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Evaluation of Nicotine in Tobacco Free Nicotine Commercial Products: Nicotine Enantiomers in Tobacco Free Nicotine

Authors:
Garrett Hellinghausen at The University of Texas at Arlington
Garrett Hellinghausen
Jauh Tzuoh Lee at The University of Texas at Arlington
Jauh Tzuoh Lee
Choyce A Weatherly at The University of Texas at Arlington
Choyce A Weatherly
Diego A Lopez at Restek Corporation
Diego A Lopez
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Abstract

Recently, a variety of new tobacco free nicotine, TFN, products were commercialized as e-liquids. Tobacco derived nicotine contains predominantly (S)-(-)-nicotine, whereas TFN products may not. The TFN products are said to be cleaner, purer substances, devoid of toxic components that come from the tobacco extraction process. A variety of commercial tobacco and TFN products were analyzed to identify the presence and composition of each nicotine enantiomer. A rapid and effective enantiomeric separation of nicotine has been developed using a modified macrocyclic glycopeptide bonded to superficially porous particles. The enantiomeric assay can be completed in < 2 minutes with high resolution and accuracy using high performance liquid chromatography with electrospray ionization mass spectrometry. The results of this study suggest the need for pharmacological studies of (R)-(+)-nicotine, which is present in much greater quantities in commercial TFN products compared to commercial tobacco-derived products. Such studies are required by the FDA for new enantiomeric pharmacological products.
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    
 
 
  
  
  
   

              
                  
                  
                 
               
                  
                 
               
                  
 
                 
           


         
           
       
        

 
        
        
       


       
         


        
  

       
      

  
       
   

     
         
       
      


     
   

   
      


         
       
           


        
            
 

     
      
       


        
        
          
     


          
            
   

         
         
         
        
          
         
     

  
          
         
      
          
       
 

       
         

       
        
         
          
 
          
      
         
           
 


                    
  

       
 

        
           
 

          
    

     
       
     

   
         
 

       
        
          
  
         
       
    

    
        
    

   
           
 

      
        
          
          
      

 
        
        
       
       
   

     
      
        
    

   
       

         
      
    

 
         
      
        
         


       
          
       

 
       
          
        
         
           
         
          
          
          
           
          
          
       
         
        
      
      
        
       
        
      
         
      
        
         
        
  
 
         
        
         
        
        
           
       
       
          
            
          
          
        
        
        
        
    
   
 
      
    
    
 
     


            

 
       
         
          
         
         
         
         
        
      
      
         
        
        
       
         
          
        
        
         
      
            
         
          
         
        
     
   
        
         
      

  
  
      
      
  
 

  
         
         
 





 

       
       
       
       
           
          
        
           
         
           
         
        
        
          
              


 
  
 
        
        
         
        
        
      

      

       
       
       
       
       
         
       
         
               
                      
   
     
          
          
          
        
          
         
           
          
 
            
   


            

            
       
          
         
      
  
         

 
        
             
            
           
        

  
           
          
        


        
        
       
   

           
 
         
         
        
        
        

         
     
       
         


        
         
        
         
          
        
      
          
         
       
          
         
        
         
          
          
         
           
         
         
         
        
          
        
           
           
        
         
         
        

 
        
   
        
      
            
         
            
           
           
          
         
         
          
           
          
      

         
        
      
       
       
        
          
        
        
          
         
         
          
       
         
      
          

         
          
         
           
         
      

          
       
  
          
           
  
               
           
       
       
           
   
          
      
        
  
     


            

              
        
         
           
        
       
          
        
     
           
       
 
  
     
  
            
        
   
           
    
         
           
        
          
       
          
     
   
         
      
               
       
      
    
          
         
 
            
       
     
              
          
   
             
          
  
                
        
     
          
       
 
               
         
 
 
         
        
   


            

