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Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia.

BACKGROUND: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. METHODS: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. RESULTS: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. CONCLUSIONS: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein-high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease.

Gemfibrozil↗

Limited proteolysis of Salmonella typhimurium nicotinic acid phosphoribosyltransferase reveals ATP-linked conformational change.

Nicotinic acid phosphoribosyltransferase (NAPRTase;EC 2.4.2.11) couples stoichiometric ATP hydrolysis with formation of nicotinate mononucleotide (NAMN) from nicotinic acid and alpha-D-5-phosphoribosyl 1-pyrophosphate (PRPP). Trypsin rapidly inactivated the ATPase and NAMN synthesis activities of NAPRTase in parallel, with cleavages at Arg-384 and Lys-374 of the 399-residue protein. ATP and PRPP each provided protection against tryptic cleavage. Limited chymotryptic proteolysis of NAPRTase exhibited very similar behavior, with specific cleavage at Phe-382 and protection by substrates. Results suggest that a solvent-exposed loop encompassing Lys-374, Phe-382, and Arg-384 is protected by ATP- or PRPP-induced conformational changes. The ability of ATP to protect even under conditions in which enzyme phosphorylation was prevented by EDTA provides evidence for a distinct ATP-induced protein conformation that acts as an intermediate in energy coupling.

Adenosine Triphosphate↗

Comparative effects of nicorandil, nitroglycerin, nicotinic acid, and SG-86 on the metabolic status and functional recovery of the ischemic-reperfused myocardium.

The effects of nicorandil (SG-75), its major metabolite (SG-86), nitroglycerin, and nicotinic acid on myocardial segment shortening (% SS) and velocity of shortening (dL/dt, mm/s) were compared with those of a control group during 15 min of coronary occlusion followed by 3 h of reperfusion in anesthetized dogs. Piezoelectric crystals were used to measure % SS and dL/dt in regions perfused by the left anterior descending (LAD) and left circumflex (LC) coronary arteries. The radioactive microsphere technique was used to measure regional myocardial blood flow, and arterial and coronary sinus blood samples were obtained for the determination of glucose and free fatty acids. All drugs were administered intravenously 30 min before and throughout the occlusion period. Nicorandil (25 micrograms/kg/min) and nitroglycerin (3 micrograms/kg/min) produced nearly equivalent reductions in the heart rate-systolic pressure product. Nicotinic acid (0.3 mg/kg/min) and SG-86 (50 micrograms/kg/min) had no hemodynamic effects. Nicotinic acid reduced free fatty acid uptake during occlusion and at 30 min of reperfusion, whereas the other three agents had no major effects on substrate utilization. During occlusion, % SS in the ischemic region was severely depressed; collateral blood flow was similar in each series. However, during reperfusion, the nicorandil- and nicotinic acid-treated animals showed a marked improvement in % SS and dL/dt, as compared with those treated with saline (control), nitroglycerin, or SG-86. The mechanism(s) responsible for the beneficial actions of nicotinic acid and nicorandil in this model are unknown but may be partially related to the effect of nicotinic acid to reduce fatty acid uptake by the ischemic myocardium and the peripheral hemodynamic actions of nicorandil.

Animals↗

Effects of indomethacin and nicotinic acid on E. coli endotoxin shock in anesthetized dogs.

The effects of single and multiple doses of indomethacin and multiple doses of nicotinic acid upon Escherichia coli endotoxin shock were studied in mongrel dogs anesthetized with sodium pentobarbital. Survival, cardiac output, plasma volume loss, and mean arterial pressure were measured. Untreated animals did not survive the procedure; animals treated with either multiple doses of indomethacin or nicotinic acid did survive for 5 hours after endotoxin. Plasma volume losses of indomethacin and nicotinic acid treated animals were substantially less (p less than 0.05) than in untreated animals. Arterialpressures of indomethacin-treated animals were greater than that of either nicotinic acid treated or untreated animals. No differences in cardiac output were noted in surviving animals.

Animals↗

Influence of prostacyclin on the antilipolytic effect of nicotinic acid in rat fat cells: a comparison with adenosine deaminase and theophylline.

Isolated rat fat cells were incubated at pH 8.5 in order to delay PGI2 inactivation. Nicotinic acid, at concentrations lower than 2 mM was ineffective in antagonizing the stimulation of lipolysis induced by norepinephrine (2 microM). The potentiation of norepinephrine effect due to PGI2 (0.1 microM) was abolished by 0.1 mM nicotinic acid and, at higher concentrations of the drug, the rate of the process fell below the one measured in the absence of PGI2, with a resulting decrease of the response to norepinephrine. Nicotinic acid (0.04-0.4 mM) antagonized the stimulation of lipolysis caused by adenosine deaminase (0.5 U/ml) or by theophylline (0.5 mM) and the potentiation of norepinephrine effect due to adenosine deaminase. In cells treated with adenosine deaminase (0.5 U/ml) or with theophylline (0.5 mM), PGI2 (40 nM) inhibited the lipolytic effect of norepinephrine (5 microM) and nicotinic acid acted synergistically with PGI2 at this level. These results indicate that the antilipolytic action of nicotinic acid is influenced by endogenous adenosine and is increased by PGI2.

