Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol.

We report two patients, a daughter and a mother, with lipoprotein glomerulopathy (LPG) who were successfully treated with niceritrol. Both patients carried a mutation in the apolipoprotein E (apoE) gene known as ApoE Tokyo/Maebashi. The daughter was found to have proteinuria at the age of 4 years. Four years later, she was diagnosed as having LPG based on a renal biopsy. She was treated with several medications including pravastatin, ethyl icosapentate, enalapril, warfarin and cyclophosphamide, all of which failed to reduce her proteinuria. At the age of 17 years, she exhibited an increase in proteinuria and a decline in renal function, despite ongoing treatment with pravastatin and enalapril. After switching from pravastatin to niceritrol, a marked reduction in the proteinuria and an improvement in renal function were observed. Her mother was found to have proteinuria at the age of 57 years and was diagnosed as having LPG based on a renal biopsy. She was also treated with niceritrol, resulting in an improvement in her proteinuria and renal function. These cases suggest that niceritrol might be a useful therapeutic option for LPG.

Antiproteinuric effect of niceritrol, a nicotinic acid derivative, in chronic renal disease with hyperlipidemia: a randomized trial.

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 > or = 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.

Resolution of typical lipoprotein glomerulopathy by intensive lipid-lowering therapy.

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.

The effects of combination therapy with niceritrol and pravastatin on hyperlipidaemia.

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.

Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients.

BACKGROUND: Patients with chronic renal failure often have alterations in lipoprotein profile including elevated very-low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), and reduced high density lipoprotein (HDL) levels. Among these changes, raised IDL has been shown as an independent risk factor for atherosclerosis in hemodialysis patients. There are a limited number of studies reporting pharmacological approaches to IDL reduction in a uremic population. METHODS: We therefore summarize the effects of lipid-lowering drugs on IDL levels in patients with chronic renal failure treated by hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: First, a nicotinic acid analog niceritrol was given to hemodialysis patients. The drug increased HDL-cholesterol by 11%, but the reductions in VLDL-, IDL- and LDL-cholesterol were not significant. Second, CAPD patients were treated with a fibric acid derivative clinofibrate, which was excreted mainly into bile unlike other drugs in this class. The fibrate resulted in a remarkable reduction in VLDL-triglycerides, although it did not reduce IDL-cholesterol. Finally, an HMG-CoA reductase inhibitor (statin) pravastatin was used in HD and CAPD patients. Pravastatin reduced IDL- and LDL-cholesterol to the same extent (by 31%). None of these treatments caused serious adverse effects. CONCLUSIONS: We propose that IDL is an important target in the management of uremic dyslipidemia. To date, statins have been shown to be suitable for this purpose, although it remains to be clarified whether such an intervention reduces the risk for atherosclerotic vascular events in the uremic population.

[Niceritrol decreases serum phosphate levels in chronic hemodialysis patients].

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, p < 0.001, Mean +/- SE) and 4.5 +/- 0.3 mg/dl (2nd weeks, p < 0.001) 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, p < 0.01) and 431.7 +/- 51.4 ng/ml (8 weeks, p < 0.01). HDL-C also increased (33.6 +/- 4.0 mg/dl vs 42.7 +/- 4.6 mg/dl, p < 0.05), 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.

Dose-dependent effect of niceritrol on plasma lipoprotein-a.

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.

Effect of niceritrol on fibrinolysis and lipoprotein (a) levels in patients with coronary artery disease.

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.

Effects of fluvastatin, a new inhibitor of HMG-CoA reductase, and niceritrol on serum lipids, lipoproteins and cholesterol ester transfer activity in primary hypercholesterolemic patients.

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.

Increased concentrations of serum Lp(a) lipoprotein in patients with primary gout.

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.

Long-term effects of niceritrol on serum lipoprotein(a) and lipids in patients with high levels of lipoprotein(a).

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 (P < 0.01). Serum levels of triglycerides and apolipoprotein E decreased significantly and high-density lipoprotein cholesterol (HDL-C) increased significantly after 12 months (P < 0.05). 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 (P < 0.05) after 6 months of niceritrol treatment. A significant correlation of percent reduction between Lp(a) and apolipoprotein B levels (P < 0.01) 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).

Use of the C64 quantitative tuning fork and the effect of niceritrol in diabetic neuropathy.

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; P < 0.05 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; P < 0.05 to 0.001), and subjective symptoms (numbness, cold, desensitization, and spontaneous pain in the lower extremities; P < 0.01 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.

Lipoprotein(A): physiologic function, association with atherosclerosis, and effects of lipid-lowering drug therapy.

OBJECTIVE: To review the structure and physiologic function of lipoprotein(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 (AVD) in both animals 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 clinical effect of slow releasing nicotinate on hyperlipemic impotent patients].

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) (p < 0.05 or p < 0.01). 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 (p < 0.05 or p < 0.01). 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.

Reduction by niceritrol treatment of serum lipoprotein(a) in normolipidemic patients with coronary artery disease.

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.

Niceritrol reduces plasma lipoprotein(a) levels in patients undergoing maintenance hemodialysis.

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).