Muzeum a Galerie Orlických Hor

Abstract BackgroundALZ‐801, an oral, brain‐penetrant small molecule inhibitor of amyloid oligomer formation is being evaluated as a disease‐modifying treatment in APOLLOE4, a Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer’s disease (AD). A concurrent Phase 2 study is in progress to study its effects on core AD biomarkers, beta‐amyloid (Aβ) and hyperphosphorylated tau (p‐tau) in APOE4 carriers with Early AD.MethodThe Phase 2 study in Czech Republic and Netherlands enrolled APOE4/4 and APOE3/4 subjects with MMSE 22‐30 (CDR‐G 0.5 or 1), who receive ALZ‐801 265 mg tablets BID for 104 weeks. Subjects were amyloid‐PET positive or A+/T+ on CSF assays (ratio of Aβ42/40×10 < 0.61, and p‐tau181 > 61 pg/ml). CSF is evaluated at 52 and 104 weeks, and plasma biomarkers at every visit. Memory tests include the Rey Auditory Verbal Learning Test (RAVLT). Primary outcome is CSF p‐tau181 reduction at 104 weeks; interim analysis on plasma was conducted when all subjects completed 26 weeks. Dr. Blennow’s laboratory (Mölndal, Sweden) performed biomarker analyses blinded to clinical data, using Lumipulse (Fujirebio) for CSF and Simoa assays for plasma. Change from baseline in observed biomarker values at each visit were analyzed with paired t‐tests (2‐sided p‐values).ResultOf 84 enrolled subjects (mean 69 years, 51% female, MMSE 25.6), 80 completed 26 weeks. Plasma p‐tau181, the interim primary outcome, showed significant 18% and 29% reductions at 13 and 26 weeks (p = 0.038 and p = 0.028). Reductions of p‐tau181/Aβ42 were also significant 21% and 30% at 13 and 26 weeks (p = 0.018 and p = 0.022). RAVLT memory scores (immediate + delayed) improved significantly at 26 weeks (p = 0.002). Most common adverse events were mild nausea with no drug‐ related serious events and no ARIA‐E at 52 weeks.ConclusionInterim Phase 2 plasma biomarker results show significant and robust reductions in plasma p‐tau181 and p‐tau181/Aβ42 at 26 weeks with memory improvement at 26 weeks. These ALZ‐801 effects on core biomarkers confirm target engagement in AD brain, and support disease modification potential of ALZ‐801. The biomarker effects, oral formulation, and favorable safety without ARIA‐E, make ALZ‐801 an attractive potential treatment for APOE4 carriers with AD.

To evaluate the influence of prior use of carbamazepine (CBZ) and other antiepileptic drugs (AEDs) with a putatively similar mechanism of action (inhibition of voltage-gated sodium channels; VGSCs) on seizure outcomes and tolerability when converting to eslicarbazepine acetate (ESL), using data pooled from 2 controlled conversion-to-ESL monotherapy trials (studies: 093-045, 093-046). Adults with treatment-resistant focal (partial-onset) seizures were randomized 2:1 to ESL 1600 or 1200 mg once daily. The primary efficacy endpoint was study exit (meeting predefined exit criteria related to worsening seizure control) versus an historical control group. Other endpoints included change in seizure frequency, responder rate, and tolerability. Endpoints were analyzed for subgroups of patients who received CBZ (or any VGSC inhibitor [VGSCi]) during baseline versus those who received other AEDs. Of 365 patients in the studies, 332 were evaluable for efficacy. The higher risk of study exit in the subgroups that received CBZ (or any VGSCi) during baseline, versus other AEDs, was not statistically significant (hazard ratios were 1.49 for +CBZ vs -CBZ [P = .10] and 1.27 for +VGSCi vs. -VGSCi [P = .33]). Reductions in seizure frequency and responder rates were lower in patients who converted from CBZ or other VGSCi compared with those who converted from other AEDs. There were no notable differences in overall tolerability between subgroups, but the incidence of some adverse events (eg, dizziness, somnolence, nausea) differed between subgroups and/or between treatment periods. Baseline use of CBZ or other major putative VGSC inhibitors did not appear to significantly increase the risk of study exit due to worsening seizure control, or to increase the frequency of side effects when converting to ESL monotherapy. However, bigger improvements in efficacy may be possible in patients converting to ESL monotherapy from an AED regimen that does not include a VGSC inhibitor.

Data on 54 new for China, India, Korea and Russia species of lichen-forming and lichenicolous fungi, including 22 new for science taxa of lichen-forming and lichenicolous fungi, i.e.: Acarospora ulleungdoensis, Amandinea trassii, Aspicilia geumodoensis, Biatora ivanpisutii, Caloplaca patwolseleyae, Catillaria ulleungdoensis, Coenogonium agonimieoides, Gyalidea austrocoreana, G. ropalosporoides, Opegrapha briancoppinsii, O. ulleungdoensis, Phyllopsora loekoesii, Psoroglaena coreana, Psorotichia gyelnikii, Rinodina oxneriana, Scoliciosporum jasonhurii, Staurothele oxneri, Stigmidium coarctatae, Thelocarpon ulleungdoense, Thelopsis loekoesii, Toninia poeltiana, Unguiculariopsis helmutii, and and 7 new species to China (Caloplaca ussuriensis, Megaspora rimisorediata, Rinodina xanthophaea, Rusavskia dasanensis, Xanthoria splendens, Zeroviella coreana, Z. esfahanensis), and 1 new species to India (Zeroviella esfahanensis), and 24 new species to Korea (Agonimia blumii, Arthonia rinodinicola, Buelliella minimula,...

A new species of saxicolous lichen is described, and named as Thelenella haradae. It occurs on exposed granite rocks of Mt. Daebang, Gyeongnam Prov., southern maritime Korea, and is similar to T. brasiliensis but differs in having wider ascospores (25–30 × 13–17 μm) and completely immersed ascomata.