Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
"r~ETHOD OF CAUSING THE REDUCTION OF PHYSIOLO~ICAL
AND/OR SUBJECTrVE REACTIVITY TO STRESS IN HUMANS
BEING SUB3ECTED TO STRESS CONDITIONS"
CRAIG B. WARREN, ~ARINA ALICE MUNTEANU,
GARY E. SCHWARTZ, CARLOS BENAIM, HENRY G.
WALTER, JR., RONALD S. LEIGHT, DONALD ARTHUR
WITHYCOMBE, BRAJA DULAL MOORHERJEE A~D
ROBERT WALTER TRENKLE
BACKGROUND OF THE INVENTION
1. Field of the Invention
.
(i) The results obtained through practice of this invention
are comparable to results obtainable from meditation and biofeed-
- back, including, notably, damping of the systolic blood pressure
surges arising from stressful situations. However, unlike medita-
tion or biofeedback, no trainin~ period is reouired in the use
of the stress reactivity-reducing substances of our invention.
The effect of the stress reacti~ity-reducing substances of our
invention occurs within four minute~ after inhalation of said
substances.
P~ (ii) Unlike a~ti-anxiety drugs, the effect of the volatile
compositions of matter employed in the practive of our invention,
~; (e.g., nutmeg oil, mace extract, neroli oil, valerian oil,
myristicin, elemicin and/or isoelemicin) is prophylactic in nature~
reducing (the phy~iological and~or subjective) reactivity to
~-~ stress when stress conditions exist. Unstressed people do not
respond to the method of this invention.
(iii) Practice of this invention may be distinquished from the
prior art employment o active e~sential oils, e.~., from nutme~,
in perfume compositions. Aside from generating ~resence of the
actives in the surrounding atmosphere at a concentration less
; than is effective to re~uce reacti~ity to stress, perfume usa~e
in modern day practice invol~es emplo~ment durin~ non-stress
occurring situations.
2. The Prior Art
The t~rm ~Aromatherapy~ is intended herein to mean the usP
of plant-derived ~ubstances; volatile ~ubstances derived from
plants for the treatment of health problems. Generally, the
volatile fraction---the essential oil fraction- -of the plant-
!derived substance ls ~3ed. The use of the volatile fractions ofplants for treatme~t of various ailments is review~ed in the
~ following three monographs:
.~:
(1) J. Valnet, "The Practice of Aromatherapy", Destiny
Books ~Division of Inner Traditions International, Ltd.
N~w York , N . Y ., 1 9 8 ~;
2726
(2) R. Tisserand, ~The Art of Aromatherapy~, Destiny
Books (Division of Inner ~raditions International, Ltd.~,
New York, N.Y., l9B3; and
~3) ~. Leunq, "Encyclopedia of Common Natural Inqredients",
J. Wiley 6 Sons Publishing Co., New York, N.Y~, 1980.
A detailed analysis of the aromatherapy folk medicine litera-
ture suggested that a number of essential oils commonly used
in perfumery might have a multiplicity of medical effects. Some
of these oils are employed in the practice of this invention.
Neroli oil is the essential oil obtained from orange blossoms.
Neroli oil has a folk medicine history as being an anti-depressant,
aphrodisiac, antiseptic, antispasmodic and of having digestive and
sedative activity. The anecdotal literature suggests that neroli
oil is an effective sedative and anti depressant and that it may
be used or insomnia, hysteria, states of anxiety and depression
tR. Tisserand, ~ Art of A~n~therapyn, cited, supra~. Tisserand
further ~tates:
~ Neroli is ~ne of the most effective sedative-
antidepressant oils: it may be used for insomnia,
¦ hysteria, states o~ anxiety and depression. It calms
and slows down the mind. It also has a notable action
on the heart, diminishing the amplitude of heart muscle
contxaction, hence its use in palpitations or other types
of cardiac spasm. Derived from this is its use in
panicky, hysterial, fearful types of people - those who
upset themselves unnecessarily, and become over wrought
over nothing. One can also see that neroli is a valuable
remedy for shock, or for disorders caused by sudden shock,
or fear, causing a strain on the heart. It is valuable
in chronic diarrhoea, when this is related to long-standing
stress or fear. Its action is slow but sure.
Oil of neroli also has a pronouncecl action on the
skln. Like lavender and geranium it can be used witn
benefit on any type of skin. It is totally non-irritant
and may be used where there is irritat:;on or redness.
1276888
-3-
It is saia ~o be useful for dry skin and broken veins.
It is one of the oils which acts on a cellular level stimu-
lating the elimination of old cell~ and the growth of
new ones. Neroli makes a luxurious, relaxing, and deodor-
ant bath oil.
Orange-flower water is soothing, digestiv~,
carminative. It makes a very useful, mild remedy for
infants ' colic, ~nd its sedative action helps to send
them to sleep. n
Valerian oil is the essential oil obtained from the root of
Valeriana Officinalis. The folk medicine literature lists the
: valerian root (fresh or dried) as being useful as an antispasmodic,
carminative, stomachic and sedative. It has been used to treat
migraine, insomnia, hysteria, fatigue and stomach cramps that
: : cause vomiting (A.Y. Leung, "Encyclopedia of Common Natural
~ Ingredients", John Wiley ~ Sons, New York, N.Y., 1980,pages 317-320).
:
Regardinq valerian oil' 5 US~ in ~ussia, Hutchens, et al,
~: ~ ~Indian Herbalogy of North America", ~published by Merco of
:~ Windsor, Ontario, Canada), 5th edition, 1974, states: !
.~
.~ "Russian Experience: Valeriana is known to Folk Medicineas having a general calming and sedative effect on the
~- centra1 nexvous system, to induce sleep and rest, spasms
of the stomach, intestines and blood vessels, nervous
heart conditions. Further acknowledgement a~ appetizer,
headache relief, hysteria, epilepsy, tape worm, diarrhoea,
lose stomach, fever.
Externally: Vapour baths given to children will quieten
and encourage restful sleep (Bello-Russ, Academy of
~ Science, Minsk, 19 65) . n
: In "Sedative Principles of Valeriana Roots n ~ Hikino, et al,Shoyakugaku Zasshi, 34, (1), 1980, pages 19-24, it is indicated
that compounds possessing sedative activity, isolated from
: valerian roots, have failed to fully account for the sedative
:~ activity exhibited by the roots per se. It is further statedtherein that, rece~tly, iridoids named valepotriates were isolated
¦las analgesic a edative principles from Inclian valerian roots.
1;~:76S~8
In this paper, a correlation between the contents of the
valepotriates and the pharmacological activity of various valerian
roots was examined. Napalese and Chinese valerian roots contain-
ing an appreciable quantity of valepo~riates showed no sedative
activity, while Japanese valerian root containing less
valepotriates inhibited stress-induced ulcer formation and pro-
longed hexobarbital-induced sleep in miGe. An extract of
"Hokkai-kisso", i.e., roots of a Japanese valerian, was frac-
tionated and the effect of each of the fractions on the enhance-
ment of hexobarbital anesthesis was tested. Ressyl glycol
diacetate, Kessyl glycol 8-acetate and Ressyl glycol 2-acetate
were obtained as active principles therefrom. The enhancement
of hexobarbital anesthesis by Kessyl glycol diacetate was assumed ~
~o be due to its inhibitory effect on the central nervous system. !
Kessyl glycol diacetate exhibited no inhibitory action on the
stress-induced ulcer production.
The chemical constituents, pharmacology and known uses of
valerlan are reviewed in: "Herbal Remedies Used in Sedative and
Antirheumatic Preparations: Part I", Phillipson, et al, The
Pharmaceutical Journal, July 21, 1984, pages 80-82.
Another potentially interestinq plant substance is nutmeg
which was impcrtant in medicine as well as in cooking. It was
used as a therapeutic by Arab physicians as early as the
7th Century A.D. for treatment for disorders of the digestive
system, kidney disease, pain and lymphatic ailments. Nutmeg is
a significant item in the Hindu Pharmacopeia wherein it has been
prescribed for fever, consumption, asthma and heart disease.
Nutmeg is employed by folk practitioners in India as an analgesic
and sedative. In large doses ttwo teaspoons or more of ground
nutmeg~, nutmeg exhibits mild hallucinogenic activity, the
description ~y Payne (R.B. Payne, New Ellgland Journal of Medicine,
269, pages 36-38 ~1963]) being illustrative of this activity.
Two college students, 19 and 2~ years old, each consumed two
tablespoons (14 grams or the equivalent of two whole seeds) of
powdered nutmeg in milk. About ~5 hours later, each had the onse~l
of a leaden feeling in the extremities and a nonchalant detached I
mental state described as "unreal" or "dreamlike". Rapid heast 1,
rates and palpitation were observed and both complained of dry
mouth and thirst. See, also, Wiel tA.l'. Weil, Ethnoph~rmacol.
Search Psychoact. Drugs ~Proc. Symp.l, 19~7, lPub. 19~9J, 188-201).¦
--5--
~2768~
The fraction of nutmeg responsible for the mild hallucino-
genic activity is suggested by the literature to be the aromatic
fraction of the oil containing safrole, methyleugenol, eugenol,
methylisoeugenol~ myristicin, elemicin, isoelemicin and
methoxyeugenol as the major components. Of these, myristicin,
elemicin and isoelemicin have been reported to be the active
molecules (A.T. Shulgin, et al, Ethnopha.rmacol. Search Psychoact.
Drugs lProc. Symp~], l967, lPub. 1979], 202-214). The myristicin-
~elemicin fraction of oil of nutmeg produ~es many of the activitiesof crude ground nutmeg but lacks adequate potency to explain
the nutme~ intoxication syndrome on a quantitative basis. Nutmeg
and synthetically-made myristicin show a mild degree of monoamine
oxidase in~i~iting activity~ The monoamine oxidase activity
is found in the volatile cQmponent of nutmeg (E.~. Truitt, Jr.,
EthnopharmaCol. Search Psychoact. Drugs [Proc. Symp.], 1967,
[Pub. 197~, 215-2~2).
Nut~eg oil, ~nown as ~ , or myristicaceae,
is the essential oil from the kernel of the fruit of t~e nut~eg
tree. The stone of the fruit is enclosed within a husk which,
when dri~d, is known as mace. "Mace Extract" is an aromatic
essence extracted from mace. nNutmeg Butter~ is a fixed oil
obtained by hot_pressing the nutmeg kernels, and contains
myristine, butyrin, olein, palmitine and s~arine. The essence
contains 80~ pinene and camphene, 8S dipentene, 6% terpenic alo~
(linalool, borneol, terpineo~.~nd ~eraniol), 44 myristicin and
various substances such as eugenol and safrol. Valnet, "The
Pr~ctice of Aromatherapy~, (supra) states that, for external use:
. ~
(a~ "nutmeg butter~ is used in liniments for the treat-
ment of rheumatic pains and toothaches; and
(b) "nutmeg butter" is used in the form ~f "nerve balm~
for treatment of rheumatic pains, the form being
a mixture of the essences of rosemary and clove
~ogether with nutmeg butter.
~;Z 7~38
--6--
A form of nutmeg oil, 1~r~tica castaneifolia (Myristacaceae~
Fi ji is described as pos~essing biologica1 acti~,rity, specifica11
in the antitumor field, in t~.S. Letters Patent 4,352,797 issued
on October 5 ~ 19 8 2 .,
At page 4 of the Jarl~aary/February 19 8 4
(Vo1. 6 , No. 1) edition of FOCUS ~orld Wildlife Fund-U.S , ~,
nutmeg is indicated as being an analsesic a~d a hal1~ir~gen. In ~e
paper "Nutmeg a5 a Narcoticn by Ralbhen in Angew . Chem . 8 3,
379 ~19713, Kalbhen dis~loses that the hallucinogenic ingredients
of nutmeg include, interalia,:
(i9 My~isticin having the structure
E lemicin having the structure:
,~
P
~~
:'
and (iii~ Isoe1emicin having the structure:
. ~
~ C~
~2~7688~
Fur~hermoxe, M _ is disclosed at Chem.
Abstracts, Vol. 101, No. 2831g (abstract of Japan Kokai ToXkyo
Koho 59/55,827) as bein~ useful in the field of drug stabilization
in conjunctiOn with the utilization of transdermal Dharmaceuticals.
Furthermore, isoelemicin having the structure.
..
O
~ ~o~f O~
.: ` .
i~ a known fla~or ingredient as set forth in U.S. ~etters
Patent 3!686,004 issued on August 22, 1972~
__
. By th~ same
to~en, myristicin having the structur~:
'' O~
:
~f,
iY disclosed as a component of the aroma of blueberries in
; J. Sci. Food A~ric., 1983, ~4~9), 992-6 (abstracted at
Chem. Ab~tracts, Vol. 99:174466rl.
~'
Furthermore, re~arding myristicin, Arctander, nPerfume ~
Flavor Chemicals (Aroma Chemicals) n ~ published by the author in
' '
76~
1969, state~ at l~no~raph 2291, that myxisticin is:
5'Pl~asant and waxm-balsamic, slightly wocsdy
odor of good tenacity. ~e undiluted material
Rhows ~ome ~p~pperines~ " .
This material, although co~nmonly fou~ld
ir~ natural oils, has found only limited use in
perfumery,, . "
T~l~ essential oils de~cribed above are al50 common perfumery
ingredients ~3 de-~cribed in Arctan~er/ "~er~ume and Flavors
~ ,
Material5 o~ Natural r~ nn~ publi5hed by the ~uthor in 1960.
Mace extract at columns 391-393; neroli oil at columns 435-437;
nutmeg oil at coll~s 442-445; and valerian oil at columns
37-630
".
. `'~.
.
