Vitamin B3

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References

[No authors listed] Clofibrate and niacin in coronary heart disease. JAMA. 1975 Jan 27;231(4):360-81.
Abstract: Men with 1 or more MIs who took 3 g q.d.had a lower incidence of nonfatal MIs and, for several years after the study ended, a lower mortality rate.

[No author given.] Drug Evaluations Subscription. Chicago: American Medical Association, Vol. II, Section 10, Chapter 3, Winter, 1994.

Bamji MS, Safaya S, Prema K. Low dose injectable contraceptive norethisterone enanthate 20mg monthly - II. Metabolic side effects. Contraception 1981 Jan;23(1):23-36.
Abstract: Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Berge KG, Canner PL. Coronary drug project: experience with niacin. Coronary Drug Project Research Group. Eur J Clin Pharmacol. 1991;40 Suppl 1:S49-51.
Abstract: Niacin was one of the treatments compared in the Coronary Drug Project, a placebo-controlled, multicenter trial of lipid-lowering drugs in the secondary prevention of coronary heart disease. A total of 1119 men, aged 30-64 at entry, were randomized to niacin and 2789 to placebo by the end of recruitment in March 1969. Although side-effects interfered with adherence to the niacin regimen, it was the most effective agent in achieving cholesterol-lowering (10% overall); other agents in the trial were clofibrate, dextrothyroxine, and conjugated equine estrogens. At the scheduled conclusion of the trial in February 1975, the niacin-treated group exhibited a statistically significantly lower incidence of definite, non-fatal myocardial infarction (MI) than the placebo group. There was a trend toward improvement in the life-table mortality curve, but this was not statistically significant. In 1981 an extended follow-up was carried out concerning vital status for the 6008 men who were still alive at the end of treatment and active follow-up in the trial in 1975 (827 in the niacin group and 2008 in placebo groups). Vital status was determined for 99.1% of these men after a mean of 9 years from conclusion of the trial. In the group previously randomized to niacin, there were 69 (11%) fewer deaths than were expected on the basis of mortality in the placebo group. This difference was significant (z = -3.52; P = 0.0004). The data also suggested that patients with a higher baseline cholesterol experienced greater benefit from niacin therapy, as did those with the best response to the drug.

Brown BG, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher VM, Zhao XQ, Albers JJ, Knopp RH.  Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol. 1997 Jul 15;80(2):111-115.
Abstract: The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs "very easy" and 72% "fairly easy" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity.

Brown BG, Zambon A, Poulin D, Rocha A, Maher VM, Davis JW, Albers JJ, Brunzell JD. Use of niacin, statins, and resins in patients with combined hyperlipidemia. Am J Cardiol 1998 Feb 26;81(4A):52B-59B.
Abstract: Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels < or = 120 mg/dL (n = 26) and those with triglyceride levels > or = 190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of "pattern A" (normal-size low-density lipoprotein [LDL] particles and triglyceride < or = 120 mg/dL) or "pattern B" (small dense LDL and triglyceride > or = 190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol-lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy.

Brown WV. Niacin for lipid disorders. Indications, effectiveness, and safety. Postgrad Med 1995 Aug;98(2):185-9, 192-193.
Abstract: Niacin can be very effective and safe in lowering low-density lipoprotein cholesterol and triglyceride levels and also in increasing high-density lipoprotein cholesterol levels. In combination with other lipid-lowering drugs (eg, bile acid sequestrants), it has reduced the incidence of cardiovascular events and stopped the progression of coronary artery lesions. It may be the most cost-effective lipid-lowering agent currently available. At lower doses, sustained-release forms of niacin may also improve patient compliance.

Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 Dec;8(6):1245-1255.
Abstract: Men with 1 or more MIs who took 3 g q.d.had a lower incidence of nonfatal MIs and, for several years after the study ended, a lower mortality rate.
The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Carlson LA, Oro L. Effect of treatment of nicotinic acid for one month on serum lipids in patients with different types of hyperlipidemia. Atherosclerosis 1973 Jul-Aug;18(1):1-9.
Abstract: 188 patients with various types of hyperlipoproteinemia were given 3 gms nicotinic acid daily. Most responsive were patients with Type V. Their cholesterols decreased 70% and triglycerides decreased 90%, followed by Type lll: decreases of 50% and 60% respectively. Both lipids were also reduced in the other types, and even patients with normal lipid levels showed a 10-20% reduction in serum lipids.

