Nicotine and Tobacco
Nicotine (C10H14N2) is a basic, colorless to pale yellow, hygroscopic, oily, volatile liquid that has an unpleasant pungent aroma and a sharp, burning, persistent taste. It is an alkaloid and in plants is found most abundantly in tobacco, constituting 0.3-5.0% of the tobacco plant by dry weight. It was first synthesized in the laboratory in 1893.
At nontoxic levels, nicotine has numerous psychoactive and physiologic effects that are perceived by users as beneficial. With respect to the central nervous system (CNS), nicotine increases dopamine, acetylcholine, norepinephrine and beta-endorphin levels creating a sense of enhanced pleasure, decreased anxiety, alert relaxation and enhanced memory. Nicotine is also an appetite suppressant, which is considered beneficial by many users. It is not surprising that nicotine is highly addictive. In fact, several studies have shown it to be more addictive than cocaine or heroin.
Smoking tobacco is by far the most common method of nicotine delivery. While nicotine itself can be toxic at high levels, there are adverse health issues associated with smoking caused by the other 4000+ products of combustion within tobacco smoke.
Products of tobacco combustion are divided into visible components, also known as “tar,” and non-visible components. Tar is a resinous mix of partially combusted particulate matter. Upon combustion of tobacco, nicotine is vaporized and attaches to tar particles, which are inhaled by the smoker. The tar transports the nicotine vapor into the deep lungs where it is quickly absorbed at the alveolar level into the pulmonary bloodstream. Tar accumulates in a smoker’s lung tissue over time and is the most destructive component within tobacco smoke. For example, tar contains polycyclic aromatic hydrocarbons (like benzopyrene), which are proven mutagens and carcinogens. The non-visible component of tobacco smoke also contains numerous harmful compounds such as acetone, lead, phenol, hydrogen cyanide, mercury, cadmium, and formaldehyde.
Negative Health Effects of Tobacco Exposure
Cigarette smoking is the most important source of preventable and premature morbidity worldwide. The adverse health care consequences of smoking tobacco are enormous and incontrovertible. According to the World Health Organization (WHO), tobacco is the second major cause of death in the world, currently accounting for one in ten deaths worldwide (5 million each year). Of the 650 million current smokers in the world today, half of these of will die from tobacco-related illness. Tobacco is the single largest preventable cause of disease and premature death. It is the primary risk factor in heart disease, stroke and chronic lung disease. In addition, it has been linked to numerous cancers, including lung, laryngeal, esophageal, mouth, bladder, cervical, pancreatic and kidney cancer. In China, for example, smoking will contribute to the death of one third of all young Chinese males (under 30 years old) currently alive. In the United States, the 1999 National Health Interview Survey estimated that 46.5 million adults smoke and that 440,000 die each year from smoking related causes. In men, smoking is estimated to decrease life expectancy by 13.2 years and in women by 14.5 years.
There are also tremendous health-related costs associated with smoking. In the United States, it is estimated that smoking-related direct medical costs total $115 billion/year, and another $82 billion/year is lost from decreased productivity. This totals $197 billion/year spent or lost dealing with smoking-related illnesses.
It is now also understood that cigarette smoke is not only harmful to the smoker, but also can affect the health of non-smokers when they passively inhale the smoke of other peoples’ cigarettes (environmental or secondhand smoke). In adults, secondhand smoke is a risk factor for numerous types of cancer (including lung and breast cancer), heart disease, lung disease and many others. Passive smoke exposure also increases the risk of disease in children and infants.
Nicotine Replacement Therapy and Smoking Cessation
There are several FDA approved nicotine replacement treatments (NRTs) available both over-the-counter and as a prescription for use in smoking cessation programs. These include:
- Nicotine Gum- Available over the counter. Available in 2mg and 4 mg dosages. Absorption occurs across the buccal mucosa.
- Nicotine Patches- Available over the counter and as a prescription. Available in 21mg, 14 mg and 7 mg/24 hours and 15 mg/16 hours. Absorption occurs transdermally.
- Nicotine Inhaler- Prescription only. Each cartridge delivers 4 mg of nicotine. Absorption occurs across the buccal and oropharyngeal mucosa.
- Nicotine Nasal Spray- Prescription only. One dose equals a .5 mg spray to each nostril (1 mg total per dose). Absorption occurs across the nasal mucosa.
-
Nicotine Polacrilex Lozenge- Available over the counter in 2 mg and 4 mg pieces. Absorption occurs across the buccal mucosa.
Other NRTs available in countries outside of the United States (not FDA approved) include sublingual tablets, nicotine water and nicotine lollipops.
None of these systems deliver significant amounts of nicotine to the alveolar level of the lungs. Instead, they rely on the absorption of nicotine across the skin or across the nasal, buccal, or oropharyngeal mucosa. Absorption is therefore much slower and less efficient than that typical of smoking. This leads to slower and much lower peak nicotine concentrations compared to those produced by cigarettes. Of the currently available NRTs listed above, the nicotine inhaler is purported to have delivery characteristics most like cigarettes. However, Lunell et al confirmed that absorption occurs primarily across the buccal mucosa (not the lungs), and that the arterial nicotine concentration spike, typical of cigarette smoking, does not occur with the inhaler.
The peak serum levels achieved with the currently available NRTs may be adequate to ameliorate or prevent withdrawal symptoms. However, they do little to satisfy the acute craving for the “buzz” created by the rapid onset, high peak serum nicotine levels typical of tobacco smoke. This may be the main reason why so few people that use NRT in attempts to quit smoking, have long-term success. They simply give in to these persistent cravings, which currently can only be satisfied through smoking.