... 16−19 The uncertainty about TFN's pharmacological and toxicological effects in humans and the promotion by ECIG manufacturers of TFN as reduced-risk compared to TDN necessitates the development of several analytical methods to resolve/quantify nicotine enantiomers and/or discern the source of nicotine. 20 For this purpose, several methods were developed using polarimetry, liquid chromatography (LC), gas chromatography (GC), nuclear magnetic resonance (NMR) spectroscopy, and accelerated mass spectrometry (AMS). This systematic review describes the various analytical methods that were reported in the literature to separate and/or quantify nicotine enantiomers and provides an overview of isotopic enrichment methods used to determine nicotine source. ...
... Similarly, LC has been extensively employed for nicotine chiral separation. 1,[3][4][5]20,21,[26][27][28]30,35 In 1987, Armstrong et al. reported the use of a packed LC microcolumn with a mobile phase saturated with a chiral selector (β-cyclodextrin) to separate nicotine enantiomers. 27 The baseline separation is usually reflected by a resolution factor (R s ) which is a quantitative measurement of the degree of separation between two chromatography peaks. ...
... Nicotine enantiomers in tobacco leaves and different tobacco products were successfully resolved within 10 min. The same group reported a rapid and effective LC-MS method for determining the concentration of nicotine enantiomers in TFN products using an LC equipped with a triple quadrupole MS. 20 The stationary phase was made of a modified macrocyclic glycopeptide bonded to superficially porous particles. An isocratic elution was carried out using a mobile phase of methanol and ammonium trifluoroacetate and the results demonstrated a very short retention time (less than 2 min) with R s = 3.0. ...
A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources
Article
Full-text available
  • Mar 2023
  • CHEM RES TOXICOL
The introduction of synthetic nicotine by the tobacco industry, also promoted as tobacco-free nicotine, presented new challenges for analytical chemists working in tobacco regulatory science to develop and optimize new methods to assess new nicotine parameters, namely enantiomer ratio and source. We conducted a systematic literature review of the available analytical methods to detect the nicotine enantiomer ratio and the source of nicotine using PubMed and Web of Science databases. Methods to detect nicotine enantiomers included polarimetry, nuclear magnetic resonance, and gas and liquid chromatography. We also covered methods developed to detect the source of nicotine either indirectly via determining the nicotine enantiomer ratio or the detection of tobacco-specific impurities or directly using the isotope ratio enrichment analysis by nuclear magnetic resonance (site-specific natural isotope fractionation and site-specific peak intensity ratio) or accelerated mass spectrometry. This review presents an accessible summary of all these analytical methods.
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... Instead, there are varying concentrations of R-and S-nicotine enantiomers in synthetic nicotine compared to the 99% S-nicotine profile of tobacco-derived nicotine; notably, some NTNs contain a racemic mixture of 50% R-nicotine and 50% S-nicotine. 1 Further, the metabolic and physiological effects of high exposure to R-nicotine remain poorly understood. 2,3 Research limited to animal models has shown a difference in the metabolic breakdown of R-nicotine compared to S-nicotine, but the physiological effects of these metabolites are not well understood. Previous testing analyses demonstrated incongruencies between the labeled nicotine concentration of some synthetic nicotine ENDS and true nicotine concentrations, and significantly greater concentrations of R-nicotine in comparison to tobacco-derived ENDS, potentially exposing individuals to higher concentrations of nicotine than advertised. ...
... Previous testing analyses demonstrated incongruencies between the labeled nicotine concentration of some synthetic nicotine ENDS and true nicotine concentrations, and significantly greater concentrations of R-nicotine in comparison to tobacco-derived ENDS, potentially exposing individuals to higher concentrations of nicotine than advertised. 3 Further, claims that a product is "tobacco-free" may reduce harm perceptions, may be incorrectly interpreted, and may increase intent to use these products. 4 Despite limited knowledge of synthetic nicotine's effects, NTN products have continued to proliferate. ...
Identification and Characterization of Synthetic Nicotine Product Promotion and Sales on Instagram Using Natural Language Processing
Article
Full-text available
  • Nov 2023
  • NICOTINE TOB RES
