U.S. patent number RE31,836 [Application Number 06/581,671] was granted by the patent office on 1985-02-19 for pharmaceutical and dietary composition.
This patent grant is currently assigned to Efamol Limited. Invention is credited to David F. Horrobin.
United States Patent |
RE31,836 |
Horrobin |
February 19, 1985 |
Pharmaceutical and dietary composition
Abstract
Composition and use of .gamma.-linolenic acid and related
materails with ascorbic acid, or ethyl alcohol, or an opiate
antagonist such as naloxone, nalorphine or levallorphan, for
treating alcoholism or moderating the effects of taking
alcohol.
Inventors: |
Horrobin; David F. (Montreal,
CA) |
Assignee: |
Efamol Limited (London,
GB2)
|
Family
ID: |
26271578 |
Appl.
No.: |
06/581,671 |
Filed: |
February 16, 1984 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
159402 |
May 15, 1980 |
04388324 |
Jan 14, 1983 |
|
|
Current U.S.
Class: |
514/474; 514/549;
514/560 |
Current CPC
Class: |
A61K
31/20 (20130101); A61K 31/23 (20130101); A61K
31/375 (20130101); A61K 45/06 (20130101); A61K
31/485 (20130101); A61K 33/30 (20130101); A61K
31/43 (20130101) |
Current International
Class: |
A61K
33/30 (20060101); A61K 45/00 (20060101); A61K
45/06 (20060101); A61K 31/20 (20060101); A61K
31/23 (20060101); A61K 31/375 (20060101); A61K
31/429 (20060101); A61K 31/185 (20060101); A61K
31/21 (20060101); A61K 31/43 (20060101); A61K
31/485 (20060101); A01N 037/02 (); A01N 037/00 ();
A61K 037/00 (); A01N 059/26 (); A01N 059/20 () |
Field of
Search: |
;424/177,128,140,312,318 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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3407 |
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Jun 1979 |
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EP |
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2352797 |
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Apr 1975 |
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DE |
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2749492 |
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May 1978 |
|
DE |
|
1082624 |
|
0000 |
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FR |
|
1240513 |
|
Jul 1971 |
|
FR |
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1159615 |
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Jul 1969 |
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GB |
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1356370 |
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Jun 1974 |
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GB |
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1493993 |
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Dec 1977 |
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GB |
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Other References
The American Journal of Clinical Nutrition 34, (1981)
252-257..
|
Primary Examiner: Phillips; Delbert R.
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
I claim:
1. A pharmaceutical composition .Iadd.in capsule or tablet or
suppository form .Iaddend.for treating alcoholism or moderating the
effect of taking alcohol consisting essentially of
.gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid,
optionally in association with linoleic acid or other fat acids,
said acids being present as such or as physiologically functional
ester or other derivative thereof, in combination with ascorbic
acid.
2. A pharmaceutical composition .Iadd.in capsule or tablet or
suppository form .Iaddend.comprising ascorbic acid in combination
with .gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid,
optionally in association with linoleic or other fat acids, said
acids being present as such or as physiologically functional ester
or other derivative thereof, the amount of said .gamma.-linolenic
or dihomo-.gamma.-linolenic acid or derivative thereof being 50 mg
to 10 g (calculated as .gamma.-linolenic acid) and the amount of
ascorbic acid being 50 mg to 50 g, or one half one third or one
quarter of said amounts.
3. A composition as claimed in claim 2 comprising from 0.1 to 1 g
of said .gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid
or derivative thereof.
4. A composition as claimed in claim 1, 2 or 3 comprising 250 mg to
5 of absorbic acid.
5. A method of treating alcoholism or moderating the effects of
taking alcohol which comprises administering an effective amount of
.gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid,
optionally in association with linoleic or other fat acids, said
acids being present as such or as physiologically functional ester
or other derivative thereon, the daily amount of said acid or
derivative being from 50 mg to 10 g.
6. A method of treating alcoholism or moderating the effects of
taking alcohol which comprises administering an effective amount
of:
(a) .gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid,
optionally in association with linoleic or other fat acids, said
acids being present as such or as physiologically functional ester
or other derivative thereof, and
(b) ascorbic acid, the daily amount of ascorbic acid being from 50
mg to 50 g.
7. A method as claimed in claim 6 when the daily amount of said
acid or derivative is 50 mg to 10 g.
8. A method as claimed in claim 5 or 6 wherein the daily amount of
said acid or derivative is 0.1 to 1 g.
9. A method as claimed in claim 6 wherein the daily amount of
ascorbic acid is 250 m to 5 g.
Description
FIELD OF THE INVENTION
This invention relates to the treatment of certain diseases and
disorders primarily, but not exclusively, in the field of human
medicine and to compositions for use therein.
GENERAL BACKGROUND
Considerable interest has been shown in recent years in the use of
prostaglandin (PG) precursors in medicine.
For various reasons it is not practical to administer
naturally-occurring prostaglandins such as PGE 1 and PGE 2 to
patients. Consequently, considerable attention has focussed on the
use of prostaglandin precursors including linoleic acid,
.gamma.-linolenic acid (GLA) and dihomo-.gamma.-linolenic acid
(DGLA).
