Note: Descriptions are shown in the official language in which they were submitted.
CA 02494743 2005-O1-28
SPECIFICATION:
This invention relates to the use of oral flush niacin, and a method for the
employment of this
vitamin, as part of a cigarette smoking cessation program, particularly in the
area of treating
physical withdrawal.
Background of Invention:
Although there have been morbidly realistic campaigns to increase awareness of
the dire
consequences of smoking-related cancers, the majority of the North American
public has been
unable to heed the warnings. Depictions of aneurysms or diseased hearts and
lungs, have not
dissuaded the die-hard smoker. Some smokers are able to terminate the habit,
but often not without
relapse. Substance addiction is frequently dismissed as being simply a matter
of lack of willpower.
However, the therapeutic industry generally neglects the persistent issue of
physiological withdrawal
from nicotine. Withdrawal includes cravings, which can suddenly overwhelm an
individual, months
or even years after cessation of the habit. Physical withdrawal should not be
underestimated. A
sufferer can experience an onslaught of symptoms of physical anxiety,
including tremor, dizziness,
nausea, sweating, or inability to mentally focus. The impact of these symptoms
imprints a negative
association on the memory, and obstructs the process of withdrawing
successfully from the clutches
of a substance.
A craving can act as a signal to an individual to ingest an element of which
the body is deficient.
However, the blind compulsivity of a craving can drive an addict to ignore the
detrimental aspects
of the substance with respect to personal health, as well as the health of
those surrounding this
seemingly helpless individual. Cravings can occur during and/or following the
conclusion of both
"taper-down" and "cold turkey" methods of smoking cessation, which primarily
employ traditional
NRTs. There is, to date, limited physiological support for the persistent
physical anxiety and virtual
mental paralysis of drug dependency. An addict's obsessive-compulsive disorder
surrounds a
substance and the behaviors related to maintaining the use of that substance.
It is the opinion of the
experimenter that an addiction should be treated in a similar manner as an OCD
is diagnosed and
medicated by the medical profession. The inventors of "Nicorette" gum have
indicated the use of a
nicotine receptor agonist in the treatment of obsessive-compulsive disorder.
(ref.pat.#2347855)
Addicts are often driven individuals, with type -"A" personalities. They tend
to over-work, often to
CA 02494743 2005-O1-28
2
the point of physical deterioration, and hence become vulnerable to developing
vitamin
deficiencies. Dr. James B. Kirkland, of the Canadian Cancer Society, studies
how niacin deficiency
in rats, can lead to the development of cancer. Additionally, he discovered
that cancer patients have
low levels of niacin.l (Kirkland et al) Recent studies have shown that "the
use of large
supplements of nicotinic acid is associated with a decrease in all-cause
mortality." 2 Flush niacin
(nicotinic acid) is chemically similar to nicotine. Both compounds produce
similar effects on the
vascular and nervous systems of the human body. Existing treatment options for
nicotine addiction
will be described in detail following a brief discussion about nicotine
replacement therapies.
Traditional NRTs, such as transdermal delivery systems, and nicotine chewing
gum, are
expensive, when used over an extended period of time. The patch and the gum
also pose a variety
of health concerns. Nicotine-based NRTs presently operate on the principle of
supplying an
addictive substance to the user, however minute this dosage may be. According
to the CPS 2000,
both NRTs have a fairly high side effect profile. The patch cannot be used
concurrently with
smoking; thereby eliminating the possibility of a less drastic scaling down of
smoked nicotine (i.e. a
"taper-down" method). The CPS also notes that transdermal delivery systems can
cause
tachycardia, vasoconstriction, hypertension, headache, insomnia, nicotine
intoxication, or
dependence. Dependence has also been reported with the nicotine gum, as well
as reports of sore
throat, and heartburn. In addition, children under the age of 18,
specifically, teens, are not advised
to use either the patch or the gum.3
Nicotine gum shares most of the same side effects as the patch, and is also
contraindicated for
users with any cardiovascular problems, peptic ulcers, and/or diabetes. The
Compendium also
states clearly that chronic consumption of nicotine is addictive and that
nicotine from any source can
be toxic. In light of these facts, it is the intention of the present
invention to propose a biologically
safe method for withdrawing from nicotine use.