Introduction There has been a rapid proliferation of synthetic nicotine products in recent years, despite newly established regulatory authority and limited research into its health risks. Previous research has implicated social media platforms as an avenue for nicotine product unregulated sales. Yet, little is known about synthetic nicotine product content on social media. We utilized natural language processing to characterize the sales of synthetic nicotine products on Instagram. Methods We collected Instagram posts by querying Instagram hashtags (e.g., “#tobaccofreenicotine) related to synthetic nicotine. Using BERT, collected posts were categorized into thematically related topic clusters. Posts within topic clusters relevant to study aims were then manually annotated for variables related to promotion and selling (e.g., cost discussion, contact information for offline sales). Results A total of 7,425 unique posts were collected with 2,219 posts identified as related to promotion and selling of synthetic nicotine products. Nicotine pouches (52.9%, n=1174), ENDS (30.6%, n=679), and flavored e-liquids (14.1%, n=313) were most commonly promoted. 16.1% (n=345) of posts contained embedded hyperlinks and 5.8% (n=129) provided contact information for purported offline transactions. Only 17.6% (n=391) of posts contained synthetic nicotine specific health warnings. Conclusions In the United States, synthetic nicotine products can only be legally marketed if they have received premarket authorization from the FDA. Despite these prohibitions, Instagram appears to be a hub for potentially unregulated sales of synthetic and “tobacco-free” products. Efforts are needed by platforms and regulators to enhance content moderation and prevent unregulated online sales of existing and emerging synthetic nicotine products. Implications There is limited clinical understanding of synthetic nicotine’s unique health risks and how these novel products are changing over time due to regulatory oversight. Despite synthetic nicotine specific regulatory measures, such as the requirement for premarket authorization and FDA warning letters issued to unauthorized sellers, access to and promotion of synthetic nicotine is widely occurring on Instagram, a platform with over 2 billion users and one that is popular among youth and young adults. Activities include direct-to-consumer sales from questionable sources, inadequate health warning disclosure, and exposure with limited age restrictions, all conditions necessary for the sale of various tobacco products. Notably, the number of these Instagram posts increased in response to the announcement of new FDA regulations. In response, more robust online monitoring, content moderation, and proactive enforcement is needed from platforms who should work collaboratively with regulators to identify, report, and remove content in clear violation of platform policies and federal laws. Regulatory implementation and enforcement should prioritize digital platforms as conduits for unregulated access to synthetic nicotine products and other future novel and emerging tobacco products.
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... Such products include nicotine in the form of a nicotine chewing gums, nicotine patches, and nicotine tablets [5]. As it is evidenced by many studies, nicotine's fatal dose in adults was specified to be 60 mg that corresponds to nicotine concentration of 2 mg/L (12.33 μM) in blood and 4 mg/L (24.66 μM) in plasma [6] In addition to that, various studies have been performed for the analysis of nicotine and cotinine in different physiological fluids rather than blood and plasma but in urine, sweat and saliva [7] with liquid chromatography, tandem mass spectroscopy [8] colorimetry and immunoassay methods [9]. According to the results of those studies, the concentration value in sweat for cotinine was 21.4 -202 ng/patch, nicotine was 150 -2498 ng/patch [7] while those values were vastly different in different body fluids, for instance the cotinine concentrations were found to be 1.5, 1.7 and 5 μg/L in serum, saliva, and urine respectively with 280-fold increase in urine and 180-fold increase in plasma [10]. ...
Recent advances in Nicotine Electrochemical biosensors: a review
Article
Full-text available
  • May 2024
The chemical compound nicotine, specifically 3-(1-methyl-2-pyrrolidinyl) pyridine, is a notable xenobiotic under investigation in the realm of electrochemical biosensors. This article emphasizes the nature of this substance and its impact on the human body. Different species with pharmacological, therapeutic, industrial, food-related, and environmental origins can now be detected using electrochemical sensors. Nicotine, an addictive substance in tobacco products and electronic cigarettes (e-cigs), is recognized for increasing the risk of cardiovascular and respiratory disorders. Careful real-time monitoring of nicotine exposure is critical in alleviating the potential health impacts of not just smokers but also those exposed to second-hand and third-hand smoke. Monitoring of nicotine requires suitable sensing material to detect nicotine selectively and testing under free-living conditions in the standard environment. A biosensor consists of a sensitive biological system and a detector system with appropriate transducers for obtaining output signals. The applications of these devices include health screening, the detection of environmental contaminants, farming, and routine medical examinations. Critical factors in its widespread commercialization will be the product's selectivity, sensitivity, stability, and lower production costs. Scientists have been working on developing a nano biosensor with a high degree of sensitivity and selectivity for the recognition of biomarkers of immune responses and cancer. An analysis of various parameters, including Limit of Detection (LOD) and monitoring nicotine concentration within the biological pH range (7-7.4), has been conducted. The objective of this analysis is to enhance sensitivity, expand linear range, and optimize optical and electrical properties. The article delves into the optimization of sensors and biosensors from an electrochemical perspective, highlighting the positive and negative effects of nicotine, as well as its metabolic pathways in the human body. The study categorizes and evaluates the latest nicotine detection sensors and biosensors based on their generation (electron transfer between multilayers) and methods (modification types or direct electrodes). The strengths and weaknesses of each are scrutinized over the past 15 years, with a focus solely on electrochemical biosensors.
