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Introduction: Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure in connection with a potentially dual mechanism, vascular and cardiac. Objectives & methods: All cases of peripheral edema or heart failure involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were included to describe their onset patterns (e.g., time to onset). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries and on the electrophysiological properties of rat ventricular cardiomyocytes. Results: A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57–85, range 32–95). The median time to onset were 23 days (IQR 10–54) and 17 days (IQR 3–30) for non-cardiogenic edema and acute heart failure, respectively. Cardiogenic and non-cardiogenic peripheral edema occurred frequently after a dose escalation (27/45, 60%), and the course was rapidly favorable after discontinuation of gabapentinoid (median 7 days, IQR 5–13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Acute application of gabapentinoids had no significant effect on Cav1.2 currents of ventricular cardiomyocytes. Conclusion: Gabapentinoids can cause concentration-dependent peripheral edema of early onset. The primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Cav1.2 blockade under the experimental conditions tested.

Abstract Background Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurrent genetic mutations, especially in genes controlling epigenetic regulation. Although the pathophysiology of diabetes is not well understood, several studies suggest a role of epigenetics in type 2 diabetes. Case presentation We report here for the first time the case of a 75-year-old Caucasian man who was treated for both diabetes and acute myeloid leukemia secondary to myelodysplastic syndrome, with a temporal association between glycemic dysregulation and the intake of 5-azacitidine. In fact, 2–3 days after starting each 7-day cycle of 5-azacitidine, he reported higher blood glucose levels, requiring an increased dose of self-administered insulin. Conclusion This observation could help to understand the pathophysiology of these two conditions and could encourage physicians to monitor blood glucose levels in patients under hypomethylating agent with a history of diabetes.

Strategies for diets in chronic spontaneous urticaria (CSU) are controversial. This systematic review assessed the interest in diet for managing CSU. We searched for original reports in MEDLINE, EMBASE, CENTRAL and LILACS. Among the 278 reports screened, 20 were included, involving 1,734 patients. Reports described 3 types of systematic diet: pseudoallergen-free diet (n = 1,555 patients), low-histamine diet (n = 223) and diet without fish products (n = 47), which induced complete remission in 4.8%, 11.7% and 10.6% of patients, respectively, and partial remission in 37.0%, 43.9% and 4.3%. Eight reports described personalized exclusion diets (66 patients) adapted to symptoms/allergological test results and led to complete remission in 74.6% of patients, although the diagnosis of CSU was doubtful. No comparative randomized studies of diets were available. The only randomized studies were based on oral provocation tests with the suspected responsible diet. Population and outcomes were heterogeneous. In conclusion, there is evidence for the benefit of diets in CSU only in individual patients with clinical symptoms. However, the level of evidence is low for the benefit of systematic diets in CSU because systematic double-blind controlled trials of diet are lacking.

Abstract Background Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. Objective The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. Methods/design This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). Discussion The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). Trial registration ClinicalTrials.gov Identifier: NCT02509468, first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.