Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons.

Wallerian degeneration (WD) is a conserved axonal self-destruction program implicated in several neurological diseases. WD is driven by the degradation of the NAD+ synthesizing enzyme NMNAT2, the buildup of its substrate NMN, and the activation of the NAD+ degrading SARM1, eventually leading to axonal fragmentation. The regulation and amenability of these events to therapeutic interventions remain unclear. Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. Results show that NAMPT and DLK inhibition cause a significant but time-dependent delay of WD. These time-dependent effects are related to NMNAT2 degradation and changes in NMN and NAD+ levels. Supplementation of NAMPT inhibition with NaR has an enhanced effect that does not depend on timing of intervention and leads to robust protection up to 4 days. Additional DLK inhibition extends this even further to 6 days. Metabolite analyses reveal complex effects indicating that NAMPT and MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. Finally, the axonal NAD+/NMN ratio is highly predictive of cADPR levels, extending previous cell-free evidence on the allosteric regulation of SARM1. Our findings establish a window of axon protection extending several hours following injury. Moreover, we show prolonged protection by mixed treatments combining MAPK and NAMPT inhibition that proceed via complex effects on NAD+ metabolism and inhibition of SARM1.

A softgel dietary supplement containing esterified plant sterols and stanols improves the blood lipid profile of adults with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled replication study.

A well-controlled clinical trial previously demonstrated the efficacy of a novel softgel dietary supplement providing 1.8 g/day esterified plant sterols and stanols, as part of the National Cholesterol Education Program Therapeutic Lifestyle Changes diet, to improve the fasting lipid profile of men and women with primary hypercholesterolemia (fasting low-density lipoprotein [LDL] cholesterol ≥ 130 and <220 mg/dL [≥ 3.37 and <5.70 mmol/L]). The purpose of this randomized, double blind, placebo-controlled crossover study (conducted July 2011 to January 2012) was to support these previous findings in a similar, but independent, sample with a different lead investigator and research site. Repeated measures analysis of covariance was used to compare outcomes for sterol/stanol and placebo treatment conditions using the baseline value as a covariate. Forty-nine subjects were screened and 30 (8 men and 22 women) were randomized to treatment (all completed the trial). Baseline (mean ± standard error of the mean) plasma lipid concentrations were: total cholesterol 236.6 ± 4.2 mg/dL (6.11 ± 0.11 mmol/L), high-density lipoprotein (HDL) cholesterol 56.8 ± 3.0 mg/dL (1.47 ± 0.08 mmol/L), LDL cholesterol 151.6 ± 3.3 mg/dL (3.92 ± 0.09 mmol/L), non-HDL cholesterol 179.7 ± 4.6 mg/dL (4.64 ± 0.12 mmol/L), and triglycerides 144.5 ± 14.3 mg/dL (1.63 ± 0.16 mmol/L). Mean placebo-adjusted reductions in plasma lipid levels were significant (P<0.01) for LDL cholesterol (-4.3%), non-HDL cholesterol (-4.1%), and total cholesterol (-3.5%), but not for triglycerides or HDL cholesterol. These results support the efficacy of 1.8 g/day esterified plant sterols/stanols in softgel capsules, administered as an adjunct to the National Cholesterol Education Program Therapeutic Lifestyle Changes diet, to augment reductions in atherogenic lipid levels in individuals with hypercholesterolemia.

Combination treatment with atorvastatin plus niacin provides effective control of complex dyslipidemias: a literature review.

