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.

Metabolism and disposition of 2-ethylhexyl-p-methoxycinnamate following oral gavage and dermal exposure in Harlan Sprague Dawley rats and B6C3F1/N mice and in hepatocytes in vitro.

1. 2-Ethylhexyl-p-methoxycinnamate (EHMC) is commonly used as an ingredient in sunscreens, resulting in potential oral and dermal exposure in humans. 2. Clearance and metabolism of EHMC in hepatocytes and disposition and metabolism of EHMC in rodents following oral (8-800 mg/kg) intravenous (IV) (8 mg/kg) or dermal (0.8-80 mg/kg representing 0.1-10% formulation concentration) exposure to [14C]EHMC were investigated in rats and mice. 3. EHMC was rapidly cleared from rat and mouse hepatocytes (half-life ≤3.16 min) and less rapidly (half-life ≤48 min) from human hepatocytes. 4. [14C]EHMC was extensively absorbed and excreted primarily in urine by 72 h after oral administration to rats (65-80%) and mice (63-72%). Oral doses to rats were excreted to a lesser extent (3-8%) in feces and as CO2 (1-4%). Radioactive residues in tissues were <1% of the dose. There were no sex or species differences in disposition in rats. 5. Following dermal application, 34-42% of an 8-mg/kg dose was absorbed in rats, and 54-62% in mice in 72-h. 6. Among numerous urinary metabolites associated with hydrolysis of the ester, two potential reproductive and developmental toxicants, 2-ethylhexanol and 2-ethylhexanoic acid were produced by metabolism of EHMC.

Synthesis, antidepressant activity, and toxicity of the erythro/threo racemates and optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol.

The erythro/threo racemates and their four optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol were synthesized and evaluated for their antidepressant activity, toxicity, and pharmacokinetics as novel triple multiple reuptake inhibitors of monoamine transmitters. The racemates and optical isomers were synthesized, respectively, through two different routes. Pharmacological data indicate that the erythro racemate (SIPI5357) that has better inhibitory activity and lower toxicity than the other racemate and optical isomers is worthy of further evaluation.

Chirality in anesthesia I: minimum alveolar concentration of secondary alcohol enantiomers.

Most studies of chirality in inhaled anesthetic action have used the enantiomers of isoflurane. These enantiomers are expensive and scarce, which limits studies, such as the preliminary identification of molecular targets of anesthetic action, that can be performed with these isomers. We hypothesized that secondary alcohols (i.e., compounds having a -CH2-CHOH-CH3 group) that are experimental anesthetics would show enantioselectivity. To test this hypothesis, we determined the minimum alveolar anesthetic concentration (MAC) of the enantiomers of the homologous series of 2-alcohols from 2-butanol to 2-heptanol in rats. Because these alcohols are partially metabolized to 2-ketones during the course of study (i.e., having a -CH2-CO-CH3 group), we independently measured the MAC of the 2-ketones. Assuming additivity of MAC of the ketones with the alcohols, we corrected for the anesthetic effect of the ketones in rats to determine the MAC of the alcohols. We found that the 2-butanol and 2-pentanol isomers were enantioselective. S-(+)-2-butanol had a MAC that was 17% larger than for the R-(-)-enantiomer, whereas S-(+)-2-pentanol had a MAC that was 38% larger than the R-(-)- enantiomer. No stereoselectivity was observed for 2-hexanol and 2-heptanol. These findings may permit studies of chirality in anesthesia, particularly in in vitro systems where metabolism does not occur, using inexpensive volatile compounds.

The effect of region of application on absorption of ethanol and hexanol through canine skin.

The effect of region of application on the percutaneous penetration of solutes with differing lipophilicity was investigated in canine skin. Skin from the thorax, neck, back, groin, and axilla regions was harvested from Greyhound dogs and placed in Franz-type diffusion cells. Radiolabelled (14C) ethanol (Log P 0.19) or hexanol (Log P 1.94) was applied to each skin section for a total of 5h. The permeability coefficient (kP, cm h(-1)) and residue of alcohol remaining in the skin were significantly (P=0.001) higher for hexanol compared to ethanol. In contrast, ethanol had a far greater maximum flux (Jmax, mol (cm2)(-1) h(-1)) than hexanol (P=0.001). A comparison of regional differences shows the kP and Jmax for ethanol in the groin was significantly lower (P=0.035) than the back. The kP and Jmax for hexanol were significantly higher (P=0.001) in the axilla than the other four skin sites. An understanding of factors influencing percutaneous drug movement is important when formulating topical preparations for the dog.

Effect of solute lipophilicity on penetration through canine skin.

OBJECTIVE: To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin. DESIGN: Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radiolabelled (14C) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19-3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (kP, cm/h), maximum flux (Jmax, mol/cm2/h) and residue remaining within the skin were determined. RESULTS: The kP increased with increasing lipophilicity (6.2 x 10(-4) +/- 1.6 x 10(-4) cm/h for ethanol to 1.8 x 10(-2) +/- 3.6 x 10(-3) cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. CONCLUSION: Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin.

The fate of leached di(2-ethylhexyl)phthalate in patients undergoing CAPD treatment.