One of the potently attractive features of a cigarette is the pleasant
physical stimulation, or in lay
terms, the 'body buzz" that a smoker derives from the habit. Traditional NRTs
do not effectively
simulate the "smokers' high". In spite of the partial supplementation of
nicotine which NRTs
provide, weight gain often becomes an additional issue upon termination of the
habit. With respect
to the patch, this method of nicotine delivery does not address a user who has
an oral fixation
combined with a nicotine addiction. One who has an oral fixation as a natural
part of their smoking
habit, would thus, remain unsatisfied. Oral fixation could be partially
gratified by subscribers to the
gum; however, cravings are still reported with this method. Since most addicts
are craving a
CA 02494743 2005-O1-28
dramatic sensation, it would be prudent to pursue a non-addictive remedy which
produces a
pleasurable effect, while maintaining a low side-effect profile.
Flush niacin is a legal, inexpensive alternative to traditional NRTs. In 2005
Canadian dollar
prices, a bottle of 90 (100mg) tablets, sells for under $6. It is as
accessible as other NRTs, being
available OTC at most health food stores. Vitamin PP has a low side-effect
profile, and can be
ingested in fairly high doses by most individuals. This is due to its water-
soluble composition,
which has a low risk of causing toxicity. Immediate-release niacin has many
therapeutic properties,
including treating atherosclerosis and cardiovascular disease (ref. pat
#2438551), specifically by
lowering VLDLs and LDLs, and elevating HDLs .3 Niacin has also been used for
decades to treat
various mental disorders, such as cognitive dysfunction (ref. pat.#2409720),
dementia, and in large
doses, schizophrenia.4 A similarity is implicated between niacin and nicotine,
(including nicotine
salts), as far as their common use as psychiatric remedies. (ref.
pat.#2341855)
Flush niacin is not physiologically addictive. However, its anxiety-quelling
effects provide
positive psychological reinforcement for repeated use. A related compound,
niacinamide, has been
documented to induce benzodiazepine-like effects in the body.5 (Prousky et al)
The present
invention employs the vasodilative ' flush " of niacin, in order to simulate
the soothing effects of
nicotine, contained in the form of a cigarette or an NRT. The obstacle of oral
fixation can be
partially resolved through the administration if niacin tablets by mouth, in a
more frequent dosing
schedule. Traditional NRTs are not legally accessible to teens. Since many
life-long addictions
begin in the vulnerable teenage years, it is crucial that a safe NRT will
become available to our
youth. Fortunately, children over 12 can be prescribed niacin by a physician,
if deemed appropriate.
Since niacin treatment is non-addictive, it can be used for months at a time.
The vitamin therapy
can then be stopped abruptly, for any reason, without the painful consequences
of withdrawal-
related symptoms.
Flush niacin is capable of arresting the craving for nicotine within minutes
of
ingestion.(ref.pat#2103399) The mechanism through which the cravings are
suppressed, is based on
a prostaglandin-mediated flushing. "Flushing" reactions are gentle surges of
blood flow to the head
and torso regions of the body. The physical sensation could be described as a
warm, tingling "body
buzz", which approximates a "smokers' buzz". Humans are only one of the
creatures of the animal
kingdom that require "surges" of blood flow for specific functions. Nicotiana
tabacum flowers are a
virtual magnet to hummingbirds, which avidly ingest the nectar. It is
postulated that since a
powerful vasodilator would be required to bring circulation to their rapidly
vibrating wings,
CA 02494743 2005-O1-28
4
nicotinic acid, (or a related compound), may be the stimulating chemical
involved. Ornithologists
are presently studying the metabolic. by-products of hummingbirds, with
observations that, in certain
circumstances, significant amounts of ammonia are excreted.6 (McWhorter et al)
An analysis of
both the hummingbird and human metabolites of nicotinic acid and nicotine, as
well as of both
species' diets, may provide further insight into nicotinic acid requirements
in humans.
For humans, smoking nicotine brings a similar vasodilative response, which
involves the release
of dopamine, and is generally perceived as pleasurable. (The term "generally"
excludes those
individuals who are clinically anxious, and notice an increase in anxiety from
nicotine ingestion.)
