Early Combination Therapy of Ketamine and Midazolam in Patients with Refractory Status Epilepticus in Hemodynamic Unstable State

The use of anesthetics is inevitable to suppress seizure activity in refractory status epilepticus (RSE). Hypotension, which is a critical side effect observed when treating RSE using a higher dosage of anesthetics that enhance γ-aminobutyric acid (GABA) activity, often requires vasopressor agents. Concomitant treatment with N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, could be effective in prolonged refractory SE, while maintaining stable blood pressure owing to the blockage of catecholamine reuptake in the systemic circulation. We report two cases of patients who had RSE with hemodynamic instability treated promptly with an early combination of ketamine and low-dose midazolam. The combination treatment effectively suppressed epileptic discharge with less hemodynamic side effects; moreover, a low dose of midazolam was required when combined with ketamine therapy. The initial combination of a third-line therapy that blocks NMDA receptors with enhanced GABAergic activity could be useful in RSE. Further studies are necessary in many variable etiologies of SE.

The Comparison of the Kidney Effects of Dipeptidyl Peptidase 4 Inhibitors and Glucagon-Like Peptide 1 Agonist-Administered Concomitant with Sodium-Glucose Cotransporter 2 Inhibitors in Japanese Patients with Type Diabetes Mellitus and Chronic Kidney Disease

Background and Aim. Strong evidence exists supporting the utility of sodium glucose cotransporter inhibitors (SGLT2is) for treating not only cardiovascular events but also renal events. We previously reported that SGLT2is improved the urine albumin-to-creatine ratio (ACR) in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Only 8% of patients were treated with SGLT2is alone, and more than 70% of them additionally received incretin-related agents, such as dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide 1 agonist (GLP1Ra). Both agents reduce the plasma glucose level with an incretin effect, but the differences in the renoprotective effects between these agents are poorly understood. Methods. We retrospectively constructed database of 763 Japanese patients with T2DM and CKD who received sSGLT2is for more than 1 year. Among these SGLT2i-treated patients, 338 were receiving concomitant DPP4i (DPP4i group), and 99 were receiving concomitant GLP1Ra (GLP1Ra group). The two groups were compared using the propensity score matching method. Results. In the matched model including 86 cases per group, the decrease in the logarithmic value of the ACR and rate of reduction in the estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) of the GLP1Ra group showed no significant difference from those in the DPP4i group ( − 0.12 ± 0.48 vs. − 0.13 ± 0.45 and − 2.3 ± 18.5 vs. − 6.2 ± 13.8 , respectively, P = 0.10 ). However, the incidence of a >6.4% decrease in the eGFR was significantly lower in the GLP1Ra group than in the DPP4i group (35% vs. 52%, respectively, P = 0.03 ). The level of hemoglobin A1c (mmol/mol) after SGLT2i treatment was significantly lower in the DPP4i group than in the GLP1Ra group in the matched model ( 58.3 ± 11.8 and 62.7 ± 14.8 , respectively, P = 0.02 ). Conclusion. Among the SGLT2i-treated patients with T2DM and CKD, concomitant treatment with GLP1Ra has a marked improving effect on the change in the eGFR.

Toxic epidermal necrolysis associated with anticonvulsants

Background and Objetives: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered as a continuum of the same process. TEN or Lyell Syndrome is the most severe form. Both entities involve an acute mucocutaneous blistering reaction associated with systemic inflammation. Materials and Methods: We present a case of a young woman who developed TEN following concomitant treatment with valproate, lamotrigine, and phenobarbital. Despite the extensive mucocutaneous detachment (over 90%), prognostic evaluation was favorable (SCORTEN score 2; probability of survival 88%), and this patient evolved satisfactorily. Five days after admission, valproate was reinitiated without any subsequent adverse reaction. Results: Causality evaluation identified both lamotrigine and phenobarbital as “very probable” (ALDEN score = 6) causes and valproate as “very unlikely” (ALDEN score = 0) cause of TEN. Conclusions: SJS and TEN are true life-threatening medical emergencies. This case emphasizes the importance of early diagnosis and treatment, including the discontinuation of the causative agent, which can be lifesaving.

