Safety, pharmacokinetics and pharmacodynamics of selgantolimod, an oral Toll-like receptor 8 agonist: a Phase Ia study in healthy subjects.

BACKGROUND: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers. METHODS: Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3 or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, PK and PD activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted. RESULTS: Single doses of 0.5-5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose. CONCLUSIONS: Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB. Australian New Zealand Clinical Trials Registration: ACTRN12616001646437.

Comprehensive review of 2-ethyl-1-hexanol as an indoor air pollutant.

OBJECTIVES: 2-Ethyl-1-hexanol (2EH), a fragrance ingredient and a raw material for the production of plasticizer di(2-ethylhexyl) phthalate, is responsible for sick building syndrome (SBS). This review aims to clarify the 2EH characteristics as an indoor air pollutant such as indoor air concentration, emission mechanism, toxicity, and clinical effects. METHODS: Scientific publications in English that has been made available on PubMed as of June 2018 and ad hoc publications in regional languages were reviewed. RESULTS: Inhalation exposure to 2EH caused mucous membrane irritation in the eyes, nose, and throat in experimental animals. Studies in human volunteers revealed an increase in olfactory irritation and eye discomfort. There has been increasing evidence of 2EH being present in indoor air in buildings. The primary sources of 2EH emissions are not building materials themselves, but instead the hydrolysis of plasticizers and flooring adhesives. In particular, compounds like di(2-ethylhexyl) phthalate present in polyvinyl chloride flooring materials are hydrolyzed upon contact with alkaline moisture-containing concrete floors. That being said, it may be observed that indoor concentrations of 2EH increased every year during summer. CONCLUSIONS: Unlike other volatile organic compounds that cause SBS, 2EH can be retained in indoor air for long durations, increasing the likelihood of causing undesirable health effects in building occupants exposed to it. As a precautionary measure, it is important to use flooring materials that do not emit 2EH by hydrolysis, or to dry concrete before covering with flooring materials.

Annual transition and seasonal variation of indoor air pollution levels of 2-ethyl-1-hexanol in large-scale buildings in Nagoya, Japan.

2-Ethyl-1-hexanol (2E1H) is a possible causative chemical for sick building symptoms; however, thus far, we do not have a clear understanding of the indoor air pollution levels caused by it. In this study, first, airborne 2E1H concentrations were measured during summer and winter from 2004 to 2007 in 67 rooms of 56 large-scale buildings in Nagoya, Japan, in order to show the seasonal variation of indoor air pollution levels of 2E1H. Then, a follow-up survey was conducted in five rooms of five buildings for more than 2 years in order to establish the annual transition of their 2E1H indoor air pollution levels. 2E1H was found to be one of the predominant volatile organic compounds in the indoor air of large-scale buildings. Its geometric mean concentration was significantly higher during summer (55.4 microg/m3) than during winter (13.7 microg/m3) (p < 0.01), although there was a significant difference in the concentrations among the buildings. High 2E1H concentrations may have been caused by high emission rates of 2E1H from floors, because of the hydrolysis of di(2-ethylhexyl) phthalate in polyvinyl chloride flooring materials or of adhesives containing 2-ethylhexyl moieties. Follow-up observations showed little decrease in the indoor air 2E1H concentrations from one year to the next, although they did show seasonal fluctuations, with an evident increase in concentrations during summer and an evident decrease during winter.

From neurotoxic to chemosensory effects: new insights on acute solvent neurotoxicity exemplified by acute effects of 2-ethylhexanol.

