Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Identification of four components from the female sex pheromone of the lima-bean pod borer, Etiella zinckenella

Four compounds, tetradecyl acetate, (Z)‐9‐tetradecenyl acetate, (E)‐11‐tetradecenyl acetate and (Z)‐11‐tetradecenyl acetate were identified from female sex pheromone extracts of Hungarian and Egyptian lima‐bean pod borers (Etiella zinckenella Tr., Lepidoptera: Phycitidae) by gas chromatography with flame ionization (FID) and electroantennographic (EAD) detection. In EAG studies these monounsaturated acetates gave the best responses in a series of other tetradecenyl acetates and tetradecenols. The four component blend of the identified components in similar ratios as in the pheromone extract attracted significant numbers of male lima‐bean pod borers in both Hungary and Egypt. In a preliminary subtraction test best capture was achieved by the ternary mixture of the monounsaturated acetates. Identification de quatre constituants de la phéromone des femelles d'Etiella zinckenella A partir de femelles d'E. zinckenella d'origines hongroise et égyptienne, nous avons isolé quatre composés par chromatographic en phase gazeuse avec ionisation de flamme et électroantennographie (EAD): l'acétate de tétradécanyl, l'acétate (Z)‐11‐tétradécényl, l'acétate (E)‐11‐tétradécényl et l'acétate (Z)‐11‐tétradécényl. Les acétates monoinsaturés donnent les meilleures réponses en EAG parmi une série d'acétates tétradécényls et de tétradécénols. Les quatre composés mélangés dans les mêmes proportions que dans l'extrait de la phéromone ont attiré un nombre significatif de mâles tant en Egypte qu'en Hongrie. Dans un test préliminaire de soustraction, la meilleure capture a été réalisée par le mélange ternaire d'acétates monoinsaturés. 1989 The Netherlands Entomological Societ

Epoxyheptadecadienes identified as sex pheromone components of Tephrina arenacearia Hbn. (Lepidoptera: Geometridae)

(Z,Z)-3,9-cis-6,7-Epoxyheptadecadiene, and (Z,Z)-6,9-cis-3,4-epoxyheptadecadiene were identified by gas chromatography/flame ionization detection-electroantennographic detection (GC/FID-EAD) and coupled gas chromatography-mass spectrometry (GC-MS) from abdominal tip extracts of Tephrina arenacearia (Lepidoptera: Geometridae), an alfalfa pest. In gas chromatography/flame ionization-single sensillum detection (GC FID-SC) analyses, specific olfactory receptor cells were found for (Z,Z)-6,9-cis-3,4-epoxyheptadecadiene, and tricosane. Synthetic samples of racemic (Z,Z)-6,9-cis-3,4-epoxyheptadecadiene attracted large numbers of male T. arenacearia into traps. Best catches were observed at 100-1000-mu-g dosages. The addition of (Z,Z,Z)-3,6,9-heptadecatriene did not influence catches. (Z,Z,Z)-3,6,9-Heptadecatriene and (Z,Z)-6,9-cis-3,4-epoxyheptadecadiene were also identified in the pheromone gland extract of Chiasma clathrata, another geometrid pest of alfalfa

Species discrimination in 5 species of winter-flying geometrids (lepidoptera) based on chirality of semiochemicals and flight season

Enantiomer separation of (6Z,9Z)-cis-3,4-epoxynonadecadiene and (3Z,9Z)-cis-6,7-epoxynonadecadiene could be achieved using chiral high-resolution gas chromatography and a cyclodextrin-bond column. (3Z,9Z)-(6R,7S)-Epoxynonadecadiene was identified from ovipositor extracts of Colotois pennaria, while in Erannis defoliaria the 6S,7R-enantiomer was found. In field trapping tests pure synthetic enantiomers caught only conspecific males of these species. (3Z,6Z,9Z)-Nonadecatriene was found in both species, while the presence of (3Z,6Z,9Z)-hencicosatriene was indicated in C. pennaria only. A 10:10:3 blend of (3Z,9Z)-(6R,7S)-epoxynonadecadiene, (3Z,6Z,9Z)-heneicosatriene, and (3Z,6Z,9Z)-nonadecatriene was found to be optimal for catching C pennaria, while E. defoliaria males were optimally caught by a 1:1 mixture of (3Z,9Z)-(6S,7R)-epoxynonadecadiene and (3Z,6Z,9Z)-nonadecatriene. (6Z,9Z)-(3S,4R)-Epoxynonadecadiene was identified from ovipositor extracts of Agriopis (Erannis) aurantiaria. In field tests the pure enantiomer proved to be a highly specific sex attractant for both the late autumn/early winter flying A. aurantiaria and the late winter/early spring flying A. leucophearia. Males of Agriopis marginaria, which fly in late winter/early spring, were attracted to (3Z,9Z)-(6S,7R)-epoxynonadecadiene. The addition of (3Z,6Z,9Z)-nonadecatriene to the S,R-enantiomer increased captures. Optimal catches were recorded with a 10: 3 epoxide-hydrocarbon blend. Enantiomer specificity in all species was confirmed in EAG measurements

Female sex pheromone of Cameraria ohridella Desch and Dim. (Lepidoptera : Gracillariidae): Structure confirmation, synthesis and biological activity of (8E,10Z)-8,10- tetradecadienal and some analogues

Mass spectrometric investigations confirmed the structure of the female produced sex pheromone of the horse-chestnut leafminer Cameraria ohridella Desch. and Dim. to be (8E,10Z)- 8,10-tetradecadienal. Pure samples prepared in a straightforward synthesi