Application of systems biology to identify pharmacological mechanisms of thrombotic microangiopathy evoked by combined activated prothrombin complex concentrate and emicizumab.

Emicizumab is a bispecific monoclonal antibody that substitutes for the function of missing or deficient factor VIII (FVIII) in people with hemophilia A (PwHA). Long-term safety and efficacy of emicizumab have been demonstrated in several clinical trials. Nevertheless, in the first of these, three cases of thrombotic microangiopathy (TMA) occurred in PwHA treated with emicizumab receiving high doses of activated prothrombin complex concentrate (aPCC), a bypassing agent used for treating breakthrough bleeds when FVIII neutralizing antibodies (inhibitors) make FVIII replacement ineffective.

Analysis of waterpipe aerosol constituents in accordance with the ISO standard 22486.

This study analyzed commercial waterpipe tobacco products in accordance with the newly developed ISO 22486 as well as with commercial waterpipes and charcoals using the ISO 22486 puffing regime for comparison. The aerosols from these products were analyzed for their nicotine, humectant, tobacco specific nitrosamine, carbonyl, benzo[]pyrene, and metal yields. Significant differences were observed among the waterpipe tobacco products when analyzed in accordance with the ISO standard 22486 and with different commercial waterpipes and charcoals.

Cancer potencies and margin of exposure used for comparative risk assessment of heated tobacco products and electronic cigarettes aerosols with cigarette smoke.

Health risk associated with the use of combustible cigarettes is well characterized and numerous epidemiological studies have been published for many years. Since more than a decade, innovative non-combusted tobacco products have emerged like heated tobacco products (HTP) or electronic cigarettes (EC). Long-term effects of these new products on health remain, however, unknown and there is a need to characterize associated potential health risks.

Selected Harmful and Potentially Harmful Constituents Levels in Commercial e-Cigarettes.

A broad range of commercially available electronic cigarette (e-cigarette) systems were tested for levels of emissions of harmful and potentially harmful constituents (HPHC), with a particular focus on the carbonyls: acetaldehyde, acrolein, and formaldehyde. The tobacco-specific nitrosamines '-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-bipyridyl)-1-butanone; the elements arsenic, cadmium, chromium, lead, and nickel; benzene; 1,3-butadiene; and benzo(a)pyrene were also quantified. The results show that except for the levels of carbonyls, all types of e-cigarettes performed in a similar manner, and emission levels for HPHCs were generally not quantifiable.

Mainstream smoke constituents and toxicity comparative analysis of 3R4F and 1R6F reference cigarettes.

A new Kentucky reference cigarette, 1R6F, has been manufactured to replace the depleting 3R4F reference cigarette. The 3R4F Kentucky reference cigarettes have been widely used as monitor or comparator cigarettes for mainstream smoke analysis and and toxicological data of cigarettes and novel tobacco products. Both reference cigarettes were analyzed in the same laboratory during the same period of time with the goal of performing a comparison of 3R4F and 1R6F.

Assessment of priority tobacco additives per the requirements in the EU Tobacco Products Directive (2014/40/EU): Part 2: Smoke chemistry and in vitro toxicology.

This publication is part of a series of three publications and describes the non-clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States shall require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Comission, 2016). This publication contains the results of a literature search, comprehensive smoke chemistry, additive transfer, and in vitro toxicity studies for the 13 priority additives (carob bean extract, cocoa powder, fenugreek extract, fig juice concentrate, geraniol, glycerol, guaiacol, guar gum, liquorice extract powder, maltol, l-menthol (synthetic), propylene glycol, and sorbitol) commissioned by the members of the Priority Additives Tobacco Consortium to independent Contract Research Organizations.

Investigation of menthol content and transfer rates in cigarettes and Tobacco Heating System 2.2.

Menthol cigarettes account for a significant market share in many countries. However, little recent data exists on menthol levels in cigarettes and in mainstream smoke, limited to some markets or specific cigarette designs, such as cigarettes containing capsules filled with flavoring liquids. Samples of mentholated cigarettes bought worldwide with a variety of cigarette designs were analyzed for menthol content in cigarettes and in cigarette mainstream smoke with two analytical machine smoking regimes.

Role of testing standards in smoke-free product assessments.

Testing standards for tobacco and related products are an important basis for product science-based regulation. The recent emergence and rapid growth of products offering an alternative to continued smoking for adult smokers who would otherwise continue to smoke, urgently calls for the establishment of quality and assessment standards relevant for these products. The two main categories of products under consideration are electronic cigarettes and heated tobacco products, which both deliver nicotine in the aerosol that is not smoke, because tobacco is not burned in the process, and in particular no solid particles are generated as a result.