::,
:
, ~ .
_, ." .
~'76~388
3. summary of the Invention
our inYentiOn is concerned with a method for causing the
reduction of physiological and/or subjective reactivi~y to stress
in a human subject to stress conditions which comprises the step
of administering transdermally or through inhalation to said
human an effective physiological and/or subjective stress reacti-
vity-reducing substance which may be one or a combination of any
one of the following materials (sometimes referred to herein as
"active(s) n);
(i~ Nutmeg oil;
lii) Mace extract;
(iii~ Neroli oil;
(iv) Valerian oil;
(v) Myristicin;
(vi) Elemicin; and
~-. (vii) Isoelemicin.
The active(s) can be administered alone or as part of a
composition which may include ethyl alcohol and/or perfumes.
:~ Perfumed articles may be employed to apply the actives. Examplesof such perfumed articles are solid or liquid anionic, cationic,
nonionic or zwitterionic detergents, fabric softener compositions
fabric softener articles, cosmetic powders, hair preparations,
deodora~t sticks, air fresheners and perfumed polymers.
. .
Specifically, with regard to dose levels, the "actives~ are
to be divided into two groups:
.::
Gro_p "ALEPH"
. ~
Nutmeg oil;
Mace Extract;
Neroli oil; and
Valerian oil
: (taken alone or in combination~.
I
~ .
~L27~8~
;`- Group ~ETH~
.i , ..
;~ I M~ristlcin
lemicin; and
~` Isoelemicin
(taken alone or in c~mbinationi.
The Grou~ nALEPH" dose or amount administ~red, for the ~ur~ose
: of our invention, is from about 13 micro~rams u~ to about
~`.. 1000 micrograms. The Gr~UP ~BETHn dose or amount administered,for th~ purpose of our invention, is from about 0.013 micrograms
up to about 50 microgram.~. When Groups ~ALEPH" and nBET~"
are used in combination9 the dosage or amount administered is
: from about 0.013 mierograms up to about 1~00 micrograms with an
upper limit of the Grou~ "BETB~ ~a~tives~ within said
~h combination being at about 50 micrograms.
The term ~amount administered~ is intended herein to mean
"amount ca}culated to have been br~athed in, retained and absorbed
into the bloodstream or transdermally absorbed into the blood-
streamn. The assumptions that underlie the calculations of the
: . above levels are presented in Tables I and II and associated
text, infra.
~;~, A preferred mode of this invention i~ administration throuqhinhalation, and to do so by incor~oratin~ the ~active(s)~ in an
enclosed environment such as a room and, accordin~lv in the
~:~ atmosphere around the occu~ant(s) of the enclosed environment.
Such is accomplished, for exam~le, by in~luding an "active" in
: an air freshening composition. Accordingly, another measure for
practice of this invention is inclusion of from about 1 up to
about 125 micrograms per liter in the air of a room o~ the stress
reactivitv_reduction ~active~s~ n of our invention.
' ~
.
~ '
,.
~L2~6888
Reduction of physiological and/or subjective reactivity to
stress resulting from practice of this invention is demonstrable
objectively by means of a decrease in the systolic blood pressure
of the human and subjectively in self-report of a significant
increase in calmness and happiness and a significant decrease in
embarrassment and anqer under stress conditions.
The method by which ~he effect of the stress reactivity
reducing substances of our invention has been ascertained is novel. This is the
first method that uses a combination of psychological measurementS,
physiological measurements and a stressor to measure the effect of
postulated stress reactivity-reducing substances taken alone or
taken further together with ethyl alcohol and/or perfume composi~
tions vr per~umed articles or colognes on physiological and/or
subjective reactivity to stress~
~'.,
~%7~ 38
-12-
DETAILED DESC~PTION OF THE INVENTION
,.'~
our invention n~cessarily also involves a method for detectin~
physiological and/or sub~ective reactivity to stress in a human
comprising testing a human likely to exhibit physiological and/or
~:~ subjective reactivi~y by:
:
measuring the initi21 blood pressure and mood
of said human; then
,~
ii) administering stress to said human by means
: ~ i of application of a stressor:
(iii) simultaneously measuring blood pressure change and
~` ~ood change r~sulting from the application of said
:~ stress to said human: thereafter
- .
iv)~ administering a postulated stress reactivitV-
reducing substance to said human; and
~ (v) simultaneously measuring the blood pressure change
-~ and mood change in said human resulting from the
~ application of said postulated stress reactivity-
:~ reducing substance during the aR?licatial of sa~d st~essor to said human.
.
: :~ As has already been pointed out, our invention is directed
to a method for causing ~he reduction of physiologi ~ and/or sub-
~: jective reactivity to stress in a human being subjected to stress
. conditions whlch comprises administering to said human an effective
i .
,;
~Z7~
amount of a substance which may be one or a mixture of:
Nutmeg oil;
Mace extract;
Neroli oil;
Valeria~ oil;
Myristici h~v ~ ~ e:
~lemicin h irg h~
; and/or
Isoelemicin having the structure:
O~
/o~o~
:
-14-~27~
taken alone or taken fusther toqether with a carrier which may
be a perf~med article or cologne and/or ethanol.
Inso~ar as the nutmeg oil, mace extract, neroli cil
and valerian oil are concerned, the various varieties of such
ma~erials are useful in the practice of our invention. Thus,
for example, Nutmeg Oil East Indian or N~tmeg Oil West Indian
are useful in the practice of our invention. Standard commercial
mace extract is useful in our invention as is the more highly
purified form thereof. Commercial valerian oil is useful in the
practice of our invention as is the refined version, doubly
: distilled Yalerian oil.
In addition, naturally occurring or synthetically produced
myristicin, elemicin and isoelemicin are useful in the practice
of our invention.
; Thus, myristicin haYing the structure:
. ~
`~ O~
0~"0
may be isolated as by distillation from Nutmeg Oil East Indian or
West Indian or Nutmeg Oil Fiji or it may be synthesized according
to the reaction sequence:
., j~
0~ O~
l I HO~[~ ~o~ H0~[~O~
~ ~27~8~13
¦¦ o /0 ,~ 0~
1~ ~' ~'~
I ~ `.,Cl~
~
,
.,
; Thus, our invention is directed to the use of one or a mixture
f the following ingredients:
Nutmeg Oil;
Mace Extract;
Valerian Oil;
Neroli Oil;
Myristicin;
Elemicin; and/or
Isoelemicin,
: ::
`:~
. .
~,276~8
-16-
which lngr~dients~ i.e., the ~active(s)W~ mav be administered
alone or further to~ether with a ~non-a~tive" cærrier comoosition
(~uch ~s (~) ethanol or (ii) a carrier ~erfume
com~osit~on or ~ ) a c~rrier perfumed article) for the
reduct~on of phy5iologic chang~ and/or subjective ~anifestations
of reactivity ~ a human bein~ ~ubjected to stress conditions.
Th~s reduction in reactivity decreases the ~ystolic blood
pressure ~urge~ caused by 5tress and generates a ignificant
increase in calmness and happiness and a si~nificant decrease
in embarrassment and an~er in said human. The ~hysiological
ch~nge and subjective manifestations of reactivity to stress
and a reduction of reactivity to ~stress~ ar~ auantifiable,
see Examples II, III, IV and ~, infra.
To repeat, the ~acti~e~ stress reactivity~reducing substances
of our invent~o~, to wit:
Neroli C)il;
Mace Extract;
IJutmeg Oil;
Valer~L~n Oil;
~Syristicin;
Elemicin; and
Isoelemicin
are, in their ~wn right, perfumery sub5tances 1cnawn in the
prior art. For example, myristi~in having the structure:
contributes an interesting spicy aroma to per~umes..
~%7G8~38
-17-
However, the terms ~carrier perfume~ and ~carrier perfume
compo~ition" ar~ ~sed herein,within an inert carrier context to
mean mixtures of organic compounds(other tha~ ~uch "a~tives")
including. for exam~le, fra~rant alcohol~, fragrant aldehydes
~uch as~for examole,the aldehyde havinq the structure:
~ "
ketones, nitriles~ ethers such as,for example,the cyclic ether
having the structure:
~ d
and the cyclic ether having the structure:
~h
(but excluding, of course, elemicin, isoelemicin and
myristicin~, and ~uch materials as lactones, hydrocarbons,
syn~hetic essential oils and natural essential oils (excluding,
of course, the natural essentia~ oils: nutmeg o~l~ valerian
oil, neroli oil and mace extract) in ~d~xture so t~at ~h~
combined ddors of the individual components produce a pleasant
or desired fragrance.
.
~27~8!38
--18--
~ lthough ~tate of th~ ært perfume and c~ologrl~ compo~ition~
are contemplated for ~arrier purposes in practice c: f
this inventiO~, the '~active5n are fragrance3, ~nd therefore
~; i 30me comments here about perfumery practices are warran~ed.
.
Perf~ame compositions usually contain (a) the main note
or the "bouquet" or foundation stone of the composition; tb)
modifier~ which round off and accom~any the maln note; (c)
fixatives which i~clude odorous substances which lend a particular
note to the perfu~e ~hroughout all .8tag~s of ~aporation and
~ubstances which retard evaporation; and ~d) toDnotes which
aEe usually low-boiling fresh smelling materials.
perfume com~ositions~ each indlvidual component will
contrihute its particular olfactory charactexistics bl~t the
overall effect of the perft~ne composit:Lon will be the sum of the
~f fe~ts of each in~lredient- Thus, individual perfumery compounds
or mixtures thereof can be use~ to alter the aroma
characteristics of a proposed perfume composition, for example,
by highlighting or moderatin~ the olfactory rea~tion cor~tributed
by anothex ingredient in the composition. The ~acti~e~" of
this invention will alter ~he aroma characteristic3 of a
carrier perfume composition in addition to causing stress
reactivity redu~tion in a human who is subjected to stress
conditions. ~herefore the aroma desired for the composit~on
~s a wh~le~Father than the ~roma Qf ~h~e~ ie.r pe~.~u~
formulation alone,should be made the basis upon which the carrier
perfume composition is formulated.
It should be appreciated that a perfume or cologne
composition containing "actives~ is b~ing administered by
inhalation, and, to the extent the composition has been
ap~lied to the skin, transdermally as well. Air freshener
compositions are administered almost entirely throuqh inhala~ion.
-19- ~27~8~
The amount of the stress reactivity reduction perfume
composition required for effective action (with r~gard to the user~
depends on many factors including the skin condition of the user;
the environmental conditions durinq the period of desired effec-
tiveness (e.g., humidity, temperature and pressure)~ the emotional
~tate of ~he user at the point in time of a~plication; the physi-
cal characteristiCs of the user including body weight and bas~
line systolic bl~od pressure at the point(s) in time of applica-
tion(s). All of which is to say that individual reactivity and
feelings of comfort by a user will determine the amount effective
for that user.
The perfume composition may be used"a5 is~ (e.g., 10~%) or in
a "cologne~. Directions for quantity to use and frequency of use,
as w211 as variations in the formulation, e~g., summer and winter
ormulations, may ~e employed to assure th~t effective levels
~: of the activesn may be administered. For the purpose of this
invention, thé term ~colo~ne~, as exemplified hereinafter, means a
perfume composition incorporated in an alcoholic or hydroalcoholic
solution. ~he perfume.composition can vary between 1 to 99% and
the balance of the formulation is comprised of alcohol or a mix-
ture of water and alcoho~. The water:alcohol weight ratio can
vary from 50:50 to 0:100. Examples of alcohols ty~ically used
in these products are SDA 39-C and SDA-40, either 190 ~proof~
or anhydrous (See ~Ethyl Alcoho~ Handbookn, 5th Edition, Published
by National Distillers and Chemical Co.). The cologne composition
can also contain solubilizing agents, emollients, humectants,
thickening agents, bacteriostats or other cosmetically-used
ingredients.
Although perfume compositions and cologne~ would normally
be considered to administer the "actives n by inhalation or
smelling, pla~ement thereof on the e~idermal skin tissue
generates, also, transdermal ~enetrative administration. -
:' ;
: ~ Perfumery materials which are compatible with the stress
reactivity reduction su~stances have been emDloyed in
aromatizin~ carrier perfumed articles. Such ~erfumed articles
in~lude fabric softener com~osit~ons, dryer-added fabric
softener articles, ~.g., BOUNCE (a Registered Trademark of the
Procter & Gamble Company of Cincinnati, Ohio~, cosmetic
powders, t~lcs, solid or liquid anionic, cationic, nonionic
or 2witterionic detergents ~nd perfumed polymers a~ well as
deodorant sticks, hair preparations and bar soaps as
exemplified, in~ra .
., .~.
-20~
Furthermore, ~erfume materials which are com~tible with the
~tre~s reactivity-reducing substances of our ~nvention h~e
been employed in ~ir fres~ener~. Th~s, a gr~at number of state-
of-the-art perfume composit~ons and perfumed articl~s are
~vailable for use 85 the non-active carrier (per~umed)
sompositio~ and (perfumed) article5 within whlch the ~actives"
; may be incorporated for practice of this ~vention.
