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Background Prostaglandin E2 (PGE2) plays key physiological roles within the body's organs and the systemic environment. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the biosynthesis of PGE2, which can lead to global PGE2 deficiency, resulting in serious side effects in the gastrointestinal, renal and other systems. In contrast, various pyridine derivatives have been found to increase endogenous PGE2 levels within multiple organs and the systemic environment. We hypothesised that the use of pyridine derivatives (nicotinic acid, nicotine, niceritrol, nicotinyl alcohol, pyridinol carbamate, pyridoxine hydrochloride and pyridostigmine bromide) can recover PGE2 levels during NSAID treatment. Methods Reassessment of experimental data on PGE2 levels in NSAIDs and pyridine derivatives treatment, and in controls from previously published, independent studies. Results Overall, in all our investigations P values for unpaired or pair-wise comparisons were not statistically significant. Conclusions We demonstrated that using pyridine derivatives along with NSAIDs, such as nonselective cyclooxygenase (COX) and selective COX-2 inhibitors, does not reduce endogenous PGE2 expression to below basal levels. This finding is based on both in vitro studies using animal and human tissues and in vivo studies performed with healthy volunteers. Using pyridine derivatives to correct a PGE2 deficiency during NSAID treatment is a novel method that we propose can offer a valuable, cost-effective therapeutic approach to preventing and treating the side effects of NSAIDs.

Some pharmacokinetic properties of nicotinic acid (NA) and niceritrol (pentaerythritoltetranicotinate) were investigated in rabbits. Niceritrol released NA at a faster rate on incubation in vitro with plasma or liver homogenate than in a pure buffer solution, indicating that niceritrol was actively hydrolyzed. After administration of niceritrol to rabbits no niceritrol was present in the plasma but metabolites, probably lower esters of niceritrol, free NA and nicotinamide were found. On oral administration of NA in a dose of 16 mg/kg higher maximal plasma levels of free NA (~6 μg/ml) were noted than after adminstration of niceritrol (1.4 μg/ml) in the same dose. A diet producing hyperlipaemia and containing 0.5% niceritrol elevated the levels of free NA in the plasma by about 2 μg/ml. It also reduced the increase in plasma cholesterol. The investigation suggests that the pharmacological and pharmacokinetic properties of niceritrol in the rabbit are similar to those in man.

The action of the hypolipaemic drug niceritrol (INN) on cholesterol accumulation in the aorta was studied in cholesterol-fed rabbits at three levels of plasma cholesterol, approximately 100, 500–1000 and 2000 mg/100 ml. This was achieved by feeding diets with three different concentrations of cholesterol. The two higher but not the lowest concentration resulted in a large increase in plasma cholesterol as well as in a moderate lipid infiltration of the aorta. On addition of 0.5–1% niceritrol to the diet there was a significant reduction of plasma cholesterol in all three series. In the series with the lowest plasma cholesterol level the degree of atherosclerotic changes were so slight that the effect of niceritrol could not be evaluated. In the series with plasma cholesterol up to 1000 mg/100 ml niceritrol markedly inhibited the lipid infiltration of the aorta. In the series with the highest plasma cholesterol level niceritrol had no protective effect. The relationship between plasma cholesterol levels and extent of aortic lipid infiltration was studied in a pooled reference material of 154 cholesterol-fed rabbits. The demonstrated type of relationship could largely explain the difference in the protective action of niceritrol in the three series.

The patient was a 51-year-old Japanese female who had been diagnosed with hyperlipidemia. At the first medical examination, her serum levels of total cholesterol (TC) and triglyceride (TG) were 482 and 205 mg/dl, respectively. Since hyperlipidemia was not improved by pravastatin, atorvastatin or niceritrol, and since the levels of thyroid-stimulating hormone (TSH) and free T4 were 730 IU/ml and 0.3 ng/dl, respectively, the patient was diagnosed as secondary hyperlipidemia with hypothyroidism. A method for the charge isolation of lipoproteins using capillary isotachophoresis (cITP) is proposed as a clinical application because it allows us to quantitatively measure electronegative low-density lipoprotein cholesterol (LDL-C), a potent marker of coronary heart disease. After 5 months of treatment with levothyroxine, Serum TC and LDL-C levels drastically decreased without statin treatment and high-density lipoprotein cholesterol (HDL-C) increased. In the lipoprotein profiles as assessed by cITP after treatment with levothyroxin, all HDL-C subfractions were increased and fast-migrating LDL/electronegative LDL appeared to be greatly reduced after treatment, while the area under the non-modified LDL peak was increased. The cITP analysis was able to obtain more information about coronary risk factors and may be clinically useful for evaluating the effect of treatment with levothyroxine in patients with hypothyroidism and secondary hyperlipidemia.

