RESUMEN
Women with onychomycosis may suffer more effects on their quality of life than men. There is limited female-specific data on the treatment of onychomycosis. Tavaborole is a topical treatment option for onychomycosis. This post-hoc study evaluated the nail plates of women using data from the tavaborole 5% Phase III studies at baseline and end of study for the areas of healthy nail and infected nail. Over 52 weeks (48-week treatment, 4-week follow up), women treated with tavaborole had an average 32% increase in healthy nail and 21% decrease in infected nail. Patients with baseline infection involving >50% of the nail plate had an average increase in percentage of unaffected nail surface area of 81% and a corresponding 51% decrease in infected nail. These analyses suggest that patients with the greatest toenail involvement at baseline had greater overall improvements than those who were less affected. This evaluation provides additional clinical guidance for treating women with onychomycosis using tavaborole. J Drugs Dermatol. 2018;17(2):168-172.
Asunto(s)
Antifúngicos/administración & dosificación , Compuestos de Boro/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Dermatosis del Pie/diagnóstico , Dermatosis del Pie/tratamiento farmacológico , Onicomicosis/diagnóstico , Onicomicosis/tratamiento farmacológico , Administración Tópica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
RATIONALE: Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response, which restores efficient ER protein folding, thus leading to protection from stress. In part, the unfolded protein response alleviates ER stress and cell death by increasing the degradation of terminally misfolded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor (ATF)6, which can induce genes that encode components of the ERAD machinery. OBJECTIVE: Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart. METHODS AND RESULTS: In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from simulated ischemia-induced cell death, whereas dominant-negative Derl3 decreased ERAD and increased simulated ischemia-induced cardiomyocyte death. CONCLUSIONS: This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.
Asunto(s)
Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Animales , Animales Recién Nacidos , Hipoxia de la Célula , Supervivencia Celular , Células Cultivadas , Perfilación de la Expresión Génica , Humanos , Immunoblotting , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , MicroARNs/genética , Microscopía Confocal , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Miocardio/patología , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Regiones Promotoras Genéticas/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción Genética , Tunicamicina/farmacologíaRESUMEN
AIMS: reSET-O is a Food and Drug Administration-cleared prescription digital therapeutic (PDT) indicated to improve outpatient-treatment retention of patients with opioid use disorder (OUD). This study examined the cost-effectiveness and budget impact of reSET-O in conjunction with treatment as usual (reSET-O + TAU) relative to TAU. MATERIALS AND METHODS: Adult patients with ≥1 OUD diagnosis, treated with buprenorphine from 1 January 2015 to 30 March 2018, were identified from Truven Health MarketScan Commercial and Medicare Supplemental Research Databases. Twelve-week healthcare resource utilization (HCRU) costs for patients categorized as adherent and nonadherent to buprenorphine treatment were estimated. Total 12-week costs included OUD treatment and other HCRU costs. The cost-effectiveness of reSET-O + TAU was modeled in accordance with prior clinical trial outcomes. The 12-week budget impact of reSET-O was modeled for a 1 million-member healthcare plan. RESULTS: Higher buprenorphine adherence was associated with lower HCRU costs in claims data. Twelve-week per-patient total costs were $305 more for those receiving reSET-O + TAU than those receiving TAU. The incremental cost-effectiveness ratio was $18.70 per 1 percentage-point increase in the treatment retention rate. The probability that reSET-O + TAU would be considered cost-effective was over 92% for willingness-to-pay thresholds of $6,000 or more. The 12-week budget impact of reSET-O was $8,908, translating to $0.003 per member per month. LIMITATIONS: The findings of the cost-effectiveness and budget impact modeling are limited by the assumptions of the models due to uncertainty around some inputs. While no model is free of bias, the inputs for this model were carefully selected to reflect contemporary treatment patterns. CONCLUSIONS: Depending on the payer's willingness to pay, reSET-O may be cost-effective in increasing buprenorphine treatment retention rates. reSET-O results in an approximate budget impact of $0.003 per member per month, depending on market share and the prevalence of the population receiving treatment for OUD.
Asunto(s)
Buprenorfina , Trastornos Relacionados con Opioides , Adulto , Anciano , Buprenorfina/uso terapéutico , Análisis Costo-Beneficio , Humanos , Medicare , Trastornos Relacionados con Opioides/tratamiento farmacológico , Prescripciones , Estados UnidosRESUMEN
There currently are 3 topical agents approved by the US Food and Drug Administration (FDA) to treat onychomycosis: tavaborole, efinaconazole, and ciclopirox. The phase 3 clinical trial designs for these treatments and their notable differences make it difficult for clinicians to interpret the data into clinical practice. For example, the primary end point predominantly used to assess efficacy in all the trials is complete cure, defined as no involvement of the nail plus mycologic cure; also, a notable number of patients fail to achieve a complete cure despite clear improvement in the nail. Despite close similarities in the end points and overall design of the clinical trials used for these agents, differences in design are notable, including the age range of participants, the range of mycotic nail involvement, the presence/absence of tinea pedis, and the nail trimming/debridement protocols used. The differences in clinical trial designs for the 3 FDA-approved topical agents and the lack of head-to-head studies makes efficacy interpretation and comparison inappropriate. This article reviews the phase 3 clinical trials that led to FDA approval of these agents, focusing on their similarities and differences.
Asunto(s)
Antifúngicos/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Onicomicosis/tratamiento farmacológico , Proyectos de Investigación , Administración Cutánea , Antifúngicos/administración & dosificación , Compuestos de Boro/administración & dosificación , Compuestos de Boro/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ciclopirox , Aprobación de Drogas , Humanos , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Estados UnidosRESUMEN
AIMS: Following injury, fibroblasts transform into myofibroblasts and produce extracellular matrix (ECM). Excess production of ECM associated with cardiac fibrosis severely inhibits cardiac function. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, regulates the function of numerous cell types. In this study, we determined the role of S1P in promoting pro-fibrotic actions of cardiac fibroblasts (CFs). METHODS AND RESULTS: S1P-mediated effects on myofibroblast transformation, collagen production, and cross-talk with transforming growth factor-beta (TGF-beta) using mouse CF were examined. S1P increased alpha-smooth muscle actin (a myofibroblast marker) and collagen expression in a S1P2 receptor- and Rho kinase-dependent manner. TGF-beta increased sphingosine kinase 1 (SphK1; the enzyme responsible for S1P production) expression and activity. TGF-beta-stimulated collagen production was inhibited by SphK1 or S1P2 siRNA, a SphK inhibitor, and an anti-S1P monoclonal antibody. CONCLUSION: These findings suggest that TGF-beta-stimulated collagen production in CF involves 'inside-out' S1P signalling whereby S1P produced intracellularly by SphK1 can be released and act in an autocrine/paracrine fashion to activate S1P2 and increase collagen production.