Cooper of Omaha was the first widely known researcher who demonostrated the efficacy of using niacin and statins in combination which reduced heart disease, blood pressure and perhaps even reduced arterial plaque. By blood flow increases it was estimated that within one year, a reduction in arterial plaque of 16% was suggested.
Those who take high-dose nicotinic acid should have their serum aminotransferase levels monitored. Aspartate aminotransferase (AST, also known as SGOT or serum glutamate oxaloacetate transaminase) and alanine aminotransferase (ALT, also known as SGPT or serum glutamate pyruvate transaminase) levels should be determined prior to starting high-dose nicotinic acid therapy, then every 6-12 weeks for one year and after one year, periodically. High-dose nicotinic acid should be discontinued if the aminotransferase levels are equal to greater than three times the upper limit of normal.
If you take a coated aspirin an hour before taking unadorned niacin in the 3 gram range, flushing, redness, and headache will be markedly reduced.
To reduce flushing with niacin, avoid proximal hot food and alcohol intake.
Be careful taking lovastatin and niacin. It should require taking COQ10 for liver protection. Rare cases of rhabdomyoisis have been found.
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They don't say what the brands of slow release niacin they are talking about.. is it inositol hexanictoinate? No.
No-flush-niacin is safe by all accounts. What it does is allow low doses of niacin into the blood over time. However I don't believe it is the same at all as what is called slow release niacin. It is not really slow release, but in fact is bound with inositol and does not cause the flushing. I can testify in my case it did not cause increase in blood sugar, liver enzymes, but definitely increased HDL by 25% and reduced LDL by 30%.
A doctor's opinion:
"The slow-release forms of niacin also have greater potential for hepatotoxicity; otherwise, there are minimal side effects, but also minimal reported efficacy. The inositol niacinate form of niacin may be less likely to cause the liver toxicity than the timed-release forms.[2]"
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The biochemical effects of niacin are principally mediated by its metabolite nicotinamide adenine dinucleotide or NAD++. NAD++ serves both coenzyme and substrate functions. NAD++ was originally called cozymase and was also known as coenzyme I and DPN or diphosphopyridine nucleotide. The positive sign in NAD++ refers to the fact that the nitrogen in the pyridine ring of niacin is positively charged in the NAD++ structure. NAD++ and its reduced form NADH (reduced nicotinamide dinucleotide) are the major hydrogen acceptor and donor, respectively, in many biological redox reactions. NAD++ is used in metabolic reactions to transfer the potential free energy stored in carbohydrates, lipids and proteins to NADH, which is used to form ATP (adenosine triphosphate).
NADP++ or nicotinamide adenine dinucleotide phosphate is formed from NAD++ via a kinase-catalyzed phosphorylation. NADP++ participates as a coenzyme in the oxidation of glucose 6-phosphate via the enzyme glucose 6-phosphate dehydrogenase. This is the oxidative reaction in the pentose phosphate pathway which produces, among other things, ribose 5-phosphate. During the oxidation of glucose 6-phosphate, NADP++ is reduced to NADPH or reduced nicotinamide adenine dinucleotide phosphate. NADPH serves as the reducing agent in fatty acid and steroid biosyntheses and serves to maintain glutathione in its reduced form.
In addition to its coenzyme role in many metabolic reactions, NAD++ also serves as a substrate in a number of biochemical reactions. The beta-N-glycosylic bond of NAD++ can be cleaved by three types of enzymes. In the process, nicotinamide and ADP (adenosine diphosphate)-ribose are formed. One type of enzyme catalyzes mono(ADP-ribosyl)ation of proteins—a posttranslational modification—by transferring ADP-ribose from NAD++ to target proteins. The enzymes are known as mono(ADP-ribosyl)transferases (mADPRTs). Mono(ADP-ribosyl)ation of endogenous proteins by bacterial toxins, such as diphtheria toxin and cholera toxin, accounts, in large part, for the pathogenic effects of these toxins. The physiological functions of endogenous mono(ADP-ribosyl)transferases are not clear. Another type of enzyme catalyzes poly(ADP-ribosyl)ation of target proteins. This enzyme is known as poly(ADP-ribose)polymerase or PARP. PARP is also known as poly(ADP-ribose) synthetase (PARS), poly(ADP-ribose)transferase (pADPRT) and PARP1. PARP is believed to be involved in DNA repair, among other things.