Purpose Lipoprotein (a) [Lp(a)] levels increase in patients with renal disease. We administered niceritrol, a nicotinic acid derivative, to patients with chronic renal disease and a high serum Lp(a) level, and studied its effects on lipid metabolism, proteinuria, and renal function. Methods Thirty-three patients with chronic renal disease whose serum Lp(a) levels were ≥15 mg/dL were randomly (but not blindly) assigned to treatment with niceritrol (n = 16) or to an untreated control group (n = 17). Parameters of lipid metabolism, excretion of urinary protein, and renal function were examined for 12 months. Results Changes in urinary protein excretion, as well as Lp(a) levels, differed significantly between the two groups. The mean (± SD) change from baseline in excretion of urinary protein was 0.77 ± 1.23 g/d in the control group compared with −1.41 ± 2.26 g/d in the niceritrol group at 12 months ( P = 0.003). Mean Lp(a) levels increased by 3 ± 10 mg/dL in the control group compared with a decrease of 10 ± 13 mg/dL in the niceritrol group at 12 months ( P =0.004). The mean creatinine clearance declined by 10 ± 12 mL/min in the control group, compared with 1 ± 13 mL/min in the niceritrol group at 12 months ( P =0.06). Conclusion Lipid levels improved with niceritrol treatment, whereas the excretion of urinary protein decreased, perhaps slowing the rate of loss of renal function in chronic renal disease.

Lipoprotein glomerulopathy (LPG), characterized by glomerular lipoprotein thrombi, presumably composed of abnormal apolipoprotein E (apoE), leads to a progressive decline in renal function and eventually results in end-stage renal failure. A successful treatment for LPG has not yet been established. The authors treated a 36-year-old woman with LPG and exhibiting a nephrotic syndrome using an intensive lipid-lowering therapy consisting of fenofibrate (300 mg), niceritrol (750 mg), ethyl-icosapentate (1,800 mg), and probucol (500 mg). After the start of treatment, a remarkable decrease in urinary protein excretion and improvement in the hyperlipidemia were obtained; proteinuria was no longer detected 11 months after the initiation of treatment. A second biopsy performed 11 months after the initiation of treatment showed the complete disappearance of the lipoprotein thrombi that had been observed in a diffuse and global manner in the first renal biopsy. These findings suggest that typical LPG could be regressed if the abnormal lipoproteinemia is controlled sufficiently.

In the present study, we evaluated the effects of combination therapy with niceritrol and pravastatin in patients with hyperlipidaemia. A total of 62 patients with hyperlipidaemia, defined as total cholesterol levels above 220 mg/dl or triglyceride levels above 150 mg/dl, were recruited. Patients were divided into two groups: Group N received initial therapy with niceritrol 750–1500 mg/day, and those in Group P, pravastatin 10 mg/day. After 8 weeks, pravastatin 10 mg/day was added to the Group N treatment regimen for a further 8 weeks, while patients in Group P were given niceritrol 750–1500 mg/day in addition to pravastatin for 8 weeks. After the 8-week combination therapy study period, total cholesterol levels were 209.6 mg/dl in Group N and 220.7 mg/dl in Group P. Decreased triglyceride and lipoprotein(a) levels and increased high-density lipoprotein cholesterol levels, neither of which were achieved by pravastatin administration alone, were achieved with the combination of pravastatin and niceritrol. We conclude that when a single lipid-lowering drug fails to show therapeutic value, attempting combination therapy with a nicotinic acid preparation and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is worthwhile.

維持血液透析患者における血清無機リン (Pi) のコントロールは, 腎性骨異栄養症の予防および治療の上で重要である. 今回, 私たちは, 抗高脂血症治療薬のniceritrol (NI) のPi低下作用について検討した. 対象および方法は, 維持血液透析患者11例 (平均年齢62.4±3.2歳, 平均透析歴9.8±7.7年) にNI 750mg/日を内服させ, 内服前2週間, 内服後8週間において, それぞれ血清中のUN, Cr, Ca, Pi, 総コレステロール (TC), HDL-C, 中性脂肪 (TG) を測定した. この間, 活性型ビタミンDおよびphosphate binderである沈降炭酸カルシウム薬 (CaCO3,) の内服量は一定であった. また, 同期間におけるCaCO3非服用例 (NI単独服用例) 6例の血清Piの推移についても検討した. 結果は, (1) NI内服により, 血清Pi値は内服前6.31±1.68mg/dl, 内服1週間後5.31±1.25mg/dlと有意に低下し (p

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 (≥30 mg/dL) is greater than 1,500 mg/d.

A 50-year-old Japanese woman with type IV hyperlipidemia was placed on a low-fat diet. This regimen was minimally effective, so lipid-lowering drugs (clinofibrate [600 mg/d] and niceritrol [750 mg/d]) were added. However, hypertriglyceridemia worsened and diabetes mellitus appeared. She then developed xanthomatous eruptions, type V hyperlipidemia, reduced postherapin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity. She was admitted to the hospital, and previous drug therapy was stopped. Dietary control and administration of the antihyperlipidemic agents pravastatin (10 mg/d) and bazafibrate (400 mg/d) led to the gradual recovery of postheparin plasma LPL and HTGL activity, conversion of type V hyperlipidemia to type IV hyperlipidemia, the disappearance of xanthomatous eruptions, and concurrent improvement in diabetes mellitus.

