Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

Background CSL112 is a new formulation of human apolipoprotein A‐I (apoA‐I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double‐blind, multicenter, dose‐ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2‐hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations \u3e3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA‐I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7‐, 3.4‐, and 6.8‐g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (\u3e3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7‐, 3.4‐, and 6.8‐g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion‐site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose‐dependent increases in apoA‐I (145% increase in the 6.8‐g group) and total cholesterol efflux (up to 3.1‐fold higher than placebo) (P\u3c0.001). Conclusions CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA‐I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

Brazilian cave heritage under siege

info:eu-repo/semantics/publishe

Basic-level emergency medical technician administration of fluids and glucose via enzyme-assisted subcutaneous infusion access.

INTRODUCTION: During disasters and mass-casualty incidents (MCIs), there may be insufficient numbers of advanced life support (ALS) providers to provide intravenous (IV) access to all patients requiring parenteral fluids and/or medications. Enzyme-assisted subcutaneous infusion (EASI) access, in which human recombinant hyaluronidase (HRH) augments subcutaneous fluid dispersion and absorption, may be useful when ALS resources are insufficient to meet intravascular access needs. The utility of the use of the EASI lies, in part, in its ease of placement by ALS personnel. OBJECTIVES: The objectives of this study were to document the feasibility, comfort, and speed/degree of infused-glucose uptake through EASI lines placed by basic-level emergency medical technicians (EMT-Bs). METHODS: Eighteen EMT-Bs instituted EASI access on each other. A total of 150 units (1 mL) of HRH were administered through the EASI line, followed by the administration of 250 mL of tracer-labeled D5W. Timed phlebotomy enabled gas chromatography/mass spectrometry characterization of glucose uptake. Enzyme-assisted subcutaneous infusion placement and comfort ratings were tracked and analyzed using non-parametric statistics and Fisher's Exact Test. RESULTS: In all 18 subjects, EASI access required only one attempt and was rated by the EMT-Bs as easy to accomplish. Glucose was absorbed quickly (within five minutes) in all subjects. The rate of infusion was rapid (median 393 mL/hour) and was comfortable for the recipients (median pain score 1/10). CONCLUSIONS: The use of EASI may be viable as a fast, simple, and reliable method for the administration of fluid and glucose by EMT-Bs

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial

BACKGROUND: Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS: We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS: The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p <0.0001) and an 17.7% relative decrease in LDL cholesterol (p <0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p <0.0001). INTERPRETATION: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed furthe