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The objective of this randomised, double blinded clinical trial was to evaluate the efficacy of prophylactic administration of 4 mg ondansetron as monotherapy versus combination therapy of 4 mg ondansetron plus 8 mg dexamethasone for the prevention of intrathecal morphine-associated pruritus in caesarean section within 24 h. A total of 194 patients were included, 96 patients in the monotherapy group and 98 in the combination group. One hour after the operation, 11.5% of patients in ondansetron group had failure of prophylaxis for pruritus compared to 13.5% of patients in the combination group (

BACKGROUND Pruritus is one of the most common problems in patients with chronic renal failure. Of all patients with end-stage renal disease (ESRD), 60-80% report pruritus during their life. AIM To compare the effect of gabapentin (GBP) and hydroxyzine (HYDZ) in treating pruritus in patients on dialysis. METHODS In a double-blind, randomized, crossover clinical trial, 32 patients on dialysis who reported pruritus were assigned randomly to receive either GBP or HYDZ for 6 weeks; the first group received GBP 100 mg/day orally and the second group received HYDZ 25 mg/day orally for 6 weeks. After this 6-week period (Period 1) there was a washout period of 2 weeks then patients were crossed over to the other drug (the first group receiving HYDZ and second group receiving GBP) and followed up for a further 6 weeks (Period 2). A visual analogue scale was used to measure pruritus intensity in the groups before and after the first and second period. RESULTS In Period 1, pruritus severity decreased from 7.1 ± 1.46 at baseline to 2.17 ± 1.82 at 6 weeks in the GBP group (P = 0.001) and from 6.83 ± 2.11 to 2.86 ± 1.67 in the HYDZ group (P = 0.001). In Period 2, pruritus severity decreased from 5.1 ± 1.61 at baseline to 1.56 ± 0.82 at 6 weeks in the GBP group (P

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

Diminazene aceturate (DA) and imidocarb dipropionate are commonly used in livestock as antipiroplasm agents. However, toxic side effects are common in animals treated with these two drugs. Therefore, evaluations of novel therapeutic agents with high efficacy against piroplasm parasites and low toxicity to host animals are of paramount importance. In this study, the 400 compounds in the Pathogen Box provided by the Medicines for Malaria Venture foundation were screened against Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi. A fluorescence-based method using SYBR Green 1 stain was used for initial in vitro screening and determination of the half maximal inhibitory concentration (IC50). The initial in vitro screening performed using a 1 μM concentration as baseline revealed nine effective compounds against four tested parasites. Two “hit” compounds, namely MMV021057 and MMV675968, that showed IC50 100 were selected. The IC50s of MMV021057 and MMV675968 against B. bovis, B. bigemina, T. equi and B. caballi were 23, 39, 229, and 146 nM, and 2.9, 3, 25.7, and 2.9 nM, respectively. In addition, a combination of MMV021057 and DA showed additive or synergistic effects against four tested parasites, while combinations of MMV021057 with MMV675968 and of MMV675968 with DA showed antagonistic effects. In mice, treated with 50 mg/kg MMV021057 and 25 mg/kg MMV675968 inhibited the growth of Babesia microti by 54 and 64%, respectively, as compared to the untreated group on day 8. Interestingly, a combination treatment with 6.25 mg/kg DA and 25 mg/kg MMV021057 inhibited B. microti by 91.6%, which was a stronger inhibition than that by single treatments with 50 mg/kg MMV021057 and 25 mg/kg DA, which showed 54 and 83% inhibition, respectively. Our findings indicated that MMV021057, MMV675968, and the combination treatment with MMV021057 and DA are prospects for further development of antipiroplasm drugs., Graphical abstract Image 1, Highlights • Nine of 400 MMV compounds suppressed the in vitro growth of piroplasm parasites. • MMV021057 and MMV675968 showed effects similar to those of DA. • Combinations of MMV021057 and DA had additive or synergistic effects on parasites. • MMV021057 and MMV675968 moderately inhibited the growth of B. microti in mice. • A combination treatment with MMV021057 and DA highly inhibited B. microti in mice.

Thalidomide has been used as an effective treatment for prurigo nodularis (PN) with a median dose of 200 mg, but the risk of peripheral neuropathy precludes long-term use. We analysed the efficacy of low-dose thalidomide (< 100 mg) in 17 patients with recalcitrant PN. Patients were initiated on thalidomide 50 mg on alternate days, and the dose was increased (doubled) in a stepwise manner, if needed, until a ≥ 50% reduction in score (partial response; PR) on a visual analogue scale (VAS) was achieved. Thalidomide then was continued at the same dose for 4 weeks to achieve ≥ 90% decrease in VAS score; if this was not achieved, the dose was increased to a maximum of 100 mg and continued until complete resolution of lesions (complete response; CR). Four patients discontinued thalidomide due to adverse effects. Four patients achieved PR, while 9 patients (n = 2 with 50 mg, n = 7 with 100 mg) achieved CR. No patient developed neuropathy. In addition, complete responders achieved an earlier ≥ 50% reduction in VAS score. Two patients relapsed after 12 months but responded to thalidomide 50 mg.