Conversion of these materials in the body is believed to be as
shown in the FIGURE.
The broad outline of this pathway is well known, and it brings out
clearly that a major function of essential fatty acids (EFAs) is to
act as precursors for prostaglandins, 1 series PGs being formed
from dihomo-.gamma.-linolenic acid (DGLA) and 2 series PGs from
arachidonic acid (AA). DLGA and AA are present in food in only
small quantities, and the major EFA in food is linoleic acid which
is first converted to .gamma.-linolenic acid (GLA) and then to DGLA
and AA. The conversion of linoleic acid to GLA is blocked by a high
fat and high carbohydrate diet, by ageing and for example by
diabetes. Stores of AA in the body in the form of lipid esters are
very large indeed. In contrast only small amounts of DGLA ester are
present.
INVENTION AND BACKGROUND
DGLA is the key substance. GLA is almost completely and very
rapidly converted in the body to DGLA and so for practical purposes
the oral administration of DGLA and GLA amounts to the same thing.
DGLA can be converted to a storage form, changed to arachidonic
acid and thence to PGs of the 2 series, or converted to PGs of the
1 series.
There is increasing evidence that PGs of the 1 series play a vital
role in a number of key areas. First, PGE 1 activates T
lymphocytes. Defective T lymphocytes are believed to be involved in
causing a wide range of allergic and inflammatory disorders and in
making individuals susceptible to cancer and infections of all
types. Second, PGE 1 is important in preventing over-production of
collagen and fibrous tissue, a factor which plays a major role in
arthritis and the so-called collagen diseases. Third, PGE 1 levels
are extremely low in patients with schizophrenia and are moderately
low in patients with depression. Fourth, PGE 1 appears to be
important in controlling cholesterol levels and necessary for the
normal actions of insulin. Fifth, PGE 1 dilates blood vessels and
may be expected to be helpful in any situation in which vessel
spasm occurs. Sixth, PGE 1 appears to inhibit the production of
2-series PG's, levels of which are raised in a wide variety of
inflammatory disorders. Seventh, PGE 1 increases production of
cyclic AMP which has anti-inflammatory effects.
There are therefore very strong reasons, and this broadly is an aim
of the present invention, for influencing the 1-series/2-series PG
balance in the body in favour of 1-series PG's and specifically for
selectively enhancing formation of PGs of the 1-series and
particularly PGE 1. The diseases and disorders below are among
those in which such action is indicated:
1. Situations in which defective T lymphocyte function has been
described such as allergic and inflammatory disorders, multiple
sclerosis, and schizophrenia.
2.
Situations in which regulation of collagen formation and breakdown
is defective including rheumatoid arthritis, systemic lupus
erythematosus, Crohn's disease and the various "collagen"
diseases.
3. Mental illnesses in which low PGE 1 levels have been reported,
including depression and schizophrenia. In depression, platelet PGE
1 production is moderately reduced whereas in schizophrenia it is
severely reduced.
4. Disorders of lipid and carbohydrate metabolism in particular
diabetes mellitus and situations in which blood cholesterol levels
are elevated.
5. Disorders in which there is a tendency of blood vessels to go
into spasm such as angina pectoris, myocardial infarction and
Reynaud's syndrome.
6. Disorders of inflammation in which there may be excessive
production of 2-series PGs from arachidonic acid, often coupled
with low levels of cyclic AMP.
Selective enhancement of 1-series PG production has been explored
in human platelets. The method is given in detail later herein but
briefly human platelets are incubated with radioactive DGLA or
arachidonic acid. The PGs produced during incubation are extracted
by conventional means and separated by thin layer chromatography,
and the amount of radioactivity appearing in each PG or related
substance is counted. PGE 1, PGF 1.alpha. and thromboxane B1 from
DGLA, and PGE 2, PGF 2.alpha. and thromboxane B2 from AA are
estimated. The results, as given herein, demonstrate the inventor's
belief that the effects of various agents on AA and DGLA conversion
can be quite different and that it is possible to selectively
enhance formation of PGE 1 and other 1-series PG compounds. The
effect is believed to be by influencing the conversion of DGLA to
the 1-series PGs.
The balance between 1-series and 2-series PGs is, the inventor
believes, significant in terms of overall control of the conversion
pathways given earlier. Such control is not understood in detail
but without restriction to the theory it appears first that PGE 2
is able to enhance the formation of 1-series PG's, and second that
PGE 1 is able to block arachidonic acid mobilisation from tissue
stores. Thus the conditions for a negative feedback control loop
exist; overproduction of PGE 2 from AA will activate PGE 1
synthesis, the PGE 1 will inhibit AA mobilisation, and production
of 2-series PG's will drop. Further, TXA 2, an unstable product of
the 2-series endoperoxides arising in 2-series PG production, also
appears to enhance 1-series PG and in particular PGE 1 production.
Thus again the activity of the 2-series PG synthesis pathway gives
rise indirectly to a material that controls that pathway.