Historically, acute solvent neurotoxicity was strongly related to reversible narcotic states that could be detected by neurobehavioral tests (e.g., simple reaction time). Nowadays, the occupational exposure to chemicals is markedly reduced and the avoidance of chemosensory effects is more important for the regulation of solvents. Exemplarily, this study examines if the chemosensory perception of 2-ethylhexanol is capable to distract performance in demanding neurobehavioral tasks. In two experiments three time-weighted average concentrations of 2-ethylhexanol (C(TWA): 1.5, 10, and 20 ppm) were investigated. In experiment A (n=24) variable concentrations over time (4h) were used, experiment B (n=22) investigated constant concentrations. The experiments were conducted in a 29 m3 exposure laboratory. Cross-over designs with randomized sequences of exposures were used. Among the 46 male participants 19 subjects reported enhanced chemical sensitivity; the other 27 subjects did not show this personality feature. During the exposure periods neurobehavioral tests were presented twice (beginning; end), the intensity of chemosensory perceptions were rated thrice. The intensity of chemosensory perceptions showed a clear dose-dependency. Subjects' performance in the vigilance test was not affected by the different exposures. Moreover, the results of neurobehavioral tests measuring executive function were neither affected by the C(TWA) concentration nor by the exposure peaks. With increasing C(TWA), a subgroup of the chemically sensitive subjects showed deteriorated accuracy in a divided attention task. Especially the 20 ppm conditions were very annoying. Only during the constant 10 ppm condition the time courses of the annoyance and nasal irritation ratings indicated some adaptation. In general, with the applied neurobehavioral tests distractive effects of acute 2-ethylhexanol exposures up to 20 ppm could not be confirmed. In sensitive groups such distractive effects of irritating solvents might be conceivable and moreover, in cooperation with researchers from cognitive neuroscience more sensitive functions and tests should be developed and incorporated.

A review of the environmental fate and aquatic effects of a series of C4 and C8 oxo-process chemicals.

Environmental fate and aquatic effects data were examined for a series of C4 (butyl acetate, 1-butanol, isobutyl alcohol) and C8 (2-ethylhexanol and 2-ethylhexanoic acid) oxo-process chemicals. Manufacturing of these chemicals requires enclosed equipment, so environmental releases are generally limited to volatilization during their use, handling or transport. C4 compounds are more soluble and volatile, and would bind to soil and sediment to a lesser extent than C8 compounds. All five compounds were readily biodegradable based on OECD and APHA tests conducted up to 28 days. Atmospheric photo-oxidation half-lives range from 0.43 to 3.8 days. Toxicity data show that all five compounds pose generally low concern to fish, invertebrates, algae, and microorganisms. Overall, the data show that inadvertent releases of these compounds into the environment would be rapidly biodegraded in soil and water, volatilize to the atmosphere subject to photo-oxidation, while any residues remaining in water would pose a negligible threat to aquatic life.

Asthma symptoms in relation to measured building dampness in upper concrete floor construction, and 2-ethyl-1-hexanol in indoor air.

SETTING: Asthma symptoms in adults in relation to the indoor environment. OBJECTIVES: To study the relationships between current asthma symptoms (wheeze or attacks of breathlessness) and the indoor environment and dampness in hospitals. DESIGN: A study among personnel (n = 87) in four geriatric hospitals in winter. Indoor air pollutants, dampness in the concrete floor, and allergens in settled dust were measured. Multiple logistic regression analysis was applied, adjusting for age, sex, atopy, and dampness in the participants' own dwellings. RESULTS: Current asthma symptoms were reported by 17%, and 8% had doctor's diagnosed asthma. Asthma symptoms were more common (adjusted odds ratio = 8.6; 95% confidence interval 1.3-56.7) in two buildings with signs of dampness-related degradation of di(ethylhexyl)-phthalate (DEHP) in polyvinyl chloride (PVC) floor material, detected as presence of 2-ethyl-1-hexanol (2-32 microg/m3) in indoor air (CAS nr 104-76-7). Asthma symptoms were related to higher relative humidity in the upper concrete floor construction, and ammonia in the floor. The newest hospital, built by an anthroposophic society, had low levels of dampness and few asthma symptoms (4%). Cat (Fel d1) and dog allergens (Can f1) were found in dust from all buildings (geometric mean 340 ng/g and 2490 ng/g, respectively). House dust mite allergens (Derp1, Derf1, or Derm1) were found in 75% of all samples (geometric mean 130 ng/g). There was no relationship between allergen levels and asthma symptoms. CONCLUSIONS: Asthma symptoms may be related to increased humidity in concrete floor constructions and emission of 2-ethyl-1-hexanol, an indicator of dampness-related alkaline degradation of plasticiser DEHP. Moreover, geriatric hospitals can be contaminated by significant amounts of cat, dog and mite allergens.