Author: Taco Tuinstra

  • Unpacking the Pouch

    Unpacking the Pouch

    Photo courtesy of Broughton

    How we can better understand the toxicological risk of nicotine in modern oral and other nicotine products

    By Libby Clarke

    Nicotine may be acutely toxic via all routes of exposure if the dose is high enough, but determining the true extent of its toxicity is challenging because of the variation in data. In 2014, Bernd Mayer highlighted the discrepancy between the generally accepted lethal dose of nicotine and documented cases of nicotine intoxication. Examining these accidental oral ingestion case studies gives us another data point for consideration when determining nicotine toxicity.

    In this article, Libby Clarke, managing consultant for toxicology at contract research organization (CRO) and scientific consultancy Broughton, explains how manufacturers can understand the true impact of oral pouches and other nicotine-based products.

    The U.S. Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health, along with other sources, report an estimated lethal dose of around 60 mg when nicotine is ingested orally. While broadly accepted by the Food and Drug Administration and other regulatory bodies, this value is derived from a series of self-experiments conducted by two individuals in the 19th century, where non-fatal adverse effects were reported.

    Mayer estimated that a dose of 60 mg of nicotine would give rise to a plasma concentration of approximately 0.18 mg per liter based on 20 percent oral bioavailability and assuming linear kinetics. Cases of fatal nicotine intoxication cited by Mayer suggest a much higher lethal nicotine blood concentration of approximately 2 mg per liter, corresponding to 4 mg per liter in plasma. Many existing case studies include data on accidental ingestion in children and infants, where the lethal dose is likely lower, as with nicotine naive adults.

    There is a significant disparity in the levels of nicotine that individuals can tolerate and a broad range in the upper level of nicotine that nonsmokers can consume without experiencing adverse effects. Research indicates that tolerance increases with repeated use of nicotine products, but the speed at which tolerance grows depends on the frequency of nicotine use, the amount absorbed systemically and individual genetics.

    Research Challenges

    Understanding nicotine toxicity is essential for determining the likelihood of adverse effects associated with certain products and concentrations, but research is limited. It is unethical to test nicotine toxicity in nonsmokers, and light or nondaily nicotine users are likely to have a lower tolerance, putting them at a higher risk of experiencing adverse effects such as dizziness, nausea and vomiting. On the other hand, established smokers have upregulated receptors in the brain, meaning many more nicotine receptors are available to bind nicotine than in nonsmokers. Therefore, the higher levels of nicotine that produce adverse reactions in nonsmokers are often required to satisfy the cravings of regular smokers.

    The wide range in tolerance among adult nicotine users makes it challenging for manufacturers to define a threshold for nicotine toxicity in their products. Meanwhile, attempting to extrapolate findings from children to adults is not recommended due to differences in metabolic capacity, which increases as people grow. There is also a vast difference in metabolic efficiency, even among adults, which limits extrapolation.

    Understanding the Effects of Nicotine

    One option is for manufacturers to review case studies, conduct postmarket surveillance (PMS) on the incidence of reported adverse effects and use surveys to understand consumer use and the subjective effectiveness of nicotine delivery. For example, Massen et al. (2020) evaluated case studies reporting the clinical symptoms and outcomes associated with accidental or intentional ingestion of nicotine-containing e-liquids, which are limited to 20 mg per milliliter in the EU. Gerdinique C. Maessen et al. reported that the highest nicotine plasma concentration in the surviving group was 0.8 mg per liter. In comparison, the lowest plasma concentration in the patients who did not survive was 1.6 mg per liter.

    Another approach is working with a CRO that can conduct dissolution, aerosol characterization for inhaled products and pharmacokinetic studies to inform on the nicotine levels being delivered to users. CROs can also conduct behavioral studies under controlled conditions to understand the use patterns for certain products and what products and strengths are used across population samples.