Background Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies. Aim To evaluate and review sex effects in the pharmacokinetics and /-dynamics of drugs used to treat itch. Methods In this narrative review we performed a PubMed and MEDLINE (Ovid) search using the terms (itch OR pruritus) AND (gender OR sex) AND (drug OR medication OR pharmacokinetics OR pharmacodynamics). Additional searches were performed for the topical and systemic drugs recommended by the European Guideline on Chronic Pruritus. Results We found numerous reports with variable levels of evidence of sex effects with respect to the pharmacokinetics and/or pharmacodynamics of 14 drug classes used for the treatment of itch, including a total of 19 systemic and 3 topical drugs. Women seem to present higher plasma levels of several drugs used in itch treatment, including tri- and tetracyclic antidepressants (e.g. doxepin, amitriptyline, mirtazapine), serotonin reuptake inhibitors (e.g. paroxetine, sertraline, fluoxetine), immunosuppressive drugs (e.g. cyclosporine, mycophenolate mofetil), serotonin receptor antagonists (e.g. ondansetron) and betablockers (e.g. propranolol). Adverse drug reactions (ADRs) were generally more common in women. Being female was reported to be an independent risk factor for QTc-prolongation associated with antihistamines and tetracyclic antidepressants. Additionally, women seem to be more prone to sedative effects of antihistamines, and to suffer from a higher frequency as well as severity of side effects with systemic calcineurin inhibitors, opioid agonists, and opioid antagonists. Women were also sensitised more often to topically applied drugs. Of note, apart from only one experimental study with capsaicin, none of these reports were designed specifically to assess the effect of sex (and gender) in the treatment of itch. Discussion/conclusion Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.

Background and aims Several pain conditions have been shown to reduce the discriminative abilities of external stimuli. The aim of this study was to investigate how cutaneous sensitization affects the tempo-spatial discrimination for both painful laser stimulation and mechanical stimulation. Methods Fifteen healthy subjects were presented with two different stimulation paradigms, a continuous line stimulation and a 2-point stimulation. Line stimulations were delivered in two different directions in lengths of 25, 50, 75, and 100 mm. Two-point distances from 0 to 100 mm were tested. The subjects reported the perceived intensity, and either direction (line stimulations) or number of perceived points (2-point stimulations). All stimuli were tested both before and after topical capsaicin (8% concentration) sensitization (30 min). Results All mechanical line stimulations were reported correctly before capsaicin and 3 stimulations (out of 240) were reported incorrectly after capsaicin. For the laser line stimulation, the directional discrimination threshold (DDT) was 69.5 mm before capsaicin and 76.3 mm after capsaicin. The 2-point discrimination threshold for laser stimulation was 70.3 mm before capsaicin and 68.0 mm after, for the mechanical stimuli it was 31.5 mm before capsaicin and 31.0 mm after capsaicin. The perceived intensities were increased for the laser line stimulations after capsaicin (linear mixed model (LMM), p p p p Conclusions The findings show how cutaneous sensitization appears to affect directional discrimination to a larger extent than the 2-point discrimination. Implications This study is the first to investigate how directional discrimination is altered during sensitization. If such measures can be optimized they may provide a new method to probe the neural mechanisms in pain patients.

Introduction Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. Methods One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). Results Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. Conclusions The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. Implications Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. Trial registration NCT01989156.

Folic acid (FA) deficiency is associated with several health problems, including megaloblastic anemia and fetal neural tube defects. Therefore, supplementation with FA is strongly recommended by governments worldwide. Recent published reports indicate that FA functions in immune system maintenance. The main objective of this study is to examine possible anti-inflammatory and antipruritic effects of FA using a mouse model of allergic dermatitis. The mouse model was developed by repetitive sensitization to the Th2-type hapten toluene-2,4-diisocyanate (TDI). During the development of allergic dermatitis, FA was orally administered to the mice at doses of 8, 160, 1000 or 10,000 μg/day for 5 weeks. The ear swelling response and scratching behavior were monitored after the TDI challenge. Serum, ear tissue and auricular lymph node samples were isolated for further analysis 24 h after the TDI challenge. The ear swelling response was reduced in a dose-dependent manner by FA administration, and a significant change was observed at a concentration of 10,000-μg/day group. Comparable results were obtained through histological evaluation and cytokine level measurement in the ear tissue samples. Oral administration of FA exhibited the inhibitory effect on T-cell infiltration and T-cell-related cytokine production in auricular lymph nodes. Scratching behavior was not altered by FA administration. The in vivo evidence was corroborated by in vitro results, which showed that FA treatment significantly interfered with T-cell proliferation in a dose-dependent manner. Our findings imply that subacute oral administration of FA elicits an anti-inflammatory response, mainly through inhibition of T-cell proliferation.