Thus, t~e stress reactivity-reducing substances can be used
alone or taken toge~her with carrier perfume ~ompositions
alone or through carrier perfumed article~. Many well known
;articles of commerce may be the carrier such as ~olid or
;liquid anionic, cationic, nonionic or zwitterionic detergents
' bar soaps, space odorants and deodorants; colognes,
: toilet w~ters, hair pre~arations, such as lacquers,
brilliantines, ~nd pomades; cosmetic pre~arations9 such as creams,
deodorants, hand lotions and sun screens: and powders, such ~s
~talcs, dus~ing powders, face powders and th~ like. When
erfume compositions are used as a~ olfactory com~onent of a
perfumed article, such as a ~olid or liq~id anionic, cationic,
nonionic or zwitterionic detergent or a cosmetic powder or
a deodorant stick, as little as 0.1% by weight of the
overall perfume and stress reactivity-reduci~g aactive(s)~
(in combination) in the perfumed article will suffice. In space
odorant aPplications~ on ~he other ha~d, as much as 99% of the combin
carrier perfume substance and stress reactivity-reducing substance
can be present. Thus, perfumed articles may contain in the range
of from about 0.1% up to about 99% of a composition of matter
consisting essentially of the stress reactivity-reducing
"active (S) n and "non-active" carrier perfume substance.
It is interesting to note that when a stress reactivity-
reducing ~active~ is used in a deodorant stick or deodorant
bar soaps to practice our invention, a twofold effect takes
place:
li) the deodorant stick itself acts as a ~deodorant" in
the axillary area o~ the human being and
(ii) the stress reactivity-reducing "active(s)~ is administe:
hy inhalation or transdermally to cause reduction in
physiological and/or subjective reactivlty to stress
in tho5e individuals subjected to stress conditions
~2761~8
-21-
thereby g~ving rise to a double efflcaciou~ re~uction ~n "malodor"
evolved from the axillary r~gions of ~uch human to the surroundin~
environment.
The term ~perfumed article" also ~ncludes solid-form
polymer-q, such as polyethylene, polypropylene and other oolymers
which contain pores within which are occluded a carrier
perfume composition combined with the ~tres~ reactivit~-reducing
~active(s)~. Such perfumed polymers can be produced as
described herein or accordinq to an~ technique well know~ to
one having ordinary s~ill in the art.
In addition, the stress reactivity-reducin~ substances of
our invention, e.g., neroli oil, nutmeg oil, mace ~xtra~t,
valerian oil, myristicin, elemicin and isoelemicin taken alone
or taken in combinatio~ may, by themselves, be absorbed into the
interstices of microporous or macroporous ~olymers~ Furthermore,
like carrier-~ of materials other than synthetic polymers can
be used to senerate a ~erfume article~ such as a gum
(e. q., guar gum, xanthan gum, or gum arabic) or an enca~sulating
compo~ition such as a gelatin (as by coacervation) or such as a
urea~formaldehyde prepolymer to form a uxea/formaldehyde polymeric
wall around a liquid center, which liquid center contains the
stress re~ctivity-reducing "active(s) n alone in conjunction with
ethanol and/or a ~ar~ier ~erfume composition.
Unli~e anti-anxiety drugs, as mentioned su~ra, the effect
of the "actives" materials is to reduce the ~hysiological and/or
subjective reactivity to stress in a oerson who is subjected to
stress conditions. Individuals who are not being subjected
to stres~ conditions do not react to the administration of
any of the above-mentioned ~act~ve(s)~ according to the
'practice of this in~ention.
Unli~e meditation or biofeedback, no training ~eriod is
required for the human who is to be treated in order to e~fect
reduction of physiological and~or subjective reactivity to
stress. The effect(sJ of an "active" material, e.g., nutmeg
oil, mace extract, neroli oil, valerian oil, myristicin,
elemicin and isoelemicin, o~curs within four ~inutes after
initial inhalation or smelling of the substance by the
individual under stress to whom the substance is aclministered.
~.27E;!3~
--22--
The wei~ht ratio of stress reactiv~ty-reducin~ ~active( )~
to the ingr~dient in the oarrier ~erfume com~osition, cologne
or the perfumant applied to ~e~erate the carri~r ~erfumed
article is in the ran~e of from about l~lao u~ to about 100:1.
Is is emphasized that the carrier perfume com~o~ition, colo~ne
and perfumant ap~lied to generate the carrier perfumed article
do not otherwise contain any other stress-reactivity reduoing
substance~, or for that matter an~ stress-affecting or
hypoten iv~ sub5tances ~mployed in the medical arts, for example,
benzodiazepine dexivatives fo~ anxiety and methyldopa or
propranolol for hypertension~
Our inv ntion expressly contemDlates the use of ethyl alcohol
i~ conjunction with the "actives~. The ethyl alcohol may enhance
he efficacy of the ~actives". As has already been ~ointed out
ethyl alcohol is a major component in standard ~ologne
compos itis~ns .
Whe~ the stress reactivity-reducin~ ~active(s)~ is used
in conjunction with ethyl alcohol, the weight ratio of
"aative (5) n to the ethyl alcohol (based upon pure ethanol) is
in the range of from about 1:99 u~ to about ~9~ he ethanol
used in conjunction with practice of our invention mav vary
from 50~ aqueous ethanol up to 100~ (absolute ethanol~.
One great advanta~e of the practice of this invention
f~r the reduetion of physiological and/or subjective reactivity
to stress in humans is the fact that the dose level of ~active(s)~
is mlniscule: being of the order of micrograms.
'
:
,,~
~9~7~
-23-
5pecifica11Y wit~ regard to dose level , the ~ctives n are
to be divided into two groups:
Group "A~E _
Nutmeg oil~
~ace extract;
Neroli oil; and
Valerian oil
~taken ~lone or in combination)
Group n BETH ~1
Myristicin;
Elemicin; and
Iso~lemicin
(taken alone or in combination).
The groUD "ALEPH" dose for the purpose of our invention
is from about 13 micrograms uo to about 1000 micrograms. The
group ~BETHn dose ~or the ~ur~ose of our inventio~ is from
about Q.~13 micrograms up to about 50 microgra~s.
When materials from the Groups ~LEPH" and "BETH~ are used
in combination, the dosag~ of ~activesW is from about 00013
micrograms up to about 1000 micrograms with an upper llmit of
the Group ~B~TH~ component within said combination being about
50 micrograms.
One of the preferred modes of this inventio~ is
administration of the ~tress reactivitv-reducing composition
by incorporatina the "active(s) n in the environment surrounding
the user. Such is accomplished, for example, by including
nactive (S) n in the air freshening composition. Accordingly,
another measure for oractice Oe this in~ention is inclusion
of from about 1 up to about }25 micrograms ~er liter of
~tress reactivity reducing ~active" in the air of a room.
Preferably, a qroup ~ALEPH" nactive" is used for this pur~ose.
~.
~i
~L~7~ 8
-24-
Reverting to "active~s)~ dosage ran~es in ~eneral,at the
u~per bound of h~ ratio of weight of a carrier perfume
compo~ition (containing no ~active5~):weight of na~tive" ~rou~
~ALEPH~ (that is, 100:1), the tot~l amount of ~erfume
composition used requires a range of from about 13 micrograms
up to about 1000 micro~rams nacti~ and thu~ requires a range
of from about 1300 micrograms (1.3 mg) up to about 100,000
microgram~ (0.1 ~m) of non-active-containing ~arrier perfume
compositionO Furthermor~, at the upper bound of the r~tio
of weisht of perfum~ composition (containing no ~active~ weight
of ~active~ Group "BETH~ (that i~ 0:1), the total amount of
perfume composition used cont3ins a range of from about 0.013
micrograms up to about 50 micrograms "actives~ and thus
oonstitutes a range of from abou 1.3 micrograms ~p to about
5000 micrograms ~5 mg) of non-active-containing carrier perfume
composition.
By the same token, at the lower limit of the ratio of
weight of a carxier perfume composition (containing no "actives n ):
weight of ~activc" Group "ALEPH" (that i9 ~ 00) ~ the total
amount of perfume composition req~ires a range of fr~ about
13 mi~rograms up to about 1000 microgram~ nactives~ and thus
require~ a range of from about ~.13 micrograms up to about
10 micrograms of non-acti~e-containing perfume composition. At
the said lower limit, the ratio of weight of perfume composition
(containing no ~activesn):weight of ~active" Group "BETH'I (that
i8~ 1:100) ~ the total amount of perfume composition used
nonetheless contains a range of from about 0.013 micrograms
up to about S0 micrograms "actives" and thus constitutes a ran~e
of from about 0.00013 micro~rams up to about 0.50 microqrams
of non-active carrier perfume composition. Thus, the working
ranges of perfume + "active~) compositions contemplated within
the scope of the inve~tion vary as fol~ows:
(a) For Group WALEPHn ~activesn - from 13 micrograms
up to 100,000 micrograms (0.1 grams); and
(b) For Group ~BETH~ nactives~ - from 0.013 micrograms
up to 5000 micrograms (5 mg~.
~76~
--25--
As previously ~ta'ced, perfumed article. contemolat~d
w~in the scope of t~is in~nt~on m~y ~ontain ln the ranqe
of from 0.1~ up to 99% by wei~ht of combined ~on-active
c~rr~er perfume an~ ~active(~)n. Also, a5 pre~iouslv stated,
the weight ratio of carrier per~ume: ~active~s)~ may vary from
about 1:100 up tQ 1~0:1.
It thexefore follows th~t 100 grams of a perfumed article
employed ~n pra~t~ce of our invention will co~tain rom about
0.1 gram~ up to about 99 .0 grams of a perfume composition
that includes ~active(s)~.
It follows also that practical restraints exist u~on ~ractiee
of this invention through perumed articles. ~r exam~le,
when administration of nacti~es~ from Derfu~ed garments is
desired, transfer of ~ac~iYes~ to the garments from perfumed
;detergent may not be ~ractical. ~owever, transfer from a
perfumed fabric softener to th~ abric is more feasible. More
oft~n than not practical restraints sim~ly challenge the skill
of the formulator when administration is sou~ht from ~erfumed
deodorant compositions, co metic ~owders, hand soa~s, and
the l~ke, for example. Some perfumed articles offer less of
a challenge to ~he formulator, or no challenge at all; air
freshener ~ompositions, for example. The ran~e of 0.1 - 99.o
gms o~ perfume co~position per 10~ grams of article shoul~ b~
considered guidelines rather than strict limits.
me uncertainty is acknowled~ed also for the~range of
13-1000 micrograms of "A~EPH~ group ~active(s)" and 0.013-5
micrograms of ~BE~H" group ~active(s) n, The experimental
effort underlying this invention may not translate exactly to
the dosage range suited to large scale practice of this
inventio~ for 5necessarily) having been conducted under
artificial conditions. For better understanding of this
inventio~ and as aid to ~ranslation of the exemplary material
~herein into large scale practice of the invention,detail5 of
the experimental conditions and dosage assumDtions made by
the i~ventor hereof are now provided.
~27~ 38
-26-
- In ~pecific,the effective dose levels for Groups "AL~PH"
: and "BETH" s~t forth abov~ con~titute estimates of auantities
breathed in and effectively taken u~ by the subjects from ~
per~E~'s blotter a~ described in Example I~, infra, or rom
a wick-vial arrangement as described in xamDle~ and IV,
infra.
The source of the stress reactivity reduction composition
was about 1.5 inches from the subject t 8 nose. For the
estimation of dosayes, the following assumptions were used:
:
~ 1. Breathing rate for an average subject at rest
.~ is 10 liters per minute.
2. The ~otal amDunt of substance breathed in ~nd re~a~x~ is 25%
of the material that is eVaDOrating. We assumed
~:~ intake of 50% of the materi~l e~aDorating from the
source. Of the material breathed in, 50% was
subsequently exhaled.
~..
: 3. The total amount of the substance effectively taken
~~ up by the body is about 10% of the breathed in and
; retained substance.
. ,
4. The average body weight of a human being is 6S ~g.
The assumptions used for estimation of dosages were based on
measured plasma levels for ~9-tetrahydrocannabinol (~9THC) that
had been administered by inhalation of marihuana smoke. For this
situation S0~ of the ~9-THC breathed in was retained and approxi~
mately 10% of the retained material was found in the p}asma.
(Nahas, G. and Paton, D., eds., "Marihuana: Biological Effects,~,
in Advances in the Biosciences, Vols. 22/23, Pergamon Press, ~.Y.,
f l979], page 289.) In addition to the abov~ assumptions, the
lZ76888
followin~ parameters were measured:
1. The ~mount of substance evaporatinq from the source
¦ of post~lated stress reactivity-reduction composition
was obtained by weight loss measuremen~s.
2. The concentration of Group "BETH" component~s), e.g.,
¦ Myristicin, Elemicin and Isoelemicin in the head-space
was measured by gas chromatography.
3. The total time that the subject breathed the stress
reactivity-reduction substances was 20 min~tes.
The following Tables I and II present a summary of our
results,
~` I
~ \ :
¦ \ 5SYACE Ll!:FT I~LANK INT13NTIONALLY
.,~. \,
I
-28- ~,27~ 3a~3
Il I ~o
11 1 ~ I I ' C
1¦ r ~ X ~
~ S: O ~ h ~ .,~ 0:
~ ~ )
:~ ~ O ~: , ~ ~ ,o
~. .~ _ _ _ _
11 ~o I ~c c ~ -c l ,,., ~D Uo~ lCI
11~u ~&~ I ~ c~
~ ~ I 1 , I ~ U o~
, `.' ~ ~ -- - - ~
:~ 11 v I v ~ , ~=~
~ o ~v ~ ~ : ~v v~
a~ ~ ~ ~ ~ ~ O
11 o ol g~
~) ~ N
F, r~ O ~ ~ _~ N
h ~ ~) ~5 0 o ô o o ~ _~
~ ~ r ~0 ~ -~0- I O
~ X ~ ~ ~
:
l ~o, I lZ76~
e t~
~ ~ I ~ O o O
~'
I
9~
. L C i
ll ~
ll~ ~ t~
::
~ -30- ~ 7G~
; i ~ O S
~ ~ ~ ~ ~ , 8 ¦ 8 h
a 5~ v ~ E v ~ E
o ~ v ~e l s 0 ~ ~1 ~ p a
tr~!~ .~ ~o ~ ~ ~ o
~ ul ~ ~r; ~ O O ~ dP
~ i9 . 2 cll .L i Q
u _ ~_ .~1 : h ~ V E S a~
- h 8 h C l ~ E :>h S ~c
~ ~ ~ ~ ~ O O O ,~, ~ a ~ a ~ I
~ : ~ ~ _ ~ ~ a~ o
O E 3 ¦ C O x I h ~ I
~ ~,~ h ~
~276888
, : .
