Needle-free electronically-controlled jet injector treatment with bleomycin and lidocaine is effective and well-tolerated in patients with recalcitrant keloids.

OBJECTIVES: The treatment of recalcitrant keloids is challenging. Although intralesional bleomycin using conventional needle injectors (CNI) is effective, it has important drawbacks, such as the need for repetitive and painful injections. Therefore, we aimed to evaluate the effectiveness, tolerability and patient satisfaction of intralesional bleomycin with lidocaine administered with a needle-free electronically-controlled pneumatic jet-injector (EPI) in recalcitrant keloids. METHODS: This retrospective study included patients with recalcitrant keloids who had received three intralesional EPI-assisted treatments with bleomycin and lidocaine. Effectiveness was assessed using the Patient and Observer Scar Assessment Scale (POSAS) at baseline and four to six weeks after the third treatment. Additionally, treatment related pain scores numeric rating scale, adverse effects, patient satisfaction and Global Aesthetic Improvement Scale (GAIS) were assessed. RESULTS: Fifteen patients with a total of >148 recalcitrant keloids were included. The median total POSAS physician- and patient-scores were respectively 40 and 41 at baseline, and reduced with respectively 7 and 6-points at follow-up ( p < 0.001; p < 0.001). The median pain scores during EPI-assisted injections were significantly lower compared to CNI-assistant injections, (2.5 vs. 7.0, respectively ( p < 0.001)). Adverse effects were mild. Overall, patients were "satisfied" or "very satisfied" with the treatments (14/15, 93.3%). The GAIS was "very improved" in one patient, "improved" in nine patients and "unaltered" in four patients. CONCLUSIONS: EPI-assisted treatment with bleomycin and lidocaine is an effective, well tolerated, patient-friendly alternative for CNI in patients with recalcitrant keloid scars. Randomized controlled trials are warranted to confirm our findings and improve the clinical management of recalcitrant keloids.

The vulvar microbiome in lichen sclerosus and high-grade intraepithelial lesions.

Background: The role of the vulvar microbiome in the development of (pre)malignant vulvar disease is scarcely investigated. The aim of this exploratory study was to analyze vulvar microbiome composition in lichen sclerosus (LS) and vulvar high-grade squamous intraepithelial lesions (HSIL) compared to healthy controls. Methods: Women with vulvar lichen sclerosus (n = 10), HSIL (n = 5) and healthy controls (n = 10) were included. Swabs were collected from the vulva, vagina and anal region for microbiome characterization by metagenomic shotgun sequencing. Both lesional and non-lesional sites were examined. Biophysical assessments included trans-epidermal water loss for evaluation of the vulvar skin barrier function and vulvar and vaginal pH measurements. Results: Healthy vulvar skin resembled vaginal, anal and skin-like microbiome composition, including the genera Prevotella, Lactobacillus, Gardnerella, Staphylococcus, Cutibacterium, and Corynebacterium. Significant differences were observed in diversity between vulvar skin of healthy controls and LS patients. Compared to the healthy vulvar skin, vulvar microbiome composition of both LS and vulvar HSIL patients was characterized by significantly higher proportions of, respectively, Papillomaviridae (p = 0.045) and Alphapapillomavirus (p = 0.002). In contrast, the Prevotella genus (p = 0.031) and Bacteroidales orders (p = 0.038) were significantly less abundant in LS, as was the Actinobacteria class (p = 0.040) in vulvar HSIL. While bacteria and viruses were most abundant, fungal and archaeal taxa were scarcely observed. Trans-epidermal water loss was higher in vulvar HSIL compared to healthy vulvar skin (p = 0.043). Conclusion: This study is the first to examine the vulvar microbiome through metagenomic shotgun sequencing in LS and HSIL patients. Diseased vulvar skin presents a distinct signature compared to healthy vulvar skin with respect to bacterial and viral fractions of the microbiome. Key findings include the presence of papillomaviruses in LS as well as in vulvar HSIL, although LS is generally considered an HPV-independent risk factor for vulvar dysplasia. This exploratory study provides clues to the etiology of vulvar premalignancies and may act as a steppingstone for expanding the knowledge on potential drivers of disease progression.

The development of in vitro organotypic 3D vulvar models to study tumor-stroma interaction and drug efficacy.