    When developing oral pouches, manufacturers must adhere to the regulatory guidelines that are starting to be brought in by some markets. The rate at which nicotine transfers from the pouch across the buccal membrane is one of the main factors associated with users experiencing adverse effects, so manufacturers should consider a range of nicotine strengths. Dissolution studies and clinical studies may provide useful data to inform nicotine exposure from pouches, and case studies and PMS may also provide valuable insights. Working with a CRO that can conduct such studies is an effective way of understanding a product’s safety profile and form part of a manufacturer’s product stewardship and duty of care responsibilities.

  • Revenue and Profit up at Ispire Technology

    Revenue and Profit up at Ispire Technology

    Photo: Freedomz

    Ispire Technology reported revenue of $42.9 million and gross profit of $6.9 million in the quarter that ended Sept. 30, reflecting growth of 59.1 percent and 43.7 percent, respectively, over the comparable 2022 quarter.

    Revenue from cannabis vaping products jumped 116.8 percent to $17.3 million, and revenue from tobacco vaping products was up 34.8 percent to $25.5 million.

    Ispire co-CEO Michael Wang attributed the growth to the company’s expansion in the United States and the reception there of its most recent product, Ispire One. “Our business strategy has clearly manifested as we continue to redefine the vaping experience, consistently delivering high-quality and groundbreaking products that align with customer preferences,” he said.

    “We remain confident in our ability to maintain our position as the leading premier precision dosing technology company as we’ve not only secured our position in existing markets but have also made inroads into new geographies, adapting swiftly to increased market demands. The establishment of a new manufacturing facility in Malaysia marks a strategic step into the Southeast Asian market, signaling our readiness for scalable operations.”

  • Malaysia Scraps Endgame Clause

    Malaysia Scraps Endgame Clause

    Image: Zimmytws

    The government of Malaysia has eliminated the generational endgame (GEG) clause from its Control of Smoking Products for Public Health Bill 2023, reports CodeBlue.

    The move follows an opinion issued by Attorney-General Ahmad Terrirudin Mohd Salleh’s that the proposed age-based prohibition—which seeks to ban tobacco and vape products for anyone born from Jan. 1, 2007—is unconstitutional because it would create two sets of laws for two different groups of citizens based on age.

    Enacting the GEG would require a change to Malaysia’s constitution, according to the attorney general, and the government was reportedly not confident it would be able to secure the required two-thirds majority in Parliament.

    Anti-smoking activists were outraged, saying that the cabinet’s decision to drop the generational provision from the bill violates the Convention of the Rights of the Child, which Malaysia ratified in 1995.

    “We believe that this is a backward step that will lead the people of Malaysia, especially children and adolescents, into the realms of nicotine addiction and drug dependence,” said Family Medicine Specialists’ Association (FMSA) President Nor Hazlin Talib.

    The FMSA urged the government to reinsert the GEG clause into the bill. “The government needs to prioritize public health over political and economic interests,” Talib said.

    In addition to the now removed GEG clause, the bill includes provisions on registration of tobacco products, advertisement, packaging and smoke-free places, among other items.

  • Juul Raises Funding

    Juul Raises Funding

    Photo: itakdalee

    Juul Labs has raised about $1.3 billion in funding, reports Reuters.

    The company has been seeking financing alternatives in a bid to protect its business as it deals with lawsuits related to the marketing of its e-cigarettes.

    Earlier this year, Juul announced a company restructuring aimed at reducing operating costs and positioning the company to continue to advance its mission during a period of regulatory and marketplace uncertainty.

    In April, the company agreed to pay $462 million over eight years to settle claims by six U.S. states, along with the District of Columbia, that it unlawfully marketed its addictive products to minors.

    In November 2022, the company secured funding from some of its early investors to help keep it afloat while cutting about 400 jobs and reducing its operating budget.

    Altria Group exited its stake in Juul earlier this year, days before announcing its purchase of Njoy Holdings for about $2.8 billion.

  • Kaival Appoints Hopkins as Executive Chairman

    Kaival Appoints Hopkins as Executive Chairman

    Image: Monster-Ztudio

    Kaival Brands Innovations Group has expanded the role of Barry Hopkins, chairman of the board, to the new position of executive chairman. In this role, Hopkins will serve as Kaival Brands’ principal executive officer. Current President and CEO Eric Mosser will continue to manage day-to-day operations of the company.