-31-
~ lthough the experlmental data i3 limited to ~dm~n~tr~tion
through inh~lation which trea~ment mode involve~ tran~nort of
~actives~ acros~ inter~al body membrane~, the ~a~tive(s)~ are
known to transport across external body membrane~, notably
~: acro~ epide~mal ti~QUe ~ee, for example, di~closure~ of
external a~plication of ~a~tives~ in folk medic~n~ and
aromatherpy art~. Practice of this invention in~ludes, then,
both transdermal ~dmini~trat~on, and throuqh inhalation with,
: it i~ believed, the 8ame dosage range for treatment by eithex
treatment mode.
~.
`; Th~ followin~ Examples II, IIS, IV and V ~et forth ~rocesses
: ~ for preparing and testing stre~s rea~tivity-reducing compositions of our inventio~. Examples foll~wing Example ~, e.g.,
xample VI, et seq, set forth incor~oration of the s~ress
reactivity-reducing substances in perfumed articles.
The following Exam~le I sets forth methods f~r analyzing
and producing certain of the stress reactivity-reducin~ substances
:` e.g., myristicin and elemicin and the like.
: .,
It is to be understood that the invention is not to be
so limited to the embodiments herein exemplified,
' '
~ '
.:
1' ~'
::.
, ~
~ `
: ;
' '
, ~
lZq68~ 1
ISOLATI~ C~F MYP~ISTICIN FROM EAST IND~
M~lTMEG C)IL AND HEAD SPACE ANALYSIS QF
. ~
East Indi~n Nutmeg Oil was carefully distilled on a 1 plate
short path column yielding the following fractions:
WEIGHT
VAPOR LIQUID OF
F~CTIC>N ~EMP . TEMP. VACl~UM FRAC~ION
NO ._ ~ C~ ( ~C) ~s i~ t~ms 1
;` 1 43/4~ 4~/4~ 2~/2~ 26.2
2 ~2 4~ 20.0 77.6
-~ 3 ~3 ~8 20.0 73.1
4 ~5 52 2~.0 67.~
- 5 45 52 20.0 ~4.0
6 ~ 5~ 2~.0 67.6
7 ~7 63 ~0.0 sa.4
~- ~ ~9 76 2û.0 62.5
g 63 82 5. 0 38 . 4
7~ 1~0 1 . 2 45. 0
11 9~1 108 1 . 2 14 . 3
: ~ 12 98 ~11 1.2 2~.6
13 100 117 1.2 26.9
. 14 96 130 1 . ~ ~7 . 9
. ~ 15 100 1~0 1.0 10.5
. ~__ _
~ ractions 13 and 14 werebulked and further purified by means
o~ distillation on a 6pinning band distillation c~lumn (Nester
~aust Autl~ Annul~r Distillati~n Unit) yielding the following
.
`'
:
' ~
-33- ~LZq68813
f r~cti~ns:
WE~ G~T
VAPOR LI QU I D VACUUM O~
FRACTIONTEMP. ~EMP. mn~/Hg lFRACTION
tao ~-C3 ~C) PRESSURE (gms)
_ _ ,
1 68/72 ~56/lS~ ~ ~ 5/0 ~ 6 1 . 7
2 ~2 161 ~.~0 2.9
3 ~4 161 û.60 3.6
1~ 4 72 lSB 0.60 ~1.2
~ 70 156 0.60 3.5
: 6 74 157 ~. 6~ 3. 2
7 71 159 0.50 ~8.2
8 71 160 0. 55 4 . 9
9 71 159 ~ . 55 3 . 6
71 161 ~. SS 2 . 5
1~ 71 ~6~ 0. 55 2 .
12 66 ~,R5 0.ss 1.7
:
:' ~
- Fractions 7-12 are bulked.
F~_~ is t~e GLC profile for bulked fractions 7-12 of the
foregoing distillation (Conditions: ~00 ' X O . 032" ~used silica/
carbowax column programmed at 75-220C at 2C per minute).
The thus-produced substantially pure myristicin was used for
. ~ further experimer ts ~s ~et forth in Examples II, et ~eq.
: ;
l _34- ~7~8
EXAMPLE ~(B~
: ~
HEAD SPACE ~ A~YSIS OF
NUTMEG OI~ AMD MACE OI~
''
~:~ 2 Grams of Nutmeg Oil East Indi~n or 7Sace Oilwas placed in
. a 25~ cc ~ingle neck receiver. ~he receiver was fitted with ~
rubber stopper into which was embedded a ~t3inless steel hook~ On
the ~o~ was plaeed a 2 cm2 stainless steel 6creen impreg~ated
~ with di~ctylphthalate. The dioctylphthalate absor~ed the ingre-
:: dients of the he~d space ab~ve the nutmeg oil for a period ~f~ 15 minutes. At the end ~f the 15 minute period, the ~topper with
:~ the scre~n was removed from the flask and the ~ereen w~sremoved
:~ from the hv~k. ~he ficreen WQS then placed in ~ ~mall clinical
centerfuge and the dioctylphthalate containin~ the ingredients
of ~he head ~pace wasseparated ~rom the ~creen by means o~
centrif~gation. The resulting product was then ~ubjected to GLC
' an~lysis (Conditions: OV-l fused silica column programmed at
~S^22DC at 2~C per minute).
~;~; Fi~ure 2 is ~he G~C profile for the head space above the
; nutmeg Oil.
The peak in~icated ~y reference numeral 10 is the peak for
: ~ thujene.
The peak indicated by reference numera~ 11 is the peak f~r
.` ~-pinene.
~ he pea~c indicated by reference numeral 12 is the peak for
sabinene.
''"'..'.
''`' '''~'
,'.'''~',
::
,5 lZ76888
: ~he pe~k ~ndicated ~y reference numeral 13 is the peak for
: ¦ B-pinen¢.
~ he pea~ ~ndic~ted by reference numer91 1~ ~6 the peak ~or
myrcene.
The peak lndicated by reference numer~l 15 ~s the peak for
G -phellandrene.
~ he peak indicated by reference numeral 16 is the peak for
6-3-carene.
. The peak indic~ted by reference numeral 17 is the peaX for
c-terpinene.
~ The peak indi~ated by reference numeral 18 is the peak for
.~ p-oyme~e.
The peak indicated ~y reference numeral 19 i5 the pe~k for
~-terpinene,
The peak indicated by reference numer~l 20 is the peak for
;~ terpin~lene O
: ; The peak indicated by reference numeral 21 is the peak f~s
; linaloolO
~ ~he pea~sindicated by reference numerals 22A and 2~B are the
: pea~s for l-hydsoxy-l-met~yl-4-isopropyl-2-cyclohexene,
The peak indicated ~y reference numeral 23 is the peak for
2-methyl-5-ethyl furan.
The peak ~ndicated by refere~ce numeral 24 is the peak for
4-terpineol.
The peak indic2ted by reference numeral 25 lc the peak fo-
~-terpineol.
~ ~ ,
:
~2~76~
-36-
¦ ~he peak ~ndie~t~ by reference ~umeral 26 is the peak fos
l-met~yl-3-hydroxy~4~ propenyl benzene.
The pea~ ~n~cated by reference numeral 27 ~ the pe2k for
; isob~rnyl ~cet~te~
The peak indicated by reference numeral 2B ~ the peak for
n-amyl methoxy benzenes.
The peak indicated by reference ~umeral 29 i5 the peak f~r
eugenol.
~ he peak ~ndicated by reference numeral 3~ is the peaX for
~ ~ terpinyl ACetateO
~ he peak ~ndicated by reference numer~l 31 ~s t~e peak or
. o-cubebene. ,,
¦ The peak $ndicated by reference n~meral 32 is the peak for
~ eugenyl me~hyl ether~
:~ The peak indicated by reference numeral 33 is the peak for
~-copene.
The peaX indicated by reference numeral 34 ls the peaX for
trans-isoeugenol~
The peak indicated by reference numeral 35 is the peak for
~-bergamotene.
. The peak indic~ted by reference numeral 36 is the peak for
~;` -pr~penyl-1,2-dimethoxy benzene.
~:: The peak indicated by reference numeral 37 ls the peak for
myrist~cin.
; ~he peak indicated by re~erence numeral 38 is the peak for
~-cadinene.
~ he peak ~ndicat~d by reference numer~l 39 is the peak fo~
¦elemicin~.
~27~88~3
~ e pe~k l~icated by ref~r~nce numeral 40 1~ the pea~ for
~-14llyl-2 ,6-~limethoxyp~enol.
,;
S~ble IY zets fo~th t~-e he~d ~p~ce constituent5 ~f nutme~ oil
~fter the 15 m$~aut~ per~od usin~ the pr~edure ~et forth, supra
~ ter a one hour perioa, using the prc~ce~ure 8et fortll, ~upral,
and ~fter ~ 2~ hour perio~, us~ng t~e pro~edure ~et forth, ~upra:
TAELE IV
' ~
5 A~t~r a ~bur~ A-t~r ~1 31ours
hu~e~ ~.1~ 2.~10 2.3D
5~0Q 25o2~ SI~
C~ e O~Ct~ 2
S~b1rl~ 2S.20 2~ 0 . ~!1.00
21~ r~ 0 a~.~ 16.S0
a.~o ~ .oo
adr~ e ~.00 1.1~ 1.10
:`
~.3 c~ IcOO ~1.00 I.00
rplr~ .00 ~.~0 ~.ao
c~no a.30 . l.-o
ll~onene ~.60 t.~10 17.00
~-'ro-p1nen~ ~.50 li.10 6 ~0
Y~ nolelle 1.20 ~1.40 2.20
L1~1~1 ~to ~r~t~ 0.50
D7~ ~ 0 2.S0 ~.BI
~T~r~1n~D~ ~r~c~ 0.20 11.60
~r~ .2~
' Pcr71~c1~l t~ac~ 0.30 0.~5
'~`
'-,:
, ~
For the purpose of the dose ~alculations, the head space
concentr~tlor~s of myri~tl~in wa~ l~ssumed to be 0~ o~ e tota~
nu~meg oll that had evapora,t~d.
::
~7~
--38--
~ ble V ~NnaSiz~s tne per~ent myr~iti~n ~n t2~e vapor ~n
~quilibrilam witl~ nutmeg oil or ~n e~u~librium wit~ mace extract
~fter 15 ~ninutess ~ 1 hDur, 2 ~ours, 3 hour5, 41 hc~urs ~nd 24 hours.
The ~nalytic~l prQcedurc f~r the determin~t~on was ~gescribed
previo~ly ~n th~ exampl~J
It Jlas been fc~und that nea~ ~autmeg Oil East ~n~ian contains
7.10- myri5tlcin and mace ext:~act contains 31.00~ myristicin.
~ABI.E: V
HEAD SPACE Sl~DY O~ N~'rMEG AND M~CE
15 ~ utes ~r~ce Tr~ce
~:our 0 .10 0 . ~0
2 Hou~s 0.40 2.00
: ~' 3 ~ours O.5o 5.00
4 l~ 0.~0 7.00
24 Hours 0. 75 ~ . Oo
'
\
\S SFACE LEFT El~'X INTENTIC~NALLY
' \
~27~8~3
--39--
Table Vl ~ets forth overall ~omposition5 o~ Nutmeg Oil E~st
Indian, Nutme~ Oil ~erpenless ~nd gwc~ other commerc~al nutmeg oils
as well ~s Ma~e Extr~ct:
.~
TAI!ILE VI
..
