Effects of niceritrol on faecal and urinary phosphate excretion in normal rats.

BACKGROUND: Phosphate binders such as aluminium hydroxide and calcium carbonate have several side-effects so that they are not ideal for clinical use. Recently we reported that administration of niceritrol at 750 mg/day to patients with HDL hypocholesterolaemia undergoing dialysis decreased the serum phosphate concentration. To clarify the mechanism of reduction of the serum phosphate concentration by niceritrol in patients undergoing dialysis, the effects of niceritrol on faecal and urinary phosphate excretion were examined in normal rats. METHODS: Niceritrol suspension in 5% gum arabic was administered for 4 days in normal rats. Faeces and urine were collected in metabolic cage and analysed for phosphate content. RESULTS AND CONCLUSIONS: Faecal phosphate excretion significantly increased in the groups with administration of 100 and 500 mg/kg niceritrol, but not in the group with 20 mg/kg. On the other hand, urinary phosphate excretion was not significantly changed in the groups on 20-500 mg/kg. Retention of phosphate was significantly suppressed in the groups on 100 and 500 mg/kg. A increased faecal phosphate excretion by niceritrol is presumably the mechanism by which serum phosphate concentration is reduced in dialysis patients.

Pentaerythritol tetranicotinate (niceritrol) decreases plasma lipoprotein(a) levels.

We determined the most effective dosage of pentaerythritol tetranicotinate (niceritrol) to reduce plasma lipoprotein(a) [Lp(a)] levels in 44 Japanese patients (16 men and 28 women; mean age, 59.2 +/- 10.8 years) with hyperlipidemia types IIa, IIb, and IV. Patients received oral niceritrol at a dosage of 750 mg (3 tablets)/d for 8 weeks, followed by 1,500 mg (6 tablets)/d for 8 weeks. Administration of niceritrol 750 mg/d for 8 weeks decreased total and low-density lipoprotein (LDL) cholesterol in patients with type IIa hyperlipidemia and decreased triglycerides in patients with type IV hyperlipidemia, but did not affect Lp(a). However, niceritrol 1,500 mg/d for 8 weeks decreased Lp(a) in patients with initial Lp(a) levels greater than 30 mg/dL in addition to decreasing total and LDL cholesterol and triglycerides. These results suggest that the effective dosage of niceritrol to reduce the serum Lp(a) concentration in Japanese hyperlipidemic patients with a high Lp(a) level (> or = 30 mg/dL) is greater than 1,500 mg/d.

Niceritrol prevents the decrease in red blood cell 2,3-diphosphoglycerate and neuropathy in streptozotocin-induced diabetic rats.

Nerve ischemia/hypoxia has been linked to the pathogenesis of diabetic complications. Red blood cell 2,3-diphosphoglycerate is an important regulator of peripheral tissue oxygenation; however, the relationship between 2,3-diphosphoglycerate concentration and diabetic complications has not been studied in detail. This investigation focused on the relationship between red blood cell 2,3-diphosphoglycerate and diabetic neuropathy, by measuring motor nerve conduction velocity and sciatic nerve blood flow in streptozotocin-induced diabetic rats. The effect of treatment with niceritrol, a nicotinic acid derivative that acts as a vasodilator and reduces serum lipid concentrations, on 2,3-diphosphoglycerate concentration and diabetic neuropathy was also examined. Untreated diabetic rats had significantly lower concentrations of red blood cell 2,3-diphosphoglycerate, higher concentrations of serum total cholesterol and triglyceride, as well as reduced motor nerve conduction velocity and sciatic nerve blood flow, compared to untreated normal rats. Niceritrol prevented these abnormalities without correcting hyperglycemia in diabetic rats, but had no effect on these parameters in normal rats. Red blood cell 2,3-diphosphoglycerate concentration and motor nerve conduction velocity showed a positive correlation with sciatic nerve blood flow and 2,3-diphosphoglycerate, respectively. These observations suggest that ischemia/hypoxia plays an important role in the development of diabetic neuropathy, and that niceritrol has a therapeutic effect on this condition by improving endoneurial ischemia/hypoxia.