Valsartan and Sacubitril Combination Treatment Enhances Collagen Production in Older Adult Human Skin Cells

Collagen is a major component of the skin’s support system, allowing for firmness, elasticity, and mechanical strength. In older adults, skin collagen production decreases significantly, and is associated with increased sagging, wrinkling, and thinning. The Renin Angiotensin System (RAS) is a key hormonal system that changes with age and affects multiple organ systems. While primary health benefits of Angiotensin (Ang) receptor type1 (AT1 R) blockers (ARBs) are believed to arise from systemic effects on blood pressure. There exists a skin-specific Renin Angiotensin System (RAS), but the impact of ARBs on older skin is unknown. Human skin fibroblasts from individuals aged 2 (young individual) and 57 (older individual) were treated with drugs that alter RAS: Valsartan (an ARB) and neprilysin inhibitor Sacubitril. Fibroblast proliferation and collagen production was quantified in response to the drug treatment using fluorescence microscopy. Fibroblasts from 57-year-old individuals were slower to proliferate and had less collagen content as compared to fibroblasts from young individual. Valsartan alone treatment had no effect on collagen production from young or old fibroblasts. In contrast, Sacubitril treatment increased collagen production by approximately three-fold in young (2.87 ± 0.27 RFU, P<.0001), and older (2.93 ± 0.53 RFU, P<.0001) fibroblasts. Concomitant treatment with Valsartan and Sacubitril increased collagen production by five-fold increase (5.36 ± 1.08 RFU, P<.0001) in young fibroblasts, and four-fold (4.18 ± 0.96 RFU, P=.003) in older cells. This study demonstrates a novel use for the widely prescribed drug combination, Sacubitril and Valsartan, which significantly improves collagen production in older adult fibroblasts.

Drug-drug interactions in atrial fibrillation patients receiving direct oral anticoagulants

Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0–1, 49.4% in category 2–3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22–55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11–16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.

Combined Effect of Cold Atmospheric Plasma and Curcumin in Melanoma Cancer

Curcumin (CUR) has interesting properties to cure cancer. Cold atmospheric plasma (CAP) is also an emerging biomedical technique that has great potential for cancer treatment. Therefore, the combined effect of CAP and CUR on inducing cytotoxicity and apoptosis of melanoma cancer cells might be promising. Here, we investigated the combined effects of CAP and CUR on cytotoxicity and apoptosis in B16-F10 melanoma cancer cells compared to L929 normal cells using MTT method, acridine orange/ethidium bromide fluorescence microscopic assay, and Annexin V/PI flow cytometry. In addition, the activation of apoptosis pathways was evaluated using BCL2, BAX, and Caspase-3 (CASP3) gene expression and ratio of BAX to BCL2 (BAX/BCL2). Finally, in silico study was performed to suggest the molecular mechanism of this combination therapy on melanoma cancer. Results showed that although combination therapy with CUR and CAP has cytotoxic and apoptotic effects on cancer cells, it did not improve apoptosis rate in melanoma B16-F10 cancer cells compared to monotherapy with CAP or CUR. In addition, evaluation of gene expression in cancer cell line confirmed that CUR and CAP concomitant treatment did not enhance the expression of apoptotic genes. In silico analysis of docked model suggested that CUR blocks aquaporin- (AQP-) 1 channel and prevents penetration of CAP-induced ROS into the cells. In conclusion, combination therapy with CAP and CUR does not improve the anticancer effect of each alone.