Background: Patients taking methadone for opioid use disorder may desire transition to buprenorphine for a number of reasons. However, the current recommended approach for this transition generally takes weeks to months as an outpatient, causing considerable discomfort to the patient and a heightened risk of relapse during the transition period. Case: We describe the case of a patient on methadone maintenance who was rapidly transitioned to buprenorphine because of her desire to not return to her methadone clinic. In order to rapidly transition the patient from methadone to buprenorphine, naltrexone was administered to precipitate acute opioid withdrawal, which was followed soon after by buprenorphine induction. Discussion: Rapid transition from methadone maintenance to buprenorphine can be accomplished in inpatients by precipitating acute withdrawal with naltrexone, providing an effective alternative for patients who cannot tolerate the typical protracted methadone taper required prior to buprenorphine induction as an outpatient.

Background Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Methods We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. Discussion Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing “standard” UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. Trial identifiers Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018–004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Because of a possible impact of capsaicin in the high concentrations on enterocyte injury (cytotoxicity) and bactericidal activity on probiotics, Lactobacillus rhamnosus L34 (L34) and Lactobacillus rhamnosus GG (LGG), the probiotics derived from Thai and Caucasian population, respectively, were tested in the chili-extract administered C57BL/6 mice and in vitro experiments. In comparison with placebo, 2 weeks administration of the extract from Thai chili in mice caused loose feces and induced intestinal permeability defect as indicated by FITC-dextran assay and the reduction in tight junction molecules (occludin and zona occludens-1) using fluorescent staining and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the chili extracts also induced the translocation of gut pathogen molecules; lipopolysaccharide (LPS) and (1→3)-β-d-glucan (BG) and fecal dysbiosis (microbiome analysis), including reduced Firmicutes, increased Bacteroides, and enhanced total Gram-negative bacteria in feces. Both L34 and LGG attenuated gut barrier defect (FITC-dextran, the fluorescent staining and gene expression of tight junction molecules) but not improved fecal consistency. Additionally, high concentrations of capsaicin (0.02–2 mM) damage enterocytes (Caco-2 and HT-29) as indicated by cell viability test, supernatant cytokine (IL-8), transepithelial electrical resistance (TEER) and transepithelial FITC-dextran (4.4 kDa) but were attenuated by Lactobacillus condition media (LCM) from both probiotic-strains. The 24 h incubation with 2 mM capsaicin (but not the lower concentrations) reduced the abundance of LGG (but not L34) implying a higher capsaicin tolerance of L34. However, Lactobacillus rhamnosus fecal abundance, using qRT-PCR, of L34 or LGG after 3, 7, and 20 days of the administration in the Thai healthy volunteers demonstrated the similarity between both strains. In conclusion, high dose chili extracts impaired gut permeability and induced gut dysbiosis but were attenuated by probiotics. Despite a better capsaicin tolerance of L34 compared with LGG in vitro, L34 abundance in feces was not different to LGG in the healthy volunteers. More studies on probiotics with a higher intake of chili in human are interesting.

This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P).Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05).A cooling trend in Tre was observed following Placebo gel application, but this significantly (p 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p 0.05). Irritation significantly differed by condition (p 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p 0.01). No other differences were observed.Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident.

Itch is the commonest skin-related symptom, associated with a high psychosocial and economic burden. While the main focus of itch research lies on a few chronic skin diseases, only little is known about the perception of itch, itch-aggravating/-relieving factors and treatment preferences in patients with acute and chronic itch of various etiology. In this cross-sectional study we assessed these aspects in 126 patients (mean age 61.7 ±18.4 years, 67 females, median itch duration 3.9 years) using a 78-item questionnaire. The diseases were categorised into 11 diagnostic groups for descriptive analysis, the three most frequent groups ("Atopic dermatitis"; "Non-atopic eczema"; "Inflammatory dermatoses") were statistically compared. Itch was most often perceived as localised 42.9%, burning (40.5%) and worrying (39.7%) with worsening in the evening (49.2%), due to warmth (42.1%) and sweating (26.2%). Whilst itch perception, itch-aggravating factors and treatment preferences differed broadly amongst patients, the itch-relieving personal strategies were more uniform ("scratching by hand 70.6%, applying topicals 57.9%). 69.8% of patients suffered from itch-related sleep disturbance, consequently affecting their relatives in 30.0%. Subgroup comparisons revealed significant differences regarding itch-aggravating factors (p=0.0012) and itch duration (p=0.0082). Patients rated the antipruritic effectiveness of phototherapy, "Complementary & alternative medicine" and "Other tablets" as high, but oral antihistamines, "Cortisone tablets" and any topical as only moderately efficacious. The preferred administration of an ideal itch treatment was "Creams/ointments" (51.6%) or "Tablets" (35.7%), only few patients preferred "injections" or "patches". Consideration of such differences and similarities in itch characteristics and treatment preferences could help to better tailor treatment in itch patients. This article is protected by copyright. All rights reserved.

