View this table: [in this window] [in a new window] Table 1. Drugs for the Treatment of Adult Dyslipidemias

Bile acid sequestrants lower LDL-C levels 15% to 30%; however, they have minimal, if any, effect on HDL-C and may increase triglyceride levels, especially in patients with borderline or high triglyceride levels.¹ Ezetimibe, a cholesterol absorption inhibitor, was recently approved by the Food and Drug Administration (FDA) and like bile acid sequestrants, reduces LDL-C levels about 18% to 24% with very little effect on HDL-C or triglyceride levels.^9-10 Fibrates generally raise HDL-C levels 5% to 15% and reduce triglyceride levels 20% to 50%, making them useful in patients with mixed dyslipidemia; however, their effect on LDL-C is variable and in patients with moderate to high triglyceride levels, they may raise LDL-C.^{1, 11}

Niacin (nicotinic acid) favorably affects all lipids and lipoproteins, making it an alternative to fibrates for treating patients with mixed hyperlipidemia, and may be used either alone or in combination with other agents.¹ This article reviews the scientific rationale and use of niacin in a variety of dyslipidemias. It discusses the different niacin formulations and the principal adverse events associated with each and provides guidance for minimizing these events and improving patient tolerance.

NIACIN FORMULATIONS

Immediate-release niacin is sold over the counter as a dietary supplement for niacin deficiency; one IR product, Niacor (Upsher-Smith, Minneapolis, Minn), has been FDA approved for lipid-altering therapy by prescription. The IR formulation is quickly absorbed and quickly excreted. Peak serum levels are obtained within 30 to 60 minutes of oral dosing and the metabolic half-life is approximately 1 hour. It is most often prescribed in multiple daily doses.¹²

Long-acting niacin, also referred to as timed-release, controlled-release, or sustained-release niacin, is created through a variety of absorption-delaying techniques¹³ that lead to dissolution times that typically exceed 12 hours but are variable even within lots of the same product.^12-14 All LA niacin products are sold over the counter for treating niacin deficiencies and none have been FDA approved for the treatment of lipid disorders.¹²

Extended-release niacin is absorbed over 8 to 12 hours, intermediate between IR and LA niacin. This makes it suitable for once-daily bedtime dosing.¹⁴ One ER niacin product is currently FDA approved for lipid lowering and is available by prescription as Niaspan from Kos Pharmaceuticals (Miami, Fla).

The differences in release characteristics among various niacin products are important because they determine how the drug is metabolized, in turn influencing the side effect profile of the product. Niacin is metabolized through 2 separate metabolic pathways (Figure 1).^{12, 15} The flushing effect with some niacin products results from prostaglandin-mediated vasodilation associated with the formation of nicotinuric acid by the conjugation pathway, while hepatotoxicity is associated with the metabolites of the nicotinamide pathway.¹²

View larger version (23K): [in this window] [in a new window] Figure 1. Niacin metabolism. Niacin is metabolized via 2 pathways. In the first pathway, it is conjugated with glycine to form nicotinuric acid (NUA). The second pathway involves a number of oxidation-reduction reactions that produce nicotinamide (NAM) and ultimately pyrimidine metabolites. 6HN indicates 6-hydroxy-nicotinamide; MNA, N-methylnicotinamide; NAD, nicotinamide adenine dinucleotide; NNO, nicotinamide-N-oxide; 2PY, N-methyl-2-pyridone-5-carboxamide; 4PY, N-methyl-4-pyridone-5-carboxamide. Reprinted with permission from Piepho,12 with permission from Excerpta Medica Inc.

The nicotinamide pathway is a high-affinity, low-capacity pathway. The IR niacin formulation quickly saturates this pathway and is predominantly metabolized through the high-capacity conjugation pathway. It is therefore associated more with flushing but not hepatotoxicity. In contrast, LA niacin is very slowly absorbed and preferentially metabolized via the nicotinamide pathway. Because of this, LA niacin rarely causes flushing but significantly increases the risk of serious, dose-related hepatotoxic effects. The ER niacin fromulation, with its intermediate absorption rate, has a more balanced metabolism between the 2 pathways. The result is less flushing and less risk of hepatotoxic effects, at least with daily doses of 2 g or less.