Flush niacin tablets may be brought with the patient to social situations,
which often trigger
cravings. Immediate administration of niacin can be of immense assistance in
the slippery slope
preceding nicotine-based relapse. It is advised that niacin be used strictly
on the advice of a health
professional.
Methodology
For the purposes of the present invention, the immediate-release form, or
flush form of
nicotinic acid is employed. The tablets should be ingested on an empty
stomach, in order to obtain
the most rapid and optimal relief. Non-flush forms of niacin, as well as
niacinamide (NAM), were
discontinued, as they were found to be ineffective in providing a vasodilative
effect. The following
table illustrates the "free nicotinic acid content" in three forms of niacin'
(Meyers et al)
flush niacin 520 mg
slow-release niacin 502.6 mg
non-flush niacin 0 mg
Based on the results of the experimenter, the degree of flushing was found to
be directly
proportionate to the content of nicotinic acid. The flush niacin brought a
vigorous prostaglandin-
mediated reaction in under five minutes. The sustained-release form was not
addressed in this
experiment, but is of future interest. Nicotinic acid content of OTC niacin
has not been federally
regulated in Canada or the United States. These formulations need to
standardized, in order to yield
reliable and repeatable experimental results.
This therapeutic application of flush niacin addresses both the realms of
physiological
withdrawal from nicotine, as well as the realm of cravings, which both surface
continually during
the process of smoking cessation. For those who are reluctant to abandon NRTs
in the forms of
CA 02494743 2005-O1-28
gums and patches, it is possible to combine a traditional NRT with immediate-
release niacin, upon
the surfacing of a craving. On a "per-craving" basis, (with or without a
traditional NRT), a
suggested dose ranges from approximately 50-200 mg flush niacin.
Utilizing flush niacin correctly in a "cold-turkey" approach can be
surprisingly powerful in
quickly subduing or arresting nicotine cravings and withdrawal. The present
invention proposes a
method that physiologically enables the smoker to immediately replace a
nicotine habit with a
supplementation regime of flush niacin. Finding the appropriate dosage should
be based on the
degree of niacin-induced flush reaction. Generally, the dosage range follows
the "per-craving"
range of 50-200mg, preferably of Swiss Brand Flush Niacin. The subject should
be assessed for a
"blushing" of the skin, as opposed to a burning or swelling of the skin. Doses
are most effective
taken 2-3 hours apart, 5-6 times daily. Dosage tolerance develops after one
month or more, and in
order to maintain the intensity of the flush, it is necessary to increase the
daily dosages,
(conservatively, in 50mg increments), until the original effect is achieved.
Tolerance, however, is
only one factor in dose modulation. Dosages require continual adjustments
according to pre-
existing medical conditions. Patients with schizophrenic disorders can have
subdued or even
negligible flushing reactions. (re~pat.#2256394) Concurrent treatment with
other anti-psychotics,
(such as quetiapine fumarate), can intensify the flush. At the proposed total
daily dosage range of
500-1000mg, toxicity is not an issue. Ranges of several grams are given in the
Compendium, and
the proper dosage range can be determined by the supervising physician. The
following tables
illustrate a recommended dosing schedule for the first month following
immediate termination of
nicotine consumption.
Example Niacin Regime in a "Cold Turkey" Method:_
Week One
_~~ E a.: ,
.,' E , ~,, g i " -.~ .~ s y ~~ , ;'.. ~ RCS c .. ~E
1 9 am 50
2 11 am 50
3 1 pm 50
4 3 pm 50
5 6 pm 50
6 9 pm 50
300 mg daily total
CA 02494743 2005-O1-28
6
Week Two
1 9 am 100
2 12 pm 100
3 3pm 100
4 6pm 100
9 pm 100
500 mg daily total
Week Four
1 9 am 200
2 12 pm 200
3 3 pm 200
4 6 pm 200
5 9 pm 200
1000 mg daily total
Note: Depending on the individual's sensitivity to flushing reactions, the
dosages for weeks three
and four may need to be increased more gradually. The patient should be
reassessed by a physician,
after the first month of therapy, regarding the continuation or modification
of a niacin
supplementation program.