Introduction The Tobacco Heating System (THS) is a “heat-not-burn” tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. Methods A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). Results Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%–96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. Conclusion Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. Implications This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. Clinical Significance Trial Registration NCT01989156 (ClinicalTrials.gov).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Chronic pruritus (CP) is often accompanied by paresthetic sensations like warmth, burning and stinging. The aim of this study was to analyze, whether divergent sensations are linked to structural and functional skin alterations in clinically diagnosed CP patients. Clinical responses to capsaicin, histamine, and to thermal and mechanical stimulation, intraepidermal nerve fiber density, and epidermal expression of transient receptor potential (TRP)-channels were investigated in healthy controls, and in CP patients, reporting either warmth (CP-W) or neuropathic sensations (CP-N). In CP-W, pinprick hyperalgesia and increased sensitivity to capsaicin were aligned with increased epidermal TRPV1 expression, while smaller histamine axon reflex erythema matched with significantly reduced intraepidermal nerve fiber density. CP-N showed earlier onset of sensations after capsaicin stimulation, significantly increased warmth detection threshold, and higher epidermal expression of TRPV4 compared to healthy controls. The present study contributes to the neurobiological understanding of the divergence of sensory sensations in CP, indicating new treatment targets.

Central sensitization induces pain augmentation in chronic pain states. An analogous mechanism is speculated for chronic pruritus. This study compared patients with chronic pruritus (n = 79) of different origins (atopic dermatitis, chronic pruritus on non-lesional skin, chronic prurigo) and healthy controls (HC, n = 54) with regard to itch intensity and qualities of sensory symptoms after selective peripheral nerve fibre activation by electrical stimulation at 5 Hz (surrogate for C-fibre function) and 2,000 Hz (surrogate for Aβ-fibre function) using a Neurometer®. Electrically-induced itch was more intense in patients with chronic pruritus than in HC, but patients with chronic pruritus did not report “itch” more often than HC at 5 Hz. Stimulation at 2,000 Hz induced more pricking and tingling, but less throbbing in patients with chronic pruritus compared with HC. Treatment with cooling compound reduced clinical and experimental itch, but did not alter the distribution of sensory symptoms. These data show hyperknesis in chronic pruritus of various origins, arguing for common central sensitization mechanisms.

Background ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. Methods This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. Results There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1–100), intravenous 94.4% (78–100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p

Pruritus is a debilitating symptom of cholestatic diseases such as primary biliary cholangitis and primary sclerosing cholangitis and often results in major reduction in quality of life for afflicted patients. Classic treatment options for the treatment of cholestatic pruritus include antihistamines, bile acid resins, serotonin reuptake inhibitors, and mu-opioid antagonists. Unfortunately, these drugs are not always successful in treating pruritus of cholestasis and may be associated with adverse effects. Recent advances in our understanding of itch pathophysiology have led to the use of butorphanol, a kappa-opioid agonist and mu-opioid antagonist, for the treatment of various forms of pruritus. Reports of butorphanol to treat cholestatic itch specifically are rare. To better understand the role of butorphanol in the treatment of cholestatic pruritus, including characterization of its side effect profile. We present a case series of eight adult patients with cholestatic disease who were treated with butorphanol in hopes of alleviating intractable pruritus. Patients were identified through a clinical data request form serviced by University of Miami Information Technology. Five out of eight patients (62.5%) reported successful reductions in itch severity after treatment with butorphanol, two patients reported no (or transient) change in itch severity, and one patient reported a paradoxical increase in itching. Side effects included somnolence, sedation, nausea, vomiting, and dizziness. Butorphanol was safe and leads to clinically significant symptomatic improvement. Clinicians should be aware of butorphanol as an off-label treatment option for pruritus of cholestasis. Further studies are needed to better characterize the effect of butorphanol on cholestatic itch.

Background Patients with breast cancer undergoing radiation therapy can experience dermatologic adverse events. Oncology nurses can advocate for radiation dermatitis (RD) prophylaxis to minimize dermatologic adverse events. Objectives This quality improvement project was conducted to evaluate the effect of implementing an RD prevention protocol. The objectives of this study were to (a) improve clinicians' knowledge of screening, assessment, and prevention of RD in patients with breast cancer and (b) decrease the incidence of RD by 10% at a tertiary care cancer center. Methods Center-wide standards of care were created and implemented. A retrospective chart analysis was performed before and after protocol implementation. An education session was used to analyze protocol effectiveness. Findings Surveys completed by nurses (N = 11) before and after the education session demonstrated a significant increase in overall confidence in assessing RD. Statistically significant increases were noted in using topical steroids for prophylaxis.

