RESUMEN
Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of µ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.
Asunto(s)
Dermatitis Atópica , Humanos , Dermatitis Atópica/metabolismo , Prurito , Dolor , Citocinas/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Moderate to severe AD can be successfully managed by systemic treatments. Current guidelines also recommend emollients or emollients 'plus' and eudermic cleansers for all AD patients to improve the skin barrier and provide anti-irritant and anti-pruritic effects. OBJECTIVES: To investigate the efficacy of skin care (in addition to systemic treatment) with an Emollient 'plus' balm designed to improve the skin barrier and skin microbiome plus a corresponding syndet compared to usual commercial emollients and cleansers. METHODS: In a randomized controlled multicenter study, patients with moderate to severe AD (Severity scoring of atopic dermatitis [SCORAD] score ≥ 40) receiving systemic treatment (cyclosporin A, dupilumab or a Janus kinase inhibitor) were randomized 1:1 to apply twice daily for 10 weeks Emollient 'plus' after pre-cleaning with the syndet (Emollient 'plus' group) or to continue with their usual emollient and cleanser (Control group). Assessments included SCORAD, pruritus on a Visual Analog Scale, Dermatology quality of life questionnaire (DLQI), efficacy and tolerance questionnaires. RESULTS: Included were 57 patients with mean age of 38 years (range 19-70 years). The mean amount of emollient used after 10 weeks was 447.3 g (range 29-1099 g) and 613.2 g (range 97-2565 g) for the Emollient 'plus' versus the Control, respectively (p = 0.0277). After 10 weeks, subjects in the Emollient 'plus' had a significantly greater reduction in current pruritus (p = 0.0277) and a greater reduction in some DLQI items compared to the Control group. CONCLUSIONS: In patients with moderate to severe AD receiving systemic treatment, the Emollient 'plus' regimen significantly improved pruritus and quality of life items compared to the control, while using 23% less product over a 10-week period. These results stress the importance of daily use of emollients, especially emollients 'plus' to improve signs, symptoms and quality of life in patients with AD.
Asunto(s)
Dermatitis Atópica , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Emolientes/uso terapéutico , Detergentes , Calidad de Vida , Resultado del Tratamiento , Prurito/tratamiento farmacológico , Prurito/etiología , Cuidados de la Piel , Índice de Severidad de la EnfermedadRESUMEN
Atopic dermatitis (AD) is a common skin disease during infancy, which imposes a considerable burden on patients, their families, and the society, requiring effective treatment options that result in rapid and sustained symptom relief. Additionally, early treatment may prevent the development of atopic comorbidities by restoring the skin barrier. Currently, topical standard-of-care for AD in infants includes emollients and topical corticosteroids (TCS) to treat and reduce the risk of flares. However, only few have been approved for infants and long-term maintenance therapy with TCS is not indicated due to potential local and systemic side effects, including skin atrophy. Accordingly, the recently updated European guidelines for treatment of AD recommend topical calcineurin inhibitors (TCIs) for long-term use, treatment of sensitive skin areas, and for use in the pediatric population. Evidence on the use of TCIs for infants has almost been exclusively collected for pimecrolimus, with >4000 infants evaluated in clinical trials, consistently confirming that pimecrolimus is a safe and effective treatment for infants with AD. Nevertheless, its use is still restricted in most countries to children above the age of 2 years due to initial and mostly theoretical safety concerns. Based on a careful review of the available evidence of clinical trials, post-marketing surveillance, and epidemiological studies, an Expert Panel of European dermatologists and pediatric allergologists concluded that these safety concerns are no longer valid. Therefore, pimecrolimus offers a safe and effective alternative to TCS in infants aged 3 months and above, and labeling restrictions in this age group are no longer justified.
