Endothelial dysfunction is a potential target for (pharmaceutical) intervention of several systemic pathological conditions. We investigated the feasibility of the EndoPAT to evaluate acute changes in endothelial function with repeated noninvasive measurements and assessed its discriminating power in different populations. Endothelial function was stable over a longer period of time in renally impaired patients (coefficient of variation 13%). Endothelial function in renally impaired and type 2 diabetic patients was not decreased compared to healthy volunteers (2.9±1.4and1.8±0.3, resp., versus1.8±0.5,P>0.05). The EndoPAT did not detect an effect of robust interventions on endothelial function in healthy volunteers (glucose load: change from baseline0.08±0.50, 95% confidence interval −0.44 to 0.60; smoking: change from baseline0.49±0.92, 95% confidence interval −0.47 to 1.46). This suggests that at present the EndoPAT might not be suitable to assess (changes in) endothelial function in early-phase clinical pharmacology studies. Endothelial function as measured by the EndoPAT could be physiologically different from endothelial function as measured by conventional techniques. This should be investigated carefully before the EndoPAT can be considered a useful tool in drug development or clinical practice.

Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges.

Aims: Whereas intravenous administration of Toll‐like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24‐hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)‐6, IL‐8 and tumour necrosis factor response followed by IL‐1β, IL‐10 and interferon‐γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well‐tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti‐inflammatory investigational compounds in proof of pharmacology studies.

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty‐four healthy male volunteers received a two‐and‐a‐half‐day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two‐and‐a‐half‐day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti‐inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti‐inflammatory effects of such compounds in a minimally invasive manner.