;~
_ _ _ _
t~ O~L Nl,qME~ Ol t~:WC~ COS~ClRL Ps~
~sr ~DL~; ~ ~ OIL N.~X; OIL E~tr~
C~oun~ 5~ XS!~M?I ~ ' .
u~ ~.5b~- ~; i.5G~ ~.65:
t .. ~ i n2tl-t2 .20 ~ 0 ~. 7D ~.?6 l .10
t~ rl! O.~D 0~15 0.~3 ~rac~
S~b~n~ne ~.73 ~-.B0 ~6.SS 0.~0 l.lO
g-Pinen~ 15.~0 ~1.61a2.0~ l.~D 2.63
~rc~n~ t.50: 7.70 ~.3D O.S0 0.~
~-Pt~21~ rer~ 0.~ l.lO ~.~0 0.1~ 0.25
uene 0.~ 0.~ ~.~15 ~.~D 0.6
n~n~ 3.~0 4.60 ~ 2.~0 1.3~
~Cgm~n~ 1 .0D ~ .~4~ .'J2 . I OSC
l1~neoæ 6.~0 ~.~0 l~ 2.9~ 3~0~
~ 3.S0 ~.92 a.-D a.~l~ a.2
Trar~-S~n~ne Ill~-et~ 0.~0 0.93 0~3~ 9.~3 ~.a5
tb,~t St~ ne 0.0~ 0.I2'Ir~lcttr~ce O.ID
~rpinolenlL~ 1.~ 3,.D0~.~S 0.'75 ~.20
tis-S~fn~n~ elr~tl~ 0.15 O.~D 0.20 0.~0 0.8B
l~ lool O.I9 ~.~100.~!0 ~.~0 O.. t~
U~ 71~01~ n) . , .. ~.~0 ~I.OD
2-p-~enthen-l.~l 0.14 0.25 0.16~race 'rr~cæ
a~ h~n-l-ol ~5~) Q.0~ ID~l~ 0.10 ~ ~r~;~
~-Eth,~)-5 i~t~l Fllr~nl~o~c~~rcte tt~c~ _ O
T~r~ineol.4 6.00 I0.-13 3.Stlli~90 1.6~
:-Ter~in~ol 11-~0 I-~B 0.470.~0 0.60
~iper1t~1 ~r~ce ~r~ce tracæl'rae~ ~r-:e
~i~er~to1 tlscH~r) l~r~c~ Trae~ ~r~ce'Ir-ce ~rac~
p-~er.th-~-erl-4-yl-Etb~1 tst~r O - . 0.6D 9.SD
S-~ole ~.~0 ~.00 ~.la l.~ 4.115
ISD ~Orr~1 Acetst~ , , _ `Tr~ce ~race
80rn,r1 Jlc~t~te 'r~ee 0,.~3 lr~ceTr~c~ lracc
t~lymol . . . ~r~c~
~ yl An1sole (~) 0.21 o.36 ~r~ceTr~ce
E- genol 0.~1 0.36 0.l0O.SD i .0~
1 Acet~te 0.~0 0.20 0.050.10 ô~3G
-Cu~bene ID.OS 0.10 ~r~el~ 0.~10 7r~e
V~n1111~n ., . _ tr~ct
Ik~l At~t~tc 0.10 0.~ 0.0~0.10 Tr~ce
~us~n~l ~eth.~ r 11.30 O.SO 0.10 î .OD 1.80
~-to~ne 11.23 0.4~ 0.16 0.93 O.SS
~rDr.i Iso E~ rol 0.31 0.60 tr~c~ 0.71 ~.30
~B~rg~otl~nc '~r~ee 0.~2 ~-~e~ ~t~ce ~r~c~
le-h,~ S~ Ell~nol ~r~ce tr~cP ~r~t~ 0.35 0.~6
~ t1t~n 1~ IGl 1
-C~d1nene lr~t~ lr3ce l~i ~r~ce o.lo
~ c~ll 0.1~ 0.-5 0.~7 l.~S 1.20
D~O~c~o1c ~cl~ . _ .. ~rDee
-All~l 2,6~ ~ Pl~ l 0.0~ 0.19 tr~t~ 2.~0 ~.OD
ffr~stl~ ,. , . ~5 ~12
Y1 ~tr~fl~c~nat~ _ _ _ ~ 10 2.~0
~1 ûtt~d~c~flDtçt _ _ _ ~.85 3.00
~rrl ?al~1t~te . O _ 1 ~D ~.0~
tt~l Olellte .. l _ 1.5D
OCtS~?~nO~C ~C~ t~ E-t~l_ ~ . _~ _1.~0
. . ~g.~ 1~.g6100.00 11~.01 -
I
-~o-
~ E ~
: IS~LA~I~N OF E~EMICIN F~M Ol~ OF EL~MI
~:
Elemicin was separate~ ~rom Oil of Elemi us~ng the following
procedure:
I! Elemi 9il (Contains 7~ ~lemol a~d 3~ Elemi~in)
~ I - 'I -
! 1 Distillati~n
¦¦ Enriched Fra~tions (Elem~l 70~ ~nd Elemicin
D h dra~on of Elemol
~; ¦ Ses~uiterpenes (70i and Elemicin 30
.1 ! ¦ Column Chromatography
-~ I l_ ~
~: ' ~ ~ Dist.
ite~E5Do~ Elemic n~ 94~ Elernicin
he 94~ Elemi~in is used ln ~hsequent Examples V, et seq.
~l i
,
,
~ 11
::::
~3L2~
-41-
EXAMPLE ~(D~
MNRISSICIN SYNSH~SIS
Myristicin for use ~n subsequent Examples II, et ~e~, w~s
~ynthesized ~sing ~s a precursor~ 1,2 dihydroxy-3-methoxy benzene
~; according to the following reaction ~equence:
HD ` ~O
~; ~ ~Bl ~ j
t)~ ~~ ~ 1 a~d
':
~ 76~
-42-
Oh ~ t ~`
~ o~O
o- I
:~
The is~lated myristicin was used in Examples V, et seq.
~1 lZ7fiE188
-43-
EX~MPLE I I
Four Dd ar~t cond~t;or,~i were tosted using l~ f~ctorial exper~- ¦
menta1 desiqn. ~nalysi~ of the resu1ts was ~ ~ two way ana1ys16
of variance. Factors were Fragr~nce ~A" ~nd ~NeutralW Fragrance
and levels were ~/- the presence o~ ct;ves~O Ana1y~is of the
results was wi~h ~he BMDP ~tatistica1 package ~nd a Digita1
Equipmen Co. (DEC) 11/780 VAX computer. ~n explanation of the
analysis of variance (ANOVP.) technique is found in:
.B~ ~ScCa11, "Fundamenta1 Statistic:s ~or Psycho10gy,~ !
2nd Ed. ~ Harco~lrt ~race Jo~ans~vich, ~aew York, t~.Y.; 19750
paqes 236-64,
¦The term ~p~ i5 the ~ignificance 1eve} as s:btained from the ~F~
test ~pplie~ to the A~C~V~ ~esults. "p~ ~5 the proba~i1ity that
the results obtained are due to random error.
The composition of the fragrances ~as as fc~ ws:
1. Fragrance ~A~ composit~c~n:
GAI.AXOLIDE ~) lRegistered Trademark
of International Flavors ~ Fragran~es
Inc.: a tricyclic ~sochroman having
the structure:
ll ~ ~b
, . 1 ..................... 0.. ~... 47.la
: Verdox la ~emic~l manufactured
by ~nternational Flavors & Fragrances
Inc. ~avi~g the tructurc:
~ 2~76~
-44-
Die~hyl ~hthA1~te ........ 0.... ~..................... O 12.6
~eac~ ~ldehyde C~eur ..... ~.................. ~....... ..10.5
~renyl Acet~te ........... ~.... ~0.~.................. ...4.0
~exyl Cin~amic ~lde~yde ....... .~.... 0............... ...2.6
~o Amyl 8utyr~e ........ 0.... .O.................... ...103
~lde~yde AA-Tr~plal l~ ~pecial~y
~an~actured by Internat~nal Flavor~
Fr~gran~es In~ h~ving the ~truc~ure:
~................................. ..Ø0~
: Veltol Plus ~ethyl maltol having
the structure:
Ço~~ ool Ij
2. ctives~ compositisn-
Nutmeg Oil East Indian ............................. ..97.10
Maee Extr~c~ r~ 0~14
Ner41i ~ O~ o.98
. D~et~y~ Phthalate .................................. ..Ø44~alerian Oil Inaia~ O~ o.~S~
. . 3. Fraqrance ~ Active:
Fragrance ~A~ ...... ~.......................... ...60.0
~Actives~ .......... ~.............. ~........... ...40.0
.
~ ~: 4. Neutral~ Fraqran~e:
.,
~ ~ Diethyl Phth~late .. ~.......................... ..100.0~
- ~
: 5. ~Neutral~ Fragrance ~ ~Actives~:
~ ~ ~iethyl Pht~alate .. ..~........................ ...50.9
- i Fraqrance ~A~ ....................... .......... ...10.
~ 'Actives".... ~...... ~.,.............. l......... ...~0.0
.' I
I
--45--
,
~ he ~ubjæcts use~ ~or the ~tu~y &7ere ~r~wn ~rom the New Haven,
Coranectil:u~ l~re~. Or~ I~undre~ ~Lnd Swenty f~ ts were u ed for
the 2xper~m~nt ox tl~rl:y ~l~bjeclts fo~ e~ch ~f th~ four ~el~s.
S~ Içtudy wl-~ run dlc~uble bl~n~. Sub~e~ts were xun ~t one ~t a
tim~ ~nd tlle ~cript was presen~e~d ~y tape recorder. 81~od pres-
sur~s ~nd heart rates wexe mehsured w~ th an lluto-
~nflatable~ pr;nt~ng, dig~t~l sp~ygn~man~reter manufactur~d ~y the q~Sceda
Medic~l Co., ~nc. vf ~o~cyc~, J~pzrl.
The prot9col allowed for ~nvestislation o th@ cardiovascular
.
~: and mood responses tQ ~ t;tressor with and without Pfragrance1'
;~ or stress reactivity reducer (S2R) trea~mentsO Th~
ob~ective was to provi~le a ~tressor that would produce a ~tress
type and level ~imilar tc~ that exper~nced ~n the work pla~e.
A further c~bjec~ive s~as tc~ n-easure both blood pressure and mood
` changes durin~ the ~tress period ~nce the litexature ~as ~h~swn
t,hat reactiv~ty to ~tress corr~lat~s with disease. The protocol
~ wàs as follow~:
:~ 1. Attachment of the ~lood pressure cuf f,
~. Questionnaire.
..
3 . Stres~ ~:
~) baseline
(b) mood ~elf report
(c) 6 low ~tress questions ~LSl)
(d) mood ~elf r~port
~e) 6 mild ~tress ques~cions (MS1)
tf ) mc~od self report
(g~ b2seline
~h) moo~ ~elf report
;,
4. ~reatmen~:
~) Fragrance ~A" c~r
b) Fragran~e "A~ ~ ~A~t~ves a or
(e) nNelJtr~l~ Fragrance or
(d) ~Neutral~ Fra~rance ~ a'Ac;ive~
., ,
~i
~2~6~
-46-
S O Stre~
~ asel ~ne
Ib3 mood ~elf repc~xt
~c) 6 low stress quest~ons (LS2)
~d) moo~ ~elf repor~
~e) ~ mild ~tress questi~ns (MS2)
( f ) moo~ ~el f repor~
(g) base l~ne
~h) mc~od ~elf report
.~ 6. Post-experimental questionnaire
7. ~emoval of recording devices and debriefing.
.i The initiaI questionnaire oontained 5~ true~false questions
~ i'taken from the Marlowe-Crowne repression test and the Bendig fo~m
::~ !'o~ the Taylor ~nxiety ~cale. It was used to classify subjects on
!!~he basis of repression and anxie~y.
: ;
: Baseline periods in~lved the ~ubject sitting ~till, sesting.
Mood self reports were made by the ubject reporting by means of
i'a ~even point ~cale (0-63 his or her degree of relaxation, anger,
anxiety, happiness, tenseness, embarrassment, calmness, fear and
,sleepiness. Neutral and mi~d stress questions were taken from
~the Pha e Association ~ests
~. I
~ I Mandlex, et ~ Response t~ Threat: Relations Among
: V~rbal and ~hysiological FindingsN ~sychological
:~ Monographs, 1961, Vol. 7~, No. 9).
Subjects were ~sked to respond as quickly as possible with the
: first phrase that came to mind followin~ presentation of a
. ~ stimulus phrasel Neutral questions included ~My name is?U
:~ Stress~phrases ~ncluded: ~The thing 1 like least about myself
~ is.~ nd ~If my child were dating someone of a difference race
: I would... ~O
:~
~7~
-~7-
Dur~ng the trxatment period ~he ~ubject ~melled one of ~he
fragran~es or po~tulated stress reactivity reducing agent~
from a RMeasuring I,lne- ~tyle perume ~lotter c~bta~ned frc~m
Franlc Orlandi, Inc. 31-û2 N~rtllern 3c>ulev~rd, Long Island City,
Queen, New Y~r~ 9Llltllo The bl~tter w~s ~bout 15 c!n lc>n~ by
abou~ cm wide. It was dippe~ ~n~o a 20~ ~olut~on ~f fr~grance
and/or postulatea stress reac~ivity redu~ing agent ~n ethyl alc~l
to a level ~f a~out 2 cm (the second red line), ~llowed to dry
fc~r five mi~utes and then pc~sitioned a~out C cm frt~m the subject's
s~c~se .
The fir!al questionnaire asked for the subjectts reactions to
tt~e exper;ment.
~ rhe analysis ~f variance of the resull:s ~howed significant
changes in sys'co~ic blc>od pressure and ~el~ report:s for lthe
subjects 6melli~g either fra~rance ~IAa plus ~actives~ or ~Ineutra
fragrance plus ~actives~ versus the ~b~ects ~mell;nq the
.fra~rance ~A~ or the ~neutr~fr~grance ~lone,
The chan~es deemed to ~e relevant to the every day ~tress
and stra~n of life were the blood pressure and mocd changes due
t~ the stress ~uestions relative t~ the low stress questions
~UMs - LS); ~ee the protocol for definiti~ns ~f M5 and LS). Tc
obtain ~ Change score for a part~ular c~ndition the changes
before and after the c~ndition were c~mpared thusly:
Change due to the fragrance ~ or~neutrala fragrance ~ N;
and N ~ (~S2 - LS2) - (~Sl - LSl).
.
In the same way a change ~core can be calculated for the
. fragrance ~A~ plus ~actives~ or the ~neutral~fragrance plus
: ~actives~. This ~hange is referred t~ as ~Aa.
'.'
~,,2~6~88
4 8-
- So o~t~in t~e ef fect of on~ eondition re~Lative to another
t~e c~anye 3core ~or on~ cond~ t~os~ can ~e ~u~tracted from ltha~
~or anot~eE. Thus, the "a~t~ves~ effect ~5 ~ N) o
For Table VI~ presented ~elow, th~ ~activesa eff~/:t was obt~ined
by pooling: the r~5ults for the fragranca ~A" plus "actiYes~ and
neutral~ pl~ls ~ tiYes~ to ~btain ~A" ~nd: poolin51 the resul~cs
fo~ the f~agrans:e ~A~ and "neu~al~ fragranc~6 to obtain ~l~
n the as~lysi~ c~ varian~:e treatment o thc resul s, t~
~,: C:hange scc~re presented be~Low ~n Table Vl~ ~Ls numericallv ec~ual to the perio y tr~al ~y "actit~s~ three-way interactions. Is~
~his con~ext, ~period" is the aYera~e of the effects a~ter
treatment relat~ve lto the effec~s before treatJnent:
: lLS~ ~ MS2~ - (LSl + HS13 averaged~ across all four trea~ments.