Patients with dyslipidemia receive a cardiovascular benefit from lowering low-density lipoprotein cholesterol (LDL-C). Atorvastatin is currently one of the most effective approved medications for lowering LDL-C, and has been shown to significantly reduce cardiovascular risk in many patient groups. However, even with substantial lowering of LDL-C with atorvastatin, patients still have a residual risk for coronary heart disease. Elevated triglyceride levels and low high-density lipoprotein cholesterol (HDL-C) levels may contribute to this risk. Approved medications targeting these secondary lipid parameters include fibrates, omega-3 fatty acids, and niacin. Among these medications, niacin provides the optimal increase in HDL-C levels and has efficacy similar to the other medications in lowering triglyceride levels. However, there are challenges to adherence with niacin treatment. The most common challenge during niacin treatment is flushing, although it typically decreases with ongoing use and can be ameliorated by pretreatment with aspirin and counseling by the prescriber. A combination of atorvastatin and niacin may provide more complete normalization of the lipid profile and increased cardiovascular benefits. A literature review of the PubMed and Embase databases was conducted for clinical studies that reported on the lipid-modifying efficacy of the atorvastatin plus niacin combination. Identified studies involved patients at risk for coronary heart disease and patients with established coronary heart disease. Overall, the studies were small but indicated that atorvastatin in combination with niacin was efficacious in normalizing lipid parameters. Larger lipid studies as well as studies evaluating cardiovascular outcomes during atorvastatin plus niacin treatment are warranted.

Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients.

OBJECTIVE: Assess the long-term efficacy and safety of prescription omega-3-acid ethyl esters (P-OM3) coadministered with simvastatin in an extension of the Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial. METHODS: COMBOS included hypertriglyceridemic patients (triglyceride [TG] >or=200 mg/dL and <500 mg/dL or >or=2.26 mmol/L and <5.64 mmol/L) with low density lipoprotein cholesterol (LDL-C) level no greater than 10% above the National Cholesterol Education Program, Adult Treatment Panel III treatment goal. After an 8-week lead-in phase with simvastatin 40 mg/day (which continued throughout the trial), subjects were randomized to 8 weeks of P-OM3 4 g/day or placebo. Completers were eligible to participate in a 24-month extension study. Those who received placebo + simvastatin in COMBOS switched to open-label P-OM3 + simvastatin ('Switchers'); those who received P-OM3 + simvastatin during COMBOS continued the same regimen (open-label) in the extension phase ('Non-switchers'). The primary endpoint was the difference between Non-switchers and Switchers in median percent change in non-high-density lipoprotein-cholesterol (non-HDL-C) from COMBOS end of treatment to Month 4 of the extension phase. RESULTS: At Month 4 from COMBOS end of treatment, non-HDL-C was reduced by a median of 9.4% in Switchers and increased by 0.9% in Non-switchers (p < 0.001). For the total population (combined Non-switcher + Switcher population), the median percent change from COMBOS baseline to Months 4, 12, and 24 was -8.3%, -7.3%, and -8.9%, respectively (all p < 0.001). This extension study revealed no unexpected safety findings. A limitation of this study was a gap between completion of COMBOS and enrollment in the extension phase for some patients; however, a post-hoc non-HDL-C sensitivity analysis performed at the 4-month primary endpoint revealed no influence of gap on study results. CONCLUSIONS: In this 24-month extension study, P-OM3 was generally well tolerated, and produced sustained reductions in non-HDL-C levels in simvastatin-treated patients with TG levels between 200 and 500 mg/dL (2.26 mmol/L and 5.64 mmol/L). CLINICAL TRIAL REGISTRY NUMBER: NCT00903409.

Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia.