Effect of niceritrol on streptozocin-induced diabetic neuropathy in rats.

Niceritrol, a drug with peripheral tissue vasodilatory and serum lipid-lowering activity, was administered for 2 mo to rats with streptozocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue. A markedly lower value of approximately 47% in sciatic nerve blood flow (SNBF) was detected in an untreated diabetic (DC) group than in a nondiabetic control group (CC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol, and fructose values were observed in the sciatic nerve and serum lipids. In contrast, a niceritrol-treated diabetic (DN) group had significantly higher SNBF, MNCV, and sciatic nerve myo-inositol values and lower serum triglyceride levels than group DC. No differences between these two groups were noted in glucose, sorbitol, and fructose levels in the sciatic nerve, or in cholesterol and glucose in serum. These findings suggest that niceritrol has a clear inhibitory effect on the development of delayed MNCV in the diabetic rat, which may be due to reduced nerve blood flow and/or decreased nerve myo-inositol levels.

Effect of niceritrol on lipid metabolism of aorta in atherosclerotic rats.

Atherosclerotic lesions were formed in the aorta of rats given a high cholesterol diet containing propylthiouracil (PTU) and vitamin D2 (atherogenic diet) for 8 weeks. The effects of niceritrol (pentaerythritol tetranicotinate), which lower the plasma lipid level, on lipid metabolism in the arterial wall of the atherosclerotic rats were studied. Niceritrol significantly decreased the plasma cholesterol level of atherosclerotic rats, which was 823 mg/100 ml, or about ten times that of control rats. On treatment with niceritrol, the cholesterol level was reduced most in the very low density lipoprotein (VLDL) fraction (d less than 1.006). Heparin-releasable lipoprotein lipase activity in epididymal adipose tissue, lipoprotein lipase activity in post-heparin plasma, and VLDL-triolein hydrolyzing activity in adipose tissue stromal vessels were all higher in niceritrol-treated atherosclerotic rats. Of the enzymes in the arterial wall concerned with cholesterol ester metabolism, acid cholesterol esterase activity was decreased in atherosclerotic rats, while niceritrol treatment increased this activity. The ratio of acyl-CoA cholesterol acyltransferase activity (ACAT) to neutral cholesterol esterase activity was higher in atherosclerotic rats than in control rats, but was lower in niceritrol-treated rats than in atherosclerotic rats. From these results, it is concluded that niceritrol modifies enzyme activities in such a way as to reduce the cholesterol ester content of the arterial wall and lower plasma VLDL and LDL cholesterol levels.

Acute effects on plasma lipids in the rat of a new long-acting nicotinic acid derivative: LG 13979.

The effects on plasma lipids and nicotinic acid concentrations of a single dose of 2-(3-pyridinecarbonylamino)-2-deoxy-1,3,4,6 dihydrogen-D-glucose tetra-3-pyridinecarboxylate (LG 13979) compared with the effects of nicotinic acid and of its known derivatives niceritrol and sorbinicate, at the same doses, were studied in the fasted rat. Results show that LG 13979 has more prolonged activity on plasma free fatty acids and triglycerides, with longer lasting and more intense activity on plasma cholesterol than these three reference standards. Free fatty acid rebound occurs after administration of nicotinic acid and niceritrol, but not after LG 13979. This pharmacodynamic profile may be explained on the basis of the kinetics of nicotinic acid plasma concentrations, which are low, constant and lasting after LG 13979 administration.

Changes in the fatty acid composition of the plasma lipid esters during lipid-lowering treatment with diet, clofibrate and niceritrol. Reduction of the proportion of linoleate by clofibrate but not by niceritrol.