    Hopkins joined Kaival Brands as chairman of the board in March 2023. He is a 40-year tobacco industry veteran with deep operational experience and industry contacts. With his expanded responsibilities, Hopkins will play a more active role in the strategic direction and oversight of the company, with a focus on accelerating revenue growth, improving operational efficiencies and executing on Kaival Brands’ strategic initiatives.

    “Since I joined Kaival Brands in March, I have become even more energized by the opportunities for our company and look forward to working with Eric and our excellent senior leadership team to refine our strategic business plan and reignite growth,” said Hopkins in a statement. “I aim to foster a culture of performance and accountability and to establish clear decision-making processes and strong communication, which are essential for moving our promising business forward.”

    Hopkins spent most of his decades-long career primarily in senior sales and marketing roles for Turning Point Brands and Altria.

  • Revenue and Profits up at Imperial

    Revenue and Profits up at Imperial

    Photo: Casimirokt | Dreamstime.com

    Imperial Brands reported an adjusted operating profit of £3.89 billion ($4.78 billion) for the fiscal year that ended Sept. 30, up 3.9 percent from fiscal 2022 when the impact of foreign exchange fluctuations and Imperial’s exit from Russia were excluded. Adjusted net revenue rose 1.4 percent to £8.01 billion

    Imperial CEO Stefan Bomhard expressed satisfaction with the results.

    “Three years into Imperial’s transformation, our investments in consumer capabilities, changes to the way we work, and a new performance culture are translating into stronger, more sustainable operational and financial outcomes,” he said in a statement.

    “In combustible tobacco, improving brand equity and investment in our salesforce capabilities has led to the third consecutive year of stable or growing aggregate market share in the five priority markets, which account for 70 percent of our operating profit. At the same time, we have offset structural volume declines with strong pricing in all key markets.

    “In next-generation products, our challenger approach, which combines partnership-based innovation with disciplined market entry, is delivering positive results. We now have credible propositions across all categories—vape, heated tobacco and oral nicotine. Following recent launches, we now offer consumers potentially reduced-harm choices in more than 20 European markets as well as the United States. This step-up in investment in Europe has driven an acceleration in net revenue growth.

    “Underpinning this broad-based progress is our continued transformation, which includes new innovation hubs in Liverpool, Hamburg and Shenzhen, modernization of legacy systems, and investments in upskilling our leaders.”

  • ‘More Initiation Through Vaping Than Smoking’

    ‘More Initiation Through Vaping Than Smoking’

    From left, Brandon Sanford, Benjamin Toll and Naomi Brownstein | Photo: MUSC

    For the first time, there are more young people who begin to use nicotine through vaping rather than through cigarettes, according to new research from the Medical University of South Carolina (MUSC).

    “We now have a shift such that there are more ‘never smokers’ who vape than established smokers,” said MUSC Hollings Cancer Center researcher Benjamin Toll, director of the MUSC Health Tobacco Treatment Program, in a statement. “That is a massive shift in the landscape of tobacco. These ‘never smokers’ are unlikely to start smoking combustible cigarettes—they’re likely to vape and keep vaping. And it’s this group, ages 18 to 24, who are going to forecast future e-cigarette users.”

    The research team used data from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal survey that’s a collaborative effort between the National Institutes of Health and the U.S. Food and Drug Administration. The survey started in 2013, and so far, there have been six waves of data collection.

    The sixth wave, consisting of survey answers from 2021, wasn’t widely available at the time the researchers completed their work. They gained access to the restricted data prior to its public release through the National Addiction and HIV Data Archive Program at the University of Michigan. 

    The Wave 6 data showed a continuing upward trend in vaping—and found that a majority of young adults who regularly vape, 56 percent, have never regularly smoked cigarettes. 

    A total of 14.5 percent of adults aged 18 to 24 reported regular use of e-cigarettes, according to the PATH Study—a figure that is higher than a previous Centers for Disease Control and Prevention report of 11 percent. Toll expects that the next wave of PATH Study data, scheduled for release in the fall of 2024, will show an even greater increase.

