Discovery of the development candidate N-tert-butyl nodulisporamide: a safe and efficacious once monthly oral agent for the control of fleas and ticks on companion animals.

Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.

Efficacy and safety of ezetimibe/simvastatin co- administered with fenofibrate in mixed hyperlipidemic patients with metabolic syndrome.

BACKGROUND: We compared the lipid-altering effects of ezetimibe/simvastatin (EZE/SIMVA) co-administered with fenofibrate (FENO) in mixed hyperlipidemic patients with (MetS) versus those without MetS. METHODS: A total of 611 patients, 20 to 79 years old, with LDL-C 130-220 mg/dL (100-180 mg/dL for patients with type 2 diabetes [T2D]), triglycerides (TG) 150-500 mg/dL, and no history of CHD or other CHD risk equivalent disease (except for T2D), were randomized in a 1:3:3:3 ratio into one of the following four treatments for 12 weeks: placebo; EZE/SIMVA 10/20 mg; FENO 160 mg; or EZE/SIMVA+FENO. MetS status was determined in 607 patients using National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Percentage change from baseline in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), TG, apolipoproteins A-I and B, and C-reactive protein was assessed in these patients with or without MetS. The primary objective was to evaluate the lipid-altering efficacy of EZE/SIMVA+FENO versus FENO monotherapy in the MetS versus non-MetS subgroups. RESULTS: At baseline, patients with MetS had a higher body mass index (BMI) and TG and lower HDL-C. At Week 12, treatment with EZE/SIMVA, FENO, and EZE/SIMVA + FENO led to similar improvements in lipid parameters in patients with MetS compared to those without MetS. Treatment with EZE/SIMVA + FENO and FENO also led to an increase in LDL particle-size pattern after 12 weeks in both subgroups of patients. CONCLUSIONS: This post-hoc analysis suggested that co-administration of EZE/SIMVA+FENO had consistent benefits on the lipid profile in mixed hyperlipidemic patients with or without MetS.

Efficacy and safety of ezetimibe/simvastatin versus simvastatin monotherapy in hypercholesterolemic patients with metabolic syndrome.

BACKGROUND: The combination of ezetimibe and simvastatin (EZE/SIMVA) inhibits intestinal absorption and hepatic synthesis of cholesterol, providing significantly greater LDL-C-lowering compared to either drug alone. We examined the efficacy and safety of EZE/SIMVAin hypercholesterolemic patients with metabolic syndrome (MetS). METHODS: We evaluated pooled data from three similarly designed, randomized, doubleblinded, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout and a 4-week diet/placebo run-in, patients received one of the following treatments for 12 weeks: EZE/SIMVA (10/10, 10/20, 10/40 or 10/80 mg); SIMVA (10, 20, 40 or 80 mg); EZE 10 mg; or placebo. For this analysis, the efficacy of EZE/SIMVA versus SIMVA was evaluated in patients with and without MetS. The primary endpoint was mean percent change from baseline in LDL-C for EZE/SIMVA (pooled across doses) versus SIMVA (pooled across doses). RESULTS: Of 2394 patients who received SIMVA or EZE/SIMVA and for whom MetS status at baseline could be determined, 31% were identified as having MetS. In the entire cohort, treatment with EZE/SIMVA led to a significant incremental reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, triglyceride (TG), and C-reactive protein compared to SIMVA and these effects were similar across the MetS and non-MetS subgroups. EZE/SIMVA was well tolerated in both the MetS and non-MetS subgroups. CONCLUSION: EZE/SIMVA significantly improved the lipid and inflammatory profiles of hypercholesterolemic patients with MetS and was well tolerated. Thus, EZE/SIMVA offers an efficacious and safe treatment option for these patients.

Comparison of the lipid-modifying efficacy and safety profiles of ezetimibe coadministered with simvastatin in older versus younger patients with primary hypercholesterolemia: a post Hoc analysis of subpopulations from three pooled clinical trials.

BACKGROUND: Despite the need for effective and well-tolerated lipid-lowering therapies for primary hypercholesterolemia in older patients, there is a relative paucity of published data on such treatments in this population. OBJECTIVE: We conducted a post hoc analysis to examine the lipid-modifying efficacy and safety profile of simvastatin (SIMVA) monotherapy, and the coadministration of ezetimibe (EZE) and SIMVA (EZE/SIMVA) in older (ie, aged>or=65 years) versus younger (ie, aged<65 years) patients with primary hypercholesterolemia. METHODS: We analyzed pooled data from 3 previously published, similarly designed, randomized, double-blind, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout, a 4-week dietary stabilization period, and a 4-week placebo run-in period, patients with low-density lipoprotein cholesterol (LDL-C) of 145 to 250 mg/dL were randomized to EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo for 12 weeks. In this post hoc analysis, the percent change from baseline to week 12 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B (apo B), triglycerides (TG), and high-sensitivity C-reactive protein (hs-CRP) for EZE/SIMVA (pooled across doses) versus SIMVA alone (pooled across doses) was compared between older and younger patients with primary hypercholesterolemia. Tolerability was assessed by adverse event reports and laboratory and vital signs assessments throughout the study. RESULTS: A total of 3083 patients aged 20 to 87 years were included in the 3 studies (2320 were aged<65 years and 763 were aged>or=65 years). Baseline lipid values and patient characteristics were similar among all treatment groups for patients aged<65 years versus those aged>or=65 years except that there was a higher percentage of females (62% vs 50%) and patients with hypertension (46% vs 29%) in the older versus younger subgroup (both, P<0.001). EZE/SIMVA was associated with greater improvements than SIMVA alone in LDL-C, non-HDL-C, apo B, TG, and hs-CRP (all, P<0.001); these effects did not appear to differ between the older and younger sub-groups (all, P=NS). Changes in HDL-C did not differ significantly between the EZE/SIMVA and SIMVA groups. More patients receiving EZE/SIMVA than SIMVA monotherapy achieved the target LDL-C level<100 mg/dL (P<0.001), regardless of age subgroup (77% vs 41% for patients aged<65 years and 85% vs 48% for patients aged>or=65 years). In the younger sub-group, the incidence of creatinine phosphokinase (CK) elevations>or=10x the upper limit of normal (ULN) was or=10x ULN were reported. In younger patients, the incidence of consecutive alanine amino-transferase or aspartate aminotransferase levels>or=3x ULN was 0% for placebo and EZE, <1% for SIMVA, and 2% for EZE/SIMVA; in older patients, it was 1% for placebo and EZE, <1% for SIMVA, and 0% for EZE/SIMVA. CONCLUSION: This post hoc analysis of pooled data from 3 previously published large clinical trials suggests that EZE/SIMVA was well tolerated and associated with improved lipid profiles in both older and younger patients with primary hypercholesterolemia.