The fatty acid composition of the plasma lipid esters has been studied during lipid-lowering treatment of 95 patients with atherosclerotic disease. During the first two months of the trial only a diet was prescribed. During the ensuing two months either clofibrate or niceritrol, a nicotinic acid ester, was added in a randomized order. During the last two months the second drug was added. The combined treatment with diet, clofibrate and niceritrol caused highly significant serum lipid reductions. The fatty acid composition in the plasma lipid esters was determined in samples from each trial period to measure the degree of dietary adherence. During dietary treatment the relative content of saturated and monounsaturated fatty acids secreased and the polyunsaturated fatty acids increased with an increasing ratio between pulyunsaturated and saturated fatty acids (P/S ratio) in the cholesterol esters and triglycerides. Only minor changes were seen in the phospholipids. The changes caused by the diet were partly reversed by clofibrate while niceritrol did not cause any major changes of the fatty acid composition. Clofibrate treatment coincided with increasing amounts of monounsaturated fatty acids, especially oleate (18 : 1), in the cholesterol esters, triglycerides and phospholipids while there were significant reductions of the content of linoleic (18 : 2) acid in both the cholesterol esters and triglycerides. The 18 : 2/18 : 1 ratio decreased significantly in all the lipid esters analyzed. However, the P/S ratio was not significantly affected, partly because the relative content of saturated fatty acids also tended to decrease during clofibrate treatment. It is concluded that addition of clofibrate treatment to patients who are on a diet enriched with polyunsaturated fats is associated with a change from polyunsaturated to monounsaturated fatty acids in the plasma lipid esters but does not significantly effect the ratio between polyunsaturated and saturated fatty acids. The fatty acid changes caused by clofibrate treatment and counteracted by an increased amount of polyunsaturated fat in the diet.

The effects of different dose regimens of niceritrol of serum lipid concentrations in man.

The lipid-lowering effects of 3 g of the nicotinic acid derivative pentaerythritoltetranicotinate (niceritrol) given either 1 g X 3 or 1.5 g X 2 have been evaluated in 18 subjects with hyperlipoproteinaemia. When 1 g niceritrol was given three times daily, the serum TG concentration fell from 3.14 +/- 0.48 to 1.86 +/- 0.18 mmol/1 (41% reduction) and the serum cholesterol concentration from 282 +/- 9 to 227 +/- 11 mg/100 ml (20% reduction). The same daily dose, given 1.5 g twice, did not significantly lower the serum TG concentration, and serum cholesterol was lowered by only 12%. Niceritrol tablets prepared with a dissolution time of 60 or 90 min had identical lipid-lowering properties. Although patients may find it practical to take niceritrol only twice daily, such a dose regimen has considerably less effect on elevated serum lipids than a thrice-daily regimen.

Cholestyramine, clofibrate and nicotinic acid as single or combined treatment of type IIa and IIb hyperlipoproteinaemia.

1. In type IIa and IIb hyperlipoproteinaemia, treatment with 16 g cholestyramine daily reduced the cholesterol concentration 23%. By adding clofibrate this effect was enhanced to a 29% reduction and at the same time clofibrate reduced the triglyceride (TG) concentration 33%. 2. The optimal cholesterol reduction with clofibrate in type II was 17% and was found after treatment with 1.5 g clofibrate/day. The optimal TG reduction appeared to be achieved with a daily dose of 2 g.3. Nicotinic acid in the form of niceritrol had another type of dose-response in type II with doses from 3 to 6 g/day. It appeared as if the optimal dose probably was above 6 g daily. The 6 g dose produced a cholesterol reduction of 22% and in type IIb there was at the same time a 50% reduction of the TG concentration. 4. By combining 3 g niceritrol with 2 g clofibrate almost the same effect on serum lipids was obtained as with 6 g niceritrol. When choosing a drug for treatment of hyperlipoproteinaemia it is necessary to consider not only the lipid lowering effect but also the side effects which are not discussed here. By combining clofibrate with either cholestyramine or niceritrol it was possible to improve the lipid lowering effect. There were no side effects which were not seen when the drugs were used alone. A more frequent use of combinations to improve the treatment of hyperlipoproteinaemia is recommended.