Dorner Von G, Fisher FW. [Zur Beinflussung der Serumlipide und -lipoproteine durch den Hexanicotinsaureester des m- Inositol.] Arzneimittelforschung 1961;11:110-113.

Gardner SF, Marx MA, White LM, Granberry MC, Skelton DR, Fonseca VA. Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control. Ann Pharmacother 1997 Jun;31(6):677-682.
Abstract: OBJECTIVE: To determine the efficacy and tolerability of the addition of low-dose niacin (1.5 g/d) in a diabetic hypercholesterolemic population who were unable to attain desired lipid control with low-dose (20 mg) pravastatin monotherapy. RESEARCH DESIGN AND METHODS: This was a prospective, open-label study conducted over a 14-week period. Twenty-three diabetic patients with low-density lipoprotein (LDL) cholesterol concentrations of at least 150 mg/dL after dietary therapy were recruited from the outpatient diabetes clinic of a university teaching hospital. After 4 weeks of dietary stabilization and baseline determination of the lipid profile and glycemic control, patients received pravastatin 20 mg once daily for 4 weeks. Laboratory parameters were reassessed and niacin was added to the regimen in qualifying patients. Over 2 weeks, patients' regimens were titrated to a maximal dosage of 500 mg tid. Patients continued to receive the combination regimen for 4 weeks and were reassessed. MEASUREMENTS AND MAIN RESULTS: Sixteen patients (14 non-insulin-dependent diabetes mellitus, 2 insulin-dependent diabetes mellitus) completed the study. Mean fasting blood sugar and fructosamine concentrations were unchanged throughout the study. Five patients required minor alterations (3 increased, 2 decreased) in their hypoglycemic regimens during the study. The addition of low-dose niacin to pravastatin therapy resulted in a significant lowering of LDL cholesterol compared with pravastatin monotherapy. CONCLUSIONS: Low-dose niacin is a promising addition to hydroxymethylglutaryl-coenzyme A reductase inhibitor therapy in the treatment of hypercholesterolemia in patients with diabetes mellitus.

Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995 Aug 1;52(15):1639-1645. (Review)
Abstract: Drug-drug, drug-food, and drug-disease interactions involving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are reviewed. The four available HMG-CoA reductase inhibitors-lovastatin, simvastatin, pravastatin, and fluvastatin-have different potentials for drug interactions, probably because of their different pharmacokinetic characteristics. Interactions of some of these cholesterol-lowering agents with cyclosporine, erythromycin, high-dose niacin, or gemfibrozil may produce myopathy with or without rhabdomyolysis. Interactions with other commonly prescribed agents, such as bile acid sequestrants, coumarin anticoagulants, and cardiovascular drugs, may alter the pharmacokinetics of either drug, but the clinical significance is generally minor. Food may affect plasma lovastatin concentrations, systemic pravastatin bioavailability, and the maximum serum concentration (Cmax) and time to achieve Cmax for fluvastatin. Hepatic dysfunction may influence the pharmacokinetics of pravastatin; all HMG-CoA reductase inhibitors are contraindicated in patients with liver disease or unexplained elevations in serum aminotransferases. Severe renal insufficiency may necessitate dosage modification in lovastatin recipients. Renal dysfunction seems to affect the pharmacokinetics of pravastatin, simvastatin, and fluvastatin only minimally, but caution is still warranted. Although the HMG-CoA reductase inhibitors rarely have severe adverse effects, they may interact, in some cases dangerously, with other drugs, with food, and with disease states.

Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981 Jan;22(1):24-36.
Abstract: The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones.