BACKGROUND Lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease and niceritrol (a prodrug of nicotinic acid) is known to reduce Lp(a) levels. Patients with coronary artery disease often have impairment of the fibrinolytic system. METHODS To elucidate the effect of niceritrol on fibrinolysis and Lp(a) levels, we examined plasminogen activator inhibitor (PAI) activity, tissue-type plasminogen activator (t-PA) antigen, and serum Lp(a) levels before and after administration of niceritrol to coronary artery disease patients with high baseline Lp(a) levels (> or = 20 mg/dl). Niceritrol was administered to 26 patients for 12 weeks at 750 mg/day. Fasting blood samples were obtained at 0800 h from each patient before treatment, after administration of niceritrol for 12 weeks and 4 weeks after the discontinuation of therapy. RESULTS There were significant reductions in PAI activity (9.9 +/- 1.8 compared with 5.4 +/- 1.6 IU/ml, P < 0.01), t-PA antigen levels (10.0 +/- 0.5 compared with 8.8 +/- 0.6 ng/ml, P < 0.05), and Lp(a) levels (49.3 +/- 5.9 compared with 42.5 +/- 5.4 mg/dl, P < 0.01) after 12 weeks of niceritrol administration. Four weeks after the discontinuation of niceritrol treatment, all these parameters returned to baseline. CONCLUSIONS This study demonstrated that niceritrol administration decreases PAI activity and t-PA antigen levels together with Lp(a) levels in patients with coronary artery disease. These observations suggest that niceritrol administration may tend to normalize fibrinolysis in such patients.

Lipoprotein-a, Lp(a), is a variant form of low density lipoprotein (LDL) that contains apolipoprotein-a, whose structure has 75-85% homology with plasminogen. Elevated plasma levels of Lp(a) are considered to be one of the independent risk factors for cardiovascular disease. We studied the effects of niceritrol, a nicotinic acid derivative, on plasma Lp(a) levels in 72 patients with hypercholesterolaemia. The dose of niceritrol was increased every 4 weeks, from 750 to 1500 and then to 2250 mg day-1. The final dose was adjusted to obtain a plasma cholesterol level less than 5.69 mmol l-1. Niceritrol led to significant decreases in plasma levels of median Lp(a), from 16.1 mg dl-1 (interquartile intervals, 8.7 to 32.8) to 11.1 mg dl-1 (interquartile intervals, 6.6 to 21), the mean reduction rate being 17.6%. In the group with pretreatment Lp(a) levels of over 20 mg dl-1, Lp(a) decreased by 10.0, 22.0 and 31.8% at the doses of 750, 1500, and 2250 mg day-1, respectively. In the group with levels less than 20 mg dl-1, only the dose of 2250 mg day-1 was effective in the reduction of Lp(a). The results suggest that the reduction of Lp(a) was dependent on the dose of niceritrol and on the pretreatment level of Lp(a). In conclusion, niceritrol is effective, in a dose-dependent manner, for reducing Lp(a) levels.

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.

A 39-year-old man presented with type III hyperlipoproteinemia in association with heterozygous familial hypercholesterolemia (FH). He had extensive tuberous xanthomas over the knees and elbows and xanthomas in the Achilles tendons. He also had palmar xanthomas. He exhibited severe hypercholesterolemia and hypertriglyceridemia. This patient was heterozygous for FH, as evidenced by low low-density lipoprotein (LDL) receptor function on lymphocytes, and had type III hyperlipoproteinemia, as determined by apolipoprotein (apo) E phenotype 2/2 in isoelectric focusing of the E isoproteins and the presence of a broad beta band on electrophoresis. Because therapy consisting of diet restrictions and lipid-lowering agents such as clinofibrate and niceritrol did not decrease serum total cholesterol ([TC] 15.26 mmol/L) and triglyceride ([TG] 10.79 mmol/L) levels effectively, the patient underwent plasmapheresis once every 2 weeks using a dextran sulfate-cellulose column. Repeated plasmapheresis markedly reduced serum TC and TG and induced complete regression of the palmar xanthoma after 6 months. The severity of tuberous xanthomas on the knees and elbows was reduced after 2.5 years. After plasmapheresis, TC decreased to 1.94 mmol/L from 10.40 mmol/L and TG decreased to 0.33 mmol/L from 7.90 mmol/L. Plasmapheresis performed with a dextran sulfate-cellulose column was highly effective in removing the lipoprotein-remnant particles in this patient, leading to generalized improvement in the lipoprotein profile.