'Tr~ s t!h~ aver~g6~ of the effects due tc: mild st~ess relative
0 those due t~:> low st~ess: (~Sl + ~qS2~ ~ tI.Sl ~ ~S2) averaged
;~cross all treatments. ~ "Acti~esU ~s the average o~ e:ffects
for the compositions containing "acti~re~ rel~tive to effects
for the compositiol-s containing no "activesn: ~ISl + LS2 + ~ 52)
avera~ed across fragrance "Aa ~ ~actives" and neutral fragrance
; ~act~ves" minus (~Sl ~ ~S2 ~ MSï + MS2~ ~veraged across
fragraslce "A" an~ the ~leutral fragran~e,
. ~ .
~ ' .
.~ i
:
-' ;
,. , ~
~Z7~
-49-
TABLE VII
~ _
E~FECT 0~ UACTIVES" (:JN M~LD STRXSS
- r - ~ I
YARI~Bl.E CHANGE SlGNlFlC~NCE ~EV~I,
~ __ . _ _
Systo11c B1c:>od Pressur~ ~ 3g. O . 08
____.____ __________~___ _____________ _________________ ___
Calmness O . 77 O . 01
________________________ _____________ _____._ _____________
~ Embarrasment -2. 31 O. 03
________ _____~_~____~_ ___~________ ___;_________ _____~_
~appiness O ~ 77 O . 0003
___________ _~ _____ ___ ____ _____~__ _____________________
~ O ~ 51 0 . 03
'.,
Thus, the presence of ~actives~ in either the fragrance ~A~
or the ~neutral~ fragrance decreases systo11c blood pressure:
increases ~almness; decxeases embarrassment; increases happiness;
-~ and decreases anger.
E~en th~ugh the subjective results in this case have been
quantified, ~t ~s $mportant to point out that they ~lso corre1ated
wit~ ~he ~ysto1ic b100d pressure ~hange.
~: .
~j _50_
EXAMPLE I I I (A ~
~ c~ odc~rant ~:~nait~ors were tested using 1~ r~al
experimental desis~n. An~lysl5 of the result~ by ~ one way analys~s
o~ v~ri~nce was done. The fActc>r wa!; ~fragrance~ or ~pos~ulated
~ress reactivity reduc~ng 2gent~; the levels were plus and
min~s "ac~ivesn. ~he details of the ~tat~stical analy~$s
techniques are presented ~n Example I~ v supra.
q~le s~ibstances tested ~re fragranoe aAn and a ~sitial of matter
composed only of ~activesa. The compositi~ of the fragrance "A"
and of t~e "actives" are presented in ~Example ~I, supra.
The sub~ect~ used for the study were drawn fr~m tl~e Union
: . Bea~h, New Jersey area (Monmouth County in the State c~f New Jersey~
Fourteerl ~ulbje~ts were used fc~r the ~tudy; ~eYen lrl each oP t~c
two c:ells. The ~cript was presented ~y tape recDrder ~snd blood
pressures were measured wi~ ~ recordin~ aute~matic sphygmomanometer
as aescri1bed i~ Example II, supr~. The experimental session
periods were the following:
~',
1. Attachmen'c of the blo~d pres~ure cuff.
2. Questi~nnaire.
3. Stress T:
~a) baseline (BL)
. ~ lb) mood self repor~
(c) S lvw 6tress questions ~LSl )
, ~d) mood ~elf report
(e) 6 mild &tress questions (MSl)
t f ) mst~d xel f ~eport .
~76~
--51--
~, Srea~e~sen~
(IRl f ra~ranc~ ) 0
~b~ ~octlves fragran~e
S. ~tress II s
~1) mo~ self report
[~ 6 low ~tress quesS~on~ ~1,52j
~3 mood ~1 report
6 mild ~tress questi3ns ~MS2)
(e) moo~ ~elf repor'c
(f3 baseline (BL2) .
6., ~stoexperimental ~u~t~onnaire.
~ i
7. Removal ~f recording aevice- ~nd debri~f ing .
. Det3ils o~ the parts of th~ protocol are set forth iJl Example II, ~upr~. During the treatmeJIt p~r~o~l th~ clts
~:~- smelled or~ of tl~e fragrance~ ~r postulatsd ~tr~ss reac~ivity
:. : redu~ng agent~ fo~ ~ one~ ~!lra~n vial ~ontain~ng a wick ~turated
ith ~ solution ~ad~ up ~f 6~- test substance a~d 40~ ~ood gr~de
ethyl ~loohol.
, .
~,
The experiment wa~ designed to 8~10w the ef fect o the
stressor and ~i) r'ra~rance or ~i~) 6txess reactivity reducing age:~t
on ~ystoli~ blood pressure. me stressor is designed to be mildy
~rus~rating ~d tension producing. m,e subj~ct d~es not have
adequate tl~e to answer t}~e quest~ons which ~re controversial and
have complex answsrs.
ure 3 ~hows the ~hange ~n ~ystoliG blood pressure during
the peri~ds of the prot~cQ.l. ~or the ~before fragrance~ or
"stress reacti~ity reducing agent~ p~riods, the moderate ~tress
questions produ~e ~out ~ 5 n~n/Hg rise in blo~d pressure relative
to the low stress questi~ns ~MSl - ISl~. In the after #fragrance~
:
or "s~ress reccti~ty redu~ing agent~ periods, ~he ~ub jects
~` ~ smelling th~ ~activesa experien~e ~ 1 mm/Rg de~sease in sy~tolic
od pressure durin~ the moderate stress questions relative ~o
`, ~
I ~76~
-52-
tJ~e low ~tres5 ~uest~ons ~hlle tlle ~ ects ~mell~n~ fragrance ~A-
exper~ence ~n ~ Hg ~ncrease ~uring the s3me per~od 5Ms2 - ~LS2).
The chanye ~or the "~ctive~ qroup relat~ve to the fraqr~nce n~
grc~p a~ follow~ s
.~Ac t iv~s a ~Oup
.
A c (MS2 - ~LS2) o IMSl ~ S ~ -6 mm/Hg
Norl-Act ives Grou
P
N ~ ~MS2 - LS2) - (MSl - LSl) G fl - 5 -- 3 mm/~g
.'; Chan~e o
P. ~ 3 ~ -9 ~ g (p ~ 0.03~ .
~; The Change soore ~hows that the ~Actives" d~creases systolic
blood pressure aurirl~ ~ mildly frustratinq eYent which has been
own in the f irst part of the experiment to increase ~ystolic
blood pressure. Th~ fragrance ~A'' does not exhibit this effect.
11
~
88
--s3 -
EXAMPLE I I I ( B )
-
prefer~e~ eRor~nt C~mp~S~t~Qn wa3 testea on ~ ~3 year ol~
male ~ ct. ~he c~mpo~it~on of th~ odor~nt ~5 61~ ~r~rance
A~ ,lan~ ~10~ t~ve~ ~se~ ~xampl~ upr~ he mod~ of
~dmin~str~t~On w~l~ ~ means of tl~ v~al-w~ck ~y~tem a5 de~cr~bed
: - ~; ln l:x~m~ III, supra . ~he test~ng proto~ol w~s the ~n~ descr~ed
ln Ex~mp~ I, 6upra, ~nd tha pr~to~ol p~riodE ~L~, ~1, MSl,
, LS2, 1452 ~nd ~L2a are ~130 descr~ n Exam~le III. ~igure ~
$hows the ~ ect'g ~ystol~c ~lood pressure ~n ~n~t~g for each of
the periods tindicat~d Sy ref'erence numeral 813. The shap~ o~E the
raph ~ ~m~l~r to that for ~h~ graoh for the ~actives~ ~roup
nd~cated by refer~nce numberal 72) presented ln Figure 30 Of
particular interest ~re systolic blood pressure changes between
51 ~nd MSl and ~52~nd MS2. T~e ~u~ect ex~erienced a 6~m~Hg
increa~e ~n ~ystol~c blQod pressure ~HSl - LSl) for the ~before
fr~gr~nc~ perio~s whereas he experienced an 8mm~Hg de~re~se
: (MS~ 2) for the ~ame perioas after ~he odorant-conditioni~g
p~r~od. Hen~e tb~ C~nge ~core t~ee Examp~e 11~, ~upra) is
the followl~g:
.~
A ~ (MS2 - ~Sl~ - ~MSl - LSl) ~ B -6 ~ -14mm/Hg.
~ This example further shows that the aactives~ composition
.~ ~ lowers a human'~ reaction ~o stre~Q.
'
;, ,-
~' '~,
:: ~
_54~ 888
EXAP~PLE IV (A)
Two odosant conditions were te~ted u~ing a f~c:torial e~speri-
~ental design. Analysis of the resulk~ by ~ one way analysis
of variance wa~ done. The factor was ~ "~ragrance" or postulated
~tress reactivity reducing "agent"]: ~he levels were plus and
~oinu~ ~ctive~W. The details of th~ ~tatistical aslalysis
technlques ~re presen ed in Exa~nple II, supra.
The ~ubstances tested were a caloposition of matter COII~pO5ed
of Ethanol/~istilled Water ~nd a c~nposition of ~atter camposed
of Ethanol,/"actiVi83~. Th~ ca~position of the "acti~7es" i~
presented in Ex~nple I~, supra.
The sub~ects used for the study were dras~n fr~n the Union
Beach, New Jersey area (Monmouth Cc~u~lty in the State of New Jersey~.
Thirty sub~ects were used for the study: fifteen in each of the
two cells~ The script wa~ presented by tape recorder and blood
pressur~ were measured with a recs:~rding automatic sphygmomano-
meter as described in Exam~le II 9 s~pra~, The experimental
session periods were the following:
1. Attach~aent of the blood pres~ur~ cu~f.
2. Que~tlonnalre..
3. 5tres~ I:
~ a ) ~a~el ine ~ BLl )
5b) mood self report
~c) 12 ~ld stres~ que~tions (VBl)
~d) ~ood self report
(e) ~erial counting e~erci3e ~MBl)
~f~ mood aelf report
4. Tr~at~nt:
~a) Eth~nol/~ater ~E) or
(b) Ethanol/~ctives SE~)
5. Stre~s II:
~) Basellne t~L2)
~ ~b~ ~ood self report
:' 5c) 12 m$1d stre3~ que~tions ~VB2)
~d) ~ood Ye}f report
(e) serial countlng e~erci~e (MB2
~f) mood ielf report
:~ 6. Po~t-esperi~ental q~e tionnalre.
7. ~e~oval of reco~ding devices and debrlefin~.
The initial ouestionnaires consist of practice mood
evaluations and a number of!other ques~ionnaires unrelated to
the main experiment,
-~r
. ~ .
~2~ 38
--55--
13a3eline period~ involved the sub~ect ~itt~ng still, re~tinq.
The ~ood 3elf reports w~re made by the 3ub~ect re~rtin~ by means
of a nine poin'c ~cale (0-9) hi~ or her d~ree of relaxation; anger
z~ruciety, happiness, terlseness, embarrassment, cal3nne~s, boredcnn,
~nd sxcitem~nt. The mild 8tre~s c~uestion3 are 8 set forth ln
E:xa~ple II, ~upra. The ~erial counting ex~ro~8e CQJlsisted
a~king sub~ects to write dowYI their respon~e~ to a ~eries of
instn~ctiOnS such as "counlt ~orward frcnn zero by fives". The
sub~ects were infonned that they would be given a bonus based
on the nulober of correct operations they perfonned.
Starting at the beginning of the trea~nent peria~, the
subjects sr6elled a fragrance or posulated stress reactivity
reducing agents fr~m a one dr~n ~ial containing a wool wick
saturated with a solution made up of 60% test substanee and 40%
food qrade ethyl alcohol. They colatinued ~Delling this fragrance
through the end of Stress II.
This protocol was designed to b~ samewhat more stressf
than that set forth in ~xam~le ~I, supra. The ~serial counting~
is designed to be a measured performance task.
The post-experi~ent ~uestionnaires consisted of the Marlowe-
Crowrle/Taylor Anxiety Scale a~d a questlonnaIre regarding the
subject ' s reaction to th0 experiment as ~t out in Ex~nple II,
~upra.
Two sets of "change scores- are calculated for this
experiment in the same manner as set out in Examples II and III,
~upra. The fir5t ~ the difference between the baseline and
verbal stress values and the second is the difference between
the baseline and ma~hematical stress values as follows:
VB ch~nge ~ (VS2 - BS2) - (V51 - BSl)
MB change = ~S2 - BS2~ - tMSl - BSl)
The effect was then calculated as the difference between the
change score for the "active~ and that of water. The significance
is determined by three-way analysis of variance as set forth in
Example II, supra.
~,-
~%~6~
-56-
Table VI~I
Effect of "Actlve~" on Stre~
Signlf icance Slgnif lcance
Varl~le VB change Level ~p) MB c~ange Level (p~
Systollc BP -6.2 o~mtHg 0.03 -1.5 ~/Hg 0~62
Dlastolic BP-6.7 mrd/Hg 0.05 -6.4 n~/ffg O.og
Relaxed 1.1 0 .11 1. ~ 0. 04
Ar~xiou~ -1 . 1 ~. 12 -3. 1 0 . 002
Tense -1 . 6 0 . 0~ -2 . 3 0 . 06
Embarra~ed -0 . 7 0 . 45 1. 5 0 ~ 04
Bored 1.9 0.06 2.4 0.06
While the level of significance varies between the stressors, the
presence of "active" reduces both systolic and diastolic blood
pressure; increases relaxation; increases bored~m: decreases
~nxiety; decr ses tension and decreases embarrassment.