EFFECTIVE AGENTS
The inventor has tested the following agents for their effect on PG
metabolism in the platelet system.
The agents, which can affect DGLA conversion at concentrations
which have no effect on AA conversion, are:
1. Vitamin C, which at concentrations from 10 .mu.g/ml to 1 mg/ml
causes a dose dependent rise in formation of PGE 1.
2. Ethyl alcohol, which at concentrations from 30 to 300 mg % also
causes a dose dependent rise in formation of PGE 1.
3. The opiate antagonist naloxone, which at 20 .mu.g/ml, reverses
an effect of 1-levorphanol at 100 .mu.g/ml in inhibiting conversion
of DGLA to PGE1. The d-isomer of levorphanol, which is devoid of
opiate activity, had no such effect. The reversal indicates that
activation of opiate receptors inhibits PGE1 formation and thus
that endogenous opioids, and opioids formed in the gut from partial
protein digestion, may inhibit PGE1 formation. This inhibition is
reversed by opiate antagonists such as naloxone, desirable in
situations where opiate excess is suspected such as schizophrenia,
coeliac disease and psoriasis. It should be noted that an opiate
action is by definition one activated by l- but not by
d-levorphanol and that an opiate antagonist is a material blocking
this l-levorphanol activation.
DETAILED DISCUSSION, VITAMIN C
In individuals who consume large amounts of vitamin C body stores
of DGLA could become seriously depleted leading to a deficiency of
PGE1 and DGLA.
The formation of endoperoxides in the conversion of AA and DGLA
involves oxygen and it has been postulated that agents like vitamin
C play a part in this so-called cyclo-oxygenase reaction. There are
reports in the literature of high concentrations of vitamin C both
enhancing and reducing PG formation, but in the inventor's belief
no one has considered that any agent may have a selective action on
the conversion of DGLA or of AA to endoperoxides and hence on to
the formation of PGs. The inventor has found that the effect of
vitamin C is in fact highly specific at physiological
concentrations (e.g. up to 2 mg/ml). At these concentrations
vitamin C has a substantial effect in enhancing formation of 1
series PGs, including PGE1, while having no significant effect on
formation of 2 series PGs. Thus the combination of vitamin C with
DGLA or GLA, an aspect of the invention, will specifically enhance
formation of 1 series PGs without affecting conversion of AA to 2
series PGs. There is strong evidence that activation of this
reaction is a major contributor to the physiological action of
vitamin C, so that anyone taking vitamin C should also be ensuring
that there are adequate levels of DGLA in the body.
ALCOHOL
The idea that ethyl alcohol may affect PG formation has several
times been considered but not with specific reference to 1 or 2
series PGs. The main experimental evidence to date has related to
conversion of AA and it has been demonstrated that extremely high
levels of ethanol can block the formation of thromboxane B2. The
relative effects of alcohol on AA and DGLA conversion have not been
considered. The inventor has found that starting at the threshold
20-30 mg %, alcohol has an effect on conversion of DGLA to 1 series
PGs, greatly enhancing their production. There is no significant
effect on conversion of AA to 2 series compounds until
concentrations of above 300 mg % are reached when the effect is an
inhibition of thromboxane B2 formation i.e. the opposite action to
the effect on the 1 series.
This effect of alcohol can account for a number of its effects,
particularly in relation to those on mood. It means that in those
who consume large amounts of alcohol there is a considerable danger
of depletion of DGLA stores and therefore of a failure of adequate
PGE1 production following a period of excess PGE1 formation. This
is a particular risk in alcoholics whose dietary intake of many
foods is likely to be defective. There is therefore a strong case
for ensuring that in those whose alcohol consumption is high, EFA
intake should be such that body levels of DGLA are maintained.
In summary, alcohol over the range of 30 to 300 mg % causes a
marked enhancement of up to 60% in the amount of 14C-DGLA converted
to PGE1. Up to 100 mg % alcohol has little effect on arachidonate
metabolism but at 300 mg % it tends to inhibit conversion of
arachidonate to PGs and particularly thromboxanes. The effects on
the 1 and 2 series PGs are therefore opposite. The threshold of the
effect is at about 20-30 mg % which is the concentration of alcohol
in human plasma at which signs of mild intoxication first appear.
300 mg % is a concentration which produces "blind drunkenness."
Alcoholic intoxication will therefore enhance formation of PGE1 and
deplete the limited body stores of DGLA. Post-intoxication
depression which is such a major factor in the development of
chronic alcoholism may well be related to a fall of PGE1 formation
due to depletion of DGLA stores. The withdrawal syndrome in chronic
alcoholics is often schizophrenia-like and may be caused by
extremely severe DGLA depletion. Further, there is evidence that
depletion of PGE1 formation is associated with increased production
of fibrous tissue, so that the development of liver cirrhosis in
some chronic alcoholics may be related to chronic depletion of
DGLA. Incidentally the stimulation of PGE1 formation by ethanol
explains the reported desirable effects of modest consumption of
alcohol (insufficient to deplet DGLA) such as prevention of heart
attacks and resistance to viral infections.