CA 02494743 2005-O1-28
A "taper-down" method would include daily documentation of all sources of
nicotine, including
cigarettes and NRTs, as well as niacin consumption. An effective way for the
body to become
adjusted to this type of weaning regimen is to initially record, but not
reduce, the number of
cigarettes. The practice of charting the habit of smoking can induce a
consciousness of the
frequency and the volume consumed of the addictive substance. Charting
consists of journaling the
date, time, number of cigarettes (whole or partial), prescribed medications,
and any other substances
consumed. There is no standard formula for a taper-down, but the principle of
minimizing
cravings, is key. One should make reductions in smoking that are so subtle
that one is barely aware
of the missing nicotine. Information from a personal chart can be a definitive
tool in determining
the suitable doses of niacin to be administered once the patient has been
entirely weaned off the
nicotine. Longer taper-downs of two months or more, are often much more
effective than "steep" or
drastic reductions in smoking frequency and/or volume.
Current Limitations:
Flush niacin has relatively few contraindications; however, patients with
peptic ulcers, diabetes,
gout, or liver problems, should not engage in niacin therapy. Children under
the age of 12, or those
with a niacin allergy or hypersensitivity, should not use niacin. In healthy
individuals, dizziness and
nausea can occur if the individual doses are too high, and such side effects
become more likely with
daily doses in excess of 1 gram. If a. dose evokes a response similar to that
of a menopausal "hot
flash", or vertigo, the individual should assume a supine position, and wait
for the uncomfortable
reaction to pass. It should subside in 10 minutes or less. In order to avoid
these types of reactions,
it is advisable to increase doses in small increments of 50 mg at a time.
Although the prostaglandin-
induced reaction is generally considered "harmless"(see pat.#6048881), an
excess of prostaglandins
have been linked to inflammatory conditions such as arthritis, fever, nausea,
and vomiting.8
Individuals with allergies to the group of "nightshade" plants, of which
tobacco is a part,9
(Reilly,L), should obtain thorough medical advice prior to commencing niacin
and/or nicotine
therapy, especially regarding dosage.
Dosing regimes are quite frequent and could pose an inconvenience, (especially
if obvious
flushing became an issue in the workplace). Slow-release formulations of
niacin tablets could
perhaps alleviate dosing frequency; however their effectiveness was not
evaluated in this
experiment. Although sustained-release formulations may pose more convenience
in terms of
CA 02494743 2005-O1-28
8
minimizing dosing frequency to 1-2 times per day, certain brands have been
reported to be
hepatoxic.' The findings of Meyers et al reveal that flush and slow-release
tablets have a similar
content of nicotinic acid. However, from the experimenter's experience, a
quantity of at least SOmg
must be released into the bloodstream at once, in order to provide any
noticeable relief from
withdrawal. It is yet to be determined whether this type of tablet could be
formulated to release an
adequate amount of niacin at the correct times of day, to effectively quell
cravings.
This experiment is fairly embryonic, as it is a novel concept in the realm of
NRTs. Due to the
fact that niacin is considered a pharmaceutical, issues of patient health and
the experimenter's
liability became limiting factors. Bearing this in mind, the majority of the
data was obtained by
testing done on the experimenter, by the experimenter. However, despite its
modest beginnings, the
present invention is being submitted with the hope that its novelty,
effectiveness, and therapeutic
properties will lead to further clinical testing, product refinement, and
advancement in preventative
medicine.
Further Applications:
The present invention utilizes the similarity in bodily sensation between the
prostaglandin-
mediated flush of niacin, and the "body buzz" of nicotine. This similarity
raises the possibility that
a niacin-deficient individual may be instinctively self medicating, by seeking
out nicotine. More
specifically, niacin-deficient individuals may be more prone to cigarette
smoking. According to Dr.
Kirkland and team, ND (niacin-deficient) rats are more susceptible to
developing cancer. If one
extrapolates these findings into the realm of humans, there is a likely
correlation between niacin
deficiency in humans, and carcinogenic development. Hypothetically, if an ND
human, (already
predisposed to cancer), were to commence a smoking habit, there would be a
compounded risk of
developing cancer.