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... Considering the chemical composition of TDN and TFN, the fundamental difference between them is chirality. The nicotine in TDN products is mostly S-nicotine (only 0.1%-1.2% is R-nicotine), while the nicotine in TFN products is a racemic mixture of R-and S-nicotine (50% R-nicotine and 50% S-nicotine) [38,39]. There is limited information on how the chirality of nicotine may impact its health effects, but it is stated that TFN is pharmaceutically pure and does not contain impurities found in TDN, including tobacco-specific nitrosamines, which may contribute to negative health effects [40,41]. ...
Vaping: Public Health, Social Media, and Toxicity
Article
Full-text available
  • Apr 2024
This viewpoint aims to provide a comprehensive understanding of vaping from various perspectives that contribute to the invention, development, spread, and consequences of e-cigarette products and vaping. Our analysis showed that the specific characteristics of e-cigarette products as well as marketing strategies, especially social media marketing, fostered the spread of vaping and the subsequent effects on human health and toxicity. We analyzed the components of e-cigarette devices and e-liquids, including the latest variants whose impacts were often overlooked. The different forms of nicotine, including salts and freebase nicotine, tobacco-derived nicotine, tobacco-free nicotine, and cooling agents (WS3 and WS23), have brought more choices for vapers along with more ways for e-cigarette manufacturers to advertise false understandings and present a greater threat to vapers’ health. Our work emphasized the products of brands that have gained significant influence recently, which are contributing to severe public health issues. On the other hand, we also discussed in detail the toxicity of e-liquid components and proposed a toxicity mechanism. We also noticed that nicotine and other chemicals in e-liquids promote each other’s negative effects through the oxidative stress and inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, a mechanism leading to pulmonary symptoms and addiction. The impact of government regulations on the products themselves, including flavor bans or regulations, has been limited. Therefore, we proposed further interventions or harm reduction strategies from a public health perspective.
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... At present, in the prior art, the main methods for the separation of enantiomeric alkaloids are liquid chromatography (LC) [17][18][19] and gas chromatography (GC) [20][21][22][23]. LC primarily uses a normal-phase chromatographic system equipped with a chiral column to directly separate enantiomeric isomers, and its normal-phase chromato-graphic system does not meet environmental requirements, which is influenced by reagents and moisture in the matrix. ...
Enantiomeric separation of four pairs of alkaloids by using a C18 column tandem polysaccharide-based chiral column
Article
Full-text available
  • Mar 2024
  • REV ANAL CHEM
Alkaloid enantiomers have different physiological and pharmacological effects, and different chiral compositions have a large impact on cigarette sensory and use safety. Studying the effects of different configurations of alkaloid enantiomers on cigarette sensory is important for the development of tobacco products, but the chiral separation of alkaloid enantiomers has become the core problem. Here, the application of a C18 column coupled with a polysaccharide-based chiral column to separate and detect four pairs of alkaloid enantiomers in tobacco and cigarette smoke of different brands was investigated. Results showed that the tandem technology of the two columns enabled the baseline separation of four pairs of alkaloid enantiomers. The resolution of enantiomers of alkaloids in different tobacco samples differed in content and ratio, showing different chiral distribution characteristics. According to the different distribution characteristics of alkaloid enantiomers, tobacco samples of different brands can be distinguished and real cigarettes can be identified.
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... It is reported that S-nicotine has a slower metabolism, higher toxicity and stronger physiological activity than R-nicotine, which was the main existing form of nicotine in tobacco and tobacco products. 1,24 However, the addictive difference between S-and R-nicotine has been unclear. Although S-and R-nicotine did not exhibit significant differences for ...
Insights into Molecular Mechanism of Nicotine Addiction Based on Network Pharmacology and Molecular Docking Strategy