'::`
::`
. .
Il ~ Z76~188
-57-
EXAMPLE ~J ( B )
Two odorant conditions were tested as set forth in Example
rv ~A), supra. The trea~ments tested were fragrance "A4 and
fragrance (NA" + "activesa). The compositior o~ these is as se~
forth in Example II, supra.
The subjects used for the study were drawn fr~m the Union
Beach, New Jersey area (monmouth County in the State of
New Jersey). Thirty-five sub~ects were used for the study:
nineteen recei~ed fragrance ~Au and sixteen fragrance t"A
"actives").
~. . .
:~ ~ The change scores and statistical confidences levels were
calculated as set forth in Example IV(A). The effect was then
calculated as the difference bet~een the change score for
:~ ("A" ~ ~activesn~ and that of "AN alone.
''..
~: Table IX
Effect of UA''+''Actlves'' on Stres
Signif icance ~;ign~f icancc
Vari~le VB changel,evel tp~ MB change Level (p)
5y~tolic BP -2 . 6 mmlHg0 . 39 -5 . 2 m~tH~ 0 . lB
.~ Dia3'colic BP -1.5 Dm/Hg 0.49 -7.2 mm/Hg 0-04
Anger -1. O O . 05 -1. O O . 05
Anxiety -1. 2 O . 04 -0 . 3 0 . 70
ffappy 0 . 8 0 . 27 1. 1 0 .13
Tense -2.Q 0.04 . -1.5 0.13
,
'.'
~. ~hus, the presence of ~actives~ reduces blood ~ressure:
::` increases happiness; reduces anxiety; reduces tension and
reduces anger. This ex~mple ~urther shows how the ~acti~es~
¦¦reduce human st 5s-
::~
~'~
, '
~27gi~
-58-
EXAMPLE rV(C~
Twc odorant conditions were tested a set forth in
Example IY(A), supra. The treatments tested were ~ragrance
"F" and fragrance ~"FN ~ "acti~es~). The composition of these
is as follows:
. 1. Fragrance "F" Composition;
Isobornyl acetate... ,.....,.......... 19.42~
Cedarwood oil...................... .. 20.65%
Bornyl acetate..................... ... 6.75%
Pine oil.................. ~...... .. 6.50%
¦Hexalydro-4,7-methanoindan-5 1
j (or 6)-yl propionate 1..../ 3.50%
Ethyl acetoacetate............... .... . 2.50%
~-Terpeneol...................... .... . 2.38%
Methyl nonylacetaldehyde......... .... . 1.56%
Linalool....................,......... 1.62~
Coumarin............. O......O......... 1.25%
Dipropylene glycol................. .. 33.86%
'' _ .
~ :~
~:~ ~
lz~6~88
-s9-
2. Yragrance "F~ + ~Acti~es":
Fragranre WF".................... ~ 60.00%
: Actives (Example II, supra)~........ 40.00
: ~,
The sub~ects used for the study were drawn fr~m theUnion Beach, New Jersey area (Monmouth County in the State of
New Jersey). 5ixty-fi~e subjects were used for the study:
: thirty three recei~ed fragrance "F" and thirty-two fragrance
("F" + ~Actives~).
: The change scores and statistical confidences levels were
calculated as set forth in Example rV(A). The effect was then
calculated as the difference between the change score for
(llFn ~ aActive5n) and that of WF" alone.
~'
~:: Table IX
Effect of "F"~"Actives" on Stre3~
: Slgniicance Significance
Varlable VB change Level ~p) ~B change Level ~p)
Sy~tolic BP -3.1 ~/Hg 0.20 -3.2 am/Hg 0.16
Diastolic BP -4.0 ~m/Hg 0.03 -4.5 mm~Hg 0.04
Calm 1.4 0.04 1.? 0.04
Thus, the presence of "actives" reduces blood pressure and
jincreases calmn s.
~ 11
.'
--60--
~X~ V
Exper$ments ~ov~ by Ex~mpl~s ~ re ~ried out
us~ng 1~ pla~e ~ tl-e ~tive~ c~mp~siti~n tne ollowing cub~an-
lly pur~ material~
~ii Nutmeq Oil E~st Indi~n5
erol~ O-~l 7
i i i ) Mace Ex'cr~t ~
v~ Yalerian O~l;
(v) MyristiC~nt
V~L) Elemicin; ~J~d
~vi i 3 I soelemic~n .
`~`'~'
. Results ~ubs~nti~lly e~e ~ame ~s t~-Pse ottained ~ Exa,~?les ~
and IV ~re obtained wh~n using th~ ~oregoing puxe material~ in-
~tead of ~be ~act~ves~.
~ ~ *
.
In the followir~ Examples VI, ~t seq, the following materials
are used in perfum~d ~rticles causiLng use of t~ese pe:rfumed
~r~icles lt~ cre~te mild ~tress reactivity reducinq effectson ~e
user:
T~BLE X
.
; (~3 ~Activ~s" compos~t~on of ~x~mple II:
. ~ 6~i) Nutm~g Oil Eas Indian ~ubstan~ially puse;
(~ii) Mace ~xtract su~stantially pure;
(iv) Neroli O~l:
~V3 Vzll~xii!lA Oil;
v~) Myristicin:
~vii) Elemicin; ~and
~Yi~ soel~mi~in.
;~
7G~8
--6 1--
-. EXA~PLE VI
PREPAIU~TION OF A COSMETIC POWDER COMPOSITION
:'`
A cosmetic pow~r ~t~ prepar~ by a~ixin~ lh X ball ~111
100 grams o$ t~lcum powder with 0~25 gr~ms of each o~ th~ cc)mpos$-
. ~: tion~ ~ ~le v~ ach o~ the cosmet~c ps:~wders prepared
~ith e~ch of t)~e ~ngredients of ~he compositi~r~s of ~atter set
fort~a ~n Tabl~ VIII,supra, cr~tes ~n eff~ct which can ~e descr~bea
. ~ as ~stress reactivity reducing~ in th~ user.
n each o~ 3 . (v~ii) taken g~lone is con~ined at ~
SO :50 ~weight:we~9ht) level ~ h ~r~granc:e "~ ~ pleas~nt apple
arom~ mparted to t~e cosme ic pc~wder.
-:
AMPLE V I I
.
-~`. P~EPARATION ~ ~ COLO~NE AND HANDXERCHIEF P~RFUME
_ _ _ __
Sach ~f th~ compositions of matter of ~a~le V~ upra, are
incorporated $nto colognes at concentr~tions o~ 2.0~, 2.5~, 3.0~,
, 3.5~, 4.0%, ~.5~ ~nd 5.0~ ~n 95~ a~ueous ethanol toge her with
~:: 4.0~, 4.5~ and 5.0~ of fragrance ~A~ o~ Example II; and ~nto
~` handkerchief per~umes at concentrati~ns of 15~ 20~, 25~, 30~ and
40% in 95~ a~ueous ethanol together with 10~ by ~eight of fragr~
; ~A~ of Example lI. Distinctive apple aromas are imparted to each
: of:th~ cologne a~d handkerchief perfumes and each of the colognes
~: and handkerchief ~erfumes gi~es rise to ~ ~stress reactivi~y-
red~c~ng~ ef~ec~ on the us~r~
:,
:~,
' ~
~2~ a
--62--
EXAMPLE VI I I
D EODORA~T ST ~[CX
..
J~ ~eod~r~nt ~tick compos~t~n i~ prl~p~re~ ontaln~9 the
following material~:
~'
dGREDIE:~TS PAR'rS BY WEIG;H~
~ropylene Gly~ol ~ O " ~ O ~ r 4 68. 00
Sodium 5tearate .. ~............ ~... i.. , 7O00
.~ Distill~ Wat~r . ~ 0 .......... ,.. , .. ~, ... 23.75
IRGASAN ~ DP -300
12, 4, ~ trichloro-2 '
hydroxy diphenyl ether,
manufactur~d by th~
Ciba-Geigy Chemic~I CoO
~nd A Tradem~rk ~f the:
Ciba-Geigy Chemic~l Co. ) . ~ , ..... 1..... 0.25
Composition containing fragrance ~AI'
(50 parts ~y we~ght~ and one o~
items ~) (viii) of ~able VII~, ~xra;
~:50 parts by weight) ~ --6-~ 1.00
, _ '
The ingr~dients ~re ~cmbined without ~activ~" substance/
fragxanc~ composit~on ~ he~ted ~o 75~ ese ~ ts are ~x~d
~r~d cc~nti~ued to Ibe heated urtil the ~odium ~earate has diso
solved. The resultin~ mixture ~s ~ooIed to 40-C ~nd the Pactive-
su}: stance~fragrance ~omposition (containing one of the stress
~e~ctiYity reduction l;ubstances of Table V~ upra) is added and
mixed at 40-t: un~ uspension is forared.
. .
l'he resultin~ suspension ~s formed into deodorant ~ti~}cs~
use there~ sers subje~ted to ~tress ~c>ndltions experien~e
reductior~ ~n phy~ qi~al ~nd/or ~;ubjective react.i~,~ity t~ stress.
38
~63--
E:SAMPLE IX
SO~ID ROO~ DEODORA~ COMPOSITION
'.
a ~olid room deodorant composition ls preparea ~ ~oll~ws:
:
~: IN~REDIENTS , ARTS BY W~IGHT
" :
PART A:
istil~ed Wa~r ~ OO~ O~ 88.4
-~ GELC~RIN A~ 15 ~1)
Mari~e Colloid~3 ~--O~ o~ 3.00
::~ Formalde~yde ... ~ .O....... ~.... O..... ~.... 0.05
:: PART ~:
Glyce~ine O~ O~ O~ 3.50
PART C:
_
Composition containing ~ragran~e ~
(50 parts by weight) and o~e of items
(i)olviii) o~ Table VIII, ~upra
(50 parts by weight) ~ O~ 1~00
P~RT D ~
Th'EEN 80 (ICI Americas) 3~O~ 4.00
~%7~ 38
--64--
~he composit$oll ~8 prepared by:
lo '8eat~ng t~e water to ~5"C and di~persing the GELCARIN
AF~; 15 thereln s
2. S1QW1Y ~d~ling t~ae glycerin wh~le ~ainta~ning tbe
fnixture ~t 85-C5
3. Combining the TWE:EN 80 ana composition containing
Uact iYes " and fragrarlce;
dding th~ EEN/(~ragrance plus "a~tives") ~omposition
tc~ the resulting ~nixture,
5O Adding formaldehy~e to the resulting mixture and
6. ~ouring the result~ng mixture into ~ mold.
- - - .. ..
~he contents ~r~ allowed to cool, the mold ~s opened i~nd the fiolid
"c~kes" ~re removea. Shz~ ~e~kes~ ~¢ placed ~ntc~ ~t~ndard air
deodorizing ~ppar~ui~ .
0~ cperatiog~ of the ~ta3~dar~1 ~ir deodorizinq apparatus as
il~ room dec~d;:~izer, ~fter ~our m~nu~es, the rc>om has an ,Destheti-
$ally pleasing apple aroma ~nd further, ~ person placed $n said
room who i~ ~ubject to ~tress ~onditions will have a Gignificant
~tress ~eactivity reduction.
Notes: 1. GELCAP~IN ~FG 15 is Carageerlan manufactured by
. Marine C~lloids, Inc. Division of FMC Corporation
vf Springfield, New Jersey 07081.
2 . ~WEEN 30 is Polyst~rbate 80 otherwise known as
~polyethylene qlycol 36 -Sorbitan Oleate, manufactured
by IC~ Americas ~nc. of Wilming~on, Delaware 19897.
;
~%~388
EXA~SPI.~ ~
BODY OIL CO POSITION
A b~dy o~l c~mposlt~on 16 prep~red ~6 follow6 8
:.
I~GREDIENT5 PAR~S BY WEIGHT
- - ~
~ineral Oil lXLEARO~ ~ ~Witco)l .. ,...... ~ 45.0
:1 Is~propyl Myristate .............. ~...... ,....... 50.0
Composition containing fragrance "A~
:: l50 parts by weight) ~nd vne of i~ems
lviii) of Table VIII, 8~pS~
~50 parts ~y weiqh~ O~O~ 5.0
The composition ~f th~s example ~s prepared by combinins the
ingredients with mixing, geing an~ filterin~.
~ ach of the ~ody ~il preparations prepared with each of the
ingredients of the compos~tions of matter ~et f~rth ln Table VIII, .
supra, creates an effect which can be described ~s Wstress
reactivity-reducing~ in the user. In addition, a pleasant apple
~roma is i~p d tc ehe u5er in e~ch case.
'
~:276~
-66-
~X~MPLE XI
HOT OIL TRE~TMENT COMPOSITION (YOR HAIR)
~ hot ~11 treatment composlt~on for hair ~ prep~rgd a~
follow~:
,
__
~t!ao:l~L-LI~9~ ING~ED~EN~S
65.9 ~.. ~.~......... ....Ol.......... UCON Lubricant 50-HB-66011)
~Unio~ Carbi~e~
30.0 ......... ....... ,............... UCON ~ubricant 50~ 40~ )
: (Union Carb~de)
3.0 .... O........... ~ .............. LAN~ROL AWS IEmery(3)
.