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) is a rare disease with a poor prognosis. To date, there's no proper in vitro modeling system for VSCC to study its pathogenesis or for drug evaluation. METHODS: We established healthy vulvar (HV)- and VSCC-like 3D full thickness models (FTMs) to observe the tumor-stroma interaction and their applicability for chemotherapeutic efficacy examination. VSCC-FTMs were developed by seeding VSCC tumor cell lines (A431 and HTB117) onto dermal matrices harboring two NF subtypes namely papillary fibroblasts (PFs) and reticular fibroblasts (RFs), or cancer-associated fibroblasts (CAFs) while HV-FTMs were constructed with primary keratinocytes and fibroblasts isolated from HV tissues. RESULTS: HV-FTMs highly resembled HV tissues in terms of epidermal morphogenesis, basement membrane formation and collagen deposition. When the dermal compartment shifted from PFs to RFs or CAFs in VSCC-FTMs, tumor cells demonstrated more proliferation, EMT induction and stemness. In contrast to PFs, RFs started to lose their phenotype and express robust CAF-markers α-SMA and COL11A1 under tumor cell signaling induction, indicating a favored 'RF-to-CAF' transition in VSCC tumor microenvironment (TME). Additionally, chemotherapeutic treatment with carboplatin and paclitaxel resulted in a significant reduction in tumor-load and invasion in VSCC-FTMs. CONCLUSION: We successfully developed in vitro 3D vulvar models mimicking both healthy and tumorous conditions which serve as a promising tool for vulvar drug screening programs. Moreover, healthy fibroblasts demonstrate heterogeneity in terms of CAF-activation in VSCC TME which brings insights in the future development of novel CAF-based therapeutic strategies in VSCC.

Reflectance confocal microscopy as a non-invasive imaging tool in vulvar high-grade squamous intraepithelial lesions and lichen sclerosus: A descriptive morphological study in patients and healthy volunteers.

Incorrect and delayed diagnosis of vulvar high-grade squamous intraepithelial neoplasia (vHSIL) and lichen sclerosus (LS) increases malignant progression risks and negatively impacts prognosis and quality of life. There is a need to improve diagnosis and monitoring. Reflectance confocal microscopy is a non-invasive imaging tool that visualizes skin structures at cellular resolution. The objectives were to explore feasibility and patient acceptability of vulvar RCM imaging and to identify RCM characteristics that are discriminative for vulvar HSIL and LS. This was a prospective, cross-sectional, observational clinical trial in patients with vHSIL and LS compared to healthy volunteers. RCM images and vulvar tissue samples were obtained. Five (5) patients with vHSIL, 10 patients with LS and 10 healthy volunteers were enrolled. In total, 100 image series of vulvar skin were obtained, including lesional and nonlesional sites. The RCM technique was considered acceptable for application by patients and healthy controls. Healthy vulvar skin was characterized by a homogenous, normal honeycomb patterned epidermis and a clear epidermal-dermal junctions. Vulvar HSIL and LS displayed an atypical honeycomb pattern of the epidermis and lymphocytic influx with presence of melanophages. Distinct features specifically observed in LS included the presence of hyalinised vessels and sclerotic areas in the dermis. RCM is a non-invasive imaging technique that is feasible and clinically acceptable to apply on vulvar skin, both in patients with premalignant lesions and healthy controls. Recognition and validation of disease-specific characteristics could make reflectance confocal microscopy a clinical tool to non-invasively aid identification of vulvar premalignancies.

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.

Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. Cancers 2022, 14, 1510.

The authors wish to make the following corrections to this paper [...].

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.

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds.

Aim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology. Methods: Literature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic" was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety. Results: In total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays. Discussion: Healthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861.

A systematic review on disease-drug-drug interactions with immunomodulating drugs: A critical appraisal of risk assessment and drug labelling.

AIM: Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling. METHOD: For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions. RESULTS: Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases. CONCLUSION: This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-α) and interleukin-1 bèta (IL-1ß) in diseases with systemic inflammation.

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial.

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (Emax ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema Emax -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.

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-1ß, 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 Human Vulvar Microbiome: A Systematic Review.

The link between cancer and the microbiome is a fast-moving field in research. There is little knowledge on the microbiome in ((pre)malignant) conditions of the vulvar skin. This systematic review aims to provide an overview of the literature regarding the microbiome composition of the healthy vulvar skin and in (pre)malignant vulvar disease. This study was performed according to the PRISMA guidelines. A comprehensive, electronic search strategy was used to identify original research articles (updated September 2021). The inclusion criteria were articles using culture-independent methods for microbiome profiling of the vulvar region. Ten articles were included. The bacterial composition of the vulva consists of several genera including Lactobacillus, Corynebacterium, Staphylococcus and Prevotella, suggesting that the vulvar microbiome composition shows similarities with the corresponding vaginal milieu. However, the vulvar microbiome generally displayed higher diversity with commensals of cutaneous and fecal origin. This is the first systematic review that investigates the relationship between microbiome and vulvar (pre)malignant disease. There are limited data and the level of evidence is low with limitations in study size, population diversity and methodology. Nevertheless, the vulvar microbiome represents a promising field for exploring potential links for disease etiology and targets for therapy.