LDL-C AND TRIGLYCERIDE EFFECTS OF NIACIN

Niacin decreases LDL-C levels by 5% to 25% and triglyceride levels by 20% to 50% (Table 1).^{1, 20} In addition, niacin favorably alters LDL composition, shifting distribution from small, dense LDL particles to larger, more buoyant particles.^21-25 This may be important to niacin's ability to reduce coronary heart disease (CHD) risk.^26-28 In the Familial Atherosclerosis Treatment Study (FATS), change in the size and buoyancy of LDL particles was the single most important factor associated with regression of coronary stenosis.²³

HDL-C EFFECTS OF NIACIN

Niacin is the most effective pharmacologic agent currently on the market for raising HDL-C levels, with increases of 15% to 35%.¹ It follows a relatively flat dose-response curve³² so most of the rise in HDL-C with niacin occurs at daily doses of 1 to 1.5 g (Figure 2).^{14, 18, 20, 32}

View larger version (21K): [in this window] [in a new window] Figure 2. Effects of immediate-release (IR) and long-acting (LA) niacin on serum lipoprotein concentrations. Low-density lipoprotein cholesterol (LDL-C) reduction follows a linear relationship with dose. Titration of the daily dose to 2 g is required to lowering LDL-C 25%. Increases in high-density lipoprotein cholesterol (HDL-C) and reductions in triglycerides (TG) follow a curvilinear relationship with dose. Reprinted with permission from Knopp.32 Copyright 1999 Massachusetts Medical Society.

NIACIN COMBINATION THERAPY

Given the superior efficacies of niacin and statins on HDL-C and LDL-C, respectively, combining them provides a regimen with greater overall lipid-altering efficacy than either drug can provide alone.¹ In one study, patients assigned to niacin plus fluvastatin had significantly greater reductions in both LDL-C (40% vs 25%) and the LDL-C/HDL-C ratio (52% vs 43%) than patients receiving niacin plus placebo.³⁶

Similar results are seen with ER niacin. In one study, the addition of 1 g/d of ER niacin to a stable dose of statin monotherapy lowered LDL-C levels an additional 8% and raised HDL-C levels an additional 24%, whereas the addition of 2 g/d of ER niacin lowered LDL-C levels an additional 20% and raised HDL-C levels an additional 27% (Figure 3).³⁷ Note the similar increase in HDL-C levels with the 2 doses but the substantially greater lowering of LDL-C with the higher dose as would be expected from the dose-dependent pattern illustrated in Figure 2. Recently, a once-daily single tablet combination of ER niacin and lovastatin became available (Advicor, Kos Pharmaceuticals). In an open-label, 52-week, multicenter study evaluating 814 dyslipidemic patients receiving 2 g of ER niacin and 40 mg of lovastatin in the fixed-dose combination tablet, LDL-C and triglyceride levels were reduced 45% and 42%, respectively, and HDL-C level was increased 41%.³⁸

View larger version (24K): [in this window] [in a new window] Figure 3. Mean percent change in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) following 1 g/d or 2 g/d of extended-release (ER) niacin when added to a stable dose of statin monotherapy. The HDL-C effect is near maximal with low-dose niacin, whereas a greater LDL-C effect requires high-dose niacin. Adapted with permission from Wolfe et al,37 with permission from Excerpta Medica Inc.

IMPACT OF NIACIN ON OUTCOMES

In both CLAS and FATS, angiographic assessments demonstrated that niacin plus colestipol produced significant reductions in the progression of atherosclerosis; moreover, regression of atherosclerosis occurred in 16% and 18% of CLAS patients at 2 years and 4 years, respectively, and in 39% of FATS patients at 2 years.^33-35 FATS also demonstrated a significant 73% reduction in the incidence of cardiovascular events in patients receiving intensive therapy with colestipol plus either niacin or lovastatin.³⁵ In a 10-year follow-up, triple therapy with niacin, lovastatin, and colestipol, compared with usual care, resulted in significantly less all-cause mortality (1.3% vs 19.8%; P<.001) and cardiovascular events (5.3% vs 18.8%; P<.001).⁴¹

Combination therapy with niacin and a fibrate has also been shown efficacious. The Stockholm Ischaemic Heart Disease Secondary Prevention Study evaluated niacin plus fibrate therapy in consecutive survivors of myocardial infarction.⁴² Compared with the control group, which did not receive drug therapy, niacin-fibrate therapy reduced CHD mortality by 36%.