OBJECTIVES--To investigate if serum Lp(a) lipoprotein (Lp(a)), a risk factor for atherosclerotic diseases, increases in patients with gout, who frequently also have atherosclerotic disease. METHODS--Fasting blood samples were taken for measurement of Lp(a) and other variables in 175 male patients with primary gout. Serum concentrations of Lp(a) were measured by enzyme linked immunosorbent assay. The median value and frequency distribution of Lp(a) in gout patients were compared with those in 172 control male subjects. In addition, we examined the effect of niceritorol on serum Lp(a) values in gout patients in whom the Lp(a) concentration was greater than 20 mg/dl. RESULTS--Serum Lp(a) was significantly higher in patients with gout than control subjects (median 15.5 mg/dl upsilon 8.6 mg/dl; p < 0.01). The frequency distribution of Lp(a) in gout was significantly shifted towards greater concentrations compared with control, although skewed distribution was noted in both groups. Serum Lp(a) concentration was not related to age, body mass index, alcohol intake, creatinine, fasting blood sugar or uric acid in patients with gout. Niceritorol decreased the serum concentrations of Lp(a) in gout. CONCLUSIONS--These observations suggest that serum Lp(a) concentrations are increased in patients with gout and may play a role as one of the risk factors for atherosclerotic diseases in gout. Niceritorol seems effective in decreasing high levels of Lp(a) in patients with gout without detrimental influence on serum uric acid concentration.

The long-term effects of niceritrol on lipoprotein(a) (Lp[a]), lipids, apolipoproteins, and fibrinogen and fibrinolytic factors were evaluated in 20 outpatients who had serum Lp(a) levels higher than 20 mg/dL. The mean ( +/- SE) levels of Lp(a) decreased from 33.6 +/- 2.3 mg/dL to 23.5 +/- 3.5 mg/dL after 12 months of niceritrol treatment (P0.01). Serum levels of triglycerides and apolipoprotein E decreased significantly and high-density lipoprotein cholesterol (HDL-C) increased significantly after 12 months (P0.05). There were no significant changes overall in fibrinogen and fibrinolytic factors, although fibrinogen concentrations showed a tendency to decrease with treatment. PAI-1 levels decreased significantly (P0.05) after 6 months of niceritrol treatment. A significant correlation of percent reduction between Lp(a) and apolipoprotein B levels (P0.01) was observed, suggesting that the Lp(a)-lowering effects of niceritrol may be due to niceritrol inhibition of apolipoprotein B synthesis, the major apolipoprotein of Lp(a). The ability of niceritrol to decrease Lp(a) levels and increase HDL-C levels, together with its tendency to lower fibrinogen levels, may help prevent coronary events in patients with high levels of Lp(a).

Effects of 16 weeks of niceritrol therapy (750 mg/d for the first 8 weeks and 1500 mg/d for the remaining 8 weeks) on serum levels of lipids, apolipoproteins, and Lp(a) were examined in diabetic patients with and without overt proteinuria. Pre-niceritrol Lp(a) levels exceeded 30 mg/dL and were comparable in both groups of patients. Pretreatment levels of lipids and apolipoproteins also were similar in both groups. Nonproteinuric patients exhibited an 18% decrease in Lp(a) and a 22% reduction in triglycerides as well as increases in high-density lipoprotein cholesterol and apolipoprotein AI. In contrast, patients with overt proteinuria showed no significant changes in serum lipids, apolipoproteins, or Lp(a) in response to niceritrol therapy. These findings suggest that the presence of overt proteinuria may affect Lp(a) metabolism in diabetic patients.

OBJECTIVE: To review the structure and physiologic function of liipoprotein(a) [Lp(a)], review the association of Lp(a) with the development of atherosclerosis, and to critically evaluate the current literature regarding the effects of lipid-lowering drug therapy on Lp(a) serum concentrations. DATA SOURCES: English language clinical and animal studies, abstracts, and review articles pertaining to Lp(a). STUDY SELECTION AND DATA EXTRACTION: Relevant human and animal studies examining Lp(a)'s role in atherosclerosis and the effect of drug therapy on Lp(a) serum concentrations. DATA SYNTHESIS: Possible physiologic functions and potential atherogenic mechanisms of Lp(a) are discussed. Evidence supporting the association of Lp(a) with atherosclerosis is presented. Studies evaluating the effects of lipid-lowering drug therapy on Lp(a) concentrations are reviewed and critiqued. CONCLUSIONS: Lp(a) concentrations are correlated with the risk of atherosclerotic vascular disease (AVO) in both animal models and human studies. Drug therapies that have produced a consistent reduction in Lp(a) concentration include niacin alone or in combination with a bile acid sequestrant or neomycin. However, additional, larger studies are needed to evaluate the ability of drug therapies to specifically reduce elevated Lp(a) concentrations. Preliminary information suggests that reduction in Lp(a) concentrations may be associated with atherosclerotic plaque regression. Although drugs are available to lower Lp(a), one cannot conclude that lowering of Lp(a) is warranted until clinical trials demonstrating beneficial effects have been published.