Head KA. Inositol Hexaniacinate: A Safer Alternative to Niacin. Alt Med Rev 1996;1(3):176-184.
Abstract: Niacin has long been prescribed for the treatment of various cardiovascular conditions, particularly the hyperlipidemias. It has been proven effective at lowering VLDL, LDL, total cholesterol and triglyceride levels while raising HDL levels. The side effects of niacin which may occur at the dosages often required for therapeutic efficacy, ranging from flushing and pruritus to hepatoxicity and impaired glucose tolerance, often prove troubling for both patient and practitioner. The need for a safer approach to niacin supplementation has resulted in the investigation of niacin esters. One of the most widely studied of these is inositol hexaniacinate (IHN). In numerous trials it has been found to be virtually free of the side effects associated with conventional niacin therapy. Extensive research has found IHN to be effective in the treatment of hyperlipidemia, Raynaud's disease and intermittent claudication. A number of other conditions which respond favorably to niacin therapy such as hypertension, diabetes, dysmennorhea and alcoholism bear further investigation.

Hoffer A. Vitamin B-3 dependent child. Schizophrenia 1971;3:107-113.
Abstract: 33 children under age 13 with disturbed behavior were placed on nicotinamide with doses increased from 1.5 to 6g q.d.along with ascorbic acid 3g q.d.and, rarely, very small doses of tranquilizers or anti-depressants. Upon recovery (free of symptoms and signs, performing well in school, getting on well with their families and community), they were switched from B-3 to placebo tablets while the ascorbic acid and other chemotherapy was unchanged. The mother and the author, but not the child, were aware of the switch. Only 1/33 children failed to respond to B-3 therapy. All relapsed within 30 days after the placebo was substituted. They recovered again when B-3 was restarted. The author suggests a trial of niacin for children showing evidence of at least 3 of the following:: 1) hyperactivity, 2) deteriorating school performance 3) perceptual changes and 4) inability to acquire or maintain social relationships.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 82-83.

Hudgins. Vitamin P, C and niacin for dysmenorrhea therapy. West J Surg. and Gyn 1954;62:610-611.
Abstract: 80 patients received 100mg niacin 2x/day and every 2-3hrs during cramps and were followed for up to 3 years. About 90% had at least some relief in their symptoms. The effectiveness of niacin seemed to be enhanced by the addition of rutin 60mg and vitamin C 300mg/day. Supplementation had to start at least 7-10 days prior to menses to be effective. Its benefits often remained for several months after discontinuation.

Kaufman. The use of vitamin therapy to reverse certain concomitants of aging. J Am Geriatr Soc. 1955;3:927.
Abstract: 663 patients receiving niacinamide were shown to have superior scores on an index of joint range of movement than 842 untreated age-matched patients.

Kime. Bell's palsy: A new syndrome associated with treatment by nicotinic acid. Arch Otolaryngol. 1958;68:28-32.
Abstract: 74 consecutive Bell's palsy patients were treated with 100mg to 250mg/day with excellent results noted in all patients within 2-4 weeks.

Kryzhanovskii GN, Shandra AA. [Effect of diazepam, carbamazepine, sodium valproate and their combinations with vitamin preparations on epileptic activity.] Biull Eksp Biol Med 1985 Nov;100(11):545-547. [Article in Russian]
Abstract: The anticonvulsive action of diazepam, carbamazepine, sodium valproate and their combinations with pyridoxal-5-phosphate, nicotinamide, and alpha-tocopherol were investigated in acute experiments on mice with corazole-induced seizures. Diazepam (0.5 mg/kg), carbamazepine (50 mg/kg) and sodium valproate (200 mg/kg) were shown to reduce convulsive intensity and lethality. Vitamins nicotinamide (250 mg/kg), pyridoxal-5-phosphate (10 mg/kg) and alpha-tocopherol (100 mg/kg) potentiated anticonvulsive action of the above antiepileptic drugs. The results of the investigation suggest the efficacy of pathogenetic therapy and give new evidence of the advisability of using vitamins in combination with synthetic anticonvulsive drugs.