Asunto(s)
Dermatitis Atópica , Inhibidores de la Calcineurina/efectos adversos , Niño , Consenso , Dermatitis Atópica/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Tacrolimus/efectos adversos , Tacrolimus/análogos & derivados , Resultado del TratamientoRESUMEN
Approval of the new topical phosphodiesterase 4 inhibitor crisaborole ointment, 2%, to treat mild-to-moderate atopic dermatitis (AD) warrants careful consideration of available efficacy and safety data for topical therapies to contribute to a better understanding of the role of crisaborole in the treatment of mild-to-moderate AD. A literature review was conducted to identify results of randomized, blinded, vehicle-controlled trials of topical agents for the treatment of AD published from January 1, 1997 to April 30, 2018. This review summarizes the efficacy and safety data of topical therapies including corticosteroids, calcineurin inhibitors, and crisaborole and it shows that comparison among available agents is difficult because of differing methodologies used across clinical trials and that there is considerable variability in safety reporting among AD trials. Published clinical studies for crisaborole demonstrate its efficacy and manageable safety profile. J Drugs Dermatol. 2020;19(1):50-64. doi:10.36849/JDD.2020.4508
Asunto(s)
Compuestos de Boro/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/administración & dosificación , Administración Cutánea , Compuestos de Boro/efectos adversos , Compuestos de Boro/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de la Calcineurina/administración & dosificación , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/farmacología , Dermatitis Atópica/patología , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/farmacología , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Humanos , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Inhibidores de Fosfodiesterasa 4/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la EnfermedadRESUMEN
As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies.
Asunto(s)
Inmunidad Adaptativa , Dermatitis Atópica , Inmunidad Innata , Microbiota/inmunología , Infecciones Cutáneas Estafilocócicas , Staphylococcus aureus/inmunología , Dermatitis Atópica/inmunología , Dermatitis Atópica/microbiología , Dermatitis Atópica/patología , Femenino , Humanos , Masculino , Piel/inmunología , Piel/microbiología , Piel/patología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/patologíaRESUMEN
BACKGROUND: Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS: We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS: In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS: In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Psoriasis/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Candidiasis/etiología , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/inducido químicamente , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Índice de Severidad de la EnfermedadRESUMEN
Cutaneous wound healing is a complex process divided into different phases, that is an inflammatory, proliferative and remodelling phase. During these phases, a variety of resident skin cell types but also cells of the immune system orchestrate the healing process. In the last year, it has been shown that the majority of cutaneous cell types express the melanocortin 1 receptor (MC1R) that binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and elicits pleiotropic biological effects, for example modulation of inflammation and immune responses, cytoprotection, antioxidative defense and collagen turnover. Truncated α-MSH peptides such as Lys-Pro-Val (KPV) as well as derivatives like Lys-d-Pro-Thr (KdPT), the latter containing the amino acid sequence 193-195 of interleukin-1ß, have been found to possess anti-inflammatory effects but to lack the pigment-inducing activity of α-MSH. We propose here that such peptides are promising future candidates for the treatment of cutaneous wounds and skin ulcers. Experimental approaches in silico, in vitro, ex vivo and in animal models are outlined. This is followed by an unbiased discussion of the pro and contra arguments of such peptides as future candidates for the therapeutic management of cutaneous wounds and a review of the so-far available data on melanocortin peptides and derivatives in wound healing.
Asunto(s)
Melanocortinas/química , Péptidos/química , Piel/metabolismo , Cicatrización de Heridas , Animales , Línea Celular , Humanos , Inflamación/metabolismo , Melanocortinas/farmacología , Ratones , Estrés Oxidativo , Péptidos/farmacología , Receptor de Melanocortina Tipo 1/metabolismo , alfa-MSH/metabolismoRESUMEN
BACKGROUND: Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). OBJECTIVE: This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. METHODS: In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. RESULTS: Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P = .02) and -1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. LIMITATIONS: The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. CONCLUSIONS: Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.
