AAD-2004, a potent spin trapping molecule and microsomal prostaglandin E synthase-1 inhibitor, shows safety and efficacy in a mouse model of ALS

While free radicals and inflammation constitute major routes of neuronal injury occurring in neurodegenerative diseases, neither antioxidants nor nonsteroidal anti-inflammatory drugs (NSAIDs) have shown significant efficacy in human clinical trials. To explore the possibility that concurrent blockade of free radicals and PGE2-mediated inflammation might constitute a safe and effective therapeutic approach to certain neurodegenerative diseases, we have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobezoic acid (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin trapping molecule and inhibited microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 230 nM. Oral administration of AAD-2004 blocked free radical formation, PGE2 formation, and microglial activation in the spinal motor neurons of SOD1G93A mice. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to ibuprofen or riluzole. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in SOD1G93A mice. Targeting both mPGES-1 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases

A randomized, open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naïve chronic hepatitis B patients

PURPOSE: Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy. METHODS: Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed. RESULTS: There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups (p = 0.0376). Biochemical response rates were similar in all groups (78–94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study. CONCLUSION: We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study

Pseudoinvasion in an Adenomatous Polyp of the Colon Mimicking Invasive Colon Cancer

Pseudoinvasion or pseudocarcinomatous invasion in an adenomatous polyp of the colon can be unfamiliar to an endoscopist. Pseudoinvasion in an adenomatous polyp represents prolapse of the adenomatous epithelium into its stalk. In most cases its morphology does not differ from of general adenomatous polyps, but in some cases it can morphologically mimic a malignant polyp with submucosal invasion due to mass-like lesioning of its stalk. This makes it difficult for endoscopists to differentiate pseudoinvasion in an adenoma from an invasive carcinoma by conventional endoscopy; instead, endoscopic ultrasonography can provide useful information for differentiating these conditions. We report on an 82-year-old man who presented with a large pedunculated polyp with a thick stalk in the sigmoid colon, which mimicked a submucosal invasive carcinoma. The patient was diagnosed with pseudoinvasion in an adenomatous polyp after segmental resection of the sigmoid colon

Real-Life Efficacy and Tolerability of Lacosamide in Pediatric Patients Aged 4 Years or Older with Drug-Resistant Epilepsy

Purpose The aim of this study was to evaluate the efficacy and safety of adjunctive lacosamide therapy in pediatric patients aged ≥4 years with drug-resistant epilepsy (DRE). Methods Medical records of children aged 4 to 19 years treated with lacosamide as adjunctive therapy for DRE were retrospectively reviewed. The patients were divided into two groups according to their age at the start of lacosamide treatment: group A (aged 4–15 years) and group B (aged 16–19 years). Changes in seizure frequency from baseline, adverse events, and the retention rate were evaluated at each follow-up visit. Results Sixty-two patients (33 males and 29 females) with a mean age of 11.4 years (range, 4 to 19) were included. The mean duration of follow-up was 20.1±12.9 months. The mean maintenance dose of lacosamide was 6.7±4.8 mg/kg/day. Forty-two patients (67.7%) were responders (≥50% reduction in seizures) with 19.4% (12/62) achieving freedom from seizures. The response rate did not differ significantly between groups A and B (67.6% vs. 68.0%, P=0.795) and was not affected by the concomitant use of sodium channel blockers. Significant independent factors associated with a good response to lacosamide treatment were a shorter duration of epilepsy (P=0.035) and fewer concomitant anti-seizure medications (P=0.002). Mild transient adverse events were observed in 20 patients (32.3%). Conclusion Lacosamide adjunctive therapy was efficacious and tolerated in children aged ≥4 years with DRE. Early use of lacosamide may be helpful for a good response to drug-resistant seizures

Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.Peer reviewe

Multipole resonance and Vernier effect in compact and flexible plasmonic structures

Spoof surface plasmons in corrugated metal surfaces allow tight field confinement and guiding even at low frequencies and are promising for compact microwave photonic devices. Here, we use metal-ink printing on flexible substrates to construct compact spoof plasmon resonators. We clearly observe multipole resonances in the microwave frequencies and demonstrate that they are still maintained even under significant bending. Moreover, by combining two resonators of slightly different sizes, we demonstrate spectral filtering via the Vernier effect. We selectively address a target higher-order resonance while suppressing the other modes. Finally, we investigate the index-sensing capability of printed plasmonic resonators. In the Vernier structure, we can control the resonance amplitude and frequency by adjusting a resonance overlap between two coupled resonators. The transmission amplitude can be maximized at a target refractive index, and this can provide more functionalities and increased design flexibility. The metal-ink printing of microwave photonic structures can be applied to various flexible devices. Therefore, we expect that the compact, flexible plasmonic structures demonstrated in this study may be useful for highly functional elements that can enable tight field confinement and manipulation