The effect of niceritrol at an ordinary dose (1500 mg/day) on the serum lipoprotein(a) (Lp(a)) concentration was investigated in 25 normolipidemic patients with coronary artery disease. The serum Lp(a) level was reduced by approximately 21% after 3 months of treatment (before treatment, 30.3 +/- 4.1 mg/100 ml; during treatment, 22.6 +/- 2.4 mg/100 ml; p < 0.01). By one month after the drug was discontinued, the Lp(a) returned to a pretreatment level (30.8 +/- 2.8 mg/100 ml). The levels of LDL-cholesterol and apoB were decreased significantly by the drug therapy; LDL-cholesterol increased closely to a pretreatment level after withdrawal of the drug. The percentage reduction of Lp(a) was significantly correlated with that of fibrinogen (r = 0.763, p < 0.01). Plasma concentration of fibrinogen was decreased in the patients whose reduction rate of Lp(a) was 30% or more. These results indicate that niceritrol has Lp(a)-lowering effect; sufficient reduction of Lp(a) may improve dyscoagulopathy of patients with coronary artery disease.

Thirty-three consecutive unselected patients with primary hypercholesterolemia received niceritrol 1.5 g daily for 12 weeks, with the effect of administering divided dose (twice daily (b.i.d.) and three times daily (t.i.d.)) evaluated. The serum concentrations of lipoprotein(a) (Lp(a)), lipids, the major apolipoproteins (apo), cholesteryl ester transfer activity and fibrinogen were determined before and after treatment. The b.i.d. and t.i.d. regimens each significantly reduced the serum levels of total cholesterol and triglyceride. The mean changes in serum lipids and lipoproteins did not differ significantly between the two groups. After 12 weeks of treatment, there was a significant decrease in total plasma cholesterol, triglyceride, low density lipoprotein cholesterol, apo A-II, apo B and fibrinogen and an increase in the high density lipoprotein cholesterol levels. Although the serum level of Lp(a) did not change in every patient, niceritrol significantly reduced the serum Lp(a) level in those with an initially high level of Lp(a) (greater than or equal to 20 mg/dl).

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 ∼ 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.

Niceritrol, 750 to 1000 mg/day, produced and maintained a decrease in serum lipoprotein(a) [Lp(a)] levels over a 12-month treatment period. Reductions in Lp(a) were more prominent in patients who had pretreatment Lp(a) levels >30 mg/dl than in patients with initial Lp(a) levels

Lp(a) has recently begun to attract attention as a risk factor of atherosclerotic disease, especially of ischemic heart disease. The Lp(a) concentration in the serum was shown to be important for chronic hemodialysis patients who have high mortality due to cardiovascular disease. Nicotinic acid derivatives, which are recognized for their capacity to lower the serum Lp(a) concentration, are effective against a high Lp(a) concentration in hemodialysis patients. In this study, niceritrol which is a nicotinic acid derivative was tested on hemodialysis patients and healthy controls by investigating the serum nicotinic acid level. Serum nicotinic acid concentration was also measured by the severity of renal dysfunction of patients untreated by niceritrol. The blood nicotinic acid concentration in healthy controls (n = 4) was changed after 2 hrs by the administration of niceritrol from 9.8 +/- 1.4 ng/ml to 192.7 +/- 23.1 ng/ml then slowly decreased. Chronic hemodialysis patients who take niceritrol every day showed the highest nicotinic acid serum concentration (500-1,000 ng/ml) on the day without hemodialysis and the serum level decreased with dialysis for 4 hrs to 25-80%. There was no significant difference in the nicotinic acid level in the serum between healthy controls (n = 10), chronic glomerulonephritis patients (n = 7), chronic renal failure patients (n = 8) and chronic hemodialysis patients (n = 17). Lp(a) concentration in the serum, however, was increased with greater severity of renal dysfunction, The side effect was not observed in any cases administered niceritrol. These data suggest nicotinate derivatives are effective for hemodialysis patients. High nicotinic acid level in the serum after treatment with niceritrol was lowered by dialysis. It is plausible that the nicotinate level in patients without niceritrol treatment did not influence the Lp(a) concentration, because there was no increase in the nicotinate level of the serum even if the patients had renal dysfunction.

