Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide: A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study.

INTRODUCTION: This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on blood/urine biomarkers and cerebral activity. METHODS: Participants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose. RESULTS: The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG). CONCLUSION: NX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing.

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aß25 - 35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aß1 - 42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aß25 - 35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aß25 - 35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.

Different phenotypes and factors associated with atopic dermatitis in the young adult Singaporean Chinese population: A cross-sectional study.

BACKGROUND: Atopic dermatitis (AD) is a chronic allergic disease typically accompanied by atopy and thus, a tendency to develop allergic diseases such as allergic rhinitis, asthma or food allergies. Currently, individuals with AD are classified into those presenting with AD alone and those presenting with AD along with other allergic diseases (AD+). It is important to identify the various endophenotypes of AD using anthropometric, environmental, socio-economic, and disease history data in order to improve disease management. To characterize the phenotypic differences among Singaporean Chinese individuals with AD alone and AD+, and identify the socioeconomic, lifestyle, and environmental factors associated with these different presentations. METHODS: Based on data collected via a standardized/validated questionnaire, 4604 participants (mean age: 22.1 years) were classified into three groups: 1) AD alone group; 2) AD with other allergic diseases group (AD+); and 3) Control group. RESULTS: Participants were less sensitized to common inhalant allergens in the AD alone group versus the Control group (67% vs. 72%, respectively; p < 0.05).High Body Mass Index (i.e., BMI > 23) was associated with the disease and the difference was more pronounced in the AD alone group compared to the AD+ group (Odds Ratio: 1.38; 95% Confidence Interval: 1.4-1.67; p < 0.001). No major differences in habits were observed between the AD alone and AD+ groups. CONCLUSIONS: The two presentations of AD may have different underlying pathogenesis and associated risk factors.

Brimonidine displays anti-inflammatory properties in the skin through the modulation of the vascular barrier function.

BACKGROUND: Rosacea is a chronic inflammatory skin disease. Characteristic vascular changes in rosacea skin include enlarged, dilated vessels of the upper dermis and blood flow increase. Brimonidine is approved for symptomatic relief of the erythema of rosacea. It acts by selectively binding to α2-adrenergic receptors present on smooth muscle in the peripheral vasculature, resulting in transient local vasoconstriction. OBJECTIVES: To provide further evidence of the anti-inflammatory potential of brimonidine across preclinical models of skin inflammation and its ability to decrease the neutrophil infiltration in human skin after ultraviolet light exposure. METHODS: The anti-inflammatory properties of brimonidine through modulation of the vascular barrier function were assessed using in vivo neurogenic vasodilation and acute inflammatory models and a well-described in vitro transmigration assay. A clinical study assessed the neutrophil infiltration in human skin after exposure to UV in 37 healthy Caucasian male subjects. RESULTS: In vitro, brimonidine affects the transmigration of human neutrophils through the endothelial barrier by modulating adhesion molecules. In vivo, in the mouse, topical treatment with brimonidine, used at a vasoconstrictive dose, confirmed its anti-inflammatory properties and prevented leucocyte recruitment (rolling and adhesion) mediated by endothelial cells. Topical pretreatment with brimonidine tartrate 0.33% gel once a day for 4 days significantly prevented neutrophil infiltration by 53.9% in human skin after exposure to UV light. CONCLUSION: Results from in vitro, in vivo and from a clinical study indicate that brimonidine impacts acute inflammation of the skin by interfering with neurogenic activation and/or recruitment of neutrophils.

Decrease in Diversity of Propionibacterium acnes Phylotypes in Patients with Severe Acne on the Back.

Propionibacterium acnes, a major member of normal skin microbiota, is subdivided into 6 phylotypes: IA1, IA2, IB, IC, II and III. This study investigated P. acnes subgroups on the face and back in patients with severe acne and in healthy controls. In 71.4% of patients with severe acne, P. acnes phylotypes were identical on the face and back, whereas this was the case in only 45.5% of healthy controls. The healthy group carried phylotypes IA1 (39.1%) and II (43.4%), whereas the acne group carried a high predominance of IA1 (84.4%), especially on the back (95.6%). In addition, the single-locus sequence typing (SLST) method revealed A1 to be the predominant type on the back of patients with acne, compared with a wide diversity in the healthy group. We report here that severity of acne on the back is associated with loss of diversity of P. acnes phylotype, with a major predominance of phylotype IA1. The change in balance of cutaneous P. acnes subgroups might be an inducing factor in the activation of P. acnes, which could trigger inflammation.