Chronic inflammation is a potential systemic risk factor for many bladder dysfunctions, including interstitial cystitis (IC). However, the underlying mechanism through which a healthy bladder protects itself from inflammatory triggers remains unknown. In this study, we identified odor compounds in urine obtained from IC patients and healthy controls. Using comprehensive solid-phase microextraction-gas chromatography-time-of-flight-mass spectrometry (SPME-GC-TOF-MS) profiling and bioinformatics, we found that levels of urinary volatile metabolites, such as menthol, were significantly reduced in IC patients, compared to healthy controls. In an attempt to understand the mechanistic meaning of our volatile metabolites data and the role of menthol in the immune system, we performed two independent experiments: (a) cytokine profiling, and (b) DNA microarray. Our findings suggest that lipopolysaccharide (LPS)-stimulated inflammatory events, such as the production and secretion of inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β) and the activation of NF-κB and associated proteins within a large signaling network (e.g., Akt, TLR1, TNFAIP3, and NF-κB), are suppressed by the presence of menthol. These findings broaden our knowledge on the role of urinary menthol in suppressing inflammatory events and provide potential new strategies for alleviating both the odor and inflammation associated with IC.

Impaired sleep due to nocturnal pruritus is a common symptom in patients with chronic pruritus. However, there is no standardized, simplified instrument for assessing sleep-related problems in patients with chronic pruritus. After a literature search, we conducted 50 interviews with patients with chronic pruritus and tested 12 items most frequently used in routine sleep questionnaires. Afterwards, 2 sleep assessment questionnaires (Pittsburgh Sleep Quality Index; Regensburg Insomnia Scale) were selected for use in 88 patients with chronic pruritus with sleep impairment due to pruritus. They were completed twice; once before optimizing their individual pruritus therapy and once again after 4 weeks. During the latter survey, 21 patients reported that pruritus no longer negatively affected their sleep. These patients also achieved a significant improvement in their sleeping behaviour in the Regensburg Insomnia Scale. Therefore, the Regensburg Insomnia Scale appears to be well-suited to assessing sleep impairment in patients with chronic pruritus.

BACKGROUND Topical capsaicin shows efficacy in the treatment of brachioradial pruritus (BRP); however, its mechanisms of action remain unclear. OBJECTIVE The effect of capsaicin on the epidermis (i.e. peripheral expression of non-neuronal sensory receptors on keratinocytes, morphological changes in innervation) is still unknown. We aimed to investigate the effect of topical capsaicin on keratinocyte expression of TRP channels and on the intraepidermal nerve fibre density (IENFD) in patients with BRP. METHODS Thirty-one patients with BRP received an 8% capsaicin patch. Biopsies in lesional and non-lesional skin were taken to assess epidermal morphology, keratinocyte expression of TRP channels and IENFD before and 3 weeks after treatment. RESULTS Treatment with the capsaicin patch led to a significant decrease in itch and paresthetic symptoms (P < 0.05). Keratinocyte morphology is unaltered after capsaicin therapy. Reduced keratinocyte expression of TRPV1 in lesional skin (P = 0.009; n = 9) normalized 3 weeks after treatment (P = 0.016; n = 10), but not the IENFD, which remained reduced in lesional epidermis. CONCLUSION The normalization of the decreased TRPV1 expression may account for the effectiveness of topical capsaicin, which does not reconstitute the reduced IENFD, arguing for a role of epidermal TRPV1 in the maintenance of BRP.

Pruritus occurs in all patients with atopic dermatitis and requires quick relief to reduce disease exacerbation and improve quality of life. Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis explores crisaborole ointment for early relief of pruritus in patients with mild to moderate atopic dermatitis from 2 phase III studies. Patients received crisaborole or vehicle twice daily for 28 days. Pruritus was graded on a 4-point scale of none (0) to severe (3). Early improvement in pruritus required a score of none (0) or mild (1), with a ≥ 1-grade improvement from baseline on day 6. Significantly more patients experienced early improvement in pruritus with crisaborole than with vehicle (56.6% vs 39.5%; p< 0.001), including at earliest assessment (day 2, 34.3% vs 27.3%; p = 0.013). Crisaborole is a topical treatment option that can rapidly relieve atopic dermatitis-associated pruritus.

Prevention of the flares is a main goal in the long-term treatment of atopic dermatitis (AD). Therefore we investigated the efficacy of a water-in-oil emollient, containing licochalcone A, omega-6-fatty acids, ceramide 3 and glycerol, for prevention of the flares in adults with mild to moderately severe AD, treated with topical steroids, that led to clearing of the inflammatory lesions and had been discontinued prior to inclusion. The study was a 12-week, double-blind, randomized, vehicle-controlled, left-right comparison test with the number of relapses, defined as re-occurrence of erythema for at least 3 consecutive days, considered the primary outcome. Compared with the vehicle, the active formulation significantly reduced the number of relapses and maintained the barrier homeostasis of the respective arm. To the best of knowledge, this is the first study to show prevention of the AD flares by the use of stand-alone emollient treatment, based on comparison with the corresponding vehicle while excluding concomitant/rescue medications.

