Preliminary clinical pharmacokinetic evaluation of bemotrizinol - A new sunscreen active ingredient being considered for inclusion under FDA's over-the-counter (OTC) sunscreen monograph.

Protection against sunburn, skin damage and the carcinogenic effects of ultraviolet light are the primary health benefits associated with UV filters used in topical sunscreen drug products. Countries such as Europe have 30+ UV filters approved for sunscreen products while the US has about 10, greatly reducing the options to provide diverse, effective sun protection products. Bemotrizinol (BEMT) is the first new sunscreen active ingredient to be evaluated for inclusion in the Over-The-Counter (OTC) sunscreen monograph using FDA's new Generally Recognized as Safe and Effective (GRASE) testing guidelines. An in vitro skin permeation test (IVPT) and clinical pilot pharmacokinetic Maximum Usage Trial (MUsT) were completed to support the GRASE determination for 6% BEMT. IVPT results indicated an oil +10% ethanol as the model sunscreen intervention for the pilot MUsT. The open-label trial revealed: BEMT concentrations rarely exceeded FDA's defined threshold (0.5 ng/mL) in plasma; no evidence for BEMT accumulation or steady-state concentrations above threshold; only one moderate and few mild treatment emergent adverse events (TEAEs). Therefore, maximal topical applications of 6% BEMT in a model sunscreen formulation did not contribute to meaningful systemic exposure. These results support the safety of BEMT 6% for human sunscreen use.

Measurement of cardiovascular and pulmonary function endpoints and other physiological effects following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers.

Acute changes in select physiological parameters associated with cardiovascular physiology (systolic and diastolic blood pressure (BP) and heart rate (HR)), pulmonary function (FVC, FEV1, and exhaled CO and NO) and adverse events were measured in 105 clinically confined subjects who were randomized into groups that either completely or partially switched from conventional cigarettes to e-cigarettes or completely discontinued using tobacco and nicotine products altogether. Use of the e-cigarettes for five days under the various study conditions did not lead to higher BP or HR values, negative respiratory health outcomes or serious adverse health events. Reductions in BP and HR vital signs were observed in most of the participants that either ceased tobacco and nicotine products use altogether or switched completely to using e-cigarettes. Pulmonary function tests showed small but non-statistically significant improvements in FVC and FEV1 measurements in most use groups. Statistically significant (p < 0.05) benefits associated with smoking reduction were also noted in exhaled CO and NO levels. All study products were well tolerated. The study findings suggest that there are potential cardiovascular and pulmonary function benefits when smokers switch to using e-cigarette products. This further reinforces the potential that e-cigarettes offer smokers seeking an alternative to conventional tobacco products.

Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers.

Changes in fifteen urine, blood and exhaled breath BoEs of HPHCs representing classes of compounds reported by FDA to be significant contributors to smoking-associated disease risks were measured in 105 clinical-confined subjects following randomization and a five-day forced-switch from usual brand conventional combustible cigarettes to: (i) exclusive commercial e-cigarette use; (ii) dual-use of commercial e-cigarettes and the subject's usual cigarette brand; or (iii) discontinued use of all tobacco or nicotine products. Levels of urinary biomarkers in subjects that completely substituted their usual cigarette with e-cigarettes were significantly lower (29-95%) after 5 days. Percent reductions in eight of nine urinary BoEs were indistinguishable to smokers who had quit smoking, except for nicotine equivalents, which declined by 25-40%. Dual users who halved self-reported daily cigarette consumption with e-cigarettes exhibited reductions (7-38%) in eight of nine urinary biomarkers, but had increase (1-20%) in nicotine equivalents. Reductions were broadly proportional to the reduced numbers of cigarettes smoked. Dual user urinary nicotine equivalents were slightly higher, but not statistically significant. After 5 days, blood nicotine biomarker levels were lower in the cessation (75-96%) and exclusive use groups (11-83%); with dual users experiencing no significant reductions. All subjects experienced significant decreases in exhaled CO. Decreases in the cessation and exclusive groups ranged from 88-89% and 27-32% in dual users. Exhaled NO increased in the cessation and exclusive groups (46-63% respectively), whereas the dual users experienced minimal changes. Overall, smokers who completely or partially substituted conventional cigarettes with e-cigarettes over five days, experienced reductions in HPHCs.