  • Strong Quarter Pyxus

    Strong Quarter Pyxus

    Photo: Pyxus Interantional

    Pyxus International reported strong top and bottom line results for the quarter that ended Sept. 20. Net income was $8.1 million compared with a loss of $1.54 million in the comparable 2022 period. Sales and other revenues were $624.25 million during the quarter compared with sales and other revenues of $505.28 million in the second quarter of 2022.

    “The momentum we built during the first quarter continued in the second quarter,” said Pyxus President and CEO Pieter Sikkel in a statement. “We delivered solid revenue growth, increased profitability, exercised operating discipline and continued to manage working capital efficiency.

    Contributing to the company’s performance was a volume increase of 10.2 percent and an increase in average market prices of 11.7 percent over the same quarter last year. The increase in leaf volume was primarily due to the accelerated timing of shipments from North America and South America and growth from Africa and Asia. Pyxus considers the higher pricing to be a feature of a market that remains generally undersupplied. The company believes the undersupplied condition of the market is also evidenced by its success in seizing opportunities to capture additional business.

    Buoyed by its quarterly performance, Pyxus revised its guidance for fiscal 2024 upward and now expects full-year sales to be in the range of $2 billion to $2.1 billion and for full-year adjusted EBITDA to be in the range of $170 million to $180 million.

  • The Core of the Confusion

    The Core of the Confusion

    Photo: Westock

    The likely origins of the prevailing misperceptions about nicotine—and how that impacts tobacco harm reduction

    By Sudhanshu Patwardhan

    A widely prevalent misperception prevailing in society is that nicotine in tobacco products causes cancer. This myth and its widespread acceptance even among healthcare practitioners worldwide was recently highlighted by a survey among 15,000 doctors from 11 countries. Nicotine misperception may be the key reason preventing the world from becoming free from risky forms of smoked and smokeless tobacco products. The origins of this misperception may have something to do with south Asia and the nasty oral tobacco products sold there.

    The Basis of Tobacco Addiction

    To achieve a world free of risky tobacco product use, understanding nicotine’s role in tobacco addiction is crucial. Tobacco addiction—in lay terms, the harmful habit of consumers of risky forms of tobacco to continue consuming despite knowing the harms to themselves and society—is primarily driven by the psychoactive effects of nicotine. The hand-to-mouth action, the action of nicotine on brain receptors, the activation of reward pathways in the brain, the release of neurotransmitters during product use and their eventual depletion, the expectation of the kick of the drug on longer term use, the craving and withdrawal effects that are mitigated by further consumption (or dosing) of nicotine, the social and cultural cues—all these point to a complex interplay. Nicotine is central to this addiction. An addiction that kills over 8 million people worldwide every year, affecting millions more in bereaved friends and families, and sees another 1.3 billion people in the world struggling to quit.

    It Is the Smoke, Stupid … or Is It Just?

    Over nearly five decades of tobacco control, thought leaders in the West have been enamored by—and have generously quoted—Michael Russell’s statement, “People smoke for nicotine, but they die from the tar” (Russell, British Medical Journal, 1976). He was right in the context of smoked tobacco. Indeed, this insight underpinned the enlightening among some tobacco control researchers in the U.K. and across the Atlantic. That in turn manifested in ground-breaking publications, e.g., the 2001 National Academy of Sciences’ Clearing the Smoke report, the 2007 U.K. Royal College of Physicians’ report Harm Reduction in Nicotine Addiction: Helping People Who Can’t Quit and the 2014 U.K. Royal College of Physicians’ report Nicotine Without Smoke: Tobacco Harm Reduction.”

    Indeed, the U.K. medicines agency’s authorization of an additional harm reduction indication for nicotine-replacement therapy (NRT) products from 2010 onward established the world’s first class of licensed tobacco harm reduction products. This is often forgotten by tobacco harm reduction advocates as well as tobacco control enthusiasts around the world, with even lesser understanding of how and why the U.K. arrived at this fork on its journey in addressing tobacco-related harms (Patwardhan, Drug Testing and Analysis, 2022).