The HDL-Atherosclerosis Treatment Study (HATS) evaluated niacin plus simvastatin combination therapy in patients with low HDL-C and normal LDL-C levels.⁴³ Compared with a mean 3.9% progression in coronary stenosis with placebo, niacin-simvastatin therapy caused a mean regression of 0.4% (P<.001) and reduced the composite primary end point of death from coronary causes, confirmed myocardial infarction or stroke, or revascularization for worsening ischemia by 60% vs placebo (P = .02).

NIACIN THERAPY IN SELECTED PATIENT TYPES

Atherogenic Dyslipidemia and the Metabolic Syndrome

In the United States, mixed lipid disorders are relatively common, especially in high-risk patients. In a study of more than 8500 men with CHD who were not receiving lipid-altering drug therapy, fasting lipid testing revealed 87% had LDL-C levels greater than 100 mg/dL (2.59 mmol/L), 63% had HDL-C levels less than 40 mg/dL (1.04 mmol/L), and 33% had triglyceride levels greater than 200 mg/dL (2.26 mmol/L).⁴⁴ Isolated lipid abnormalities were rare; only 8% of patients had isolated low HDL-C and only 1% had isolated hypertriglyceridemia. Furthermore, only 7% of patients had LDL-C levels less than 100 mg/dL (2.59 mmol/L) and HDL-C levels at or above 35 mg/dL (0.91 mmol/L).

Atherogenic dyslipidemia is the combined presence of elevated triglycerides, increased remnant lipoproteins (ie, remnant VLDL), reduced HDL-C, increased small LDL particles, and increased number of lipoprotein particles. It frequently occurs in association with other cardiovascular risk factors, metabolic syndrome, and diabetes mellitus, and is associated with premature atherosclerosis.¹

Adequate treatment of patients with atherogenic dyslipidemia first requires lowering LDL-C to goal and then non–HDL-C to goal. Non–HDL-C includes all apolipoprotein B–containing lipoproteins, VLDL, intermediate-density lipoproteins, and LDL. If LDL-C (which in most laboratories also includes intermediate-density lipoprotein cholesterol) has been reduced to goal and triglyceride levels are greater than 200 mg/dL (2.26 mmol/L), the non–HDL-C level will often be elevated because of an elevated VLDL-C. The non–HDL-C goal is set 30 mg/dL (0.78 mmol/L) above the LDL-C goal by the latest Adult Treatment Panel (ATP III).¹

Reducing non–HDL-C to goal is accomplished by uptitrating the statin dose or selecting therapies that lower triglyceride levels (Table 1). In patients with significant LDL-C elevations, a statin is generally required. Thereafter, statin therapy may be advanced if the triglyceride level is only modestly elevated (ie, 200-350 mg/dL [2.26-3.95 mmol/L]), or niacin or a fibrate may be added to the statin to lower triglyceride levels and achieve the non–HDL-C goal when triglyceride levels are significantly elevated (ie, >350 mg/dL [3.95 mmol/L]). Niacin's effect on triglycerides is among the best of the agents available.¹ In patients with hypertriglyceridemia and modest LDL-C elevations, niacin lowers triglyceride levels 20% to 50% and LDL-C about 20% at a 2-g/d dose (Figure 2).³²

Diabetes

Approximately 70% of patients with diabetes will die of some form of cardiovascular disease.⁴⁵ Patients with diabetes typically have lipid abnormalities associated with atherogenic dyslipidemia.¹ Niacin's effects on the lipid profile (raising HDL-C level, lowering triglyceride and LDL-C levels, and increasing LDL particle size) make it a good option for this type of mixed dyslipidemia. Significant improvements in lipid parameters in patients with diabetes similar to those without diabetes have been shown with niacin therapy.^46-50 However, niacin can adversely affect glucose levels and may necessitate initiation or intensification of hyperglycemic therapy in patients with impaired fasting glucose levels or diabetes.⁵¹ Some small studies, generally using relatively high IR niacin doses (ie, 3-4.5 g/d), found significant rises in blood glucose levels in both diabetic and nondiabetic subjects. Other studies, using smaller daily doses (ie, 1.5 g/d), have detected few or no such alterations.^47-50