: O.l .... ~.... ~......... O... O.O...... Propyl Paraben
l.Q .... ~ .O.... ..~............. Composition containinq
fragrance ~Au (50 parts ~y
weight) ~d one of ~tems
(i)-(viii~ of Table V~IX,
~upra ~5~ ~arts by weight1
:
~e comp~sitio~ of t~s example ~s prepared by ~imply adding
the in~redients in order while mixing.
i . .
; Each ~f the r2sulting hot oil treatment ~omposit~ons prepared
witb ea~h of the ln~red~ents ~f the c~mp~ itio~s of ~attes set
or~h in Table VII~,s~pra, c~eates an ~ffe~t ~hich can be descr~ as
~6tress react~vity-reducinga ~n the user. In addition~ a ple~sant
apple ~roma i~ imp~rted to the user.
Nc~tes:
1. UC~N $ubricant 50-HB-660 is ~polypropylene slycol~ 12-
bl~tyl ether manufactured ~y the t1nion Carbide
.~ Corporation of E~anbury, t:onnecti~ut 06817.
2. UCON Lubricarlt 50-HB-400 ~s (polypropylene glycol) 9-
t: utyl et~er manufactured by the Union ~arbide
; ~ Co~po~tion of Danbury, Connectict~t 06B17.
3. LAN~OL AWS ~s ~ water dlspersable alkoxylated
Lanolin Qil mas~ceted by Emery Industries o~
. ~ cirJcinnatt, Oh$o 4S202.
~' ,
, ~ ~
~:7~8~3
EX~P~E x I I
AEROSOL Ro~M SPR~Y COMPOSITION
~ . .. __
aerosol rc~om ~pr~y compos~t~n ~ re~ared ~ ollows:
NG~EDI~NTS ~I~rs ~ G~I~
~PAN 80~ O~ O~ O~ Q
Composit~on ~ntaining fragrance ~
50 parts ~y weight) and one of ~tems
viii~ of Table VIII, supra
(50 parts ~y weight3 ~ . 0.25
Dist~lled Water ~ D~ O~O~O~O~ 68D75
Pr~el~an~ A-~6~ o~ 3~.00
~, . . .
An aerosol room ~pray is prepared ~ follows-
1. adding the wa~er to an ~erosol container;
,
2. m~x~ng the compos~tior~ containing fragrance "A~ ~nd
~actives" and the SPAN 8Q;
3~ ~dding the ~ragrance/nactiv~s~/SPAN 80 composi~ion ~o
the container;
. crimping on ~n ~eros~l va~ve;
SO psessurizing th~ c~ntainer with Pr~pellant A-46; and
; 6. fittin~ ~n actuator ~o the valve~
When the resulti~g c~mposit~on is ~prayed from the ~erosol
CDntainer int~ ~ 20' x 20' x 10' nonmally ventilated room
i
,~
~L2~6~
--68--
,~
(~65F), ~ter four m~nute~ , the r~om t~as ~n ~e~h~$e~11y
pleasing ~pple ~roma an~, further, ~ n placed ~n ~aid room
who i~ s~jecte~ tt~ ~tres~ ct)n~it~n~ w~ll have ~ acignifican~
~tres- react~v~ty reduc~ n.
' :
~to~es:
PAN 1~0 1~ S~rbltan Ol~ate~ manufactur~ by
~CI ~mericas Tnc., o Wilmington, Delawar~ 19897,
2. PrQP~11ant A~q6 ~ mixtur~ 5 weight percent
~sob~ltane ~nd 15 weight percent propane.
. :~
, ~ .
~, . . '
.
~ .
~",'`',
'
'
:: :
~ .:
: ~a
38~
--69--
DESCRIPTION OF THE DRAWINGS
_, _
Fi~ure 1 is ~he GLC profi~e of the head-space above nutmeg
oil measured ac~ording to the procedure of Example I(B) (Condi-
tions~ 1 fused sili~a col~mn pro~rammed at 75-220C at
2C per minut~. The nutmeg oil is East Indian Nutmeg Oil.
F ~ is the GLC profile for bulked fractions 7-12 of
the second distillation of nutmeg oil East Indian according to
the procedure of Example I~A) (Conditions; 400' x 0.032"
carbowax/fused silica column programmed at 75-220C at 2C per
minute).
F ~ is a graph showing systolic blood pressure change
(mm/~gj v~ protocol p~riod fora o~osition of "actives" containing
nutmeg oil, mace extract~ neroli oil and valerian oil as well as
for a composition containing a fragrance denGted as fragrance "A~
as described, infra~ which does not contain any "actives n . The
actives" of our invention cause the reduct~on of physiological
and/or subjective reactivity to stress in a human. The means for
determininq the plot~ of data on the graph of Figure 3 is set
forth in Example III.
F gure 4 is a graph showing systolic blood pressure (mm/Hg)
vs.protocol period for a composition cont~ng both ~i) "actives"
~containing nutmeg oil, mace extract, neroli oil and valerian
oil) and, in addition, (ii) a composition de~ote~ herein as fraqranoe
~AI' ~as aescribed, infra~. The "actives" of oux invention cause
jthe reduction of physioloqical and/or subjective reactivity to
stress in a human. The means for determining the plo~ o data on
the graph of Figure 4 is set forth in Example IV.
Fiyure 5 is a cutaway side elevation view of apparatus used
in preparing perfume-containinq and stress reactivity-reducing substance-
containing polymers of oux invention.
Figure 6 is a cross sec~ional vi.ew taken along lines 6-6 of
_ .
.~ Figure 5~
;
'' '~
~27~
-70-
EXPI~ATION OF THE D~AWINGS
Fi~ure 1 is a GLC profile for the head-space above nutmeg
oil East Indian as determined according to the procedure of
Example I (B) (GLC Conditions: OV-l fused silica colwnn progra~Ted
at 75-220C at ;~C per minute),
The peak indicated by reference nwneral 10 is the peak for
~-thujene.
' The peak indicated by reference numeral il is the peak for
~-pinene.
The peak indicated by reference numeral 12 is the peak for
sabinene.
The peak indicated by reference numeral 13 is the peak for
~-pinene.
The peak indicated by reference numeral 14 is the peak for
myrcene.
The peak indicated by reference numeral 15 is the peak for
a-phellandrene.
The peak indicated by reference numeral 16 is the peak for
~-3-carene.
: ~
The peak indicated by re~erence numeral 17 is the peak for
~ ~-terpinene.
; ' The peak indicated by reference numeral 18 is the peak for
'I p-cymene.
', The peak indicated by reference numeral 19 is the peak for
i~-terpinene.
~68~
-71-
The peak indicated by reference numer~l 20 i5 the peak fo~¦terpinolene.
, The peak ~ndicated by reference numeral 21 is the peak for
linalool~
The pea~ indic~ted by reference numerals 22A and 22B are the
peaks for l-hydroxy-l-methyl-4-isopropyl-2-cyclohexene.
~` The peak indicated by reference numeral 23 is the peak for
2-methyl-5-ethyl fuxan.
,
The peak indicated by reference numeral 24 is the peak for
4-terpineol.
~ he peak i~dicated by referenoe numeral 25 is the peak for
~-terpineol.
:::
The peak indica~ed ~y reference numeral 26 is the peak for
l-methyl~3-hydroxy-4-isopropenyl benzene.
': ~ 1.
The peak indicated by reference numeral 27 is the peak for
¦isobornyl acetate.
The peak indicated by reference numeral 28 is the peak for
n-amyl methoxy benzenes.
I The peak indicated by reference numeral 29 is ~he peak for
¦'eugenol.
!,
I ~he peak indicated by reference numeral 30 is the peak for
terpinyl acetate.
The peak indicated by reference numeral 31 is the peak for
cubebene.
The peak indicated by reference numeral 32 is the peak for
eugenyl methyl ether.
~ ! ~
~ 7E;~
The pea~ indicated by reference numeral 33 is the peak for
copene.
The pea~ indicated by reference numeral 34 is the peak for
trans-isoeugenol.
The peak indicated by reference numeral 35 is the peak fvr
~-bergamotene.
The peak indicated by reference numeral 36 is the peak for
4-propenyl-1,2-dimethoxy benzene.
:: The peak inclicated by reference numeral 37 is the peak for
;~ myristicin.
::d I The peak indicated by reference numeral 38 is the peak forl ¦~-cadinene.
!
¦ The peak indicated by reference numeral 39 is the peak for
elemicine.
~: The peak indicated by reference numeral 40 is the peak for
: 4-allyl-2,6-dLmethoxy phenol.
Figure 3 sets forth the effect on ~lood pressure changes
(of a human subject to stre~ cond~tions) of:
(i~ a composition of "actives" as set forth in Example Il
` according to the protocol of Example III; and
~ii) a fragrance composition entitled fragrance "A"
specifically described according to Example II
~; with the changes in blood pressure being in units of mm/Hg.
;1 The graph indicated by reference numeral 71 is the graph of
systolic blood pressure (mm/Hg) versus protocol period (e.g.,
BLl, LS1, MSl, F, LS2, MS2 and BL2) defined in Example II
for fragrance "A-; that is,the fragrance that cloes not contain
.~. l I
~z776~38~3
~actives~, e.g., nutmeg oil, mace extract, neroli oil and
valerian oil. The protocol periods are as foll~ws:
3Ll - baseline in ~Stress I";
LSl - 6 low stress questions in "Stress l";
MSl - 6 mild stress q~estions in "Stress I~;
F - two blood pressure points during applic~tion of
fragrance "A" between "Stress 1" and "Stress II";
LS2 - 6 low stre s questions in "Stress II n;
MS2 - 6 mild stress questions in "Stress II";
BL2 - baseline at end of "Stress II~.
The graph indicated by reference numeral 72 is the graph
; of systolic blood pressure ~mm/Hg) versus pxotocol period when
using the "actives" mixture, that is,the mixture of nutmeg oil,
mace extract, neroli oil and valerian oil "actives compositionU
of Example II using the protocol of Example III. The meaning
of each protocol period is as follows:
BLl - initial baseline for "Stress I n;
LSl - 6 low stress questions for "Stress I";
MSl - 6 mild stress questions for "Stress I"
F - two blood pressure points during a~plication of
: stress reactivity-reduction composition (nactives")
~ after "Stress I n;
~LZ768s8
-74-
LS2 ~ low stre~ questions for ~tress II~;
MS2 - 6 mild stress questions for nStress XI~:
:
BL2 - end ~aseline for "Stress II~.
,
Figure 4 sets forth the ef~ect on blood pressure (of a human
subject to stress conditions) of a composition of ~actives" tas
~r ~: set forth in Example II3 according to the ~rotocol of Example III
~` and in combination with a fragrance composition denoted as
~ragrance ~A", ~;th the blood pressure being in units of mm/Hg and
with the measurements ~eing made accQrding to the procedure of
Example IV.
The graph indicated by reference numeral 81 is the graph
;! '~ of systolic blood pressure (mm~Hg) vs.protocol period (e.g., BLl,
~: LSl, MSl, F, LS2, MS2 and BL2~ defined in Example IV for the
~ combination: fragrance "A" and "activesn, e.gc, nu~ oil, mace
extract, neroli oil and valerian oil. The protocol periods are
as follows:
~ '
baseline in "Stress I";
. ~ LSl - 6 low stress questions in ~Stress I";
,~ . :
MSl - 6 mild stress questions in "Stress I a;
F two blood pressure points during application
of the combination: fragrance "A" and "actives"
. between "Stress I" and "Stress IIn;
.`,~ `~,'i
:; LS2 - 6 low stress questions in ~Stress II";
~ ~,
~ MS2 - 6 mild stress questions in "Stress II";
.,i~ .:
~ ~; BL2 - baseline at end of "Stress II n .
~'
`: ~
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~ ~6~8
-75-
~ I~L~ nd 6 lllustrates 8 Dreferred m~thod for pr~oarinq
composition8 for th~ pra~ice of our lnvention~ A thermo~la~tic
polymer, e.g., polyethyle~e, is h~ated to about 220-250~ in
a conta~ner 212 of the kind illustrated in Figures 5 and 6.. A
formulation containing fragran~e a5 well as stxess reactivity-
reduction "active(s)~ (which includ~s o~e or a combination Oe the
: following:
Nutmeg oil;
Macc extra~t,
Neroli oil:
~ Valerian oil;
-.~ Myristicin;
Elemi~in; and/or
Isoelemicin)
' ~ .
is then quickly added to the li~uified thermoplastic polymer.
The lid 228 i~ DUt in place and the asitatins means 273 is
actuated. The temperature is main~ained at about 225F and the
mixing is continued for about 5-15 minutes. The valve "V" is
then opened to allow flow of the molten thermoplastic polymer
enriched with fragrance and ~active" substance containing one
or a combination of:
Nutmeg oil;
Neroli oil;
~ Valerian oil;
:; Mace extract:
Myristicin;
Elemicin; and/or
~:. Isoelemicin
to exit through the orifices 234. The li~uid falling through the
orifices 234 solidifies almost instantaneously upon impact with
moving cooled conveyor 238. The thermoplastic polymer beads or
pellets 224 having pronounced physiological and/or subjective
reactivity reduction (to stress) effects are thus formed.
. ~D
~2768~
7 6-
h~ conveyor 238 is moved using conveyor rollers 240 a~d 2~12.
The vessel 212 is heated using heating coil~ 212A powered using
power input supplies indicated by reference n~nerals 214, 216,
224, 222, 220 and 226. The solidified beads containing
stress reacti~vi~y reduction ~ are indicated by
244 traveling into container 245 where they are used for subse-
quent processing. The conYeyor i~ cooled usin~ a ~oc31ing device
indicated by reference numera}s 248, 256, 250 zl~nd 25~4.
. ~
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