RESUMO
Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.
RESUMO
BACKGROUND: Pregnant women have an increased risk for complications and hospitalizations when infected with the influenza virus in the second or third trimester. Additionally, infants under six months of age are most vulnerable when contracting pertussis. Immunization against influenza and pertussis during pregnancy provides protection for mother and neonate against influenza and for neonates against pertussis pending protection through infant immunization. In Belgium, a gradual increase in pertussis cases over the past decade was observed. This study was undertaken to document vaccination coverage for influenza and pertussis and factors related to vaccination status in pregnant women. METHODS: Two hundred and fifty pregnant women completed a questionnaire during their third trimester. Vaccination data were collected and reasons for non-vaccination were noted as well as socio-demographic data which are known to influence vaccination coverage. RESULTS: A documented vaccination coverage of 42.8% for influenza and 39.2% for pertussis was observed. Taking into account doses which were not documented, but administered according to the expectant mother, coverage for influenza would increase to 62% and for pertussis to 46%. The most important reasons for non-vaccination were the absence of a recommendation by medical staff (9.6%) and delay in vaccination (8.4%). The GP was the most important vaccinator. Pregnant women with a lower education and those with a foreign origin were more vulnerable for non-vaccination. CONCLUSION: Incomplete documentation is the most important barrier in determining the vaccination status of pregnant women. Immunization during pregnancy needs further integration through vaccination campaigns aimed at both health care providers and pregnant women.
