Mechanisms of Pain Hypersensitivity in a Human Skin Inflammation Model - A Double-blind, Randomized, Placebo-controlled Crossover Study
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 42
- Locations
- 1
- Primary Endpoint
- Skin Perfusion
Study Overview
Brief Summary
The main goal of this double-blind, randomized, placebo-controlled crossover study is to understand the molecular mechanisms of inflammation-induced increased pain sensitivity (hyperalgesia). These mechanisms are studied using a recently established human model of skin inflammation that mimics aspects of skin infection. A localized inflammatory response in the skin of healthy volunteers is elicited by locally injecting a small, safe dose of Lipopolysaccharide (LPS), a major component of gram-negative bacteria.
The study addresses three key research questions:
- Role of RAGE: To investigate if certain inflammatory effects of LPS, which contribute to hyperalgesia, are mediated by a signaling pathway involving the RAGE receptor.
- Pain Sensitization: To examine how skin inflammation affects pain caused by acidic stimuli, and to differentiate this from purely mechanical pain.
- Role of TRPV1: To determine if the contribution of the TRPV1 ion channel to acid-induced pain is different in inflamed skin.
Participants will undergo an experimental session 4.5 hours after LPS injection to measure skin blood flow (using laser speckle imaging), mechanical pain sensitivity (using specialized tweezers), and pain induced by injecting a solution, of which the pH is gradually decreasing (acid-induced pain).
The study has minimal risks due to the small, safe doses of substances used ('microdosing') and aims to lay the groundwork for developing new treatments for inflammatory pain conditions.
Detailed Description
Inflammation is recognized as a major contributor to both acute and chronic pain conditions. To develop new treatments for inflammatory pain, it is essential to understand the underlying molecular mechanisms. The skin is particularly suitable for such studies due to its accessibility. This study builds on a previously established human skin model that reflects the proinflammatory aspects of skin infection, aiming to investigate the mechanisms of inflammation-induced hyperalgesia, using various painful stimuli.
Skin and soft tissue infections encompass a range of conditions caused by gram-positive and gram-negative bacteria, often involving multiple pathogens. These infections can range from superficial and relatively harmless, like furuncles, to severe and life-threatening, such as necrotizing fasciitis. Lipopolysaccharide (LPS), an immunogen component of gram-negative bacterial cell walls, is commonly used in clinical research. LPS induces a strong immune response and has been safely applied in human studies both intravenously and intradermally. When injected intradermally at doses of 5-15 ng, LPS produces localized inflammatory lesions that resolve within 48 hours and do not cause systemic symptoms (CITs).
LPS acts mainly through Toll-like receptor 4 (TLR4) on immune cells, but also potentially through the receptor for advanced glycation end products (RAGE; CIT), which may directly sensitize sensory neurons (CIT). This study uses co-injection of the RAGE antagonist Azeliragon to explore the role of RAGE in LPS-induced hyperalgesia. The TLR4 antagonist Resatorvid will also be tested by co-injection. Determining the involvement of these signalling pathways could guide the development of future therapeutic agents.
A prior exploratory pilot study (n = 12) mapped the time course and degree of pain hypersensitivity following LPS application using laser speckle imaging to measure hyperemia, a contact heat stimulus to study potential thermal hyperalgesia, tweezers to study potential mechanical hyperalgesia and intradermal acidic injections to study acid-induced pain. The current study builds on this to assess whether LPS-induced hyperalgesia is mediated, at least in part, through RAGE-dependent pathways. In addition, the involvement of transient receptor potential cation channel subfamily V member 1 (TRPV1) in acid-induced pain will be investigated in the inflammation model, by co-injecting TRPV1 antagonist BCTC with the acidified solution. Previous research showed that injection of acidic fluid induces pain in non-inflamed skin, which is fully TRPV1-dependent (CIT), but it remains unclear whether this also applies to an inflamed condition.
Study objective and hypotheses The aim of this study is to elucidate the mechanisms of LPS-induced hyperalgesia, which leads to three independent research questions.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Masking Description
To ensure double-blind conditions, all solutions are prepared and numbered by an independent laboratory technician who is not involved in the experiment. Both the participants and the experimenter are blinded to the injected substances (LPS, Azeliragon, Resatorvid, BCTC) and to whether solutions contain neutral or acidic solutions for the acid-induced pain model. Familiarization injections are administered unblinded for safety and tolerability assessment. Blinding is maintained until the end of each subject's participation. Randomization sequences are generated and stored separately and are only accessible to unblinded personnel in case of emergency.