Asunto(s)
Isoindoles/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Prurito/tratamiento farmacológico , Adulto , Anciano , Enfermedad Crónica , Diarrea/inducido químicamente , Método Doble Ciego , Fatiga/inducido químicamente , Femenino , Humanos , Isoindoles/efectos adversos , Masculino , Persona de Mediana Edad , Nasofaringitis/inducido químicamente , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Prurigo/complicaciones , Prurito/etiología , Escala Visual AnalógicaRESUMEN
Chronic pruritus is a bothersome symptom in psoriasis vulgaris and can profoundly reduce quality of life (QoL). In this exploratory analysis of the PSORITUS study, the impact of pruritus on QoL in 130 subjects with moderate-to-severe psoriasis was assessed using the ItchyQoL questionnaire. The majority of patients (n = 127) had to scratch their itchy skin regularly, which led to painful skin and frustration (mean ± standard deviation; SD ItchyQoL scores; 4.50 ± 0.56; 3.80 ± 1.09 and 4.20 ± 0.87, respectively). Changes in either temperature or season led to a worsening of itching in most of the patients (n = 126; mean ± SD ItchyQoL score; 3.80 ± 1.02). Many patients felt ashamed (n = 125) or embarrassed (n = 127) due to their itchy skin (mean ± SD ItchyQoL scores; 3.90 ± 1.26 and 3.40 ± 1.19, respectively). The results demonstrated the ItchyQoL questionnaire as a validated tool responsive to treatment for detailed insights into chronic pruritus in patients with psoriasis.
Asunto(s)
Costo de Enfermedad , Prurito/diagnóstico , Psoriasis/diagnóstico , Calidad de Vida , Encuestas y Cuestionarios , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Crónica , Fármacos Dermatológicos/uso terapéutico , Desconcierto , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prurito/tratamiento farmacológico , Prurito/psicología , Psoriasis/tratamiento farmacológico , Psoriasis/psicología , Reproducibilidad de los Resultados , VergüenzaRESUMEN
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).
Asunto(s)
Antipruriginosos/uso terapéutico , Aprepitant/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Prurigo/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antipruriginosos/efectos adversos , Aprepitant/efectos adversos , Estudios Cruzados , Método Doble Ciego , Resistencia a Medicamentos , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Prurigo/diagnóstico , Prurigo/inmunología , Calidad de Vida , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Crisaborole ointment is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Using pooled data from two phase 3 studies (NCT02118766/NCT02118792), mediation modeling determined the interrelationship among pruritus, quality of life (QoL), and treatment. Patients aged ≥ 2 years received crisaborole ointment 2% or vehicle twice daily for 28 days. QoL measures were Dermatology Life Quality Index (DLQI) (≥ 16 years) and Children's Dermatology Life Quality Index (CDLQI) (2-15 years). Pruritus was assessed by the Severity of Pruritus Scale (4-point scale from 0 to 3). The indirect effect of crisaborole on QoL mediated through its effect on pruritus was 51% (DLQI model, p < 0.05) and 72% (CDLQI model, p < 0.05). Direct effect (other effects) on QoL was 49% (DLQI model, p < 0.05) and 28% (CDLQI model, p > 0.05). Mediation modeling shows that crisaborole affects QoL mostly indirectly through pruritus severity reduction.
Asunto(s)
Compuestos de Boro/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Prurito/tratamiento farmacológico , Administración Cutánea , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/psicología , Femenino , Humanos , Masculino , Pomadas , Prurito/diagnóstico , Prurito/psicología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
Olfactory receptors (ORs) were first described as specialized chemoreceptors in the nasal epithelium. In the last two decades, ORs have also been detected to be functionally expressed and active in different nonolfactory tissues of the human body, because they used to react to specific odour stimuli. In this study, we conducted a characterization of the extranasal OR2A4/7 expressed in primary human melanocytes and sections of the human skin. OR2A4/7 expression could be demonstrated at the transcript and protein level. We uncovered elevated intracellular cAMP and Ca2+ levels accompanied by elevated p38 and reduced p42/44 MAPK phosphorylation following odourant (cyclohexyl salicylate; CHS) stimulation of melanocytes. These results were associated with enhanced melanin biosynthesis in conjunction with the growth inhibition and differentiation of melanocytes. Our findings highlight the participation of OR2A4/7 in human primary melanocyte physiology and suggest an alternate mechanism that regulates melanogenesis.