Integrin αvß6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions.

Surgical removal of vulvar squamous cell carcinoma (VSCC) is associated with significant morbidity and high recurrence rates. This is at least partially related to the limited visual ability to distinguish (pre)malignant from normal vulvar tissue. Illumination of neoplastic tissue based on fluorescent tracers, known as fluorescence-guided surgery (FGS), could help resect involved tissue and decrease ancillary mutilation. To evaluate potential targets for FGS in VSCC, immunohistochemistry was performed on paraffin-embedded premalignant (high grade squamous intraepithelial lesion and differentiated vulvar intraepithelial neoplasia) and VSCC (human papillomavirus (HPV)-dependent and -independent) tissue sections with healthy vulvar skin as controls. Sections were stained for integrin αvß6, CAIX, CD44v6, EGFR, EpCAM, FRα, MRP1, MUC1 and uPAR. The expression of each marker was quantified using digital image analysis. H-scores were calculated and percentages positive cells, expression pattern, and biomarker localization were assessed. In addition, tumor-to-background ratios were established, which were highest for (pre)malignant vulvar tissues stained for integrin αvß6. In conclusion, integrin αvß6 allowed for the most robust discrimination of VSCCs and adjacent premalignant lesions compared to surrounding healthy tissue in immunohistochemically stained tissue sections. The use of an αvß6 targeted near-infrared fluorescent probe for FGS of vulvar (pre)malignancies should be evaluated in future studies.

Omiganan Enhances Imiquimod-Induced Inflammatory Responses in Skin of Healthy Volunteers.

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%-30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%-2.83; P = 0.02). Interferon regulatory factor-driven and NFκB-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNÉ£), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases.

Results of phase 2 trials exploring the safety and efficacy of omiganan in patients with human papillomavirus-induced genital lesions.

AIMS: To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL). METHODS: Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire. RESULTS: Twenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%; P = .045) in AGW patients only. CONCLUSION: Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients.

An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine.

AIMS: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model. METHODS: In this double-blind, placebo-controlled, four-way cross-over trial, 12 healthy male subjects received oral mecamylamine 10 and 20 mg, intravenous scopolamine 0.5 mg and placebo. Pharmacokinetics were analysed using non-compartmental analysis. Pharmacodynamic effects were measured with a multidimensional test battery that includes neurophysiological, subjective, (visuo)motor and cognitive measurements. RESULTS: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml-1 for the 20 mg dose. Mecamylamine had a dose-dependent effect decreasing the adaptive tracking performance and VAS alertness, and increasing the finger tapping and visual verbal learning task performance time and errors. Scopolamine significantly affected almost all pharmacodynamic tests. CONCLUSION: This study demonstrated that mecamylamine causes nicotinic receptor specific temporary decline in cognitive functioning. Compared with the scopolamine model, pharmacodynamic effects were less pronounced at the dose levels tested; however, mecamylamine caused less sedation. The cognitive effects of scopolamine might at least partly be caused by sedation. Whether the mecamylamine model can be used for proof-of-pharmacology of nicotinic acetylcholine receptor agonists remains to be established.

Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.

A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine. Mecamylamine's estimated clearance was 0.28 ± 0.015 L min-1. The peripheral volume of distribution (291 ± 5.15 L) was directly related to total body weight. Mecamylamine impaired the accuracy and increased the reaction time in tests evaluating short term working memory with a steep increase in the concentration-effect relationship at plasma concentrations below 100 µg L-1. On the other hand, mecamylamine induced a decrease in performance of tests evaluating visual and fine motor coordination at higher plasma concentrations (EC50 97 µg L-1). Systolic and diastolic blood pressure decreased exponentially after a plasma mecamylamine concentration of 80 µg L-1, a known effect previously poorly studied in healthy subjects. The developed mecamylamine PKPD model was used to quantify the effects of nicotinic blockade in a set of neurophysiological tests in humans with the goal to provide insight into the physiology and pharmacology of the nicotinic system in humans and the possibility to optimize future trials that use mecamylamine as a pharmacological challenge.