Article
  • Sep 2023
For exploring the molecular mechanism of nicotine addiction, nicotine addiction-related targets and signaling pathways were analyzed using network pharmacology and molecular docking. The target proteins of nicotine and addiction were obtained from SEA and Gene Cards database, respectively. Then, the overlapped targets of nicotine and addiction were considered as the targets of nicotine addiction. The protein–protein interaction (PPI) networks were constructed based on STRING and Cytoscape software, and the hub targets of nicotine addiction were screened based on CytoHubba and MCODE plug-ins. In addition, GO function analysis and KEGG pathway enrichment analysis were carried out for nicotine addiction targets. Finally, molecular docking was used to verify the key targets of nicotine addiction. The results showed that 87 target proteins were at least involved in nicotine addiction, and the hub targets included DRD2, CHRM1, MAOA, MAOB, CHRNA7 and SLC6A4. GO function analysis referred to 591 GO entries and 31 signaling pathways were obtained through the analysis of KEGG. Molecular docking showed that nicotine could bind to the surface-active pockets of protein MAOA, MAOB, CHRNA7, DRD2 and SLC6A4 using less minimum binding free energy (< –5 Kcal/moL), which was mainly from hydrogen bond and hydrophobic interaction. Summarily, molecular mechanism of nicotine addiction is very complex and involves in various target proteins and pathways based on network pharmacology analysis, in which target proteins MAOA, MAOB, CHRNA7, DRD2, SLC6A4 can directly interact with nicotine and cooperatively regulate different pathways such as neural ligand receptor interaction and nicotine addiction pathways to induce addiction.
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On the Greenness of Separation Modes Containing Compressed Fluids
Article
  • Oct 2024
  • ANAL CHIM ACTA
Background: In the past three decades, liquid chromatography (LC) has been recognized as a significant environmental, health, and safety burden due to its heavy reliance on toxic organic solvents. Various chromatographic modes are in vogue today for complex analyses, such as sub/supercritical fluid chromatography (SFC) and enhanced fluidity liquid chromatography (EFLC). These modes are often advertised as "universally green" compared to the traditional allliquid reversed (RPLC) and normal phases (NPLC). Quantitative greenness evaluations must be done to validate or invalidate this assumption and allow separation scientists to make educated choices when deciding on what mode to use. Results: In this work, we modify the Analytical Method Greenness Score (AMGS) to include the cycle time of the instrument, and with the help of the first-order optimality condition (by setting the AMGS gradient = 0), we show that SFC and EFLC are not always the greenest option as they are often thought to be. Most of the greenness metrics have ignored the cycle time of instruments, yet this key component changes the entire AMGS response to flow rate. The complex case of separating tobacco alkaloid enantiomers (nicotine, nornicotine, anabasine, and anatabine) was selected as an illustrative example for comparing and contrasting separation modes using the modified greenness metric. These enantiomers have been selected due to their notorious difficulty in separation over the past 30 years. Using this family of molecules, four unique retention patterns were observed covering a wide variety of retention phenomena seen in small molecule enantioseparations. Significance: The modified AMGS metric will assist practicing analytical chemists in assessing the environmental impact of their separation methods from a single run in a given chromatographic mode. The proposed methodology identifies the minimum AMGS score corresponding to the greenest separation for routine chemical analysis.
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Nicotine and Cardiovascular Health: When Poison is Addictive – a WHF Policy Brief
Article
Full-text available
  • Jan 2024
Nicotine is universally recognized as the primary addictive substance fuelling the continued use of tobacco products, which are responsible for over 8 million deaths annually. In recent years, the popularity of newer recreational nicotine products has surged drastically in many countries, raising health and safety concerns. For decades, the tobacco industry has promoted the myth that nicotine is as harmless as caffeine. Nonetheless, evidence shows that nicotine is far from innocuous, even on its own. In fact, numerous studies have demonstrated that nicotine can harm multiple organs, including the respiratory and cardiovascular systems. Tobacco and recreational nicotine products are commercialized in various types and forms, delivering varying levels of nicotine along with other toxic compounds. These products deliver nicotine in profiles that can initiate and perpetuate addiction, especially in young populations. Notably, some electronic nicotine delivery systems (ENDS) and heated tobacco products (HTP) can deliver concentrations of nicotine that are comparable to those of traditional cigarettes. Despite being regularly advertised as such, ENDS and HTP have demonstrated limited effectiveness as tobacco cessation aids in real-world settings. Furthermore, ENDS