Alternative Nicotine Delivery Systems
Even though the adverse health effects of smoking are well understood and publicized (especially in developed nations), smoking remains very prevalent. According to the WHO, 650 million people in the world smoke cigarettes. Fifteen billion cigarettes are sold daily (10 million every minute). Most of these smokers are located in East Asia and the Pacific regions. In China alone there are 300 million smokers, more than the entire population of the US. It is estimated that Chinese smokers consume 1.7 trillion cigarettes per year (or 3 million cigarettes per minute). In general, smoking prevalence is increasing in the developing world and falling in developed nations. However, even in the most “developed” nations, where public awareness of the adverse health effects of smoking are well known, a big portion of the population continues to smoke. For example, 20.9% of all adults in the United States (45.1 million people) smoke cigarettes.
Given the personal and public health problems caused by smoking, physicians and public health care organizations (including the CDC and WHO) agree that the best thing that smokers can do is to quit. However, even with the wide availability of NRTs and newer non-nicotine drugs (varenicline, bupropion, etc), long term success is seen only in 3-7% of the general population.
All the chronic adverse health effects caused by nicotine addiction currently come from the use of tobacco (most notably smoking) as a delivery device (not the nicotine itself). Thus, even though many smokers recognize the ill-effects of tobacco exposure and want to stop, their addiction to nicotine as delivered by the inhalation of tobacco smoke, prevents them from quitting since there are currently no true alternatives. It stands to reason that a safe, effective, long-term alternative nicotine delivery (AND) system capable of providing nicotine to the user in a way analogous to tobacco smoke would have great appeal to these individuals. In addition, as such a platform becomes more popular; it would have the potential of significantly reducing the aggregate impact of smoking-related diseases on a global scale.
Neurophysiologists suspect that one of the keys to nicotine addiction lies within the brain at the receptors where nicotine first takes effect. These nicotinic acetylcholine receptors are the focus of the Brain Imaging Division of the Department of Psychiatry at Yale University’s School of Medicine and the Center for Nicotine and Tobacco Use Research at Yale University. These researchers discovered that the radiotracer ligand, ( S )-5-[ 123 I]iodo-3-(2-azetidinylmethoxy) pyridine of A-85380, also known as [ 123 I]5-I-A-85380, could be safely used in humans and is currently the most reliable way to measure the nicotine in human brains.
Next Safety tobacco addiction expert, Matthew Bars, MS, CTTS, and the Yale University School of Medicine are currently engaged in the development of a research protocol to demonstrate the lung and brain uptake of nicotine from the Next Safety pulmonary drug delivery platform. The Company expects that this research will also demonstrate arterial blood nicotine levels and the pharmacotherapeutic effects of “clean” nicotine delivery via a pulmonary drug platform.
These findings will compare the pharmacodynamics of Next Safety’s pulmonary nicotine delivery and other older and established nicotine replacement medications. This study will also examine the difference between smoked cigarettes and the Next Safety pulmonary device.
“The pulmonary delivery of ‘clean’ nicotine to the human brain has the potential to eliminate tobacco cravings in a similar manner as smoking a cigarette. This would be the gold standard of tobacco addiction treatment.” said Bars. “I have taken the liberty of calling the Next Safety pulmonary nicotine delivery platform the ‘NEXT STEP’ because this next step in the treatment of tobacco addiction has the potential of saving hundreds of millions of lives worldwide,” Bars continued. Besides being a consultant to Next Safety and the pharmaceutical industry, Mr. Bars is also the Director of the Tobacco Cessation Program for the New York City Fire Department.
Smoking Cessation Market
Smoking cessation represents one of the largest opportunities for life science companies in terms of both public health impact and commercial potential. The growth of the smoking cessation market is expected to rise dramatically, driven by the increase in public awareness of the dangers of smoking, the development of pharmacotherapies for treatment of nicotine addiction and legislation. Political moves worldwide are leading to national bans of smoking in public places, with the long-term aim to reduce the cost to the health sector.
The total global smoking cessation market is estimated to have been $1.7 billion in 2007. According to “Smoking Cessation and Addiction Treatments: A World Market Analysis,” the global smoking cessation market is expected to exceed $2.3 billion by 2010, primarily because of Chantix (sold outside the U.S. as Champix). Matt Bars, Next Safety smoking cessation consultant, believes, however, that this is significantly underestimating the Next Safety pulmonary nicotine delivery market. Given the similarity in nicotine delivery between the traditional cigarette and the Next Safety platform, the anticipated pharmacokinetic profile and resultant subjective user feelings, a global harm reduction-marketing model in addition to a smoking cessation model would provide a more accurate estimate of Next Safety’s sales potential. Global cigarette sales in 2002 exceeded $340 billion; Next Safety should be able to secure a percentage of this market.
Recent clinical tests performed under an IRB at Carolinas Medical Center in Charlotte North Carolina with Next Safety’s pulmonary delivery device confirm a novel method for delivering inhaled nicotine. Previous research has established that cigarettes’ addictive qualities are in part due to the immediate systemic uptake of nicotine and delivery to the pleasure centers of the brain. The levels found in test subjects using Next Safety’s nicotine delivery device demonstrate rapid systemic nicotine delivery that is not obtainable by oral, nasal, or transdermal routes. The speed with which the nicotine is inhaled and enters the blood using the Next Safety device will help address the addictive qualities of nicotine that are unique to the inhaled route previously only available by cigarettes. The inability of previous nicotine replacement products to mimic the pharmacokinetics of a cigarette has limited their efficacy for smoking cessation.