Introduction Background. We recently reported that the administration of niceritorol (a nicotinic acid derivative which In chronic renal failure (CRF ), phosphate (Pi) retenimproves lipid metabolism and peripheral circulation, tion may lead to secondary hyperparathyroidism and and is used for the treatment of hyperlipidaemia and a progression to end-stage renal disease [1]. Dietary impaired peripheral circulation) to patients with hyper- Pi restriction or Pi binders can slow the progression of phosphataemia undergoing dialysis decreased the experimental CRF [2]. Conversely, a diet high in Pi serum phosphate (Pi) concentration. We found that can accelerate the progression toward end-stage renal this was due to an acceleration of faecal Pi excretion disease [1,2]. The current therapy for hyperphosby niceritrol. phataemia in patients with CRF consists of the adminMethods. Intestinal brush border membrane vesicles istration of Pi binders. Pi binders reduce intestinal Pi (BBMVs) were prepared from rat jejunum, and the absorption, but have several side eVects. New and safe Na+-dependent and Na+-independent Pi transport drugs which can inhibit intestinal Pi transport are activities in these vesicles were measured. In addition, needed, and the molecular structure and regulation of the functional Pi transporter from rat small intestine intestinal Pi transport should thus be elucidated. was injected in Xenopus oocytes, and the eVect of Niceritorol is a nicotinic acid derivative which nicotinamide on the levels of its expression were meas- improves lipid metabolism and peripheral circulation, ured by northern blotting. and is used for the treatment of hyperlipidaemia and Results. The Na+-dependent component was signific- impaired peripheral circulation. We reported that the antly decreased in the BBMVs isolated from rats administration of niceritorol to patients undergoing treated with nicotinamide, while the Na+-independent dialysis for the treatment of high-density lipoprotein component was not changed. Kinetic studies demon- (HDL) hypocholesteraemia caused a reduction of the strated that the decreased activity was due to reduction serum Pi concentration [3]. Our results indicated that of the V max value and not an elevation of the K m an acceleration of faecal Pi excretion might be involved values. When poly(A)+RNA from rats treated with the mechanism underlying the reduction of the serum nicotinamide was microinjected into Xenopus oocytes, Pi concentration which is observed in patients underthe Pi transport activity was significantly decreased going dialysis. On the basis of these observations, we compared with that in the control animals. In addition, concluded that nicotinamide significantly decreases there were no significant changes in Na/Pi cotrans- intestinal Pi transport activity. porters and activators, but the vitamin D receptor The intestinal Pi transport process occurs by both a mRNA level was reduced to 80% of the control level. sodium-independent, nonsaturable process and via an Conclusions. These observations suggest that nicotina- active, sodium-dependent component of phosphate mide may regulate the expression of a major functional absorption, mainly in the duodenum and jejunum [4]. Na/Pi cotransporter in the rat small intestine. However, the regulation of intestinal Pi transport is not well understood, in part because of the lack of

aluminium and calcium containing antacids have sideeVects such as aluminium encephalopathy [1], alumiBackground. Phosphate binders such as aluminium hydroxide and calcium carbonate have several side- nium osteopathy [2] or microcytic anaemia [3,4], and hypercalcaemia [5,6 ] or reduced iron absorption [7] eVects so that they are not ideal for clinical use. Recently we reported that administration of niceritrol respectively. Administration of polymers, e.g. ion exchange resin, was attempted [8], but they nonat 750 mg/day to patients with HDL hypocholesterolaemia undergoing dialysis decreased the serum phos- specifically adsorb not only phosphoric ions, but also other bases such as HCO’ , Cl’, SO2’ 4 , proteins, phate concentration. To clarify the mechanism of reduction of the serum phosphate concentration by organic acids, and drugs administered. Clinically eVective phosphate binders with fewer side-eVects are niceritrol in patients undergoing dialysis, the eVects of niceritrol on faecal and urinary phosphate excretion required for dialysis patients. Niceritrol is a nicotinic acid derivative which were examined in normal rats. Methods. Niceritrol suspension in 5% gum arabic was improves lipid metabolism and peripheral circulation, and is used for the treatment of hyperlipidaemia administered for 4 days in normal rats. Faeces and urine were collected in metabolic cage and analysed and disturbances of the peripheral circulation [9‐11]. We reported that administration of niceritrol at for phosphate content. Results and conclusions. Faecal phosphate excretion 750 mg/day to patients undergoing dialysis for treatment of HDL hypocholesterolaemia caused reduction significantly increased in the groups with administration of 100 and 500 mg/kg niceritrol, but not in the of the serum phosphate concentration [12]. This observation was confirmed in a randomized, double blind

The usefulness of niceritrol as a lipid-lowering agent is limited by a prostaglandin-mediated flushing reaction after each dose occurring in the early stages of treatment. We have tested the effect of premedication with aspirin on the reaction to 250 mg niceritrol in 30 healthy male volunteers using both subjective and observed assessments of severity. Both 300 mg and 600 mg of aspirin significantly reduced the severity of flushing when compared with placebo. No significant difference was seen between the two dose levels. Prior dosing with aspirin may increase acceptability of niceritrol and hence improve compliance.

