CA2494743A1 - Flush niacin used as oral supplementation for treating withdrawal in a smoking cessation program - Google Patents

Abstract

The present invention addresses a vitamin and a method for the cessation of cigarette smoking. The physiological symptoms of nicotine withdrawal can range from distressing to severe, in nature.
Flush niacin (nicotinic acid) tablets are employed as an atypical NRT, in a suggested dosing regime.
This immediate-release form of vitamin PP provides a rapid benzodiazepine-like effect as it passes through the blood-brain barrier, to effectively quell the subject.

Description

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 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 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, 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 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 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.

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 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.

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.

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 2341855 Oct.,1999 Meconi,R. Germany A61 P 25/ 18 Siemund,V. A6IK 3I/465 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 2438551 Jan.,2002 Hayward,C.M. U.S.A A61K 31/00 Perry, D.A. A61P 9/10 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 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.

Claims (4)

1. A method of alleviating or reducing the symptoms of physical withdrawal and cravings associated with tobacco cigarette smoking, consisting of the oral administration of flush niacin.

2. The method in accordance with claim 1, wherein the flush niacin is orally administered in the forms including, but not limited to, tablet, pill, capsule, powder, solution, liquid, lozenge, or chewing gum.

3. The method in accordance with claim 2, wherein the flush niacin is administered in a total amount ranging from, but not limited to, approximately 50 mg to approximately 1000 mg per day.

4. The method in accordance with claim 3, wherein the flush niacin is administered in a regime comprised of, but not limited to, five to six doses per day, of 50 mg to 200 mg per dose.