NAD++ is also involved in the biosynthesis of signaling molecules. A third type of beta-N-glycosylic bond-cleaving enzymes catalyzes the formation of cyclic ADP-ribose (cADPR). Cyclic ADP-ribose is an intracellular calcium mobilizing agent. The enzyme that catalyzes the synthesis of cyclic ADP-ribose is called ADP-ribosyl cyclase. NADP++ is also involved in the biosynthesis of signaling molecules. NADP++ leads to the formation of NAADP++ (nicotinic acid adenine dinucleotide phosphate) and cADPRP (2'-phospho cyclic ADP-ribose). NAADP++ and cADPRP are also intracellular calcium mobilizing agents.
The enzyme poly(ADP-ribose) polymerase(PARP) is a highly abundant nuclear protein, the physiological role of which is not yet clear. PARP poly(ADP-ribosyl)ates various nuclear proteins as well as itself. PARP is thought to be involved in a number of biological processes, including DNA repair and replication, cell differentiation and cellular apoptosis. DNA damage appears to enhance the activity of PARP. In damaged cells, PARP binds to DNA and becomes enzymatically activated. Once activated, PARP automodifies itself through poly(ADP-ribosyl)ation. This results in its inactivation and its dissociation from DNA breaks. This dissociation is necessary for DNA repair.
Recently, it has been found that NAD+ plays a key role in life-span extension by calorie restriction in the yeast Saccharomyces cerevisiae. It does so by serving as the cofactor for an NAD+-dependent histone deacetylase, an enzyme that removes acetyl groups from the lysine residues of histone proteins, thus promoting genomic silencing. Maintenance of genomic silencing may be critical to longevity either by repressing genomic instability or by preventing inappropriate gene expression. A similar mechanism may operate in metazoans, including humans.
As mentioned above, niacin is used either to refer to both nicotinic acid and nicotinamide or to nicotinic acid itself. Nicotinic acid, in addition to being known as niacin, is also known as pyridine-3-carboxylic acid, vitamin B3, 3-pyridinecarboxylic acid, pyridine-beta-carboxylic acid, antipellagra vitamin and pellagra preventive factor. The molecular formula of nicotinic acid is C6H5NO2. The molecular weight of nicotinic acid is 123.11 daltons and the structural formula is:
MECHANISM OF ACTION
Nicotinic acid in gram doses, but not nicotinamide, lowers serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL) and triglycerides. High-dose nicotinic acid also increases serum levels of high-density lipoprotein cholesterol (HDL-C) and decreases serum levels of lipoprotein (a) [Lp(a)] and apolipoprotein B-100 (Apo B). The mechanism of the antihyperlipidemic action of nicotinic acid is not well understood. It is thought that this effect is mediated, in part, via decreases in the release of free fatty acids from adipose tissue, thereby decreasing the influx of free fatty acids into the liver, the hepatic reesterification of free fatty acids and the rate of production of hepatic very low-density lipoprotein (VLDL). A decrease in the hepatic production of VLDL reduces the level of circulating VLDL available for conversion to LDL. Another hypothesis holds that nicotinic acid directly inhibits hepatic synthesis or secretion of apolipoprotein B-containing lipoproteins. Still another hypothesis holds that nicotinic acid has the potential to cause a generalized inhibition of synthetic function in the liver. This mechanism may be considered a manifestation of nicotinic acid hepatotoxicity resulting in decreased LDL-cholesterol. However, this liver-damaging hypothesis would not explain the HDL-elevating effect of nicotinic acid. The mechanism by which nicotinic acid elevates HDL is unknown.
High dose nicotinic acid has been found to significantly decrease cardiovascular and cerebrovascular events in those with coronary heart disease. It is thought that this effect is due, in part, to nicotinic acid's antihyperlipidemic activity.
PHARMACOKINETICS
Both nicotinic acid and nicotinamide are efficiently absorbed from the stomach and small intestine. At low amounts, absorption is mediated by sodium-dependent facilitated diffusion. Passive diffusion is the principal mechanism of absorption at higher doses. Doses of up to three to four grams of nicotinic acid and niacinamide are almost completely absorbed. Nicotinic acid and nicotinamide are transported via the portal circulation to the liver and via the systemic circulation to the various tissues of the body. Nicotinic acid and nicotinamide enter most cells by passive diffusion and enter erythrocytes by facilitated transport.
Nicotinic and nicotinamide are metabolized through different pathways. Nicotinic acid is not directly metabolized to nicotinamide. It undergoes a number of metabolic steps to yield NAD+ which in turn can be converted to nicotinamide. Nicotinamide can be directly converted to nicotinic acid. Nicotinic acid is metabolized to nicotinic acid mononucleotide (NicMN, nicotinic acid ribonucleotide). NicMN is also the first niacin metabolite to which dietary L-tryptophan is converted. NicMN is converted to nicotinic acid adenine dinucleotide (NicAD, desamido-NAD+). NicAD is converted in turn to NAD+. NAD+ has a number of metabolic opportunities. These include, the formation of nicotinamide, NADP+, nicotinamide 5'-mononucleotide (NMN), cyclic ADP-ribose and nicotinic acid dinucleotide phosphate (NAADP). NAD+ also serves as the substrate for mono- (ADP-ribosyl)ation and poly(ADP-ribosyl)ation reactions. Nicotinamide is converted to nicotinic acid via the enzyme nicotinamidase. Nicotinamide is also metabolized to NMN which in turn is converted to NAD+.
In the liver, the principal catabolic product of high doses of nicotinic acid is the glycine conjugate of nicotinic acid called nicotinuric acid. The principal catabolic products of nicotinamide are N'-methylnicotinamide, N' -methyl-5-carboxamide-2-pyridone, N'-methyl-5-carboxamide-4-pyridone and nicotinamide-N-oxide.
High doses of nicotinic acid are excreted in the urine as unchanged nicotinic acid and the glycine conjugate of nicotinic acid nicotinuric acid. High doses of nicotinamide are excreted in the urine as unchanged nicotinamide, N'-methylnicotinamide, N'-methyl-5-carboxamide-2-pyridone, N'-methyl-5-carboxamide-4-pyridone and nicotinamide-N-oxide.
The pharmacokinetics of the various forms of nicotinic acid (immediate-release, intermediate-release, extended-release) differ in certain particulars. The time to reach peak serum concentrations of the immediate-release or crystalline form of nicotinic acid is approximately 45 minutes following ingestion. The time to reach peak serum concentrations of the extended-release form of nicotinic acid is from 4-5 hours following ingestion. Administration of nicotinic acid with food maximizes its availability. Nicotinic acid-induced flushing, which is due to vasodilation, occurs within 20 minutes following ingestion of immediate-release nicotinic acid and may last for up to one hour.
Nicotinic acid has been tested for its effects on cardiovascular-disease risk factors in a number of major trials. In the largest of these, the effect of nicotinic acid monotherapy on cardiovascular endpoints was investigated. The study included 8,341 men who had suffered myocardial infarction. In this randomized, six-year study, nicotinic acid, given in 1 gram doses three times a day, decreased cholesterol levels by 10% and triglyceride levels by 26%. There was a decrease of 27% in recurrent non-fatal heart attacks among the nicotinic-acid treated subjects. They also experienced 26% fewer cerebrovascular events.
In a five-year randomized, placebo-controlled study of 555 survivors of myocardial infarction, nicotinic acid, in combination with clofibrate, was found to significantly decrease total and cardiac mortality. Total mortality declined by 26%. Nicotinic acid was given in 1 gram doses three times daily. Clofibrate was given in 1 gram doses twice daily.
In another well-controlled study of men aged 40 to 59 who had undergone coronary artery bypass, nicotinic acid used in combination with colestipol significantly decreased disease progression in some and significantly increased disease regression in some others, compared with placebo.
Various studies have shown that nicotinic acid can significantly lower total cholesterol, LDL-cholesterol, triglycerides and lipoprotein (a) levels. It can also increase HDL-cholesterol levels.
Nicotinic acid may be an effective and safe lipid-modifying agent even among those with diabetes. A recent report of the analysis of data from the Arterial Disease Multiple Intervention Trial (ADMIT), showed that those with and without diabetes who received crystalline nicotinic acid (3,000 milligrams/day) had significantly increased levels of HDL-cholesterol and decreased levels of LDL-cholesterol and triglycerides after 18 weeks of treatment.
Glucose levels were only modestly increased among subjects with and without diabetes. Among those with diabetes, HbA1c levels were unchanged in the nicotinic acid group, but decreased in the placebo group. No significant differences in nicotinic acid discontinuation or hypoglycemic therapy were noted in those with diabetes assigned to nicotinic acid vs placebo.
A newer extended-release nicotinic acid, used once daily, either as monotherapy or in combination with lipid-lowering drugs, has demonstrated the same favorable effects on lipids in clinical trials. This form may be less hepatotoxic than slow-release nicotinic acid. |