Since phosphorus retention in hemodialysis (HD) patients is known to be an important factor in the development of secondary hyperparathyroidism and renal osteodystrophy, phosphate binders have been needed for the control of serum phosphate levels (P). However, the calcium-containing phosphate binders that have been used widely can cause a rise in serum calcium levels and cause secondary hypoparathyroidism. We have recently experienced decreases in P after the administration of niceritrol (NT), a prodrug of nicotinic acid, for the treatment of low HDL-cholesteremia (HDL-C) in HD patients. The aim of the present study was to assess the mechanism of the P-lowering effect of NT in comparison with nicomol (NC), another prodrug of nicotinic acid. NT (750 mg/day) or NC (600 mg/day) was given orally to 10 or 14HD patients respectively. Blood samples were collected before the first dialysis of each week for the determination of serum urea nitrogen (UN), Cr, Ca, P, total cholesterol (TC), triglyceride (TG) and HDL-C. Serum nicotinic acid concentration (NAC) by gas chromatograph mass-spectrometry method was determined before, 4 weeks and 8 weeks after the administration of these drugs. After NT administration, P was decreased from 6.2 +/- 0.4 mg/dl to 5.1 +/- 0.4 mg/dl (1st week, p0.001, Mean +/- SE) and 4.5 +/- 0.3 mg/dl (2nd weeks, p0.001) with no change in UN, Cr or Ca levels; these significant decreases in P lasted for 8 weeks. NAC increased significantly after NT administration from 25.5 +/- 1.3 ng/ml to 549.8 +/- 102.2 ng/ml (4 weeks, p0.01) and 431.7 +/- 51.4 ng/ml (8 weeks, p0.01). HDL-C also increased (33.6 +/- 4.0 mg/dl vs 42.7 +/- 4.6 mg/dl, p0.05), but TC and TG did not change. In contrast, no significant changes were observed in P, NAC and HDL-C after NC administration. These discrepancies could be ascribed to the differences in serum NAC levels. These data suggest that NT could be useful for the control of P in HD patients. However further studies are needed to confirm the mechanism of the P-lowering effect of NT.

Effects of a combination therapy of fluvastatin, a new inhibitor of HMG-CoA reductase, and niceritrol on lipid metabolism were investigated measuring a wide range of parameters in 42 patients with primary hypercholesterolemia. After a wash-out period patients were randomly allocated to 1 of the 2 groups, the fluvastatin-preceding group (G-1) and the niceritrol-preceding group (G-2). In G-1 fluvastatin monotherapy (30 mg/day) significantly decreased total cholesterol (TC) and LDL-cholesterol (LDL-C). There was no significant change in HDL-cholesterol (HDL-C), triglyceride (TG) and lipoprotein (a) (Lp(a)). Further effect in HDL-C and TG was observed after the addition of niceritrol (750 mg/day). On the other hand, in G-2, while niceritrol alone (750 mg/day) produced no significant change in TC, LDL-C, HDL-C, TG and Lp(a), the addition of fluvastatin (30 mg/day) reduced TC and LDL-C levels significantly. Cholesterol ester transfer (CET) activity was significantly reduced by niceritrol monotherapy. After the concomitant use of the 2 drugs CET activity was significantly reduced only in G-2. No significant change in lipoprotein lipase and hepatic triglyceride lipase activities were observed in the 2 groups at either point in time. No serious adverse effect was observed in this study. It is concluded that fluvastatin is an effective drug for lowering LDL-cholesterol and causes no adverse alteration in lipid metabolism. Combination with niceritrol at a dose of 750 mg/day dose not appear to augment or attenuate beneficial effects of fluvastatin.

We investigated the usefulness of the C64 quantitative tuning fork in assessing vibratory sensation in patients with diabetic neuropathy. The vibratory sensation scores determined by using the C64 quantitative tuning fork were significantly correlated with severity of subjective symptoms of numbness, cold, desensitization, spontaneous pain in the upper and lower extremities, and vertigo, as well as measurements of neurologic function (threshold of vibratory sensation, the coefficients of variation of the R-R intervals of the electrocardiogram at rest, and the motor nerve conduction velocity [MNCV] of the lower extremities; P0.05 to 0.01). Subsequently, we evaluated the effects of niceritrol on neurologic function in the same patients by using the C64 quantitative tuning fork, other neurologic function tests, and the change in severity of subjective symptoms before and after therapy. Niceritrol significantly improved measures of neurologic function (vibratory sensation scores, MNCV of the upper extremities, and sensory nerve conduction velocity of the lower extremities; P0.05 to 0.001), and subjective symptoms (numbness, cold, desensitization, and spontaneous pain in the lower extremities; P0.01 to 0.001). Our results suggest that the C64 quantitative tuning fork is a convenient and objective tool for assessing the severity of diabetic neuropathy and that niceritrol is useful for the treatment of this disease.