Thus DGLA and materials giving it in the body (the "oil", see
later) are of value in at least three ways.
1.
In mild to moderate consumers of alcohols, to help prevent
depletion of body stores of DGLA, post-intoxication depression and
other short and long term features such as elevated cholesterol
levels related to essential fatty acid deficiency.
2. In chronic alcoholics undergoing withdrawal, to replenish DGLA
stores and maintain PGE1 formation, thus preventing the worst
features of withdrawal.
3.
In chronic continuing consumers of alcohol, to partially or
completely avoid long term adverse effects such as cirrhosis of the
liver.
OPIATE ANTAGONISTS
Morphine and related opiate drugs have actions on many tissues of
the body. These actions are believed to be due to activation of a
specific "receptor" which is chemically complementary to the drugs.
The opiate receptor is identified in three main ways:
1. Morphine and drugs with a similar action activate it and produce
a biological effect.
2. l-levorphanol binds to and activates the opiate receptor whereas
its d-isomer does not. Effects which are produced by l-levorphanol
and not by d-levorphanol are considered to be due to activation of
the opiate receptor.
3. Certain compounds bind to the receptor but fail to activate it
or only activate it partially. These compounds prevent the opiates
activating the receptor and are therefore known as antagonists or,
if they can weakly activate the receptor, as partial
agonists/antagonists. The purest known antagonist is naloxone and
drug actions which are blocked by naloxone are considered to be due
to activation of opiate receptors.
Within the last five years it has become apparent that the opiate
receptors exist because there are a series of natural compounds
known as opioids, some of which are produced within the body and
some of which are produced in the gut as a result of partial
protein digestion. There is strong suggestive evidence that these
compounds are involved in schizophrenia and possibly in other
disorders such as coeliac disease and psoriasis.
Using human platelets the inventor has been able to demonstrate
that l-levorphanol but not d-levorphanol is able to block the
formation of 1 series PGs from DGLA without blocking the formation
of 2 series PGs from AA. The effect of l-levorphanol can be blocked
by naloxone. The natural opioid, .beta.-endorphin, has an effect
similar to levorphanol and this effect can also be reversed by
naloxone.
Platelets from schizophrenics are known to produce very small
amounts of PGE1 from DGLA: normal platelets treated with
l-levorphanol or .beta.-endorphin thus behave like schizophrenic
platelets. Thus:
1. Opiate drugs and opioids are able to block formation of PGE1.
These effects can be reversed by opiate antagonists such as
naloxone.
2. If one wants to ensure maximum formation of 1 series PGs from
DGLA, especially in situations in which there may be endogenous
opioids, DLGA should therefore be administered in conjunction with
opiate antagonists such as naloxone.
The studies suggest that in diseases where there is overactivity of
an opioid at some site, then opiate antagonists oppose this action
and enhance the conversion of DGLA to PGE1. Such overactivity may
be produced by excess amounts of a normal opioid, the presence of
an abnormal opioid, or abnormal tissue sensitivity to normal opioid
levels. It is of interest that a natural defect of conversion of
DGLA to PGE1 in schizophrenic platelets can be limited in normal
platelets by incubation with l-levorphanol.
Therefore, in conditions in which it is desirable to increase
formation of PGE1 by increasing intake of DGLA, GLA or their
precursors, the effect is enhanced by opiate antagonists in
situations where there is an excess of endogenous opioid activity.
Examples of such conditions include schizophrenia and coeliac
disease. Opiate antagonists known per se and used clinically
include nalorphine, levallorphan and naloxone but there is no
restriction to these for use in the present invention. Naloxone, as
a pure antagonists, is preferred.
MATERIALS AND METHODS
The detailed technique with platelets is given below by way of
example.
(1-.sup.14 C)arachidonic acid and (1-.sup.14 C)
dihomo-.gamma.-linolenic acid were used, diluted with hexane to
specific activities of about 5.mu.Ci/.mu.mol. One day expired (2
days old) human platelets were obtained and used within 48 hours of
expiration. One unit was centrifuged at 1000 g for 15 minutes and
the supernatent drawn off. The platelet pellet was resuspended in
Tris-NaCl-EDTA buffer, made up of 0.15 M NaCl, 0.15 M Tris HCl at
pH 7.4 and 0.077 M NaEDTA (90:8:2 v/v/v). The platelets were
recentrifuged, the supernatant removed and the pellet resuspended
in Krebs-Henseleit buffer (without calcium) at pH 7.4. The washed
platelets suspension contained about 1-2% red blood cells. All
glassware used in the preparation of the platelets was
siliconized.
Four equal sized 1 ml aliquots of the platelet suspension,
containing 10.sup.9 platelets/ml were incubated with e.g. 0.5
.mu.Ci .sup.14 C-DGLA for five minutes. At the beginning of the
incubation the material under test was added to the suspensions.
