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We tested an inexpensive controlled-release nicotinic acid product (Bronson Pharmaceuticals, LaCanada, CA) and compared it with the standard, more expensive, controlled release product, Nicobid (Rorer Pharmaceuticals), by measuring the 24 hour urinary recovery of nicotinic and nicotinuric acids from ten subjects following 500 mg oral ingestion of each product. Nicotinuric acid is the major detoxification product of nicotinic acid and may serve as a simple quantitative index of hepatic biotransformation of nicotinic acid. Although both products demonstrated controlled release profiles, the rate of appearance of nicotinic and nicotinuric acid in the urine as well as the rate of in vitro drug dissolution of the Bronson product were more rapid compared with Nicobid. Moreover, the total amounts of nicotinic acid and nicotinuric acid recovered in the urine after 24 hours were greater for the Bronson product (P less than .05). Since sustained presentation of nicotinic acid to the liver may correlate with clinical antihyperlipidemic effects, our results suggest that the Bronson product may prove to be a clinically useful preparation.
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Nicotinic alcohol, nicotinic acid and nicotinamide caused disaggregation of platelet clumps formed on collagen strip superfused with blood of anaesthetized cats. This effect was completely blocked by pretreatment of cats with 50 mg/kg of acetyl salicylic acid. Disaggregatory substance formed in cat's blood disappeared when blood had been passed through silicone coil warmed to 37 degrees C for 15 min. None of the tested substances had any disaggregatory activity when applied directly on collagen strip. It is postulated that the effect of nicotinic acid derivatives is mediated by prostacyclin which they release.
Nicotinic acid has been used as a cholesterol-lowering agent for a few decades already, whereas the cytoprotective and antiviral properties of nicotinamide are slowly gaining attention. In both cases however, very high doses are needed to achieve a therapeutic effect, resulting in blood concentrations sometimes as high as 15 mM. Based on their common pyridine functionality, we hypothesized that these two molecules could inhibit human P450 enzymes. In vitro inhibition studies demonstrate that, at their therapeutic concentrations, both nicotinic acid and nicotinamide inhibit CYP2D6 (Ki = 3.8 +/- 0.3 and 19 +/- 4 mM, respectively). Nicotinamide also inhibits CYP3A4 (Ki = 13 +/- 3 mM) and CYP2E1 (Ki = 13 +/- 8 mM). As expected for nitrogen-containing heteroaromatic molecules, spectrophotometric analysis indicates that the inhibition occurs via coordination of the pyridine nitrogen atom to the heme iron.
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Nicotinic acid is an effective agent for elevating HDL cholesterol but is limited by side effects. In order to improve tolerance and lipid levels, we combined low-dose nicotinic acid with bezafibrate. We gave low-dose (mean 435 mg/day) nicotinic acid to 37 patients with low HDL cholesterol, bezafibrate (mean 476 mg/day) to 58 patients with elevated total cholesterol and both agents (mean nicotinic acid 435 mg/day and bezafibrate 512 mg/day) to 25 patients with low HDL cholesterol and elevated total cholesterol. A total of 53 additional patients were followed as controls. Three intervals of treatment were studied: 0-6, 6-12 and > 12 months. The combination of drugs resulted in significant (P < 0.05) percentage changes in total cholesterol, triglycerides and total/HDL cholesterol compared to nicotinic acid alone and significant (P < 0.04) percentage changes in HDL cholesterol compared to bezafibrate alone. It is concluded that low doses of nicotinic acid may result in significant changes in HDL cholesterol; when combined with bezafibrate significant alterations in total cholesterol, triglycerides and total/HDL cholesterol also result.
Two chemically unrelated inhibitors of lipolysis were used in order to differentiate between the effect of FFA depression and a possible FFA-unrelated drug effect, respectively, on the plasma concentrations of GH, cortisol, and glucagon. Saline infusion served as a control experiment. In eight healthy male volunteers, a similar FFA depression by either iv infusion of nicotinic acid (3-pyridine-carboxylic acid, NA) or oral intake of an adenosine derivative, N(6)-allyl-N(6)-cyclohexyl-adenosine (AD-D), was followed by a significant GH increase (to 22.1 +/- 6.2 and 9.6 +/- 2.9 ng/ml at 240 and 270 min, respectively). Due to the large scatter of the GH concentrations during NA infusion, these responses were not significantly different. No GH increase occurred when the FFA depression was prevented by addition of a lipid infusion. In contrast, plasma cortisol and glucagon both increased significantly (by 107.4 micrograms/liter at 270 min and by 48.4 pg/ml at 60 min, respectively) during NA- but not during AD-D-induced FFA depression. Addition of the lipid infusion abolished the cortisol increase during NA infusion but had no influence on basal cortisol concentrations during AD-D intake. It lowered glucagon to values slightly below basal concentrations when added to the NA infusion and more markedly during AD-D administration. The results provide evidence that 1) depression of plasma FFA per se stimulates the secretion of GH, and 2) the increase of cortisol and glucagon during NA infusion is probably unrelated to the FFA depression. Hence, the stimulatory effect of FFA lack on glucagon secretion needs to be reconsidered.
Seventy-one patients (forty-two males and twenty-nine females aged forty-five to seventy-six) with disturbances of fat metabolism were treated for three years with clofibric acid and nicotinic acid derivatives. Regular gas chromatographic analyses of the composition of cholesterol ester and triglyceride fatty acids in the serum showed an increase of linoleic, linolenic, arachidonic, and eicosane-pentaenoic acids and a decrease of palmitic, palmitoleic, stearic, oleic, and eicosanetrienic acids during treatment. These changes were far more strongly marked than under monotherapy. Possible causes of the observed changes include selective competitive inhibition of unesterified serum fatty acids, inhibition of lipolysis, effects upon hepatogenic fatty acid metabolism and LCAT, as well as better utilization of alimentary polyunsaturated fatty acids as a result of combination treatment. The increase of polyunsaturated fatty acids and the decrease of saturated and monounsaturated fatty acids with their reciprocal relations to the prostaglandin metabolism may be considered a positive vasoprotective effect which is of particular importance in middle and old age.
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Nicotinic acid and nicotinamide inhibit in vitro the acetyl-CoA-carboxylase activity of partially purified enzyme from chicken liver. The incorporation of 10, 20, 50 and 100 mkmoles of nicotinic acid or nicotinamide into the incubation medium (0,9 ml) leads to the inhibition of the enzyme activity by 19, 45, 70 and 100% and by 39, 51, 60 and 78%, respectively. NADH+ and NADP+ at concentrations by one order of magnitude lower than those of nicotinic acid and nicotinamide decrease the enzyme activity in a similar manner. The constants of inhibition by the above-mentioned compounds were calculated with respect to ATP, acetyl-CoA and citrate.
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The inhibitory effect of vitamin E-nicotinate upon the hydrogen peroxide (H2O2)-induced platelet aggregation was found to be greater than that of either vitamin E alone or the combination of vitamin E and nicotinic acid. Nicotinic acid showed no inhibitory effect. It was suggested that the effect of vitamin E-nicotinate was not due to the additive effect of vitamin E and nicotinic acid produced by hydrolysis, but to the unique and distinctive property of vitamin E-nicotinate itself.