Investigation and comparison of the transfer of TSNA from tobacco to cigarette mainstream smoke and to the aerosol of a heated tobacco product, THS2.2.

Tobacco-specific nitrosamines (TSNA) levels in tobacco cut filler and cigarette smoke were measured in more than 1000 commercially available cigarettes sampled between 2008 and 2014. Relative contributions to their transfer from tobacco to the mainstream smoke in terms of direct transfer by distillation, pyrorelease, and pyrosynthesis were evaluated on the basis of the comparison with the transfer of nicotine from tobacco to smoke. N'-nitrosonornicotine (NNN) was transferred essentially by distillation, while N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-bipyridyl)-1-butanone (NNK) and N'-nitrosoanabasine (NAB) were transferred by pyrorelease or pyrosynthesis as well.

Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes.

There has been a sustained effort in recent years to develop products with the potential to present less risk compared with continued smoking as an alternative for adult smokers who would otherwise continue to smoke cigarettes. During the non-clinical assessment phase of such products, the chemical composition and toxicity of their aerosols are frequently compared to the chemical composition and toxicity of the smoke from a standard research cigarette - the 3R4F reference cigarette. In the present study, it is demonstrated that results of these analytical comparisons are similar when considering commercially available cigarette products worldwide.

Novel approach for selective reduction of NNN in cigarette tobacco filler and mainstream smoke.

Research conducted during past decades to reduce the level of the tobacco specific nitrosamine N-nitrosonornicotine (NNN) and its precursor nornicotine in tobacco yielded identification of three tobacco genes encoding for cytochrome P450 nicotine demethylases converting nicotine to nornicotine. We carried out trials to investigate the effect of using tobaccos containing three non-functional nicotine demethylase genes on the selective reduction of NNN in cigarette tobacco filler and mainstream smoke. Our results indicate that the presence of non-functional alleles of the three genes reduces the level of nornicotine and NNN in Burley tobacco by 70% compared to the level observed in currently available low converter (LC) Burley tobacco varieties.

Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014.

The evolution of the levels of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mainstream (MS) cigarette smoke is investigated based on smoke and tobacco chemistry data of cigarette brands sold by Philip Morris International (PMI) between 2000 and 2014. A total of 315 cigarette samples representing a wide range of product and design characteristics manufactured by PMI between 2008 and 2014 were analyzed and compared to a previously published dataset of PMI brands manufactured in 2000. The data indicate that there is a substantial reduction of NNN and NNK levels in tobacco fillers and MS cigarette smoke per mg of tar and per mg of nicotine using Health Canada Intense (HCI) machine-smoking regime.

Considerations for comparative tobacco product assessments based on smoke constituent yields.

Cigarette smoke is a complex mixture of more than 8000 smoke constituents. The quantification of selected mainstream smoke constituent yields is one of the methods to evaluating and comparing the performance of different products. Numerous regulatory and scientific advisory bodies have used cigarette smoke constituent yield data for reporting and product comparison purposes.

Differences in cadmium transfer from tobacco to cigarette smoke, compared to arsenic or lead.

Arsenic, cadmium and lead levels in tobacco filler and cigarette smoke were determined in a 568-sample worldwide survey. Median tobacco levels for arsenic, cadmium and lead were 237, 769 and 397 ng/g respectively, comparable to those previously reported albeit somewhat lower for lead and cadmium. Median mainstream smoke yields for arsenic, cadmium and lead were <3.

Menthol addition to cigarettes using breakable capsules in the filter. Impact on the mainstream smoke yields of the health Canada list constituents.

Cigarettes with menthol capsules embedded in the filter have been introduced recently in many countries. At the same time, concerns have been expressed that filter performance could be affected by the crushing of the capsule therein, altering mainstream smoke constituent yields, ultimately with the potential to impact the toxicity of these products. The present study investigates the possible mechanisms underlying differences in smoke constituent deliveries following the crushing of a menthol capsule in a cigarette filter.

Formation of mainstream cigarette smoke constituents prioritized by the World Health Organization--yield patterns observed in market surveys, clustering and inverse correlations.

The WHO TobReg proposed mandating ceilings on selected smoke constituents determined from the market-specific median of nicotine-normalized yield distributions. Data validating this regulatory concept were obtained from essentially single-blend surveys. This process is strongly impacted by inverse correlations among yields.