Intradermal substance P as a challenge agent in healthy individuals

Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose-dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking. This open-label, two-part, prospective enabling study of SP intradermal challenge in healthy participants aimed to understand and distinguish between wheal and flare responses following various SP doses. Part 1 included one challenge visit to determine optimum SP dose range for evaluation in part 2, which determined variability in 20 participants and used intradermal microdialysis (IDM) for SP-challenged skin sampling. At 5, 15, 50, and 150 pmol doses, respectively, posterior median area under the curve (AUC; AUC0-2h ) was 4090.4, 5881.2, 8846.8, and 9212.8 mm2 /min, for wheal response, and 12020.9, 38154.3, 65470.6, and 67404.4 mm2 /min for flare response (SP-challenge visit 2). When the challenge was repeated ~2 weeks later, no carryover effect was observed. IDM histamine levels were relatively low, resulting in low confidence in the data to define temporal characteristics for histamine release following SP challenge. No safety concerns were identified using SP. Wheal and flare responses following intradermal SP challenge were dose-dependent and different. The results indicate that this challenge model is fit-for-purpose in future first-in-human studies and further assessment of novel drugs targeting dermal inflammatory disease responses, such as chronic spontaneous urticaria, chronic inducible urticaria, and pseudo-allergic reactions.Drug Delivery Technolog

Dermatoscopy and Optical Coherence Tomography in Vulvar High-Grade Squamous Intraepithelial Lesions and Lichen Sclerosus:A Prospective Observational Trial

Objective This study aimed to examine potential discriminatory characteristics of dermatoscopy and dynamic optical coherence tomography (D-OCT) on vulvar high-grade squamous intraepithelial lesions (vHSIL) and lichen sclerosus (LS) compared with healthy vulvar skin. Methods A prospective observational clinical trial was performed in 10 healthy volunteers, 5 vHSIL and 10 LS patients. Noninvasive imaging measurements using dermatoscopy and D-OCT were obtained at several time points, including lesional and nonlesional vulvar skin. Morphologic features of vHSIL and LS were compared with healthy controls. Epidermal thickness and blood flow were determined using D-OCT. Patients reported tolerability of each study procedure, including reference vulvar biopsies. The main outcome measures were feasibility and tolerability of imaging modalities, dermatoscopy and OCT characteristics, OCT epidermal thickness and D-OCT dermal blood flow. Results The application of dermatoscopy and D-OCT is feasible and tolerable. In vHSIL, dermatoscopic warty structures were present. In LS, sclerotic areas and arborizing vessels were observed. Structural OCT in the vulvar area aligned with histology for hyperkeratosis and dermal-epidermal junction visualization. Currently, the OCT algorithm is unable to calculate the epidermal thickness of the uneven vulvar area. Dynamic optical coherence tomography showed statistically significant increased blood flow in LS patients (mean ± SD, 0.053 ± 0.029) to healthy controls (0.040 ± 0.012; p =.0024). Conclusions The application of dermatoscopy and D-OCT is feasible and tolerable in vHSIL and LS patients. Using dermatoscopy and D-OCT, the authors describe potential characteristics to aid differentiation of diseased from healthy vulvar skin, which could complement clinical assessments.</p

Comparison of a flexible versus a rigid breast compression paddle: pain experience, projected breast area, radiation dose and technical image quality

To compare pain, projected breast area, radiation dose and image quality between flexible (FP) and rigid (RP) breast compression paddles. The study was conducted in a Dutch mammographic screening unit (288 women). To compare both paddles one additional image with RP was made, consisting of either a mediolateral-oblique (MLO) or craniocaudal-view (CC). Pain experience was scored using the Numeric Rating Scale (NRS). Projected breast area was estimated using computer software. Radiation dose was estimated using the model by Dance. Image quality was reviewed by three radiologists and three radiographers. There was no difference in pain experience between both paddles (mean difference NRS: 0.08 ± 0.08, p = 0.32). Mean radiation dose was 4.5 % lower with FP (0.09 ± 0.01 p = 0.00). On MLO-images, the projected breast area was 0.79 % larger with FP. Paired evaluation of image quality indicated that FP removed fibroglandular tissue from the image area and reduced contrast in the clinically relevant retroglandular area at chest wall side. Although FP performed slightly better in the projected breast area, it moved breast tissue from the image area at chest wall side. RP showed better contrast, especially in the retroglandular area. We therefore recommend the use of RP for standard MLO and CC view

A multimodal, comprehensive characterization of a cutaneous wound model in healthy volunteers

Development of pharmacological interventions for wound treatment is challenging due to both poorly understood wound healing mechanisms and heterogeneous patient populations. A standardized and well-characterized wound healing model in healthy volunteers is needed to aid in-depth pharmacodynamic and efficacy assessments of novel compounds. The current study aims to objectively and comprehensively characterize skin punch biopsy-induced wounds in healthy volunteers with an integrated, multimodal test battery. Eighteen (18) healthy male and female volunteers received three biopsies on the lower back, which were left to heal without intervention. The wound healing process was characterized using a battery of multimodal, non-invasive methods as well as histology and qPCR analysis in re-excised skin punch biopsies. Biophysical and clinical imaging read-outs returned to baseline values in 28 days. Optical coherence tomography detected cutaneous differences throughout the wound healing progression. qPCR analysis showed involvement of proteins, quantified as mRNA fold increase, in one or more healing phases. All modalities used in the study were able to detect differences over time. Using multidimensional data visualization, we were able to create a distinction between wound healing phases. Clinical and histopathological scoring were concordant with non-invasive imaging read-outs. This well-characterized wound healing model in healthy volunteers will be a valuable tool for the standardized testing of novel wound healing treatments

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers

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

Surgical repair of distal biceps tendon ruptures : a biomechanical comparison of two techniques

PURPOSE: To compare pain, projected breast area, radiation dose and image quality between flexible (FP) and rigid (RP) breast compression paddles. METHODS: The study was conducted in a Dutch mammographic screening unit (288 women). To compare both paddles one additional image with RP was made, consisting of either a mediolateral-oblique (MLO) or craniocaudal-view (CC). Pain experience was scored using the Numeric Rating Scale (NRS). Projected breast area was estimated using computer software. Radiation dose was estimated using the model by Dance. Image quality was reviewed by three radiologists and three radiographers. Results : There was no difference in pain experience between both paddles (mean difference NRS: 0.08 +/- 0.08, p = 0.32). Mean radiation dose was 4.5 % lower with FP (0.09 +/- 0.01 p = 0.00). On MLO-images, the projected breast area was 0.79 % larger with FP. Paired evaluation of image quality indicated that FP removed fibroglandular tissue from the image area and reduced contrast in the clinically relevant retroglandular area at chest wall side. CONCLUSIONS: Although FP performed slightly better in the projected breast area, it moved breast tissue from the image area at chest wall side. RP showed better contrast, especially in the retroglandular area. We therefore recommend the use of RP for standard MLO and CC views