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Age between 18 and 70 years
- •Full legal capacity
Exclusion Criteria
- •Participant of another study, ongoing or within the last four weeks
- •Current medication intake (except hormonal contraception) or drug abuse
- •Female subjects: Positive pregnancy test or breastfeeding
- •Body temperature above 38°C, diagnostically verified
- •Known allergic diseases, in particular asthmatic disorders and skin diseases
- •Sensory deficit, skin disease or hematoma of unknown origin in the physical examination of the test site
- •Symptoms indicating respiratory tract infection
Arms & Interventions
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #01
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (neutral pH)
- SIF (acidic pH)
- LPS + RES (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH)
- LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #03
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH + BCTC)
- LPS (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH)
- SIF (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + RES (acidic pH)
- LPS + AZE (neutral pH)
- LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #04
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH + BCTC)
- LPS (acidic pH + BCTC)
- SIF (acidic pH)
- LPS + AZE (neutral pH)
- SIF (neutral pH)
- LPS + AZE (acidic pH)
- LPS + RES (acidic pH) 10. LPS + RES (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #05
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH)
- LPS (acidic pH + BCTC)
- LPS (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (acidic pH)
- SIF (acidic pH)
- LPS + RES (neutral pH)
- SIF (neutral pH) 10. LPS + RES (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #06
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (acidic pH)
- LPS + AZE (acidic pH)
- LPS (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH + BCTC)
- LPS + RES (acidic pH)
- SIF (acidic pH) 10. SIF (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #07
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (neutral pH)
- LPS + AZE (acidic pH)
- LPS (acidic pH + BCTC)
- LPS + RES (neutral pH)
- LPS (acidic pH)
- LPS + RES (acidic pH)
- LPS (neutral pH)
- SIF (neutral pH)
- SIF (acidic pH + BCTC) 10. SIF (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #08
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + AZE (acidic pH)
- LPS + RES (neutral pH)
- LPS + AZE (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (acidic pH)
- SIF (acidic pH)
- LPS (neutral pH) 10. SIF (acidic pH + BCTC)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #09
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (neutral pH)
- LPS + RES (acidic pH)
- LPS + AZE (acidic pH)
- SIF (neutral pH)
- LPS + AZE (neutral pH)
- SIF (acidic pH)
- LPS (acidic pH + BCTC)
- SIF (acidic pH + BCTC)
- LPS (acidic pH) 10. LPS (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #10
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- LPS + RES (acidic pH)
- SIF (neutral pH)
- LPS + RES (neutral pH)
- SIF (acidic pH)
- LPS + AZE (acidic pH)
- SIF (acidic pH + BCTC)
- LPS + AZE (neutral pH)
- LPS (neutral pH)
- LPS (acidic pH + BCTC) 10. LPS (acidic pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF neutral pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng / SIF neutral pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng / SIF acidic pH + BCTC 1 µM (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH (Drug)
Sequence #02
Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows:
- SIF (acidic pH)
- SIF (acidic pH + BCTC)
- SIF (neutral pH)
- LPS (neutral pH)
- LPS + RES (acidic pH)
- LPS (acidic pH)
- LPS + RES (neutral pH)
- LPS (acidic pH + BCTC)
- LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)
Intervention: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH (Drug)
Outcomes
Primary Outcomes
Skin Perfusion
Time Frame: 4.5h after the (non-)LPS injections
The degree of hyperemia, quantified by laser speckle imaging, will be analyzed using ImageJ. The following steps describe the protocol for analyzing the (non-)inflamed spots of one forearm of a subject. To determine the volume under the surface (VUS, in analogy to an area under the curve, but for a 2-dimensional signal) of the flux change, for each of the previously injected skin spots a ROI covering the flow increase is adapted. The flux change (Δflux) is determined by subtracting from the average of the ROI the average signal of the surrounding forearm, and multiplying this with the ROI area. Any widespread or systemic change, which is not expected to occur, would be present in both the test site and the surrounding forearm and would therefore be corrected for by the chosen analysis approach. The analyzing person will be blinded concerning the type of injection. The variable is measured in arbitrary units (A.U.).
Secondary Outcomes
- Pain AUC(Between 4.5h and 5.5h after the (non-)LPS injections)
Investigators
Stefan Heber
Principal Investigator
Medical University of Vienna