The reaction was stopped after five minutes by addition of 1/10
volume of 10% formic acid. The suspension was then extracted three
times with ethyl acetate and the fractions pooled and dried under
vacuum. The extract was then taken up with 5 ml chloroform/methanol
(2/1, v/v). Recovery of radioactive material in the extract was
checked by taking 50 .mu.l of the chloroform/methanol and counting
by liquid scintillation. Recovery was in the range 80-95% in most
experiments.
The chloroform/methanol extract was then reduced in volume to 1 ml
under dry prepurified nitrogen. Thin layer chromatography was
carried out on 500 .mu.g precoated, prescored silica gel G
Uniplates (Analtech). Plates were activated by heating to
100.degree. C. for 1 hour immediately prior to use. The solvent
system was chloroform:methanol:acetic acid:water (90:8:1:0:8).
Reference compounds (PGsE1 and F1.alpha. and thromboxane B1) were
run at the same time and visualized by phosphomolybdic acid spray
followed by brief heating. The bands on the plates corresponding to
the reference PGE1, PFG1.alpha. and TXB1 were scraped off and
eluted with 20 ml acetone. Each elution was then evaporated to
dryness and counted by liquid scintillation (Beckman 100 LS
counter).
Using the same batch of platelets at the same time exactly similar
experiments were carried out with .sup.14 C-AA and PGE2,
PGE2.alpha. and TXB2 as reference compounds. Three experiments were
performed with DGLA and three with AA.
RELATIONSHIP TO PREVIOUS PROPOSALS
The above approaches may be used in combination with other
materials as disclosed in the earlier patent applications of the
inventor namely European Nos. 79300079.5 and 79300546.3
(Publication Nos. 0 003 407 and 0 004 770; U.S. Ser. Nos. 004 924
and 029 058).
Among these materials are a number believed to act by enhancing
mobilisation of DGLA reserves, including zinc, penicillin and
.beta.-lactam antibiotics generally, and also penicillamine,
phenformin and levamisole when the other effects of these materials
are acceptable.
Further, since there is evidence that thromboxane A2 may indirectly
enhance formation of PGE 1, substances such as colchicine,
amantadine and melatonin, and also griseofulvin, vinblastine,
vincristine and interferon as discussed in the pending patent
applications and believed to act through increasing the production
or effect of thromboxane A2, can also be used in conjunction with
the materials of the present invention.
As appears from the earlier patent applications, in searching for
ways to regulate PGE1 formation the inventor has previously
concentrated on the conversion of DGLA stores to free DGLA since
this is believed to be a key rate-limiting step and since it has
also been believed that factors which regulate conversion of free
arachidonate to PGs will also regulate conversion of free DGLA to
PGs. The present work has been more on the conversion of DGLA and
of AA to the respective PGs, and as noted above it has been found
that the factors regulating the two PG pathways are in some
respects quite different. The discoveries on which the present
application is based however build on and add to the earlier
inventions rather than superseding them.
THE PRESENT INVENTION
In the light of the general discussion above the present invention
in its various aspects may be summarised as:
A. A method of treating alcoholism or moderating the effects of
taking alcohol which comprises administering an effective amount of
.gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid,
optionally in association with linoleic and if desired other fat
acids, said acids being used if desired as physiologically
functional derivatives thereof.
B. A pharmaceutical composition specifically therefor, comprising
.gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid, as
above, alone or in an acceptable pharmaceutical vehicle.
C. A method of moderating the effects of taking alcohol or of
treating alcoholism which comprises administering an effective
amount of .gamma.-linolenic acid or other material as above, in
conjunction with (a) an effective amount of a material enhancing
physiological conversion of DGLA to 1 series PGs, and in particular
PGE1, without at the same time substantially enhancing synthesis of
2 series PGs, or specifically, (b) an effective amount of one or
more materials selected from ascorbic acid, ethyl alcohol, and
opiate antagonists.
D. A pharmaceutical composition per se, comprising
.gamma.-linolenic acid or other material as above in conjunction
with said material (a) or (b), alone or in an acceptable
pharmaceutical vehicle.
E. A method as C, comprising further administering an effective
amount of (c) a material enhancing physiological synthesis of 1
series PGs, and in particular PGE1, by mobilisation of DGLA
reserves, or of (d), specifically, zinc, a .beta.-lactam antibiotic
as described herein, penicillamine, lavamisole or phenformin.
F. A pharmaceutical composition per se, as D, further comprising
said material (c) or (d), alone or in an acceptable pharmaceutical
vehicle.
G. A method as C comprising further administering an effective
amount of (e) a material enhancing production or effect of
thromboxane A2, or of (F) specifically, melatonin or colchicine or
amantadine.
H. A pharmaceutical composition per se as D, further comprising
said material (e) or (f), alone or in an acceptable pharmaceutical
vehicle.