Ideally, it should become standard practice for physicians to measure niacin
levels in adults,
teens, and especially those individuals demonstrating a tendency toward, or
engaged in, an active
cigarette smoking addiction. If flush niacin were introduced to addicts who
are still in an early
stage of nicotine addiction, smoking-related mortality could be drastically
reduced. Advances in
preventative medicine may deal the tobacco industry an enormous financial
blow; however, the
returns lie in the more profitable prospect of raising human life
expectancies.
CA 02494743 2005-O1-28
9
DISCLOSURE:
The applicant, J.D. Globus, has made a disclosure to Pfizer U.S.A's "Drug
Pfinder" project,
dated Nov.25, 2004.
Extended Hypothesis:
The principal forms of niacin that exist in animal tissues are documented as
NADH and
NADPH.1° (Basu and Dickerson). Although both of these molecules are
considered to be high-
energy coenzymes of nicotinic acid, Champe and Harvey state that "the
electrons of NADPH are
destined for use in reductive biosynthesis." In the case of NADH, the
electrons are intended for
transfer to oxygen. It may be relevant to make a distinction between the two
coenzymes, based on a
comparison of their energizing potentials. NADPH is used for many "labour-
intensive" metabolic
processes, such as destroying free radicals and assisting immune function
through phagocytosis. It
is also used as an energy-rich source for the biosynthesis of steroids and
fatty acids.8 A correlation
may exist between the actions of NADPH, and the prostaglandin-induced-surge of
circulation
produced by flush niacin. The experimenter encourages a more refined
investigation into the
molecules) that may be responsible for the energizing properties of vitamin
PP.
CA 02494743 2005-O1-28
11
REFERENCES CITED
Patent Documents
2103399 Nov.,1993 Naito,A.T. U. S.A. A61 K47/26
2256394 May 1997 Glen, A.LM U.K. A61 K4900
A61 K31 /45
5
2341855 Oct.,1999 Meconi,R. Germany A61 P 25/ 18
Siemund,V. A6IK 3I/465
A61 K 9/70
2347855 Oct.,1999 Carlsson, A. Sweden A61K 31/44
Carlsson, M.
2409720 Nov.,2001 Coe.,J.W. et al. U.S.A. A61K 45/06
A61 P 25/28
2438551 Jan.,2002 Hayward,C.M. U.S.A A61K 31/00
Perry, D.A. A61P 9/10
C07C 275/28
6048881 Feb.,1999 Joseph,W.K. U.S.A A61K 031/44
Other References (Endnotes):
1. Kirkland, James B. et al. (Jan.2002), Article
8: Niacin deficiency decreases bone marrow poly
(ADP-Ribose) and the latency of ethylnitrosourea-induced
carcinogenesis in rats, In: Nutrition and
Cancer, v132, i1p.108(7)
2. The Journal of Nutrition, (2002)v.132, p.l 19
3. The Compendium of Pharmaceuticals and Specialties047, Pub: Bruce,
2000, pp.1043-1 L.D.
4. The Compendium of Pharmaceuticals and Specialties
1982, p.380
CA 02494743 2005-O1-28
12
5. Prousky, J. et al. (2004) Niacinamide's potent role in alleviating anxiety
with its
benzodiazepine-like properties: a case report, In: Journal of Orthomolecular
Medicine, (in press)
6. McWhorter, Todd J. et al, (Sept-Oct 2003), Are hummingbirds facutatively
ammonotelic?
Nitrogen excretion and requirements as a function of body size, In:
Physiological and Biochemical
Zoology, v76i5p.731(13)
7. Meyers, C. Daniel et al (Dec. 16. 2003). Varying cost and free nicotinic
acid content in over-
the-counter niacin preparations for dyslipidemia, In: Annals of Internal
Medicine, v139, i12,
p.996(7)
8. Champe, P.C., Harvey, R.A. ( 1.987), Uses of NADPH and regulation of enzyme
activity, In:
Biochemistry, 2"d edition, (multiple refs.p187,177 and 223,pp.113-115)
Lippencott
9. Reilly, Lee (Nov 1998), Attack of the Killer Tomatoes, In: Vegetarian
Times, n255, p.98(2)
10. Basu, T.K., Dickerson, J.W. (1996),Vitamins in Human Health and Disease,
p.39,
Wallingford Books.