Reductions in biomarkers of exposure, impacts on smoking urge and assessment of product use and tolerability in adult smokers following partial or complete substitution of cigarettes with electronic cigarettes.

BACKGROUND: Electronic cigarettes (e-cigarettes) are popular alternatives to conventional cigarettes among adult smokers wishing to reduce their exposure to harmful smoke constituents. However, little information exists on the relative internal exposures resulting from the exclusive or dual use of e-cigarettes. METHODS: Measurements of product use; adverse events; changes in smoking urge; and blood, urine and exhaled breath biomarkers of exposure (BoE) representing toxicants believed to contribute to smoking related diseases were made at baseline and after five days of product use in 105 clinically-confined smokers randomized into groups that partially or completely substituted their usual brand combustible cigarette with commercial e-cigarettes, or discontinued all nicotine and tobacco products. RESULTS: Subjects switching to e-cigarettes had significantly lower levels (29 %-95 %) of urinary BoEs after 5 days. Nicotine equivalents declined by 25 %-40 %. Dual users who substituted half of their self-reported daily cigarette consumption with e-cigarettes experienced 7 %-38 % reductions, but had increases (1 %-20 %) in nicotine equivalents. Blood nicotine biomarker levels were lower in the cessation (75 %-96 %) and e-cigarette use groups (11 %-83 %); dual users had no significant reductions. All groups experienced significant decreases in exhaled CO (27 %-89 %). Exhaled NO increases (46 %-63 %) were observed in the cessation and e-cigarette use groups; dual users had minimal changes. By Day 5, all groups had greater reductions in smoking urge compared to cessation. However, reductions were larger in the dual use group. No serious adverse events were observed. CONCLUSIONS: Exposures to harmful smoke toxicants were observed to be lower in smokers who completely or partially replaced their cigarettes with e-cigarettes over five days.

Nicotine delivery, tolerability and reduction of smoking urge in smokers following short-term use of one brand of electronic cigarettes.

BACKGROUND: This randomized, partially single-blinded, 6-period crossover clinical study of adult smokers compared the nicotine pharmacokinetics, impacts on smoking urge and tolerability of various formulations of one brand of e-cigarettes with that of a tobacco cigarette. METHODS: Five e-cigarettes with different e-liquid formulations containing 1.6 % and 2.4 % nicotine and a conventional tobacco cigarette were randomized among 24 subjects under two exposure sessions consisting of a 30-min controlled and a one-hour ad lib use period to assess plasma nicotine levels, impacts on smoking urge and adverse events. The 30-min controlled use session comprised an intensive use of the e-cigarettes with a total of 50 puffs taken every 30 s for comparison to a single conventional cigarette having a typical machine-measured nicotine yield (~0.8 mg). Ad lib product use conditions provided insight into more naturalistic product use behaviors and their accompanying smoking urge reductions. Adverse events (AEs) were assessed by the Principal Investigator. RESULTS: Significant (p < 0.05) increases in plasma nicotine concentrations occurred within 10 min of controlled e-cigarette use and significant (p < 0.001) reductions from baseline smoking urge were observed within 5 min. E-cigarette and cigarette nicotine plasma levels were comparable for up to one hour of use. After both sessions (90 min), nicotine exposure was the highest for the cigarette, with all e-cigarettes showing 23 % to 53 % lower plasma concentrations. During controlled use, peak reduction in smoking urge for e-cigs occurred later than for the cigarette. After completion of both sessions, significant smoking urge reduction persisted for most of the tested e-cigarettes, albeit at levels lower than that provided by the tobacco cigarette. Nicotine content, vehicle differences, and the presence of menthol did not significantly affect smoking urge reduction by the e-cigarettes. No subjects were discontinued due to AEs. The most frequently reported AEs events included cough, throat irritation, headache, and dizziness. CONCLUSIONS: Blood plasma nicotine levels obtained from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine were significant, but lower than those of conventional tobacco cigarettes, yet the reduction in craving symptoms were broadly comparable. The types of AEs were consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated. TRIAL REGISTRATION: http://ClinicalTrials.gov identifier: NCT02210754 . Registered 8 August 2014.