Average Response Ratio (before/after)" is the ratio
of jaw contractions occurring in the last two-thirds of the
intertone interval relative to contractions occurring in the first
third of the intertone interval. These effects are statistically
significant.
TABLE 3
__________________________________________________________________________
Before Nicotine During Nicotine After Nicotine Administration
Administration Administration
__________________________________________________________________________
Average number of masseter contrac- 7.9 2.1 5.5 tions Average
contrac- tion force 34 12 29 (.mu.volts) Average response ratio 1.7
4.25 2.8 (before/after)
__________________________________________________________________________
EXAMPLE 4
Eleven food deprived albino rats were studied in a test in which
they responded on a switch for food. Aperiodically during this test
a tone was presented and followed by an electric shock (Estes, W.
K. and Skinner, B. F., J. exp. Psychol., 1941, 29, 390-400).
Stabilized performance showed all subjects to be responding for
food except during the tone preceding shock. Administration of
nicotine in a dosage range from 0.05 - 0.4 mg/kg produced recovery
of responding in this anxiety producing situation during the tone.
Responding during other portions of the test was unaffected. This
result is similar to the reported effects of chlorpromazine, a
major tranquilizer.
TABLE 4
__________________________________________________________________________
NICOTINE DOSAGE (mg/kg)
__________________________________________________________________________
.025 .05 .1 .2 .4 .8 1.6
__________________________________________________________________________
Response Increase Suppression Ratio -.07 +.12 +.04 +.04 +.19 -.02
-.05 Difference from Controls
__________________________________________________________________________
These results are statistically significant.
EXAMPLE 5
Four squirrel monkey subjects were tested in a procedure as in
Example 4. Stable performance showed a suppression of responding
for food during the tone preceding shock. Administration of
nicotine in dosages from 0.1 - 0.4 mg/kg produced a return of
responding during the tone signalling shock. Performances in the
other portions of the test were unaffected by the drug
administration. This result is similar to the reported effects of
chlorpromazine, a major tranquilizer.
TABLE 5
__________________________________________________________________________
NICOTINE DOSAGE (mg/kg)
__________________________________________________________________________
.05 .1 .2 .4 .6 1.2
__________________________________________________________________________
Response Increase Suppression Ratio -.03 +.13* +.07* +.09* -.18
-.34 Difference from Controls
__________________________________________________________________________
*Wilcoxon Signed Ranks Test p<.05
Subsequent to our invention, we reported some of these results in
"Smoking Behavior; Motives and Incentives," W. L. Dunn (ed.), V. H.
Winston (Washington, D.C.), 1973, 171-195. This article and the
references listed therein are incorporated herein by reference,
particularly with regard to the significance of our test
results.
* * * * *