Prospective Study of Pathogenesis of Atrophic Acne Scars and Role of Macular Erythema.

BACKGROUND: There are few studies on the natural history of acne lesions including the antecedents of atrophic scars.

STUDY DESIGN: Prospective study of relationship between primary (papules, pustules, comedones) and secondary lesions (atrophic scars, macular erythema, and hyperpigmentation) over 6 months. Subjects (n=32) had moderate facial acne including 10 or more atrophic acne scars and were their own control via randomized split-face design. Lesions were mapped 2x/week for 2 months and every 2 weeks thereafter until month 6 to track pathogenic progression.

RESULTS: Clinical assessment showed acne scars continuously forming throughout the 6-month study period. While the majority (66.2%) of these scars did not resolve by study endpoint, the remainder were transient. The likelihood of a scar developing from a primary acne lesion was 5.7%, and almost all scars arose from erythematous macules or hyperpigmentation (83%) and some (16%) developed directly from papules and pustules. Duration of papules was a key factor in the risk of scarring. The majority (81.7%) of the scars remaining at 6 months were still present at 2-year follow-up.

CONCLUSIONS: Atrophic acne scars continuously form, some resolve, and evolve primarily from inflammatory and post-inflammatory lesions. Clinicians should closely monitor patients with macular erythema for scarring.

J Drugs Dermatol. 2017;16(6):566-572.

Effect of a lotion containing the heat-treated probiotic strain Lactobacillus johnsonii NCC 533 on Staphylococcus aureus colonization in atopic dermatitis.

OBJECTIVE: Staphylococcus aureus dominates the skin microbiota in patients with atopic dermatitis (AD), with bacterial loads correlating with disease severity. The aim of this exploratory study was to investigate the effect of a cosmetic lotion containing heat-treated Lactobacillus johnsonii NCC 533 (HT La1) on S. aureus colonization in AD patients. METHODS: This open-label, multicenter study was performed in AD patients in Germany. First, detection of S. aureus was performed in all patients using the swab or scrub-wash method of sampling, followed by quantitative culture or quantitative polymerase chain reaction. Repeatability and reproducibility of all method combinations were evaluated to select the best combination of sampling and quantification. Second, a lotion containing HT La1 was applied to lesional skin twice daily for 3 weeks. Scoring using local objective SCORing Atopic Dermatitis (SCORAD), measurement of S. aureus load, and lesional microbiome analysis were performed before and after the 3-week treatment period. RESULTS: Thirty-one patients with AD were included in the study. All sampling and quantification methods were found to be robust, reproducible, and repeatable for assessing S. aureus load. For simplicity, a combination of swab and quantitative polymerase chain reaction was chosen to assess the efficacy of HT La1. Following application of a lotion containing HT La1 to AD lesions for 3 weeks, a reduction in S. aureus load was observed in patients, which correlated with a decrease in local objective SCORAD. Interestingly, high baseline skin concentrations of S. aureus were associated with good responses to the lotion. CONCLUSION: This study demonstrated that the application of a lotion containing HT La1 to the lesional skin of patients with AD for 3 weeks controlled S. aureus colonization and was associated with local clinical improvement (SCORAD). These findings support further development of topical treatments containing heat-treated nonreplicating beneficial bacteria for patients with AD.

New Patient-Oriented Tools for Assessing Atrophic Acne Scarring.