OBJECTIVES: To evaluate the degree of exposure to and the fate of di(2-ethylhexyl)phthalate (DEHP) and its major derivatives mono(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid (PA) in patients undergoing regular continuous ambulatory peritoneal dialysis (CAPD) during a 4-hour dwell period. DESIGN: Prospective, controlled. SETTING: Teaching hospital, Department of Nephrology. PARTICIPANTS: Seven elderly patients on stable CAPD using Fresenius instruments and dialysate and 6 age-matched healthy controls. INTERVENTIONS: During a routinely performed peritoneal equilibration test (PET), blood and dialysate samples were drawn before and 120 and 240 min after the dwell was started. In addition, blood samples were taken from a group of volunteers participating in a pharmacological study. MEASUREMENTS: Quantitative analysis of DEHP and its hydrolysis products was performed by selected ion-monitoring gas chromatography/mass spectrometry, operating the mass spectrometer in a combined positive and negative ion chemical ionization mode. RESULTS: Serum concentrations of DEHP and PA were significantly higher in patients (median: 0.079 microgram/mL, range: 0.032-0.210 microgram/mL; and 0.167 microgram/mL, range: 0.097-0.231 microgram/mL, respectively) than in controls [0.0195 microgram/mL, range: 0.016-0.025 microgram/mL (p = 0.0027) and 0.0120 microgram/mL, range: 0.006-0.034 microgram/mL (p = 0.0026), respectively]. Concentration of MEHP in the fluid of CAPD bags prior to use was four times higher than that of the parent compound. During the first 4 hours of dwell time, the concentrations of MEHP and 2-EH in dialysate consistently decreased from 0.177 (range: 0.137-0.239 microgram/mL) to 0.022 microgram/mL (range: 0.005-0.058 microgram/mL) (p = 0.017), and from 0.087 (range: 0.075-0.097 microgram/mL) to 0.05 microgram/mL (range: 0.023-0.064 microgram/mL) (p = 0.017), respectively, while the concentration of DEHP remained stable. Remarkably high concentrations of PA (0.129 microgram/mL; range: 0.038-0.466 microgram/mL) were found in CAPD bags prior to use, and these concentrations tended to increase during dwell time, without statistical significance, however (0.135 microgram/mL; range: 0.073-0.659 microgram/mL, p = 0.062). CONCLUSIONS: Patients on CAPD are regularly exposed to considerable amounts of phthalic ester derivatives, mainly to MEHP and PA. MEHP seems to be well absorbed by the peritoneal membrane. The long-term effects of this exposure remain to be elucidated.

Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat.

1. Excretion balance studies were conducted with 2-ethylhexanol (2-EH) in female Fischer 344 rats following single high (500 mg/kg) and low (50 mg/kg) oral doses of [14C]2-EH, following repeated oral dosing with unlabelled 2-EH at the low level, following dermal exposure for 6 h with a 1 g/kg applied dose of [14C]2-EH, and following a 1 mg/kg i.v. dose of [14C]2-EH. 2. The high, low and repeated low oral dose studies with 2-EH showed similar excretion balance profiles of [14C], with some evidence of metabolic saturation at the high dose. 3. No evidence of metabolic induction was seen following the repeated low oral dosing. 4. All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 5. The dermal dosing resulted in only about 5% absorption of the 1 g/kg dose, with the major portion of the dose recovered unabsorbed from the dermal exposure cell at 6 h. 6. Urinary metabolites eliminated following the oral and dermal doses were predominantly glucuronides of oxidized metabolites of 2-EH, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.

On the mechanism of detergent modification of myosin structure and function.

The concentration dependences of the activation of myosin subfragment-1 (S1) Mg-ATPase by the detergents CHAPS and C12E8 were determined at 23 degrees C in 25 mM Tris (pH 7.0), 250 microM EDTA, 5 mM MgCl2, and 100 microM ATP. At detergent concentrations expected to bind hydrophobic S1 surface areas equally, C12E8 caused an 8.5-fold greater increase in activity than CHAPS, which suggests that detergent binding to the surface of S1 is not the mechanism of activation. At detergent concentrations above their critical micelle concentrations, C12E8 was also much more effective than CHAPS, suggesting that micelles are not involved. A series of n-alcohols (which do not form micelles) with from 3 to 10 carbons all increased S1 Mg-ATPase activity as much or more than C12E8. The largest increase (5.7-fold) was caused by n-hexanol. The more hydrophobic alcohols activated S1 at lower concentrations. A linear plot of the alcohol concentration that caused 50% of maximum activity versus the number of carbons in the alcohol, indicated the apparent free energy of binding per CH2-group was -0.60 +/- 0.03 kcal/mol. There were two indications that alcohol binding caused an S1 conformational change. The intrinsic fluorescence increase of S1 during steady-state activity was reduced from 17.5 to 12.8%, and the apparent hydrodynamic rotational mobility of fluorescently labeled S1 was decreased 25% by the present of n-hexanol. The data suggest that S1 activation by C12E8 and by n-alcohols is due to hydrophobic binding to S1 at non-surface sites, which causes an S1 structural change.

Limitations of hairless mouse skin as a model for in vitro permeation studies through human skin: hydration damage.

Hairless mouse skin currently provides a popular model membrane for studies in human percutaneous absorption. Although some similarities between the two skin types have been demonstrated, the effects of prolonged hydration on hairless mouse skin have not previously been rigorously examined. We have measured in vitro the effects of hydration at 31 degrees C on the permeabilities of hairless mouse skin and human abdominal and scalp skin to a model polar compound (water) and a lipid material (hexanol). The permeability of hairless mouse skin rose dramatically, especially to water (fiftyfold increase), whereas the human skin was more stable. We also compared the effects of stripping the stratum corneum with the effects of 8-d hydration for hairless mouse and human abdominal skin. Hydration of hairless mouse skin was as effective as tape-stripping in eliminating the stratum corneum barrier, whereas stripping human skin was far more damaging than hydration, suggesting that prolonged hydration mechanically disrupted mouse skin but not human skin. Histological examination of fresh and hydrated tissues confirmed this suggestion. We therefore recommend that hairless mouse skin is not used as a model for human tissue during in vitro permeation studies under conditions of long-term hydration, i.e., greater than three days.