Several recent studies have added to our understanding of the use of niacin in a diabetic population. The Arterial Disease Multiple Intervention Trial (ADMIT) included subjects with and without diabetes randomized to IR niacin or placebo for 48 weeks.⁴⁸ Small but significant increases in glycosylated hemoglobin (A_1c) levels were seen in niacin-treated patients with diabetes, but not in those without diabetes. Glucose levels rose as niacin was titrated from 1 to 3 g/d, but subsequently returned to baseline 6 weeks after achieving a stable niacin dose. Presumably, adjustments in the insulin dose, made in 13% of the diabetic patients, partially accounted for the return of glucose to baseline levels. However, niacin therapy did not significantly affect the use of oral hypoglycemic agents and, for patients using insulin at both their first and final visits, did not significantly affect insulin dose. Moreover, withdrawal due to glucose intolerance was not significantly different between the niacin (4 of 64 subjects) and placebo (2 of 61 subjects) groups.

In the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT), patients with type 2 diabetes were randomized to treatment with ER niacin or placebo. Fasting blood glucose levels initially rose at visits 4 and 8 weeks but returned to baseline by week 16 of ER niacin therapy. As in ADMIT, alterations in hypoglycemic therapy may partially account for this return to baseline, with a trend for worsening glycemic control requiring the addition or intensification of drug therapy with increasing doses; however, this trend was not statistically significant.

Recently, CDP investigators reported that fasting and 1-hour postprandial blood glucose levels were increased in patients assigned to the IR niacin group in their study (the magnitude of the increase was not specified).⁵² However, they also reported that nonfatal myocardial infarction or all-cause death after 6 years of therapy was reduced 29% and 12%, respectively, among patients with a 1-hour postprandial glucose level of less than 140 mg/dL (7.77 mmol/L) compared with a reduction of 42% and 20%, respectively, among patients with a 1-hour postprandial glucose level of 220 mg/dL (12.2 mmol/L) or higher. This suggests that the CHD risk reduction associated with niacin use in the overall study was preserved in diabetic patients despite an increase in blood glucose levels.

The risks vs benefits of treating diabetic patients with niacin must be weighed by health care providers. Niacin therapy is often appropriate for the lipid abnormalities encountered in these patients. Moreover, it is not contraindicated and can be successfully tolerated by most diabetic patients without deterioration in their glucose control. When statins are not adequate to achieve lipid targets, niacin can be considered, with appropriate adjustment of hypoglycemic therapy to maintain glucose under good control.

Isolated Low HDL-C

Niacin is an ideal choice to treat isolated low HDL-C levels because of its superior HDL-C–raising effect at low, very tolerable doses. In an early study of patients with fasting HDL-C levels less than 35 mg/dL (0.91 mmol/L) and triglyceride levels less than 250 mg/dL (2.82 mmol/L), IR niacin resulted in a significant 30% increase in HDL-C level.⁵³ In another study, patients with HDL-C levels less than 40 mg/dL (1.04 mmol/L), LDL-C levels less than 160 mg/dL (4.14 mmol/L), and triglyceride levels less than 200 mg/dL (2.26 mmol/L) experienced a greater increase in HDL-C with IR niacin than with gemfibrozil (35% vs 15%; P<.005); combining the 2 drugs was not statistically different from niacin monotherapy.⁵⁴

Evidence of clinical benefit from raising HDL-C levels in patients with isolated low HDL-C is mostly theoretical. A few trials have included patients with normal total cholesterol and low HDL-C levels.^{43, 55-57} Although outcomes improved with treatment, the inclusion of patients with hypertriglyceridemia in these trials makes it difficult to determine the relative contribution of raising HDL-C vs lowering triglycerides.