Psoriasis is one of the most common chronic inflammatory diseases that is characterized by well-defined erythematous plaques, with typical histopathological findings of lymphocytic infiltration and epidermal hyperplasia. Topical treatments of psoriasis are either associated with limited response or with side effects. Up to date, topicals targeting neuroimmune axis in psoriasis or psoriasiform dermatitis have not been explored. Here, we investigated whether percutaneous delivery of capsaicin could attenuate the pathological change of psoriasiform inflammation. Imiquimod-induced psoriasis-like murine model was used to evaluate therapeutic effects from topical application of capsaicin. An additional model of psoriasiform dermatitis induced by direct IL-23 injection was used to identify the level of action from capsaicin in this neuroimmune axis. Cutaneous inflammation was assessed by erythema level and ear thickness change. Key cytokines, infiltrating cells in the skin, and draining lymph node cells were investigated. The results showed that capsaicin administration obstructed the activation of IL-23/IL-17 pathway induced by imiquimod, presenting with significantly reduced psoriasiform dermatitis both in gross appearance and microscopic features. Tissue gene expression of psoriatic core cytokines induced by imiquimod (including IL-23, IL-17A, IL-22, TNF-α, and IL-6) were greatly decreased by capsaicin application. This protective effect from capsaicin could be hampered by direct intradermal injection of IL-23. Conclusion: Epicutaneous delivery of capsaicin on imiquimod-treated murine skin could significantly decrease expression of multiple inflammatory cytokines and the severity of prototypic change of psoriasiform inflammation. The beneficial effect imposed by capsaicin reinforces the neuroimmune contribution towards psoriasiform inflammation and provides a potential non-steroidal therapeutic alternative for topical treatment of psoriasiform dermatitis.

BackgroundThe DNAX adaptor protein 12 (DAP12) is a transmembrane adaptor molecule that signals through the activation of Syk (Spleen Tyrosine Kinase) in myeloid cells. The purpose of this study is to investigate the role of DAP12 and Syk pathways in inflammatory bowel diseases (IBDs).MethodsDAP12 deficient and DAP12 transgenic, overexpressing an increased amount of DAP12, mice and Syk deficient mice in the C57/BL6 background were used for these studies. Colitis was induced by administering mice with dextran sulfate sodium (DSS), in drinking water, or 2,4,6-trinitrobenzene sulfonic acid (TNBS), by intrarectal enema.ResultsAbundant expression of DAP12 and Syk was detected in colon samples obtained from Crohn’s disease patients with expression restricted to immune cells infiltrating the colonic wall. In rodents development of DSS colitis as measured by assessing severity of wasting diseases, global colitis score,and macroscopic and histology scores was robustly attenuated in DAP12-/- and Syk-/- mice. In contrast, DAP12 overexpression resulted in a striking exacerbation of colon damage caused by DSS. Induction of colon expression of proinflammatory cytokines and chemokines in response to DSS administration was attenuated in DAP12-/- and Syk-/- mice, whereas opposite results were observed in DAP12 transgenic mice. Treating wild-type mice with a DAP-12 inhibitor or a Syk inhibitor caused a robust attenuation of colitis induced by DSS and TNBS.ConclusionsDAP12 and Syk are essential mediators in inflammation-driven immune dysfunction in murine colitides. Because DAP12 and Syk expression is upregulated in patients with active disease, present findings suggest a beneficial role for DAP12 and Syk inhibitors in IBD.

To assess the sensitivity of corneal cold receptors to a known transient receptor potential melastatin 8 (TRPM8) agonist, menthol, in dry eye and normals, and to determine whether factors such as disease duration or age affect responses.Dry eye disease (DED) (N = 33) and normal (N = 15) subjects were randomly assigned to receive RohtoMean (±SD) ages were similar, 62.2 ± 8.6-year (DED) versus 53.5 ± 7.6-year (normal). Corneal sensitivity scores were not different between groups. Mean cooling scores at 0.5-4 min post-menthol instillation were significantly higher in DED subjects (P ≤ 0.03). Sum cooling scores were significantly higher (P = 0.04) in DED subjects with a disease duration10 years (N = 18, 28.3 ± 2.58) versus ≥10 years (N = 15, 20.2 ± 2.76). Age did not affect cooling response in either group.DED subjects had greater sensitivity to cold than normal subjects. DED duration, and not age, was critical to cooling sensitivity. The finding that cooling scores were higher in subjects with DED for less than 10 years compared to more than 10 years suggests that corneal cold receptor sensitivity decreases as the duration of DED increases.

Background Atopic eczema (AE) is a chronic inflammatory and pruritic skin disease. There is still an unmet need for topical anti-inflammatory and anti-pruritic substances exhibiting an excellent safety profile. The endocannabinoid system is known to regulate various aspects of cutaneous barrier and immune functions, thus targeting it may be a valid approach for alleviating the symptoms of AE. Objective To assess the putative efficacy of Echinacea purpurea-derived alkylamides (Ec. extract) activating cannabinoid (CB)-2 receptors in exerting anti-inflammatory effects and alleviating symptoms of AE. Methods In vitro anti-inflammatory efficiency was investigated by monitoring the effects of Ec. extract on poly-(I:C)-induced pro-inflammatory cytokine expression (Q-PCR) and release (ELISA) of HaCaT keratinocytes. Irritancy and sensitization potential (assessed by Human Repeat Insult Patch Test; Clinical trial 1); clinical efficiency in alleviating symptoms of AE (Clinical trial 2) as well as effects on human skin structure and lipid content (Clinical trial 3 followed by transmission electron microscopy and HPTLC) were investigated in randomized double blind clinical trials. Results Ec. extract significantly reduced mRNA expression as well as release of poly-(I:C)-induced pro-inflammatory cytokines (IL-6 and IL-8) in keratinocytes. Thus, not surprisingly, the well-tolerated (Clinical trial 1) Ec. extract-based cream reduced local SCORAD statistically significantly, not only compared to baseline, but also compared to the comparator (Clinical trial 2). Of great importance, besides the in vitro anti-inflammatory effects, administration of the Ec. extract-based cream also resulted in significantly higher levels of overall epidermal lipids, ceramide EOS (ω-esterified fatty acid + sphingosine sphingoid base), and cholesterol at Day 15 compared to baseline as well as significantly greater numbers of intercellular lipid lamellae in the intercellular space (Clinical trial 3). Conclusion The investigated Ec. extract shows great potential in alleviating cutaneous symptoms of AE, and by exerting remarkable anti-inflammatory actions and restoring the epidermal lipid barrier, it will be very likely a well-tolerated, powerful novel ingredient for the adjuvant therapy of AE.

Background and objectives Uremic pruritus in patients on hemodialysis is associated with depression, lower quality of life, and mortality. We studied the prevalence, awareness, and treatment of pruritus to assess how well this important condition is currently managed internationally. Design, setting, participants, & measurements Data from 35,452 patients on hemodialysis in up to 17 countries from the Dialysis Outcomes and Practice Patterns Study were analyzed to describe pruritus prevalence from 1996 to 2015. Data from 6256 patients and 268 medical directors in 17 countries in 2012–2015 were analyzed to describe predictors, effects, medical directors’ awareness, and treatment of pruritus. Results Patients very much or extremely bothered by itching declined from 28% in 1996 to 18% in 2015. In 2012–2015, among patients nearly always or always bothered by itching, pruritus had a major effect on work and social life; 18% used no treatment for pruritus, and 17% did not report itching to health care staff. In total, 69% of medical directors underestimated the prevalence of pruritus in their unit. Managing high serum phosphorus and low Kt/V was ranked as the most important intervention, but no relationship was found between these factors and pruritus; 57% of medical directors used oral antihistamines for first-line chronic treatment of pruritus. Gabapentin was used by 45% as first-, second-, or third-line treatment. Nalfurafine was only used in Japan. Conclusions The prevalence of pruritus in people on hemodialysis is decreasing but remains underestimated. Large numbers of patients on hemodialysis with severe pruritus do not receive treatment. There is wide variation in the use of unlicensed medications for the treatment of pruritus. These data provide a benchmark for initiatives to improve the management of uremic pruritus. Multimedia This article contains multimedia at https://vimeo.com/49458473 This article contains multimedia at vimeo.com/49455976

Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance.

Introduction Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]). Methods In this parallel-group study, Japanese adult smokers (23–65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases. Results One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group. Conclusions Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases. Implications In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes.

Introduction Local governments are pursuing policies to limit the availability of menthol cigarettes at the point-of-sale. Although African Americans are disproportionately impacted by menthol cigarettes, little is known about African American smokers’ perspectives on emerging menthol policy. The purpose of this study was to fill a gap in the literature by exploring African American adult (25+) smoker perspectives on menthol and a local menthol sales restriction. Methods In-depth semi-structured interviews were conducted with African American smokers (n = 27) in the Minneapolis–St. Paul area June–September 2017. Interviews explored smoking behaviors, harm perceptions, perspectives of menthol in the community and reactions to local menthol sales restrictions. The framework method guided identification of key themes and synthesis of findings. Results Almost all (96%) participants smoked Newport cigarettes. The majority of participants indicated that menthol cigarettes were more harmful than non-menthol cigarettes, citing strength and additives and because they were targeted to African Americans. Some participants were receptive to policy change while others viewed the policy as inconvenient and unfair. Overall, there was a lack of understanding of the policy’s intended public health impact. Some participants indicated that the policy would have no impact on their purchasing or smoking behaviors while others who were contemplating quitting noted that a menthol restriction was encouragement to prompt a quit attempt. Conclusions Sales restrictions can provide a unique opportunity to persuade menthol smokers to quit. Efforts are needed to increase awareness and support of these policies as well as to support African American menthol smokers achieve cessation. Implications There is growing momentum to restrict local menthol tobacco sales; however, little is known about perceptions among populations most impacted. In Minneapolis–St. Paul, where menthol restrictions were passed in 2017, African American smokers expressed limited awareness and uneven policy support. While some participants were unconvinced the restriction would impact smoking, others indicated it would encourage decreased consumption and prompt quit attempts. There is a need for public education to increase awareness of menthol’s harms, to help menthol smokers quit, and to increase support for menthol policies.