DOSE RANGES
Dose ranges for ascorbic acid, opiate antagonists and alcohol in
humans are as follows:
Ascorbic acid
outer limits 50 mg to 50 g per day
desirable dose 250 mg to 5 g per day
Naloxone
outer limits 0.1 to 500 mg/day for example orally or parenterally
in four or six divided doses
desirable dose 10 mg to 200 mg/day
Nalorphine
outer limits 1 mg to 5 g/day for example in divided doses orally or
parenterally
desirable dose 10 mg to 2 g/day
Levallorphan
outer limits 0.2 mg to 1 g/day for example in divided doses given
orally or parenterally
Alcohol
outer limits 5 to 500 ml/day
desirable dose 50 to 200 ml/day
Dose ranges for materials auxiliary to those of the invention are
discussed elsewhere herein. All the materials may be given in doses
of for example one half, one third or one quarter of the above
amounts. The amounts are related to those quoted earlier for
platelet and other experiments, though of course a precise relation
cannot be given in view of variation in inactivation and excretion
rates and volume of distribution.
PACKS
If it is not desired to have compositions comprising the active
materials together, as listed above, packs may be prepared
comprising the materials presented for separate or part joint and
part separate administration in the appropriate relative amounts,
and such packs are within the purview of the invention.
DIETARY COMPOSITIONS
The invention is chiefly described in terms of pharmaceutical
compositions, but it will be understood that the .gamma.-linolenic
and other acids, being in the nature of dietary supplements, could
be incorporated in a dietary margarine or other foodstuffs; such
foodstuffs, possibly containing other active materials and
generally referred to in this description as dietary or
pharmaceutical compositions, are within the purview of the
invention and thus of the term pharmaceutical compositions, packs
or the like used in the claims.
VETERINARY APPLICATIONS
It will be understood that where a disorder of a kind calling for
treatment in animals arises, the invention while described
primarily in terms of human medicine and treatment is equally
applicable in the veterinary field.
AMOUNTS OF ACTIVE MATERIALS (ADJUNCTS TO PRESENT INVENTION)
Amounts of materials are:
______________________________________ Zinc 2.5 to 800 mg/day,
preferably 10-80 mg calculated as zinc .beta.-lactam antibiotics
0.5 to 10 g/day Penicillamine 50 mg to 10 g/day Phenformin 10 mg to
5 g/day Levamisole 10 mg to 2 g/day Colchicine 0.3 to 15 mg/day,
preferably 0.6 to 2.4 mg Melatonin 10 mg to 5 g/day Amantadine 100
mg to 1000 mg/day Griseofulvin 0.5 to 5 g/day Vinblastine 0.5 to 5
mg/kg/week (average weight 70 kg) Vincristine 0.1 to 1.0 mg/kg/week
(average weight 70 kg) Interferon (by injection) 1 .times. 10.sup.5
to 1 .times. 10.sup.8 ______________________________________
units/day
Detailed discussion of suitable amounts and forms of use is
contained in the published patent applications referred to earlier,
to which reference may be made. In particular the .beta.-lactam
antibiotics are conveniently any of the known penicillin and
cephalosporin antibiotics (including semi-synthetic antibiotics)
such as, for example, penicillin G, penicillin N, penicillin V,
cephalexin, cephalothin, ampicillin, amoxycillin, cloxacillin and
cephaloglycin. Any of these materials may be used in the form of
their physiologically functional non-toxic derivatives, for example
alkali metal salts e.g. sodium and potassium salts, and salts with
organic bases, and reference to an antibiotic herein includes
reference to such derivatives.
AMOUNTS OF .gamma.-LINOLENIC AND OTHER ACIDS SPECIFICALLY
A preferred daily dosage for all purposes for an adult (weight ca
75 kg) is from 0.05 to 0.1 up to 1, 2, 5 or even 10 g as required
of .gamma.-linolenic acid or equivalent weight calculated as
.gamma.-linolenic acid or a physiologically functional derivative
thereof. Amounts in particular may be 0.1 to 1.0 g daily.
Corresponding doses of the Oenothera oil containing 8 to 10% of
.gamma.-linolenic acid, are easily calculated. In place of, or in
addition to, .gamma.-linolenic acid, one may use
dihomo-.gamma.-linolenic acid or a physiologically functional
derivative thereof, in amounts equivalent in molar terms to
.gamma.-linolenic acid and calculated as such. This dosage can for
example be taken as a single dose or divided into 2, 3 or 4
subdivisions thereof as convenient.
FORMS AND SOURCES OF .gamma.-LINOLENIC AND OTHER ACIDS
Convenient physiologically functional derivatives of
.gamma.-linolenic acid and dihomo-.gamma.-linolenic acid for use
according to the invention for all the purposes described include
the C.sub.1 -C.sub.4 alkyl (e.g. methyl)esters and the glycerides
of the acids.
If desired, pharmaceutical compositions may be produced for use in
the invention by associating natural or synthetic .gamma.-linolenic
acid (or a physiologically functional derivative thereof) and/or
dihomo-.gamma.-linolenic acid (or a physiologically functional
derivative thereof), as such, with an acceptable pharmaceutical
vehicle. It is at present convenient to incorporate the
.gamma.-linolenic acid into compositions in the form of an
available oil having a high .gamma.-linolenic acid content, hence
references to "oil" herein.