INTRODUCTION: Scarring on visible areas such as the face is associated with negative psychological impact. Many patients with acne have clinically relevant scarring for which they seek treatment, implying that there is an impact on their lives. Currently there are no validated tools to assess the burden of atrophic acne scarring from the patient's perspective or to assess treatment benefit. METHODS: Two patient-reported outcome measures, the self-assessment of clinical acne-related scars (SCARS) and the facial acne scar quality of life (FASQoL) tools, both specific to facial atrophic acne scarring, were developed according to Food and Drug Administration guidance methodology. Patient interviews were conducted first to elicit patient-important concepts about scarring, then to validate patients' understanding of wording in the tools. These tools focus on symptoms (SCARS) and psychological and social well-being (FASQoL) and were designed to be suitable for self-completion and to be rapidly completed (2-5 min) within a clinical research setting. RESULTS: Concept elicitation interviews were conducted with 30 subjects and cognitive interviews with 20 subjects. With acne scarring, important concepts for patients included size, surface area affected, counts, and depth. The SCARS and FASQoL tools were shown to address relevant concepts that were easily understood by patients. CONCLUSION: Two patient-reported measures, SCARS and FASQoL, have been developed to help clinicians assess the severity and impact of acne scars. Responsivity of these instruments to treatment will require further evaluation. FUNDING: Galderma R&D, Sophia Antipolis, France.

Prediction of persistence of combined evidence-based cardiovascular medications in patients with acute coronary syndrome after hospital discharge using neural networks.

In the PREVENIR-5 study, artificial neural networks (NN) were applied to a large sample of patients with recent first acute coronary syndrome (ACS) to identify determinants of persistence of evidence-based cardiovascular medications (EBCM: antithrombotic + beta-blocker + statin + angiotensin converting enzyme inhibitor-ACEI and/or angiotensin-II receptor blocker-ARB). From October 2006 to April 2007, 1,811 general practitioners recruited 4,850 patients with a mean time of ACS occurrence of 24 months. Patient profile for EBCM persistence was determined using automatic rule generation from NN. The prediction accuracy of NN was compared with that of logistic regression (LR) using Area Under Receiver-Operating Characteristics-AUROC. At hospital discharge, EBCM was prescribed to 2,132 patients (44%). EBCM persistence rate, 24 months after ACS, was 86.7%. EBCM persistence profile combined overweight, hypercholesterolemia, no coronary artery bypass grafting and low educational level (Positive Predictive Value = 0.958). AUROC curves showed better predictive accuracy for NN compared to LR models.

Time-to-event analysis with artificial neural networks: an integrated analytical and rule-based study for breast cancer.

This paper presents an analysis of censored survival data for breast cancer specific mortality and disease-free survival. There are three stages to the process, namely time-to-event modelling, risk stratification by predicted outcome and model interpretation using rule extraction. Model selection was carried out using the benchmark linear model, Cox regression but risk staging was derived with Cox regression and with Partial Logistic Regression Artificial Neural Networks regularised with Automatic Relevance Determination (PLANN-ARD). This analysis compares the two approaches showing the benefit of using the neural network framework especially for patients at high risk. The neural network model also has results in a smooth model of the hazard without the need for limiting assumptions of proportionality. The model predictions were verified using out-of-sample testing with the mortality model also compared with two other prognostic models called TNG and the NPI rule model. Further verification was carried out by comparing marginal estimates of the predicted and actual cumulative hazards. It was also observed that doctors seem to treat mortality and disease-free models as equivalent, so a further analysis was performed to observe if this was the case. The analysis was extended with automatic rule generation using Orthogonal Search Rule Extraction (OSRE). This methodology translates analytical risk scores into the language of the clinical domain, enabling direct validation of the operation of the Cox or neural network model. This paper extends the existing OSRE methodology to data sets that include continuous-valued variables.

Development of a rule based prognostic tool for HER 2 positive breast cancer patients.

A three stage development process for the production of a hierarchical rule based prognosis tool is described. The application for this tool is specific to breast cancer patients that have a positive expression of the HER 2 gene. The first stage is the development of a Bayesian classification neural network to classify for cancer specific mortality. Secondly, low-order Boolean rules are extracted form this model using an Orthogonal Search based Rule Extraction (OSRE) algorithm. Further to these rules additional information is gathered from the Kaplan-Meier survival estimates of the population, stratified by the categorizations of the input variables. Finally, expert knowledge is used to further simplify the rules and to rank them hierarchically in the form of a decision tree. The resulting decision tree groups all observations into specific categories by clinical profile and by event rate. The practical clinical value of this decision support tool will in future be tested by external validation with additional data from other clinical centres.