Efficacy and Safety of Cyclosporine Treatment in Autoimmune Cytopenias: The Experience of Two Italian Reference Centers

Background: Autoimmune cytopenias (immune thrombocytopenia ITP, autoimmune hemolytic anemia AIHA, and chronic idiopathic neutropenia CIN) are a heterogeneous group of disorders characterized by the presence of autoantibodies directed against platelets (PLT), erythrocytes, and neutrophils (ANC). Frontline steroids are the mainstay of treatment, although most patients relapse and require 2 nd line therapies which slightly differ according to disease subtype. Rituximab is mainly effective in AIHA, although only a fraction of cases would experience long-term relapse-free. Splenectomy may be contraindicated due to age and risk of thrombotic and infectious complications and thrombopoietin-receptor agonists (TPO-RA), effective in more than 70% of ITP patients, may result in great PLT fluctuations and increased bone marrow reticulin fibrosis. Cyclosporine (CyA) is an immunosuppressant used for over 30 years in the post-transplant setting and in the treatment of aplastic anemia. It is a manageable oral drug with known toxicities and its plasma concentrations may be monitored to optimize treatment. However, few data exist about its efficacy in autoimmune cytopenias either used as single drug or in combination with other treatments. Aim: The aim of this study was to evaluate the efficacy and safety of CyA in a cohort of patients with ITP, AIHA, and CIN, followed at two reference hematology centers in Milan, Italy. Methods: Medical charts of consecutive patients treated with CyA 3-5 mg/ kg day in the last 20 years were evaluated. Responses were assessed at 3, 6 and 12 months, and divided into partial (PR, for Hb&gt; 10 g/dL; PLT&gt; 30x 109/L and ANC&gt; 0.8 x 109/L) and complete (CR, for Hb&gt; 12 g/dL; PLT&gt; 100x109/L; ANC&gt;1 x 109/L). Adverse events were recorded according to CTCAE criteria. Results: 41 patients, 27 ITP (66%), 11 AIHA (27%) and 3 CIN (7%), were included, 16 men (39%) and 25 women (61%), with a median age of 60 year (21-81). The median time from diagnosis to CyA start was of 10 years (5-15), with a median of 3 (1-8) previous therapy lines. Most patients were receiving concomitant treatment including steroids (N=13), IVIG (3), or TPO-RA (14). Reasons to start CyA included no response to previous treatments (N=27), platelets fluctuations (N=5) or bone marrow fibrosis (N=5) on TPO-RA, and contraindication for splenectomy (N=4). Median duration of CyA therapy was 5 years (1-9) and 34 patients (83%) responded: 34% CR, 44% PR at month+3; 39% CR and 39% PR at month+6; and 26%CR and 43%PR at month+12 (Figure 1). Specifically, median PLTs increased by 32 x10^9/L at month+3, by 121 x10^9/L at month+6, and by 43 x10^9/L at month+12. Median Hb improved by 0.5 g/dL at month+3, by 1 g/dL at month+6, and by 2,6 g/dL at month +12. Median ANC augmented by 0.7 x10^9/L at month +3, by 1.7 x10^9/L at month +6, and by 0.07 x10^9/L at month +12. Importantly, 9 patients could stop steroids, and 10 subjects discontinued or tapered TPO-RA (5 each). Better responses were observed in ITP patients with baseline bone marrow hypocellularity (p = 0.01), absence of reticulin fibrosis (p=0.02), and in those not previously splenectomized (p=0.04). Among AIHA cases, those with IgG+C direct antiglobulin test positivity showed higher percentage of non-response (67 versus 22% in IgG+). Adverse events were mainly G1-2, occurring in 52% of patients, and included asthenia, dyspnea, myalgia, nausea, vomiting, diarrhea and abdominal pain, epistaxis, petechiae and an Escherichia Coli cystitis. Three patients on concomitant long-term steroids developed a G3 event (1 pulmonary embolism, 1 Aspergillus lung infection and 1 bronchitis), and 1 died for Pneumocystis jirovecii pneumonia. Conclusion: Cyclosporine was effective in about 80% of highly pretreated patients and allowed tapering/discontinuation of concomitant treatments in 63% of cases. Responses were higher in those with ITP, and hypocellular bone marrow without reticulin fibrosis. The occurrence of infectious episodes, including a fatal pneumonia, warrants careful surveillance in this heavily pretreated patient population. Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals: Honoraria.