At the present time known natural sources of oils having a high
.gamma.-linolenic acid content are few (there are no known natural
sources of significant amounts of dihomo-.gamma.-linolenic acid).
One source of oils currently available is the seed of Evening
Primrose species such as Oenothera biennis L. and Oenothera
lamarckiana, the oil extract therefrom containing .gamma.-linolenic
acid (about 8%) and linoleic acid (about 72%) in the form of their
glycerides together with other glycerides (percentages based on
total fatty acids). Other sources of .gamma.-linolenic acid are
Borage species such as Borago officinalis which, though current
yield per acre is low, provide a richer source of .gamma.-linolenic
acid than Oenothera oil. Recent studies on fungi which can be
cultivated by fermentation promise a fungal oil source.
The seed oil extracts referred to above can be used as such or can
for example if desired be fractionated to yield an oily composition
containing the triglycerides of .gamma.-linolenic and linoleic as
the main fatty acid components, the .gamma.-linolenic acid content
being if desired a major proportion. Seed oil extracts appear to
have a stabilising effect upon any dihomo-.gamma.-linolenic acid or
physiologically functional derivative thereof.
PHARMACEUTICAL PRESENTATION
The compositions according to the invention are conveniently in a
form suitable for oral, rectal, parenteral or topical
administration in a suitable pharmaceutical vehicle, as discussed
in detail for example in Williams U.K. Pat. No. 1 082 624, to which
reference may be made, and in any case very well known generally
for any particular kind of preparation. Thus for example tablets,
capsules, ingestible liquid or powder preparations, creams and
lotions for topical application, or suppositories, can be prepared
as required. Injectable solutions of hydrolysed Oenothera oil may
be prepared using albumin to solubilise the free acid.
Advantageously a preservative is incorporated into the
preparations. .alpha.-Tocopherol in a concentration of about 0.1%
by weight has been found suitable for the purpose.
It will be understood that the absolute quantity of active
ingredients present in any dosage unit should not exceed that
appropriate to the rate and manner of administration to be employed
but on the other hand should also desirably be adequate to allow
the desired rate of administration to be achieved by a small number
of doses. The rate of administration will moreover depend on the
precise pharmacological action desired.
The following Examples serve to illustrate pharmaceutical
compositions useful in treatment according to the invention:
EXAMPLES
Pharmaceutical compositions contain a unit dose of an oil extract
from the seeds of Oenothera biennis L., and of one of the active
materials of the present invention, optionally with methyl
dihomo-.gamma.-linolenate and/or zinc oleate and/or penicillin V
and/or any of the other active materials referred to herein
directly or by cross reference to other patent applications of the
inventor. They may be presented by encapsulation of the natural oil
in soft gelatin capsules by known methods.
The oil is extracted from the seeds by one of the conventional
methods of extraction such as cold pressure, screw pressure after
partially cooking the seed, or solvent extraction.
Fractionation of a typical sample of this oil shows a yield of
97.0% oil in the form of methyl esters, with the relative
proportions:
______________________________________ Palmitate 6.15 Stearate 1.6
Oleate 10.15 Linoleate 72.6 .gamma.-Linolenate 8.9
______________________________________
As preservative, .alpha.-tocopherol is added to the oil in a
concentration of 0.1%.
Gelatin capsules containing oil extracts prepared as described
above, each having the following contents of active ingredients
(0.5 g oil extract=ca 0.045 g .gamma.-linolenic acid), are prepared
in conventional fashion.
The following are specific examples of capsules that may be given,
two capsules three times a day, in treatment of the conditions
listed earlier.
EXAMPLE 1
______________________________________ Oil extract 0.5 g Zinc
sulphate 10 mg ______________________________________
Two capsules may be administered thrice daily in the treatment of
alcoholism, giving a daily dose of .gamma.-linolenic acid of ca
0.27 g. Capsules without zinc are an alternative. Zinc oleate 20 mg
is an alternative to zinc sulphate.
EXAMPLES 2(a)-2(e)
Similarly to Example 1 the following may be administered:
______________________________________ (a) Oil extract 0.5 g Methyl
dihomo-.gamma.-linolenate 10 mg Zinc sulphate 20 mg (b) Oil extract
0.5 g Penicillin V 0.25 g
______________________________________
(Levamisole 25 mg, penicillamine 100 mg or phenformin 25 mg are
alternatives to penicillin here and in (c) and (d) below).
______________________________________ (c) Oil extract 0.5 g
Penicillin V 0.25 g Zinc sulphate 10 mg (d) Oil extract 0.5 g
Methyl dihomo-.gamma.-linolenate 10 mg Penicillin V 0.25 g Zinc
sulphate 10 mg (e) Oil extract 0.5 g Methyl
dihomo-.gamma.-linolenate 10 mg
______________________________________
EXAMPLE 3
The treatment of disorders with .gamma.-linolenic acid or
equivalent in combination with ethyl alcohol, as described earlier
may be carried out by giving the materials of Examples 1 and 2 as
there set out with the alcohol in any convenient form to give 30 to
300 mg % alcohol in the body.