Adenosine Deaminase↗

Nicotinic acid: new/old drug. Immediate or sustained release: too risky for a drug with no proven benefit.

(1) For patients with hypercholesterolaemia requiring primary or secondary prevention, pravastatin, simvastatin and atorvastatin have a proven benefit in terms of mortality and/or morbidity. Gemfibrozil and cholestyramine have a proven impact on morbidity. (2) The lipid-lowering properties of immediate-release nicotinic acid have been known for about 50 years, as have its frequent and sometimes severe adverse effects. About 70% of patients experience cutaneous flushing, and 20-30% develop gastrointestinal adverse effects. Hepatotoxic effects occur in about 2% of patients, especially in those using high daily doses or sustained-release formulations. (3) The clinical evaluation of immediate-release nicotinic acid is mainly based on two comparative placebo-controlled trials. One, involving 5000 patients monitored on average for 15 years, showed no effect on survival. One trial suggested that immediate-release nicotinic acid reduced the risk of recurrent myocardial infarction. (4) Sustained-release nicotinic acid has not been evaluated in terms of its effect on morbidity or mortality. It has been shown to lower LDL cholesterol and triglyceride levels and to raise the HDL cholesterol level. (5) This new pharmaceutical formulation has a profile and frequency of known adverse effects similar to those of immediate-release nicotinic acid. (6) When hypercholesterolaemia persists despite an appropriate diet, it is best to use one drug with a proven preventive impact on mortality and/or morbidity. This is not the case for sustained-release nicotinic acid. (7) When statin therapy is inadequate, it remains to be shown whether adding another cholesterol-lowering drug is beneficial in terms of morbidity and mortality. If, in rare cases, combination with a statin is envisaged, it is best to use gemfibrozil or cholestyramine. Note that gemfibrozil should only be combined with a statin with the greatest caution.

Anticholesteremic Agents↗

The nicotinic acid provocation test and unconjugated hyperbilirubinaemia.

It has been suggested that the nicotinic acid provocation test is useful in the diagnosis of Gilbert's syndrome. We compared the response to intravenous nicotinic acid of patients with Gilbert's syndrome and with chronic liver disease. There was no significant difference in the mean rise in unconjugated serum bilirubin between the two groups. A sensitivity of 70% and specificity of 60% were obtained. All of 5 patients with chronic liver disease and a raised fasting unconjugated serum bilirubin had positive tests. We suggest that the nicotinic acid test is positive in unconjugated hyperbilirubinaemia regardless of cause. It is of no value in differentiating Gilbert's syndrome from liver disease.

Bilirubin↗

Murine glial cells regenerate NAD, after peroxide-induced depletion, using either nicotinic acid, nicotinamide, or quinolinic acid as substrates.

The potential for regeneration of intracellular pyridine nucleotide levels from different precursors, after peroxide-induced NAD depletion, in cultured glial cells was investigated. Cultured murine glial cells showed a decrease in intracellular NAD levels of >40% after treatment with H2O2 (100 microM). Removal of the H2O2 followed by a 2-h incubation did not result in NAD recovery in the absence of precursors. However, NAD levels increased significantly in these cells after the following substrate additions, at minimum effective concentrations of 1 mM for quinolinic acid (QUIN), 500 microM for nicotinamide, and 2 microM for nicotinic acid. The regeneration of significant amounts of NAD from nicotinic acid at doses 250 and 500 times lower than either nicotinamide or QUIN indicates a preferred route for NAD biosynthesis in glial cells in vitro, probably via nicotinic acid phosphoribosylation.

Animals↗

[A new method for determination of nicotinic acid in plasma].

A new and sensitive method for the detection of nicotinic acid in plasma is described. Human or rat plasma-samples from pharmacological or pharmacokinetic studies are lyophilized and extracted with methanol. After removal of the solvent the residue is converted with N-Methyl-N-trimethylsilyltrifluoracetamide to the trimethylsilylester of nicotinic acid, separated by vpc and detected with a mass selective detector via the fragment 180 amu. 6-Methyl-nicotinic acid is used as internal standard (fragment 194 amu). With this method a detection limit of 100 ng/ml plasma is reached.

Animals↗

Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: an in vitro model of the niacin flush.

Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D2 (PGD2) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD2 secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD2 secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1-3 mM) induced PGD2 secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD2 secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD2 secretion. Pre-incubation of the cells with aspirin (100 microM) entirely prevented the nicotinic acid effects on PGD2 secretion. The PGD2 secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6 microM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect.

Aspirin↗

Nitrilase-Catalyzed Production of Nicotinic Acid from 3-Cyanopyridine in Rhodococcus rhodochrous J1.

The nitrilase which occurs abundantly in cells of Rhodococcus rhodochrous J1 catalyzes the direct hydrolysis of 3-cyanopyridine to nicotinic acid without forming nicotinamide. By using resting cells, the reaction conditions for nicotinic acid production were optimized. Under the optimum conditions, 100% of the added 3-cyanopyridine could be converted to nicotinic acid, the highest yield achieved being 172 mg of nicotinic acid per 1.0 ml of reaction mixture containing 2.89 mg (dry weight) of cells in 26 h.

Journal Article↗

Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I.

We tested the hypothesis that treatment with nicotinic acid results in a differential blood lipid response in subjects classified as having a low-density lipoprotein (LDL) pattern A or B. One hundred eighty hypercholesterolemic subjects were randomized to placebo (n = 61), immediate-release niacin (3,000 mg/day, n = 59), or extended-release niacin (1,500 mg/day, n = 60) for 14 weeks. Lipids and lipoprotein cholesterol were determined with enzymatic methods. LDL subclass distribution was determined with 2% to 16% polyacrylamide gradient gel electrophoresis. Extended- and immediate-release niacin had significant effects on the decrease of triglycerides, total cholesterol, LDL cholesterol, apoprotein B, lipoprotein(a), and apoprotein A-I and significantly increased high-density lipoprotein cholesterol. The 2 nicotinic acid compounds and doses significantly increased mean LDL peak particle diameter and percent distribution in large LDL I and IIa, with a significant decrease in small LDL IIIa, IIIb, and IVb. In patients with LDL pattern B compared with those with pattern A, extended-release niacin (1,500 mg/day) increased LDL peak particle diameter significantly more and decreased the percent distributions of small LDL IIIa, LDL IIIb, and LDL IVa significantly more. With 3,000 mg/day, immediate-release nicotinic acid in patients with LDL pattern B exhibited a significantly greater increase in LDL peak particle diameter and large LDL IIa and IIb and significantly greater decreases in small LDL IIIa, IIIb, and IVa compared with patients with pattern A. These differences in response between patients with LDL pattern A and those with pattern B were not reflected by changes in the standard lipid profile, including apoproteins A-I and B. Nicotinic acid has a significantly different effect on lipids and lipoprotein subclass distribution in subjects classified as having LDL subclass pattern A or B. Nicotinic acid has a significantly greater effect on the decrease of small LDL subclass distribution and increase in LDL peak particle diameter in pattern B versus pattern A.

Adult↗

Effectiveness of nicotinic acid and bezafibrate alone and in combination for reducing serum triglyceride level.

OBJECTIVE: To study the effectiveness of nicotinic acid and Bezafibrate alone and in combination for reducing triglyceride level. DESIGN: It was a randomised, prospective, longitudinal study. SETTING: Patients attending a private clinic, and medical department of Kathmandu Medical College, Sinamangal. METHODS: This study included 83 consecutive patients, 19 females and 64 males with hypertriglyceridaemia (defined as serum triglyceride >200mg/dl) attending the department of medicine, Kathmandu Medical College, Sinamangal and private clinic. MAIN OUTCOME MEASURES: Statistically significant reduction of serum triglyceride level. RESULT: 51 out of 83 patients completed the study in which Nicotinic acid alone reduced the serum trygleceride level from 320.62 +/- 104.23 to 182.55 +/- 46.21, which is a reduction of 138.07 +/- 85.69 (P. value = 001). Bezafibrate when given alone also reduced triglyceride level significantly from 345.25 +/- 181.03 to 203.30+/-93.59 which is a reduction of 141.95 +/- 121.130 (P value= .001). When a combination of both drugs was given the reduction of 472.73+/-247.53 (P value =.002) was achieved. CONCLUSIONS: Nicotinic acid is a very effective drug in reducing serum triglyceride level and its effectiveness is similar to Bezafibrate. There is no added benefit of giving a combination of nicotinic acid and Bezafibrate in reducing serum triglyceride level.

Bezafibrate↗

Dissociation between vascular and metabolic effects of nicotinic acid in Gilbert's syndrome.

The relationship between the vasodilating and the hyperbilirubinaemic effect of low and high doses (50 and 300 mg i.v.) of nicotinic acid was studied in baseline conditions and after indomethacin pretreatment in healthy controls and patients with Gilbert's syndrome (a condition characterized by fluctuating, nonhaemolytic unconjugated hyperbilirubinaemia). The hyperbilirubinaemic effect of nicotinic acid was confirmed to be more pronounced in Gilbert's syndrome patients than in controls. The magnitude of hyperbilirubinaemia in the two groups was not dependent on the dose of nicotinic acid or indomethacin pretreatment. A dose-dependent vasodilation which was inhibited by indomethacin could be demonstrated in both controls and Gilbert's syndrome subjects. Vasodilating properties of nicotinic acid were therefore found to be dissociated from the effect on bilirubin.

Adolescent↗