Hypertriglyceridemia

The National Cholesterol Education Program has recently affirmed an important association between hypertriglyceridemia and CHD risk.¹ Which drug to use often depends on the degree of hypertriglyceridemia and the patient's LDL-C level. In patients with very high triglyceride levels (500 mg/dL [5.65 mmol/L]), niacin or fibrates are usually required. The triglyceride lowering with statins (eg, 25%-40%) is greatest in patients with very high triglyceride levels, but this lowering would generally not be sufficient to bring triglyceride levels to the normal range of less than 150 mg/dL (1.70 mmol/L). In patients with less severe hypertriglyceridemia (ie, 200-350 mg/dL [2.26-3.95 mmol/L]), statin monotherapy may be useful. When LDL-C is only modestly elevated in the presence of hypertriglyceridemia, niacin or a fibrate alone may be used.^{1, 58-59} However, because fibrates typically raise LDL-C levels 5% to 30% in these patients, they must usually be coadministered with a statin.^{1, 60}

NIACIN OR FIBRATES

The degree of dyslipidemia may be another factor. In an early trial, subjects received first gemfibrozil (0.6 g twice daily) then IR niacin (1.5 g 3 times per day) for 8 weeks separated by an 8-week control period.⁶¹ Gemfibrozil produced a 25% fall in fasting triglyceride levels but no change in LDL-C or HDL-C level. Niacin similarly did not affect LDL-C, but increased HDL-C levels by 30% and decreased triglyceride levels by 35%. In a subsequent randomized, double-blind trial, ER niacin (2 g/d) produced a 2-fold greater increase in HDL-C level (26% vs 13%; P<.001) than gemfibrozil (0.6 g twice daily); gemfibrozil produced a greater fall in triglyceride levels (40% vs 29%; P = .02) but also a significant rise in LDL-C level (9% vs 0%; P = .004).¹¹ The presence of elevated lipoprotein(a) levels may also influence therapy selection. Lipoprotein(a) is an emerging cardiovascular risk factor with a strong association with CHD risk^62-63 and has been reported to have synergy with accompanying LDL-C elevation in increasing CHD risk.¹ Niacin is the only lipid-modifying agent that significantly affects lipoprotein(a), with reductions of 20% to 38%.⁶⁴ Therefore, in patients with dyslipidemia that includes elevated lipoprotein(a) levels, niacin would be the preferred agent.

Concomitant disorders and the need for additional medications are also determining factors in whether to use niacin or fibrate therapy. Because of strong protein binding, fibrates have the potential for significant drug-drug interactions.¹ In addition, combining gemfibrozil with a statin increases the risk of myopathy.^{1, 65-66} Although myopathy may also occur when niacin is added to a statin, the incidence is much lower than combination statin-fibrate therapy.⁶⁶

The principal limitation of niacin is the potential for sustained-release niacin to cause adverse hepatotoxic effects and for IR niacin and, to a lesser extent, for ER niacin to cause bothersome side effects such as flushing. These side effects, discussed below, often lead to hesitancy in prescribing niacin. However, they can be significantly reduced to the point that niacin can be tolerated during long-term therapy by 70% or more of patients.

ADVERSE EFFECTS OF NIACIN THERAPY

Consistent with its intermediate absorption profile, ER niacin produces less flushing than IR niacin and fewer hepatotoxic effects than LA niacin. This has been demonstrated in one randomized trial that directly compared ER and IR niacin. The ER niacin regimen produced significantly less flushing than IR niacin (Figure 4) without increasing the risk of elevated liver enzymes or hepatotoxic effects.²⁵ In another study with ER niacin, flushing occurred in approximately 50% of the patients during the initial 4 weeks of therapy but resolved in most by week 24.⁷¹ Only 5% of study patients discontinued ER niacin therapy as a result of flushing (less than the 10% to 50% reported with IR niacin). Elevations in liver enzyme levels greater than 2 times the upper limit of normal occurred in 2.6% of patients, mostly in those receiving combination therapy with either a statin or bile acid sequestrants, and most resolved without a dose reduction.

View larger version (20K): [in this window] [in a new window] Figure 4. Incidence of all flushing episodes between office visits during 16 weeks of therapy with escalating doses of extended-release (ER) niacin (n = 74 patients) and immediate-release (IR) niacin (n = 76 patients). Reprinted from Knopp et al,25 with permission from Elsevier Science.

As previously discussed, hyperglycemia is another important side effect associated with niacin therapy. In most well-controlled clinical trials, mean changes in fasting blood glucose levels are generally modest and transient.^{48-50,68, 71} Niacin-induced hyperglycemia does not occur in all patients; it is more prevalent in patients with diabetes, 10% to 35% of whom it is estimated will require a change in hypoglycemic therapy.^{48, 50} In addition, a few patients with impaired fasting glucose levels (and not diabetes) may develop diabetes, requiring initiation of hypoglycemic therapy. The prevalence of these effects appears to be similar with IR and ER niacin, although percent increases tend to be higher with IR niacin; less is known about the effect of LA niacin on these parameters.