To investigate the efficacy of reducing plasma lipoprotein(a) (Lp(a)) as well as low density lipoprotein cholesterol (LDL-C) levels on the prevention of restenosis after PTCA, LDL-apheresis was attempted on a total of 54 patients at six institutions. LDL-apheresis using a dextran sulfate cellulose column has been proven to be an effective method for reducing both plasma Lp(a) and LDL-C levels. As a subgroup (apheresis-drug combined group), 29 of the 54 patients were given Pravastatin (HMG CoA reductase inhibitor) and Niceritrol (Nicotinic Acid) in addition to LDL-apheresis to maintain low plasma levels of both Lp(a) and LDL-C through the follow-up period of 5 months after PTCA. Patients whose plasma Lp(a) levels were reduced by more than 50% showed a lower restenosis rate than those whose plasma Lp(a) levels were reduced by less than 50% (21.2% vs. 52.4%, P = 0.0179), especially in patients with high plasma Lp(a) levels above 30 mg/dl where a much lower restenosis rate (15.0%) was observed. Furthermore, in the apheresis-drug combined group, the restenosis rate was 11.8% regardless of baseline plasma Lp(a) levels, including even those below 30 mg/dl. In conclusion, in patients with high plasma Lp(a) levels, a greater than 50% reduction in Lp(a) levels by LDL-apheresis is effective in preventing restenosis after PTCA. If the plasma Lp(a) reduction rate is greater than 50%, LDL-apheresis combined with lipid-lowering drugs such as niceritrol and pravastatin seems to be more effective, even in patients with low plasma Lp(a) levels.

Perycit (Pentaerythriol Tetranicotinate), a slow releasing drug, is one of the drugs used for treating hyperlipemia. Patients with erectile dysfunction (impotence) associated with hyperlipemia increasingly seek help at urological services. This study investigates the clinical effect, both objective and subjective of Perycit on anti-hyperlipemia as well as on impotence. Twenty patients with a more than one year history of impotence with hyperlipemia were enrolled in this randomized, single-blind study. Decrease of total cholesterol, and triglyceride, as well as the increase of high density lipoprotein cholesterol in the study group (Perycit, 500 mg, tid, for 3 months) were significantly different from the pre-treatment period and in the control group (Trental, 100 mg, tid, for 3 months) (p0.05 or p0.01). Moreover, improvement in sexual function was shown to be better in the study group than in either the pretreatment period and control groups, objectively and subjectively (p0.05 or p0.01). Tolerable facial flush was found in 3 of these 20 patients, but no major side effects were encountered. In conclusion, this study indicates Perycit is effective for anti-hyperlipemia as well as for aiding improvement of sexual dysfunction. Since it is a slow-releasing preparation, the side effect is minimal. It is recommended for patients with hyperlipemia alone, or those who suffer from combined erectile dysfunction.

Lp(a) is an LDL-like lipoprotein carrying the apoprotein(a) glycoprotein and has recently been recognized to be an independent risk factor for coronary heart disease. We studied plasma Lp(a) levels in 40 patients undergoing maintenance hemodialysis (24 male, 16 female; aged 16-83 years). Fasting plasma Lp(a) levels were measured by an enzyme-linked immunosorbent assay. The median value of plasma Lp(a) concentrations in hemodialysis patients was significantly higher than that of the normal volunteers (26.0 +/- 2.7 vs. 10.8 +/- 3.7 mg/dL, p.05). Lp(a) levels did not correlate with age, duration of hemodialysis, total cholesterol, triglyceride, HDL cholesterol, or LDL cholesterol. The 11 patients whose plasma Lp(a) concentrations exceeded 20 mg/dL received niceritrol, a prodrug of nicotinic acid, at a dosage of 500 mg t.i.d. for 4 weeks. The plasma Lp(a) levels were significantly lower after 4 weeks of treatment (38.3 +/- 4.2 vs. 31.5 +/- 3.2 mg/dL, p.01).

Seventeen patients with heterozygous familial hypercholesterolemia were sequentially treated with: a low cholesterol, fat restricted diet; diet and probucol (500 mg/day); and diet, probucol and niceritrol (1500 mg/day). Concentrations of plasma cholesterol decreased from 348 + 49 mg/dl on diet alone to 304 + 32 mg/dl, to 256 + 30 mg/dl on diet and probucol, and fell to 212 + 41 mg/dl on the combined regimen with niceritrol. Concentrations of LDL-cholesterol declined 13% on diet, and 26% on diet and probucol; the subsequent addition of niceritrol resulted in a 42% fall from the baseline. Plasma concentrations of apolipoprotein B fell 37% on the combined regimen with niceritrol. As a result, normal levels of cholesterol (less than 230 mg) were achieved in thirteen subjects treated with this new combination therapy. Moreover, atherogenic index improved with the addition of niceritrol. These results suggest even a small dose of niceritrol affords opportunity to maintain normal lipid profile in heterozygous familial hypercholesterolemia when given in combination with probucol.