A randomised, parallel group clinical study was performed to evaluate the safety profile of an e-vapour product (EVP; 2.0% nicotine) in smokers of conventional cigarettes (CCs) switching to use the EVP for 12 weeks. During the study, no clinically significant product-related findings were observed in terms of vital signs, electrocardiogram, lung function tests and standard clinical laboratory parameters. Adverse events (AEs) reported by EVP subjects were more frequent during the first week after switching to the EVP. The frequency of AEs reduced thereafter and out of a total of 1515 reported AEs, 495 were judged as being related to nicotine withdrawal symptoms. The most frequently stated AEs were headache, sore throat, desire to smoke and cough reported by 47.4, 27.8, 27.5 and 17.0% of subjects, respectively. Only 6% of AEs were judged as probably or definitely related to the EVP. Additional observations in EVP subjects included a decrease in the level of urine nicotine equivalents by up to 33.8%, and decreases in the level of three biomarkers of exposure to toxicants known to be present in CC smoke (benzene, acrolein and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone). The decrease in nicotine equivalents coincided with an increase in nicotine withdrawal symptoms, measured by a questionnaire, which subsided after two weeks. The data presented here shows the potential EVPs may offer smokers looking for an alternative to CCs.
External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1). Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-ζ) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1 could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.
Antihistamines have been in clinical use for more than 70 years to treat allergic and nonallergic symptoms including relief from cold and flu symptoms. Despite their widespread use, pharmacokinetic (PK) data are sparse for older, first-generation antihistamines. This phase 1 single-center open-label, randomized, single-dose, 3-way crossover trial evaluated the PK profiles of 2 doses of film-coated triprolidine caplets (2.5 and 5 mg) compared with a reference combination tablet (triprolidine 2.5 mg + pseudoephedrine 60 mg) in 24 healthy adults. Blood samples were collected predose and at specified intervals across a 24-hour period after administration, and triprolidine was quantified using liquid chromatography-tandem mass spectrometry. Maximum plasma concentration of triprolidine for the 2.5 mg and dose-normalized 5 mg single-agent tablets were comparable (8.4 versus 7.1 ng/mL, respectively) and higher for the combination tablet (9.5 ng/mL). PK parameters, including time to maximum plasma concentration (ß1.5 hours) and elimination half-life (ß4 hours), were comparable between the 3 treatment arms. The safety profile of this sedating antihistamine was as expected; however, adverse effects were reported in a markedly higher proportion of women than men. There were no significant sex differences in any of the measured PK parameters.
Triprolidine, a first‐generation antihistamine for allergic rhinitis, has a shorter half‐life and fewer persistent effects relative to other antihistamines and may be useful in the treatment of temporary sleep disturbance. Patients aged ≥18 years old were randomized 1:1:1 to receive either triprolidine 2.5 mg (n = 65), triprolidine 5 mg (n = 66), or placebo (n = 67) on 3 consecutive nights. Sleep disturbance index was monitored via wrist actimeter. Subjective measures were assessed via diary card. Triprolidine 2.5 mg had a significantly lower sleep disturbance index versus placebo on night 1 (P = .02); however, when adjusted for outliers, sleep disturbance index did not significantly differ between either dose of triprolidine versus placebo on night 1. Adjusted sleep disturbance index was significantly lower with triprolidine 2.5 and 5 mg versus placebo on night 3 (P = .0017 and P = .011, respectively) and for the mean of all 3 nights (P = .01 and P = .015, respectively). Sleep latency was significantly improved for triprolidine 2.5 mg versus placebo on nights 2 and 3 and for the mean of all 3 nights and for triprolidine 5 mg versus placebo for the mean of all 3 nights. Subjective measures showed those on both doses of triprolidine felt more refreshed on awakening versus placebo for the mean of all 3 nights, with no increase in daytime sleepiness. The frequency of adverse events was similar across groups. The optimum dose of triprolidine for treatment of temporary sleep disturbance was 2.5 mg. There were improvements in both objective and subjective measures of sleep quality versus placebo, with no safety concerns raised.
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