Other potential adverse effects of niacin include hyperuricemia and gout, cardiac arrhythmias, tachycardia, palpitations, hypotension, dizziness, chills, edema, migraine, insomnia, acanthosis nigricans, and activation of peptic ulcer disease and are seen to varying extents with all niacin formulations.^{18, 72-73}

It is widely believed that combining niacin with a statin increases the risk of muscle toxic effects. Myopathy (generally defined as creatine kinase level >10 times the upper limit of normal plus muscle symptoms including weakness, soreness, or pain) has been reported in a small number of cases with niacin monotherapy,^74-75 and myopathy and rhabdomyolysis have been reported with both IR and LA niacin in combination with a statin.^76-78 The true incidence of muscle side effects, however, cannot be determined from these isolated case reports. It is probably very low and indistinguishable from that seen with statins alone, ie, approximately 2 to 4 cases of myopathy per 1000 treated patients. Of 601 FDA-reported statin-induced cases of rhabdomyolysis, 4 (0.7%) were associated with niacin-statin combination therapy.⁶⁵

IMPROVING ADHERENCE WITH NIACIN THERAPY

With IR niacin, the biggest hurdle to overcome is the flushing effect. Tolerance develops such that within several weeks of initiating niacin therapy approximately 60% of patients will have only mild flushing and only about 3% will continue to have severe flushing.⁶⁸ Unfortunately, many patients discontinue niacin therapy before developing this tolerance or initiating other approaches to lessen symptoms.⁸⁰ In addition, approximately 20% of patients receiving IR niacin experience symptoms of gastrointestinal irritation. Usually, these symptoms are transitory and can be minimized by taking IR niacin with food.⁶⁸ Alternatively, ER niacin can be used since, relative to placebo, it does not increase the frequency of gastrointestinal symptoms²⁰ and may, by itself, promote better patient adherence than IR niacin by allowing once-daily dosing. Table 2 lists these and several other practical steps for limiting symptoms and improving adherence with niacin therapy.^{14, 18, 80-82} Importantly, LA niacin should not be used to avoid flushing and should not be substituted for IR niacin at doses of 2 g/d or more because of the associated risk of hepatotoxic effects.^{67, 83} If used at all, the dose should be kept to 2 g/d or less and the patient should be monitored for liver toxicity.⁶⁷

View this table: [in this window] [in a new window] Table 2. Steps to Prevent and Reduce Niacin-Induced Symptoms and Improve Adherence

As with all therapies, long-term adherence depends on good patient education. This includes frank discussion about benefits expected from lipid-modifying therapy and potential adverse drug effects, including how long they might last and how to lessen their consequences. Following this discussion, it is important to obtain the patient's acceptance of the therapy being advocated. Aspirin administration 30 minutes before the morning dose should be recommended, if not contraindicated. Finally, the overriding message needs to be the importance of continuing therapy in order to achieve long-term CHD risk reduction.

CONCLUSIONS

Given the superior efficacies of niacin and statins with regard to HDL-C and LDL-C, respectively, their combination is an ideal choice for patients with abnormalities of more than 1 lipid parameter or when monotherapy is insufficient for achieving lipoprotein goals. Several studies have confirmed the safety and efficacy of this combination. Although it is widely believed that combining niacin with a statin increases the risk of muscle toxicity, this risk appears to be extremely low and may not be significantly different from that of statin monotherapy. The greatest potential advantage of this combination, confirmed in several small studies, is the additional reduction in cardiovascular risk that may be achieved when HDL-C–raising effects of niacin are added to the well-documented beneficial LDL-C–lowering effects of statins. A large clinical trial with niacin vs placebo randomly added to a statin background is needed to fully establish this benefit.

From National Clinical Research and Virginia Commonwealth University, Richmond. Dr McKenney has served as a consultant for AstraZeneca and Pfizer; received speaking honoraria from AstraZeneca, Kos Pharmaceuticals, Merck, and Pfizer; and received research grants from AstraZeneca, BMS, GSK, Kos Pharmaceuticals, Merck, Pfizer, Sanyko, and Schering Plough.

REFERENCES