EXAMPLES 4 to 10
The treatment of disorders with ascorbic acid or opiate
antagonists, as described earlier, may be carried out by giving the
following in the way set out in Example 1:
______________________________________ 4. Oil extract 0.5 g
Ascorbic acid 100 mg Zinc sulphate 10 mg 5. Oil extract 0.5 g
Ascorbic acid 100 mg Colchicine 0.2 mg Zinc sulphate 10 mg 6. Oil
extract 0.5 g Ascorbic acid 100 mg Colchicine 0.2 mg Penicillin V
250 mg 7. Oil extract 0.5 g Ascorbic acid 200 mg Naloxone 5 mg 8.
Oil extract 0.5 g Zinc sulphate 10 mg Naloxone 5 mg 9. Oil extract
0.5 g Zinc sulphate 10 mg Nalorphine 5 mg 10. Oil extract 0.5 g
Zinc sulphate 10 mg Levallorphan 5 mg Colchicine 0.2 mg
______________________________________
It will be understood throughout that while a full theoretical
discussion of what is believed to be the reason for the
effectiveness of the compositions proposed is given to aid
understanding, the invention is in no way to be limited by this
discussion
VALUE OF OIL+VITAMIN C
A not uncommon condition, particularly in the elderly, is the sicca
syndrome of lacrimal and salivary failure which, when coupled with
connective tissue disease and in particular rheumatoid arthritis,
is known as Sjogren's syndrome. The function of T lymphocytes is
also impaired. No treatment has been known to increase tear and
saliva flow, and lubricant drops and mouthwashes have to be
resorted to, often as frequently as several times an hour.
The inventor's belief is that impaired PGE1 production is at the
bottom of the difficulties and has found that in the NZB/W mouse,
the animal model for Sjogren's syndrome, .gamma.-linolenic acid, as
a precursor for PGE1, or PGE1 itself, can correct many of the
immunological abnormalities of the strain. Moreover in the platelet
system already referred to, the following changes in formation of
products of DGLA metabolism were found at physiological levels of
Vitamin C, there being no change in production of the corresponding
AA metabolism products.
______________________________________ Ascorbic level Product level
% 10 .mu.g/ml 33 .mu.g/ml 100 .mu.g/ml
______________________________________ TXB1 130 147 171 PGE1 134
144 184 PGF1.alpha. 107 123 150
______________________________________ Control = 100%; 10 .mu.g/ml
ascorbate = 5.7 .times. 10.sup.-5 M.
The inventor has therefore conducted a small-scale human trial.
The first patient was a 52 year old woman with a history of classic
moderate rheumatoid arthritis of three years' duration. She also
had a three-year history of dry mouth and dry eyes necessitating
use of lubricant eye drops. Associated with these disorders were
brittle, frequently cracking nails and hypersensitivity of the
hands to soaps and detergents. This patient had been on high dose
(7.5 g/day) vitamin C for a year. This had produced a subjective
sense of well-being and some slight improvement in the dry eyes and
mouth. 50 mg/day pyridoxine (desirable for normal EFA metabolism)
and 6.times.0.6 ml Evening Primrose oil capsules per day were added
to the regime. One month later eyes and mouth were normal, nail
quality had substantially improved and the patient could expose her
hands to soaps and detergents without adverse effects.
Four other patients with long-established Sjogren's syndrome have
been tried on this regime and in all four there has been
substantial improvement in tear and saliva production. One of these
four was a patient who had developed the syndrome while taking
practolol.
VALUE OF OIL+ETHANOL
The following results were obtained by the platelet techniques
given in detail earlier:
______________________________________ Alcohol (ethanol) 0 33 100
300 concentration mg/100 ml DGLA conversion 100 160 200 230 to
PGE1, PGF1 and TXB1 (total as % of control) AA conversion to 100
110 90 100 PGE2, PGF2 and TXB2 (total as % of control)
______________________________________
The variation in the FIGURES for AA conversion is not significant,
but that for DGLA conversion shows a dose-related and substantial
rise at these physiological ethanol concentrations, with the
significance for PG metabolism and treatment of the effects of
taking alcohol already discussed at length herein.
VALUE OF OIL+OPIATE ANTAGONISTS
In the platelet system l-levorphanol reduced formation of 1-series
PGs, an effect abolished by naloxone and not shown by
d-levorphanol. The concentrations concerned had no effect on
production of 2-series PGs from AA. Thus if the levels of
l-levorphanol used correspond to levels of natural opiates that are
undesirably high, in which natural 1-series PG production may be
expected to be suppressed, use of naloxone may be expected to
assist.
In the table below results are expressed as percentages of control
counts obtained without the drug and are the mean of three
determinations:
______________________________________ Amount of PGE1 TXB1
l-levorphanol (precursor DGLA)
______________________________________ 18 ng/ml 23% 20% 18 .mu.g/ml
72% 76% ______________________________________
It will be noted that an increased amount of l-levorphanol showed a
reduced suppression effect. Such FIGURES are frequently seen in PG
work, higher concentrations showing a reduced or even reverse
effect to lower concentrations.
* * * * *