Asunto(s)
Melaninas/biosíntesis , Melanocitos/fisiología , Receptores Odorantes/metabolismo , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , AMP Cíclico/metabolismo , Humanos , Ligandos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Salicilatos/química , Salicilatos/farmacología , Transducción de SeñalRESUMEN
BACKGROUND: The substance P/neurokinin 1 receptor pathway is critical in chronic pruritus; anecdotal evidence suggests that antagonism of this pathway can reduce chronic itch. OBJECTIVE: To assess the safety and efficacy of the substance P/neurokinin 1 receptor antagonist serlopitant in treating chronic pruritus. METHODS: Eligible patients with severe chronic pruritus who were refractory to antihistamines or topical steroids were randomized to serlopitant, 0.25, 1, or 5 mg, or to placebo, administered once daily for 6 weeks as monotherapy or with midpotency steroids and emollients. The primary efficacy end point was percentage change in visual analog scale pruritus score from baseline. RESULTS: Serlopitant treatment resulted in a dose-dependent decrease in pruritus. The mean percentage decreases from baseline visual analog scale pruritus scores were statistically significantly larger with the 1- and 5-mg doses of serlopitant (P = .022 and P = .013, respectively) than with placebo at week 6. No significant safety or tolerability differences were detected among the groups. LIMITATIONS: The sample size was insufficient for subgroup analyses of the efficacy of serlopitant for chronic pruritus on the basis of underlying conditions. CONCLUSIONS: Serlopitant, 1 mg and 5 mg daily, was associated with a statistically significant reduction in chronic pruritus and was well tolerated (NCT01951274).
Asunto(s)
Isoindoles/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Prurito/diagnóstico , Prurito/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Itching is a prevalent plaque psoriasis symptom. Ixekizumab, an IL-17A antagonist, has demonstrated rapid, significant improvements in itch severity over 12 weeks in Phase III psoriasis trials (UNCOVER-1, UNCOVER-2). We assessed the long-term (through 60 weeks) effect of ixekizumab maintenance therapy (80-mg ixekizumab every 4 weeks [IXEQ4W]) on itch severity, using the Itch Numeric Rating Scale, in psoriasis patients who received ixekizumab, placebo, or etanercept for 12 weeks in the Phase III UNCOVER-3 trial. After 12 weeks, patients either continued or switched to IXEQ4W. Mean improvements in itch severity achieved with 12 weeks of ixekizumab (-4.7 to -5.1) were maintained through 60 weeks with IXEQ4W (-4.9 to -5.0). Patients who initially received placebo or etanercept experienced rapid itch severity improvements after switching to ixekizumab at Week 12 (Week 12, placebo: -0.6; etanercept: -3.8; Week 60, placebo/IXEQ4W: -4.9; etanercept/IXEQ4W: -4.7). Ixekizumab maintenance therapy sustained improvements in itch severity through 60 weeks.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Prurito/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Adulto , Etanercept/uso terapéutico , Femenino , Humanos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Prurito/etiología , Psoriasis/complicaciones , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Tofacitinib is an oral Janus kinase inhibitor. This post-hoc analysis aimed to investigate the psychometric properties of the Itch Severity Item (ISI), a numeric rating scale from 0 (no itching) to 10 (worst possible itching) for pruritus in psoriasis, and review the effect of tofacitinib on pruritus in patients with psoriasis participating in Phase 3 studies (N = 3,641). The ISI showed high test-retest reliability (intra-class correlation coefficient: 0.84). The clinically important difference was defined as a 1.48-point change, using Patient Global Assessment as an anchor. Mean changes from baseline in ISI scores with tofacitinib were significantly greater than placebo by Day 2 and exceeded the clinically important difference by Week 4 and Week 2 for tofacitinib 5 and 10 mg twice daily, respectively. The sound psychometric properties of the ISI as an assessment tool for pruritus in psoriasis were confirmed. Tofacitinib provided clinically meaningful improvements in psoriatic pruritus versus placebo.