    Metaphorically separating nicotine from its toxic delivery system that burned tobacco allowed Russell and the subsequent generations of public health thought leaders to pave the way for nicotine in cleaner forms to be formulated in various delivery systems, starting with medically licensed nicotine gums, patches and lozenges and culminating in Hon Lik’s invention of the e-cigarette. Heated-tobacco products launched by large tobacco multinationals also entered the market, with companies keen to “unsmoke” the world and phase out combusted tobacco, just like electric batteries in place of combustion engines in automobiles. Or Coke Zero and Pepsi Max instead of Coke and Pepsi. Right? Wrong! This narrative ignores oral tobacco consumption by nearly 300 million tobacco users, living mostly in Asia and Africa, and the attending oral and pharyngeal cancer-related morbidity and mortality.

    Smokeless Tobacco’s Harms: A Collective Blind Spot

    One estimate suggests that nearly 10 percent of doctors in the U.K. are of Indian or Pakistani origin and a sizeable number from Africa and the rest of Asia as well. There is even a higher proportion of healthcare professionals from these continents in mental health settings. Training in south and southeast Asia or Africa inevitably exposes doctors to patients presenting with the harms of oral tobacco.

    Current medical curricula in these countries (or in fact anywhere else in the world) do not go into any level of detail when it comes to treating smoked or smokeless tobacco addiction. During medical education, it is quite common to simply identify the myriad diseases that tobacco is responsible for and to require trainee doctors to advise patients to quit. Which nicotine-replacement therapy to prescribe, why, how to provide behavioral counselling for tobacco de-addiction, the need for follow-up and relapse prevention, the impact of smoking on specific drugs’ metabolism and reduced efficacy are skills and knowledge that are not imparted at any stage of clinical training to doctors, dentists or nurses anywhere in the world.

    There are millions of healthcare professionals in Asia and Africa and hundreds of thousands of expatriate doctors and nurses from these continents in Europe, America and the Middle East who have seen oral cancer patients, most likely resulting from oral tobacco use. They have seen firsthand the harms from oral tobacco products.

    Unsurprisingly, telling them that tobacco harm reduction can be achieved by going smoke-free or by switching to “smokeless tobacco products” or giving “safer” nicotine alternatives will be perceived as fake news at best, disingenuous and dishonest at worst. Even licensed NRTs are not spared in this misperception, with many clinicians worried about nicotine causing cancer and NRT addiction with longer term use. This may result in inadequate NRT being prescribed for not long enough, thus making relapse more likely.

     

    The use and harm profile of south Asian and African smokeless tobacco products is often not mentioned when championing snus (and therefore smokeless tobacco) as harm reduction. This can only add to the distrust of the industry and tobacco harm reduction advocates by the public health community.

    Nicotine Misperception: The Likely Origin Story

    There is an unprocessed wrong belief that most health experts and lay people have come to harbor: tobacco = nicotine = cancer. Toxicants, including carcinogens, are delivered during consumption of most tobacco products: from the smoke due to combustion of tobacco in the case of cigarettes/cigars/cigarillos and bidis, or added/formed in the manufacturing and storage of Asian and African oral tobacco products, e.g., chemicals, slaked lime, areca nut-specific nitrosamines and tobacco-specific nitrosamines (TSNAs).

    The exception to these is Swedish-style pouched smokeless tobacco (snus). Through decades of evolving manufacturing standards and innovation, concentrations of carcinogens such as TSNAs and other toxicants in Swedish-style snus have been engineered to be minimal. The population level effects of the “Swedish experience” with snus in enabling a transition to a smokefree nation with the attending lowest male lung cancer rates in the EU, are the darling of tobacco harm reduction advocates. However, the use and harm profile of south Asian and African smokeless tobacco products is often not mentioned when championing snus (and therefore smokeless tobacco) as harm reduction. This can only add to the distrust of the industry and tobacco harm reduction advocates by the public health community.

    In the absence of a curriculum that does not specifically distinguish nicotine’s psychoactive properties and dependence-causing potential from the toxicants formed or present in smoked or most smokeless tobacco products, healthcare professionals may easily conflate the tobacco products’ harms with nicotine.

    Furthermore, their experience with patients from south Asia and Africa makes it logical for them to unconsciously do so. There are already lazy parallels with other widely prevalent addictions afflicting the world: e.g., alcohol. The nuance, however, is lost, that unlike nicotine, ethanol is the psychoactive component as well as the chemical that harms the liver and brain cells.

    Lay media add to the confusion. Globally, tobacco control slogans and campaigns have run for decades now, most often using simple one-liner messages against nicotine. There was no need or place for nuance for those wanting to rid the world of the indirect harms of nicotine. It could even be justifiable for some to do so to achieve their utopian prize of a tobacco-free society (not to be confused with a society free from the harms of tobacco, a worthy goal).

    The problem arises when nicotine, the very chemical that is vilified in the prevalent anti-tobacco narrative, when delivered in clean systems is recognized as a key solution for the 1.3 billion users of risky smoked and smokeless tobacco products. E.g., the World Health Organization has NRT on its model essential medicines list for treating tobacco dependence.

    Nicotine: An Orphan Drug

    Eighty percent of the world’s users of risky tobacco products, nearly 900 million people, live in low-income and middle-income countries (LMICs). Most of them do not have access to affordable and appealing safer forms of nicotine-replacement products, including NRT. A majority of healthcare professionals in those countries wrongly believe that nicotine in tobacco products causes cancer. In these countries, tobacco cessation treatments are either unavailable or delivered by healthcare professionals who are not trained in the art and science of nicotine replacement and behavioral interventions.

    For too long, pharma and tobacco companies have shied away from owning nicotine, with pharma perhaps worried about the optics of selling a psychoactive substance with such global harms, albeit due to the dirty delivery system it is currently sold in. Tobacco companies care about their own brand and product and may prioritize brand building over broader product-agnostic market conditioning about nicotine. The result is that a large swathe of countries that lack the sophistication or the academic rigor and experience of the U.K.’s tobacco control community or the U.S.’ Food and Drug Administration find themselves accepting hand-me-down anti-tobacco-harm-reduction rhetoric.

    Light at the End of the Tunnel?

    A rush to launch new nicotine products globally without adequate disentanglement between tobacco and nicotine education will only lead to more knee-jerk reactions and bans. That shall slow down any ambition to make the world smoke-free, or to be more precise, free from risky tobacco products. Achieving nicotine literacy through education and practice may be the much-needed game changer. In theory, most countries, including LMICs, have NRT on their national essential medicines list.

    That does not necessarily translate into actual availability and affordability for cessation. Anyone truly invested in tobacco harm reduction should recognize that much groundwork needs to be laid first to get the new generation of healthcare students and future practitioners to be nicotine confident—starting with NRT. Tobacco cessation, underpinned by tobacco harm reduction principles, should be taught, practiced and experienced in LMICs through well-regulated healthcare ventures and partnerships.

    Consumers, healthcare practitioners and governments first need to see the success with cessation using conventional NRTs but also recognize the need for a wider choice of safer nicotine alternatives to wean off the 1.3 billion current tobacco users. Only then will the conditions be ripe for companies to responsibly market their nicotine innovations to adult tobacco users in such markets.

  • UAE Firm Buys BAT’s St. Petersburg Assets

    UAE Firm Buys BAT’s St. Petersburg Assets

    Photo: Igor Sobolev

    BFI Holding of the United Arab Emirates has purchased the St. Petersburg asset of BAT, reports Kommersant, citing data from Russia’s Unified State Register of Legal Entities.

    According to the Abu Dhabi Global Market registry, one of BFI Holding’s owners is Faruk Ener, who previously was responsible for Russia, Turkiye, the Caucasus, Central Asia and Belarus at BAT.

    BAT started operating in Russia in 1991. Three years later, the company began producing its own tobacco products in St. Petersburg. After the start of hostilities in Ukraine in May 2022, BAT announced the suspension of investments in Russia and later transferred the business in Russia and Belarus to a consortium led by the Russian