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Hess Marcussen posted an update 6 months, 1 week ago
Topical corticosteroids are often utilized as the first-line treatment for vulvar lichen sclerosus (VLS). However, there is wide variability in dosing regimens, as well as a lack of consensus on maintenance dosing. Available guidelines on dosing frequency and regimen continuation for VLS are based on clinical expert opinion and do not necessarily reflect the pharmacokinetics of topical corticosteroids. Over the past few decades, there have been many advances in the techniques used to measure the local and systemic absorption of topical corticosteroids. These techniques have led to a greater understanding of the pharmacokinetics and bioavailabilities of these medications. However, it is not clear how this new information has been applied in evaluating dosing regimens and commonly cited risks when considering short- and long-term use in different vulvar dermatoses. This purpose of this review is to evaluate the available evidence on pharmacokinetics, absorption rates, and concentration levels of topical corticosteroids in lesional and nonlesional skin. Additionally, the evidence regarding commonly cited risks of topical corticosteroid use, including dermal thinning, adrenal suppression, systemic immunosuppression, and tachyphylaxis are reviewed. Differences in the effects of topical corticosteroids on the varied tissues of the vulva are specifically explored. Finally, these considerations are applied to evaluate the current treatment guidelines for VLS to provide direction in determining an evidenced-based dosing regimen and to inform future research in this area. Mautz TT, Krapf JM, Goldstein AT. Topical Corticosteroids in the Treatment of Vulvar Lichen Sclerosus A Review of Pharmacokinetics and Recommended Dosing Frequencies. Sex Med Rev 2021;XXXXX-XXX.Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.
Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10kb C-to-T splicing mutation in the CFTR gene.
We have screened, in FRT cells expressing the 3849+10kb C-to-T splicing mutation, ~30 2′-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10kb C-to-T allele.
A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2′-Methoxy Ethyl modification (2’MOE).
The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.
The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.
Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy and SCN1A gene mutations. In some cases, non-SCN1A gene mutations can present with a phenotype very similar to that of Dravet syndrome. The aim of this study was to compare phenotypes of patients with SCN1A and non-SCN1A gene mutation-related Dravet syndrome.
Thirty-six patients with Dravet syndrome-like phenotypes were followed from July 2017 to December 2019. We retrospectively analyzed their clinical profiles and genetic surveys.
Of the 36 enrolled patients, 15 (41.7%) had SCN1A mutations, one (2.8%) had an SCN8A mutation, one (2.8%) had an STX1B mutation, and five females (13.9%) had PCDH 19 mutations. The median age at first seizure onset was 7 months in those with SCN1A mutations, 1.3 years in those with PCDH19 mutations, and 10 months for the remaining patients. The majority of the patients with SCN1A mutations had status epilepticus (80% vs. 20%)onset with focal seizure type, and relatively young age at seizure onset. ML792 The patients with PCDH19 mutations had a relatively high rate of abnormal brain magnetic resonance imaging findings.
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