Asunto(s)
Antipruriginosos/uso terapéutico , Piperidinas/uso terapéutico , Prurito/diagnóstico , Prurito/prevención & control , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Encuestas y Cuestionarios , Ensayos Clínicos Fase III como Asunto , Humanos , Valor Predictivo de las Pruebas , Prurito/etiología , Psoriasis/complicaciones , Psicometría , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Melatonin (Mel) is the major biologically active molecule secreted by the pineal gland. Mel and its metabolites, 6-hydroxymelatonin (6(OH)Mel) and 5-methoxytryptamine (5-MT), possess a variety of functions, including the scavenging of free radicals and the induction of protective or reparative mechanisms in the cell. Their amphiphilic character allows them to cross cellular membranes and reach subcellular organelles, including the mitochondria. Herein, the action of Mel, 6(OH)Mel, and 5-MT in human MNT-1 melanoma cells against ultraviolet B (UVB) radiation was investigated. The dose of 50 mJ/cm² caused a significant reduction of cell viability up to 48%, while investigated compounds counteracted this deleterious effect. UVB exposure increased catalase activity and led to a simultaneous Ca++ influx (16%), while tested compounds prevented these disturbances. Additional analysis focused on mitochondrial respiration performed in isolated mitochondria from the liver of BALB/cJ mice where Mel, 6(OH)Mel, and 5-MT significantly enhanced the oxidative phosphorylation at the dose of 10-6 M with lower effects seen at 10-9 or 10-4 M. In conclusion, Mel, 6(OH)Mel and 5-MT protect MNT-1 cells, which express melatonin receptors (MT1 and MT2) against UVB-induced oxidative stress and mitochondrial dysfunction, including the uncoupling of oxidative phosphorylation.
Asunto(s)
Melanoma/metabolismo , Melatonina/metabolismo , Melatonina/farmacología , 5-Metoxitriptamina/farmacología , Animales , Calcio/metabolismo , Catalasa/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de la radiación , Melatonina/análogos & derivados , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Fosforilación Oxidativa/efectos de los fármacos , Fosforilación Oxidativa/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Rayos UltravioletaRESUMEN
Chronic pruritus is difficult to treat. Current treatment options are frequently ineffective and new therapeutic approaches are urgently needed. Avenanthramides are active substances in oats that exhibit anti-inflammatory effects. Their potential to interrupt pruritus mechanisms was investigated in this study. It was found that the synthetic analog dihydroavenanthramide D (DHAvD) can interact with the neurokinin-1 receptor (NK1R) and inhibit mast cell degranulation. DHAvD also affects inflammatory processes and reduces secretion of the cytokine interleukin-6. Our findings indicate that DHAvD may act as a NK1R inhibitor and could be a promising candidate for topical treatments of chronic pruritus.
Asunto(s)
Mastocitos/efectos de los fármacos , Prurito/tratamiento farmacológico , Receptores de Neuroquinina-1/metabolismo , ortoaminobenzoatos/uso terapéutico , Animales , Señalización del Calcio/efectos de los fármacos , Línea Celular , Enfermedad Crónica , Evaluación Preclínica de Medicamentos , Humanos , Ratas , Sustancia P , ortoaminobenzoatos/farmacologíaRESUMEN
Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation, the NADPH oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (HDFs) and skin fibrosis. Using the pan-Nox inhibitor diphenyleneiodonium (DPI) as an initial tool, we show that gene expression of collagen type I, α-smooth muscle actin (α-SMA) and fibronectin 1 is suppressed in HDFs. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of RNA and protein expression of Nox4, p22phox and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immunolocalized to the endoplasmic reticulum. Importantly, TGF-ß1 had a dose- and time-dependent upregulating effect on NADH activity and Nox4 gene expression in HDFs. Genetic silencing of Nox4 as demonstrated by siRNA in HDFs as well as in murine fibroblasts established from Nox4 knockout mice confirmed that TGF-ß1 -mediated collagen type I gene, α-SMA and fibronectin 1 gene expressions were Nox4-dependent. This TGF-ß1 effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin-induced scleroderma mouse model. DPI treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knockdown by siRNA reduced skin collagen synthesis, α-SMA and fibronectin 1 expression in vivo. Finally, analyses of HDFs from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors, whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases.