Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

Background Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. Methods One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose- escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Results Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non- significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose- dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. Conclusion Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. Trial registration EudraCT Number: 2009-011234-99. Registered 23 June 2009

PENERIMAAN KONSUMEN TERHADAP KERNAS NATUNA

Kernas merupakan makanan khas natuna yang terbuat dari daging ikan tongkol (Thunnus tonggol) dan sagu butir dengan bahan tambahan seperti tepung maizena dan bumbu pelengkap lainnya. Penelitian ini mengenai tentang penerimaan konsumen terhadap kernas natuna, yang bertujuan untuk mengetahui tingkat penerimaan atau kesukaan konsumen terhadap kernas. Tahapan penelitian ini meliputi persiapan bahan baku dan bumbu, pengolahan dan uji organoleptik. Dari hasil penelitian uji tingkat kesukaan terhadap kernas dengan bahan tambahan tepung maizena tidak memiliki pengaruh yang nyata terhadap beberapa parameter uji organoleptik. Perlakuan terbaik berdasarkan hasil uji tengkat kesukaan terdapat pada perlakuan K2 ( maizena 2%) dengan nilai rata-rata kenampakan 131.75, aroma 127.78, rasa 127.45 dan tekstur 123.38. Penutup hasil uji organoleptik berdasarkan tingkat kesukaan dari 80 panelis tidak terlatih

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

Abstract Background Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. Methods One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Results Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. Conclusion Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. Trial registration EudraCT Number: 2009-011234-99 . Registered 23 June 2009

In Vivo Assessment of Macular Vascular Density in Healthy Human Eyes Using Optical Coherence Tomography Angiography

To quantify density of macular vascular networks over regions of interest in healthy subjects using optical coherence tomography angiography (OCTA). Prospective cross-sectional study. Setting was the Retina and Oncology Services of Wills Eye Hospital. Subjects with no known systemic disease and without retinal pathology were included. OCTA was performed on a 3 × 3-mm region centered on the macula and en face angiograms of the superficial and deep vascular networks were acquired. Vascular density was calculated using an automated image thresholding method over regions of interest. Foveal and parafoveal vascular density were calculated. The differences between vascular networks, sexes, and fellow eyes and correlation between vascular density, signal strength, and age, as well as reproducibility of measurements, were evaluated. A total of 198 healthy eyes were imaged, from which 163 eyes of 122 subjects were included based on image quality criteria. In the parafoveal region, deep vascular density was significantly higher than the superficial (52% ± 2.4% vs 46% ± 2.2%; P .05). There was a negative correlation between vascular density and age that persisted upon adjusting for signal strength. Vascular density measurements were highly correlated between separate imaging sessions with intraclass correlation coefficients of over 0.85 for all assessments. Calculation of vascular density using OCTA is a reproducible and noninvasive method to quantitate individual networks within the macula. Understanding normal values and their correlations could affect clinical evaluation of the macula in healthy patients and disease states

The CO-19 Project

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library

Additional file 1: Figure S1. of Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

Study MS-LAQ-101 flow chart. Figure S2. Average plasma concentrations of laquinimod on Day 21 after repeated daily administration. Figure S3. Exposure-dose plots of laquinimod after multiple dose administration. Table S1. Distribution of study drug termination reasons. Table S2. Biochemistry shift analysis to abnormal levels. Table S3. Hematology shift analysis. (DOCX 276 kb

Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results

3106 Background: FORE8394 is a selective inhibitor of class 1 (V600) and 2 (activating non-V600) BRAF alterations that avoids paradoxical MAPK pathway activation. Consistent with the paradigm shift to optimal dosing vs identifying the maximal tolerated dose, integrated pharmacokinetic (PK), genomics, safety, and efficacy data, and exposure-response modeling were used to identify the recommended dose (RD). Methods: In a single arm phase 1/2a study, patients (pts) age ≥3 years with advanced solid or CNS tumors with BRAF alterations received FORE8394 900-3600 mg/day with or without the PK enhancer cobicistat (cobi) until progression. Efficacy pts had class 1 or 2 BRAF alterations & ≥1 post-baseline assessment (mITT); the BRAF V600 MAPKi naïve, non CRC subset provided a homogenous subset to also inform dose selection. PK was evaluated after single and repeated dosing. Results: To date, 110 pts (age range 4-86 years) received ≥1 dose of FORE8394; 58% had ≥2 prior lines of therapy, 25% had prior MAPKi. PK was independent of age or weight. Cobi increased FORE8394 exposure 2-3-fold. Exposure increased with dose, with less than proportional increase at doses >900 mg BID. Higher Cmax and trough levels were achieved with QD vs BID/TID. Objective (confirmed) responses were observed at all doses; however, objective response rate (ORR) was greatest (50%) at 900mg QD + cobi, with no further increases in ORR at higher doses. Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). Similarly, treatment-emergent adverse events (TEAEs) ≥Grade 3 (G3) increased at the higher doses. Only 1 pt discontinued FORE8394 due to treatment-related AE (G3 bilirubin; 3600 mg/day). Conclusions: Based on the entirety of safety, PK, and efficacy data, the optimal RD of FORE8394 in Phase 2 is 900 mg QD + cobi in pts ≥10 years old. This achieved targeted efficacious exposures with robust antitumor activity and favorable safety. This dose optimization is consistent with current guidelines, avoids higher exposure that may lead to higher toxicity and compromise dose intensity. QD dosing also allows for a convenient dosing regimen. A Phase 2 study at the RD is ongoing in pts with recurrent V600E BRAF-mutated primary CNS tumors and advanced solid or CNS tumors with BRAF fusions. Clinical trial information: NCT02428712 . [Table: see text