have also been associated with an increased risk of cardiovascular disease. In contrast, nicotine replacement therapies (NRT) are proven to be safe and effective medications for tobacco cessation. NRTs are designed to release nicotine in a slow and controlled manner, thereby minimizing the potential for abuse. Moreover, the long-term safety of NRTs has been extensively studied and documented. The vast majority of tobacco and nicotine products available in the market currently contain nicotine derived from tobacco leaves. However, advancements in the chemical synthesis of nicotine have introduced an economically viable alternative source. The tobacco industry has been exploiting synthetic nicotine to circumvent existing tobacco control laws and regulations. The emergence of newer tobacco and recreational nicotine products, along with synthetic nicotine, pose a tangible threat to established tobacco control policies. Nicotine regulations need to be responsive to address these evolving challenges. As such, governments should regulate all tobacco and non-medical nicotine products through a global, comprehensive, and consistent approach in order to safeguard tobacco control progress in past decades.
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Synthetic nicotine e-liquids sold in US online vape shops
Article
  • Apr 2023
Synthetic nicotine (relative to tobacco-derived, or "natural" nicotine) is an emerging feature of e-cigarettes including e-liquids in the online marketplace. This study investigated a total of 11,161 unique nicotine e-liquids sold in online stores in the US during 2021, using keyword matching approach to identify the feature of synthetic nicotine based on product description texts. We showed that in 2021, 2.13% of nicotine-containing e-liquids in our sample were marketed as synthetic nicotine e-liquids. About a quarter of the synthetic nicotine e-liquids that we identified were salt-based; the nicotine strength varied; and those synthetic nicotine e-liquids had a variety of flavor profiles. Synthetic nicotine containing e-cigarettes are likely to remain in the market and manufacturers might market those products as "tobacco-free," to attract consumers who this feature as healthier or less addictive. It is important to monitor synthetic nicotine in the e-cigarette marketplace and assess how this feature influences consumer behaviors.
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Concentration of Nicotine and Glycols in 27 Electronic Cigarette Formulations
Article
Full-text available
  • May 2016
  • J ANAL TOXICOL
Personal battery-powered vaporizers or electronic cigarettes were developed to deliver a nicotine vapor such that smokers could simulate smoking tobacco without the inherent pathology of inhaled tobacco smoke. Electronic cigarettes and their e-cigarette liquid formulations are virtually unregulated. These formulations are typically composed of propylene glycol and/or glycerin, flavoring components and an active drug, such as nicotine. Twenty-seven e-cigarette liquid formulations that contain nicotine between 6 and 22 mg/L were acquired within the USA and analyzed by various methods to determine their contents. They were screened by Direct Analysis in Real Time™ Mass Spectrometry (DART-MS). Nicotine was confirmed and quantitated by high-performance liquid chromatography–tandem mass spectrometry, and the glycol composition was confirmed and quantitated by gas chromatography–mass spectrometry. The DART-MS screening method was able to consistently identify the exact mass peaks resulting from the protonated molecular ion of nicotine, glycol and a number of flavor additives within 5 mmu. Nicotine concentrations were determined to range from 45 to 131% of the stated label concentration, with 18 of the 27 have >10% variance. Glycol composition was generally accurate to the product description, with only one exception where the propylene glycol to glycerin percentage ratio was stated as 50:50 and the determined concentration of propylene glycol to glycerin was 81:19 (% v/v). No unlabeled glycols were detected in these formulations. LINK TO FREE ARTICLE ACCESS: http://jat.oxfordjournals.org/cgi/reprint/bkw037? ijkey=8BDu5z9k19hiLJZ&keytype=ref
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Spectroscopic Studies on Nicotine and Nornicotine in the UV Region†
Article
Full-text available
  • May 2013
  • CHIRALITY
The UV absorption and electronic circular dichroism (ECD) spectra of (R)- and (S)-nicotine and (S)-nornicotine in aqueous solution were measured to a significantly lower wavelength range than previously reported, allowing the identification of four previously unobserved electronic transitions. The ECD spectra of the two enantiomers of nicotine were equal in magnitude and opposite in sign, while the UV absorption spectra were coincidental. In line with previous observations, (S)-nicotine exhibited a negative cotton effect centered on 263 nm with vibronic structure (π-π1 * transition) and a broad, positive ECD signal at around 240 nm associated with the n-π1 * transition. As expected this band disappeared when the pyridyl aromatic moiety was protonated. Four further electronic transitions are reported between 215 and 180 nm; it is proposed the negative maxima around 206 nm is either an n-σ* transition or a charge transfer band resulting from the movement of charge from the pyrrolidyl N lone pair to the pyridyl π* orbital. The pyridyl π-π2 * transition may be contained within the negative ECD signal envelope at around 200 nm. Another negative maximum at 188 nm is thought to be the pyridyl π-π3 * transition, while the lowest wavelength end-absorption and positive ECD may be associated with the π-π4 * transition. The UV absorption spectra of (S)-nornicotine was similar to that of (S)-nicotine in the range 280-220 nm and acidification of the aqueous solution enhanced the absorption. The ECD signals of (S)-nornicotine were considerably less intense compared to (S)-nicotine and declined further on acidification; in the far UV region the ECD spectra diverge considerably. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc.