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Objective: To evaluate the effectiveness of the menthol package (lip hydration and ice popsicles) compared to a package of non-menthol measures (lip hydration and ice popsicles) as a way to relieve thirst in patients in the Anesthetic Recovery Room. Method: Randomized and parallel trial study, with 120 patients randomized patients in an experimental group - menthol measurements (n=59) and control group - measures without menthol (n = 61). Results: There was a significant (p

In brachioradial pruritus and notalgia paraesthetica, the 8% capsaicin patch is a novel and effective, but cost-intense, therapy. Routine data for 44 patients were collected 6 months retrospectively and prospectively to first patch application. The cost to health insurance and the patient, and patient-reported outcomes were analysed (visual analogue scale, numerical rating scale, verbal rating scale for pruritus symptoms, Dermatological Life Quality Index, and Patient Benefit Index). Mean inpatient treatment costs were reduced by €212.31, and mean outpatient treatment and medication costs by €100.74 per patient (p.p.). However, these reductions did not offset the high cost of the patch itself (€767.02 p.p.); thus the total cost to health insurance increased by €453.97 p.p. (p ≤ 0.01). The additional costs of therapy to the patient decreased by €441.06, thus the overall cost p.p. remained approximately the same (€3,306.03 vs. €3,318.94). Capsaicin patch therapy resulted in reduced pruritus, improved quality of life and greater patient benefit, thus long-term cost-efficiency analyses are necessary.

Sarcoptic mange is a parasitic disease causing severe pruritus, self-induced skin lesions and secondary infections. In many cases, an antipruritic treatment is useful to decrease clinical signs of the disease. Oclacitinib is a synthetic janus kinase-1 (JAK1) inhibitor, that selectively inhibits cytokines involved in inflammation and pruritus. The aim of this retrospective study was to evaluate efficacy of oclacitinib in alleviating pruritus and inflammation in dogs affected by scabies. Forty-four clinical records of dogs containing the words sarcoptes and oclacitinib were selected among dermatologic cases recorded within the last 5 years (2014-2019). Thirty-one of 44 cases with confirmed sarcoptic mange infestation were included. All dogs were treated at day (D)0 with systemic antiparasitic drugs (e.g. moxidectin, sarolaner, afoxolaner) in association with oclacitinib at 0.5 mg/kg by mouth every 12 hours for 14 days followed by oclacitinib administration every 24 hours for another 14 days. Visual Analogic Scale (VAS) was recorded at D0 and D30. Selected cases were 16 females and 15 males, median age was 4.5 years, majority were crossbred dogs. Mean VAS recorded at D0 was nine, and after onemonth decreased to three. Telephone follow up information, collected seven days after discharge, reported a significative decrease in pruritus within 24 hours. Our results suggest that the association of oclacitinib inhibition of JAK1 dependent cytokines (allergic and inflammatory associated IL2, IL4, IL6, IL13 and pruritogenic associated IL31) with conventional antiparasitic treatment, may be useful to provide quick relief from pruritus and decrease inflammation in dogs with sarcoptic mange.

Menthol has been shown to contribute to the appeal of tobacco products in humans. However, factors such as sex, age and menthol concentration remain unclear in the interaction between menthol and nicotine. To understand these factors, we utilized a mouse model to determine the impact of menthol on oral nicotine consumption. A range of menthol concentrations (oral and systemic) were tested with or without oral nicotine using the two-bottle choice paradigm in adolescent and adult female and male C57BL/6J mice. Moreover, genetically modified mice were used to investigate the role of α7 nicotinic acetylcholine receptors (nAChRs) on the effects of menthol. Menthol addition to nicotine solution increased oral nicotine consumption in C57BL/6J mice in a sex- and menthol concentration-dependent manner. At lower menthol concentrations, female mice demonstrated an enhancement of nicotine consumption and male mice showed a similar behavior at higher menthol concentrations. Menthol drinking alone was only significantly different by sex at 60 μg/ml menthol concentration where female mice had higher menthol intake than males. Menthol administered both orally and systemically (intraperitoneal) increased oral nicotine consumption. Adolescent female mice had a higher nicotine intake at lower menthol concentrations compared to their adult counterparts. While α7 nAChR wild type mice consumed more mentholated nicotine solution than nicotine only solution, this effect was abolished in KO mice. Effects of menthol are concentration-, sex-, age-, and α7 nAChR-dependent. Oral and intraperitoneal menthol increases nicotine intake, suggesting that sensory, peripheral, and/or central mechanisms are involved in effects of menthol on oral nicotine consumption.