Focal Neurotoxicity Associated With Topical 5-Fluorouracil.

Topical 5-Fluorouracil (5-FU) is an antineoplastic chemotherapy drug used to treat precancerous and cancerous skin growths, such as actinic keratoses (AKs), squamous cell carcinoma in situ, and superficial basal cell carcinoma. The topical agent may rarely cause neurotoxic adverse effects. Multiple cases of systemic 5-FU and capecitabine chemotherapy-induced neuropathies have been reported. However, until now, the topical administration of the drug has not been reported to cause neurotoxicity. We present a case of an 83-year-old male who was prescribed topical 5-FU 5% cream to treat AKs on the left anterior scalp and returned weeks later with the development of focal neurotoxicity in the treatment area. He presented with focal paralysis of the left medial frontalis muscle, with initial loss of sensation followed by intermittent pain and paresthesias, persisting four months after the cessation of therapy. He was referred to a neurologist and received a diagnosis of supraorbital neuralgia. The temporal relationship of symptom onset and the localization of symptoms to the treated area strongly suggests that the medication contributed to the observed neurologic effects. These effects are more likely to be observed in patients with a genetic deficiency of dihydropyrimidine dehydrogenase (DPD), which is responsible for the majority of 5-FU degradation (80%), therefore potentially leading to toxic levels of unmetabolized 5-FU. Providers should be aware of the potentially neurotoxic effects of topical 5-FU in order to properly counsel patients and to consider this as a possible etiology of neurologic deficits in patients using this drug.

Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression.

Background: Inflammatory cells within atherosclerotic lesions secrete various proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. The relative contributions of specific proteases to atherogenesis is not well understood. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We have previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as an endogenous modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. Methods: We designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models. Results: HTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo , HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after systemic administration to Apoe -/- mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr -/- mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. Conclusions: These data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

Dennd5b-Deficient Mice are Resistant to PCSK9-Induced Hypercholesterolemia and Diet-Induced Hepatic Steatosis.

Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b-/- mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b+/+ mice, Dennd5b-/- mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b-/- compared to Dennd5b+/+ mice. Additionally, Dennd5b-/- mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b+/+ mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b-/- liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.