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Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products. Final rule
Article
  • May 2016
The Food and Drug Administration (FDA) is issuing this final rule to deem products meeting the statutory definition of "tobacco product,'' except accessories of the newly deemed tobacco products, to be subject to the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act). The Tobacco Control Act provides FDA authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, smokeless tobacco, and any other tobacco products that the Agency by regulation deems to be subject to the law. With this final rule, FDA is extending the Agency's "tobacco product'' authorities in the FD&C Act to all other categories of products that meet the statutory definition of "tobacco product" in the FD&C Act, except accessories of such newly deemed tobacco products. This final rule also prohibits the sale of "covered tobacco products" to individuals under the age of 18 and requires the display of health warnings on cigarette tobacco, roll-your own tobacco, and covered tobacco product packages and in advertisements. FDA is taking this action to reduce the death and disease from tobacco products. In accordance with the Tobacco Control Act, we consider and intend the extension of our authorities over tobacco products and the various requirements and prohibitions established by this rule to be severable.
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Electronic cigarettes for smoking cessation: A randomised controlled trial
Article
  • Sep 2013
  • LANCET
Electronic cigarettes (e-cigarettes) can deliver nicotine and mitigate tobacco withdrawal and are used by many smokers to assist quit attempts. We investigated whether e-cigarettes are more effective than nicotine patches at helping smokers to quit. We did this pragmatic randomised-controlled superiority trial in Auckland, New Zealand, between Sept 6, 2011, and July 5, 2013. Adult (≥18 years) smokers wanting to quit were randomised (with computerised block randomisation, block size nine, stratified by ethnicity [Māori; Pacific; or non-Māori, non-Pacific], sex [men or women], and level of nicotine dependence [>5 or ≤5 Fagerström test for nicotine dependence]) in a 4:4:1 ratio to 16 mg nicotine e-cigarettes, nicotine patches (21 mg patch, one daily), or placebo e-cigarettes (no nicotine), from 1 week before until 12 weeks after quit day, with low intensity behavioural support via voluntary telephone counselling. The primary outcome was biochemically verified continuous abstinence at 6 months (exhaled breath carbon monoxide measurement <10 ppm). Primary analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000866000. 657 people were randomised (289 to nicotine e-cigarettes, 295 to patches, and 73 to placebo e-cigarettes) and were included in the intention-to-treat analysis. At 6 months, verified abstinence was 7·3% (21 of 289) with nicotine e-cigarettes, 5·8% (17 of 295) with patches, and 4·1% (three of 73) with placebo e-cigarettes (risk difference for nicotine e-cigarette vs patches 1·51 [95% CI -2·49 to 5·51]; for nicotine e-cigarettes vs placebo e-cigarettes 3·16 [95% CI -2·29 to 8·61]). Achievement of abstinence was substantially lower than we anticipated for the power calculation, thus we had insufficient statistical power to conclude superiority of nicotine e-cigarettes to patches or to placebo e-cigarettes. We identified no significant differences in adverse events, with 137 events in the nicotine e-cigarettes group, 119 events in the patches group, and 36 events in the placebo e-cigarettes group. We noted no evidence of an association between adverse events and study product. E-cigarettes, with or without nicotine, were modestly effective at helping smokers to quit, with similar achievement of abstinence as with nicotine patches, and few adverse events. Uncertainty exists about the place of e-cigarettes in tobacco control, and more research is urgently needed to clearly establish their overall benefits and harms at both individual and population levels. Health Research Council of New Zealand.
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The binding and regioselectivity of reaction of (R)- and (S)-nicotine with cytochrome P-450cam: Parallel experimental and theoretical studies
Article
  • Jan 1993
(S)- and (R)-nicotine were used to test a theoretical model for the binding and regioselectivity of cytochrome P-450. Theoretical studies predict that the binding of (R)-nicotine will be more favorable than the binding of (S)-nicotine by between 0.400 and 0.600 kcal. A parallel experimental study determined that the binding constants differed by 0.333 kcal. The overall metabolic rate of (R)-nicotine is 1.4-fold faster than (S)-nicotine which is consistent with the predicted difference in binding energy. Product formation is theoretically predicted to occur at a faster rate at the 5' methylene group than at the N-methyl group of the pyrrolidine ring for both enantiomers. This prediction was confirmed by the experimental results. The factors that are important in the differential binding of the two enantiomers are discussed. The agreement between theory and experiment indicates that the force field used in these calculations may be of general applicability for the prediction of the binding of substrates to P-450cam.
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HPLC separation of the enantiomers of nicotine and nicotine-like compounds
Article
  • Jan 1993
  • CHIRALITY
A sensitive and reproducible HPLC method utilizing a commercially available chiral α1-acid glycoprotein (AGP) phase has been developed to separate and quantify the enantiomers of nicotine. The method is suitable for routine use as indicated by column life. The quantification of (R/S:0.05/99.95)-nicotine or (R/S:99/1)-nicotine was possible. In addition, the separation or at least partial separation of the enantiomers of nornicotine and nornicotine-derived compounds was achieved. © 1993 Wiley-Liss, Inc.
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Optically pure (+) nicotine and biological comparisons with (-)-nicotine
Article
  • Feb 1979
Optically pure (+)-nicotine has been obtained from (+/-)-nicotine using a combination of d-tartaric acid and di-p-toluoyl-l-tartaric acid. As the di-d-tartrate salt, (+)-nicotine is less potent than (-)-nicotine di-l-tartrate in producing lethality in mice, on blood pressure in anesthetized rats, and in the isolated guinea-pig ileum, indicating substantial stereospecificity for nicotine receptors. Potency ratios are 0.14, 0.06, and 0.019, respectively.
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Macrocyclic Antibiotics as a New Class of Chiral Selectors for Liquid Chromatography
Article
  • May 1994
There are a large number of antibiotic macrocycles which include several different structural types. Three representative macrocyclic compounds were covalently linked to silica gel and evaluated by HPLC for their ability to resolve racemic mixtures as well as for their stability and loadability. Over 70 compounds were resolved. In some cases separations were achieved that have not been reported on any other chiral stationary phase (CSP). These stationary phases appear to be multimodal in that they can be used in both the normal-phase and reversed-phase modes. Different compounds are resolved in each mode. There does not appear to be any deleterious effects to the stationary phases or any irreversible changes in the enantioselectivity when changing from one mode to another. The diversity of functionality of some of these chiral selectors is only approached by that of glycoproteins. Consequently, enantioseparation may be possible via several different mechanisms including pi-pi complexation, hydrogen bonding, inclusion in a hydrophobic pocket, dipole stacking, steric interactions, or combinations thereof. While all other CSPs avail themselves of the same type of interactions, they are not all necessarily available in a single chiral selector and in relatively close proximity to one another. Macrocyclic antibiotics seem to have many of the useful enantioselectivity properties of proteins and other polymeric chiral selectors without their inherent problems of instability and low capacities.
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Separation of nicotine and nornicotine enantiomers via normal phase HPLC on derivatized cellulose chiral stationary phases
Article
  • Jan 1998
  • CHIRALITY
This paper describes the enantiorecognition of (±)nicotine and (±)nornicotine by high-performance liquid chromatography using two derivatized cellulose chiral stationary phases (CSPs) operated in the normal phase mode. It was found that different substituents linked to the cellulose backbone significantly influence the chiral selectivity of the derivatized CSP. The results showed that, in general, the tris(4-methylbenzoyl) cellulose CSP (Chiralcel OJ) surpasses tris(3,5-dimethylphenyl carbamoyl) cellulose CSP (Chiralcel OD). On the former column, the resolution (±)nicotine and (±)nornicotine enantiomers depended largely on mobile phase compositions. For the separation of the nicotine enantiomers, the addition of trifluoroacetic acid to a 95:5 hexane/alcohol mobile phase greatly improved the enantioresolution, probably due to enhanced hydrogen bonding interactions between the protonated analytes and the CSP. For (±)nornicotine separation, a reduction in the concentration of alcohol in the mobile phase was more effective than the addition of trifluoroacetic acid. Possible solute-mobile phase-stationary phase interactions are discussed to explain how different additives in the mobile phase and different substituents on the cellulose glucose units of the CSPs affect the separation of both pairs of enantiomers. Chirality 10:364–369, 1998. Published 1998 Wiley-Liss, Inc.†
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