Prescription omega-3 acid ethyl esters (P-OM3) are commonly used for treatment of very high triglyceride levels, often in combination with a statin, to lower persistent hypertriglyceridemia. This randomized, crossover trial evaluated 6 weeks of combination therapy with simvastatin 20 mg/day plus P-OM3 4 g/day or placebo in 39 men and women (average age 58 years) with a triglyceride concentration 200 to 600 mg/dl and non-high-density lipoprotein (non-HDL) cholesterol greater than their National Cholesterol Education Program treatment goals after a 5-week diet lead-in. Non-HDL cholesterol decreased from baseline (209 mg/dl) by 40% for P-OM3 + simvastatin compared with 34% for placebo + simvastatin (p <0.001). Favorable changes for P-OM3 + simvastatin versus placebo + simvastatin were also observed for very low-density lipoprotein (VLDL) cholesterol (-42% vs -22%), triglyceride (-44% vs -29%), total cholesterol (-31% vs -26%), HDL cholesterol (+16% vs +11%), apolipoprotein B (-32% vs -28%), total cholesterol:HDL cholesterol ratio (-39% vs -33%), triglyceride:HDL cholesterol ratio (-51% vs -37%), and systolic (-5.0 vs 0.3 mm Hg) and diastolic (-3.3 vs -1.8 mm Hg) blood pressures (p <0.05 for all). VLDL particle concentration and size decreased and LDL particle size increased significantly more with P-OM3 + simvastatin than with placebo + simvastatin (all p <0.05). Changes in LDL cholesterol, LDL particle concentration, HDL particle size and concentration, and apolipoprotein A-I did not differ significantly between treatments. In conclusion, P-OM3 + simvastatin appears to be a useful therapeutic option for the management of mixed dyslipidemia.

Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study.

BACKGROUND: The number of patients with multiple lipid abnormalities is increasing. Lipid treatment guidelines are established for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The importance of treating HDL-C and triglycerides is gaining recognition. OBJECTIVE: To determine, in patients who had been treated previously with simvastatin 40 mg/day, the efficacy, safety, and tolerability of two regimens of a combination of proprietary niacin, extended-release core, coated with 40 mg/day simvastatin (NER/S), compared to 80 mg/day simvastatin monotherapy (S80). METHODS: High-risk patients (n = 343) with dyslipidemia were treated for 24 weeks with NER/S (1000/40 mg/day or 2000/40 mg/day) or S80. RESULTS: Median percentage change from baseline to week 24 in non-HDL-C in either NER/S group was noninferior to S80 (-11.3%, -17.1%, and -10.1%, respectively). Changes in LDL-C were comparable (-8.6%, -11.6%, and -12.7%, respectively). Doubling the dose of simvastatin (S80) did not alter HDL-C, triglycerides, or lipoprotein(a); however, both NER/S doses resulted in significant improvements in all three parameters (+21.9%, -31.8%, and -21.0%, respectively, for NER/S 2000/40 mg/day). The safety of NER/S was consistent with the safety profile of each individual component. Treatment with both doses of NER/S was well tolerated; 59% of patients experienced flushing, 78% of flushing was mild or moderate in intensity, 49% of those who flushed during dose titration did not flush during weeks 13 to 24, and only 4.6% of patients discontinued because of flushing. CONCLUSION: NER/S provides similar reductions in non-HDL-C and LDL-C compared to doubling the simvastatin dose to 80 mg; however, only NER/S resulted in improvements in HDL-C, triglycerides, and lipoprotein(a).

Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia.

A prescription form of omega-3 fatty acids has been approved by the United States Food and Drug Administration as an adjunct to diet for the treatment of very high triglyceride levels. The active ingredients of omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are responsible for the triglyceride lowering. The prescription product contains a total of 0.84 g of these two active ingredients in every 1-g capsule of omega-3 fatty acids. The total EPA and DHA dose recommended for triglyceride lowering is approximately 2-4 g/day. Fish oil products containing EPA and DHA are available without a prescription, but the American Heart Association advises that therapy with EPA and DHA to lower very high triglyceride levels should be used only under a physician's care. In patients with triglyceride levels above 500 mg/dl, approximately 4 g/day of EPA and DHA reduces triglyceride levels 45% and very low-density lipoprotein cholesterol levels by more than 50%. Low-density lipoprotein cholesterol levels may increase depending on the baseline triglyceride level, but the net effect of EPA and DHA therapy is a reduction in non-high-density lipoprotein cholesterol level. Alternatively, patients may receive one of the fibrates (gemfibrozil or fenofibrate) or niacin for triglyceride lowering if their triglyceride levels are higher than 500 mg/dl. In controlled trials, prescription omega-3 fatty acids were well tolerated, with a low rate of both adverse events and treatment-associated discontinuations. The availability of prescription omega-3 fatty acids, which ensures consistent quality and purity, should prove to be valuable for the medical management of hypertriglyceridemia.

Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia.

PURPOSE: A review of the key properties and trial results associated with prescription omega-3 fatty acids (P-O3FA) and a description of its place in the treatment of hypertriglyceridemia and coronary heart disease (CHD) risk are presented. SUMMARY: P-O3FA is made from the fish oil extracted from the fish carcass, which is put through a purification process that refines, esterifies, purifies, and concentrates the ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Each 1-g capsule provides 840 mg of EPA and DHA; the remaining 160 mg contains other omega-3 and omega-6 fatty acids, saturated fatty acids, and monounsaturated acids. When used at a daily dose of 4 g in patients with very high triglycerides (> or = 500 mg/dL), P-O3FA reduces triglycerides by an average of 45% and very-low-density-lipoprotein cholesterol by more than 50%. Changes in high-density-lipoprotein (HDL) cholesterol and non-HDL cholesterol are usually modest. P-O3FA has been tested in the GISSI-Prevenzione trial - a large, multicenter, open-label, randomized, controlled trial conducted in 11,324 patients. The results of the trial demonstrated significant reductions in all endpoints with the use of P-O3FA. CONCLUSION: P-O3FA has demonstrated an efficacy and safety in adult patients with high and very high triglycerides adjunct to diet, and the reduction in serum triglyceride levels was dependent on the baseline triglyceride levels. A large controlled clinical trial is necessary to determine if P-O3FA can be used to reduce CHD risk, either as combined with hydroxymethylglutaryl-coenzyme A reductase inhibitors or as monotherapy.

Torcetrapib/atorvastatin combination therapy.

Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy lipid-altering drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.

National survey of pharmacists about coronary heart disease, hypercholesterolemia, nonprescription statintherapy, and pharmacists' services.

OBJECTIVE: To determine the beliefs and attitudes of pharmacists about the significance of high blood cholesterol, coronary heart disease (CHD), nonprescription statin therapy for patients at moderate risk for CHD, and their role in support of cholesterol-lowering treatments in patients. DESIGN: Cross-sectional survey. SETTING: Nationwide sample of licensed pharmacists in ambulatory practice in the United States drawn randomly from databases of the American Pharmacists Association. PARTICIPANTS: 104 independent pharmacists and 169 chain pharmacists. INTERVENTION: Web-based survey. MAIN OUTCOME MEASURE: Respondents' indication of strong agreement with questionnaire statements (selecting 8, 9, or 10 on a 10-point scale). RESULTS: The survey found that 75% and 61% of pharmacists believed strongly that CHD and high blood cholesterol levels, respectively, are significant health problems facing Americans, and 60% believed that not enough is currently being done to reduce this risk. Pharmacists indicated that they very regularly advised patients about prescription and nonprescription treatments (75%) and encouraged adherence to them (78%); a smaller but substantial proportion regularly monitored patient response to prescription (33%) and nonprescription therapies (15%) and provided point-of-care cholesterol testing (7%). The survey also revealed that the majority of pharmacists (68%) would support consumers interested in purchasing a nonprescription statin product and 82% believed such a product would be more effective than currently available cholesterol-lowering dietary supplements. Pharmacists were concerned that patients pursuing nonprescription statins might discontinue their prescription cholesterol-lowering medications (79%), experience adverse effects (79%), and not be able to self-manage their use of a nonprescription statin product (78%). CONCLUSION: Community pharmacist members of APhA believe that CHD and cholesterol are important problems facing many people, routinely provide services that support patients who wish to self-administer nonprescription therapies, and would be interested in supporting consumers who wish to carry out therapy with a nonprescription statin.