Leklem JE, Brown RR, Rose DP, Linkswiler H, Arend RA. Metabolism of tryptophan and niacin in oral contraceptives users receiving controlled intakes of vitamin B6. Am J Clin Nutr 1975 Feb;28(2):146-156.

Malloy MJ, Kane JP, Kunitake ST, Tun P. Complementarity of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolemia. Ann Intern Med 1987;Nov;107(5):616-623.
Abstract: OBJECTIVE: To compare the effectiveness of the ternary-drug combination of colestipol, niacin, and lovastatin with binary combinations of those drugs in treating patients with familial hypercholesterolemia. DESIGN: An open sequential study of serum lipoprotein responses in patients receiving diet alone (mean duration, 4 months); colestipol and niacin with diet (mean duration, 9 months); and colestipol, niacin, and lovastatin with diet (mean duration, 15 months). SETTING: Metabolic ward and lipid clinic of a university medical center. PATIENTS: Twenty-two patients with clinical characteristics of familial hypercholesterolemia (low-density-lipoprotein cholesterol, greater than 8.48 mmol/L; 21 of 22 with tendon xanthomas). INTERVENTIONS: Diet: less than 200 mg/d of cholesterol and less than 8% of total calories from saturated fat; colestipol, 30 g/d; lovastatin, 40 to 60 mg/d; and niacin, 1.5 to 7.5 g/d. MEASUREMENTS AND MAIN RESULTS: Mean total serum cholesterol and low-density-lipoprotein cholesterol levels of 4.86 +/- 0.62 mmol/L (188 +/- 24 mg/dL SD) and 2.89 +/- 0.54 mmol/L (112 +/- 21 mg/dL SD), respectively, were significantly lower during ternary-drug treatment than during colestipol-niacin treatment (p less than 0.003) or during treatment in which other possible binary combinations were given. The cholesterol content of very low-density-lipoproteins was lower and high-density-lipoprotein cholesterol levels higher during this phase than during the colestipol-niacin phase. CONCLUSIONS: Colestipol, lovastatin, and niacin are mutually complementary in treating hypercholesterolemia. This regimen produces reductions in serum cholesterol levels similar to those associated with regression of atheromatous plaques in animal studies.

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Mohler H, Polc P, Cumin R, Pieri L, Kettler R. Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature 1979 Apr 5;278(5704):563-565.
Abstract: In this animal study nicotinamide resulted in anti-aggressive, anti-conflict, muscle relaxation, and hypnotic actions with effectiveness similar to that of minor tranquilizers. Jonathan Wright MD, wants to publish an article named, Valium is an abnormal brain constituent with nicotinamide-like actions. It is postulated that nicotinamide supplementation results in the increased conversion of lactate to pyruvate. Lactate is thought to produce anxiety when it is in high amounts in the body.

Moore. Treatment of MS with nicotinic acid and Vitamin B-1. Arch Int Med. 1940;65:18.
Abstract: patients showed improvement after IV injections of 100mg B3 and 60mg of B1.

Murray M. Lipid-lowering drugs vs. Inositol hexaniacinate. Am J Natural Med 1995;2:9-12.

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O’Keefe JH Jr, Harris WS, Nelson J, Windsor SL. Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia. Am J Cardiol 1995;76:480-484.

Osmond and Hoffer. Massive niacin treatment in schizophrenia: Review of a nine year study. Lancet 1962;1:316-320.
Abstract: 30 patients were randomly divided into 3 groups and received either niacin, nicotinamide, or placebo, usually in addition to Electric Convulsive Therapy, for 33 days. On follow-up, 10 patients in the niacin group 3g q.d.were well an average of 23/26 months and 11 patients in the niacinamide group were well an average of 26/27 months while 9 patients in the placebo group were only well an average of 11/23 months.
Note: This study has been criticized on the following grounds:
1) The population was not homogeneous.
2) There were variations in treatments.
3) The control studies were not concurrent.
4) The definition well was ambiguous.
5) Readmission to other hospitals was not reported.
6) The niacin flush was not controlled.

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Rasool AA, Hussain AA, Dittert LW. Solubility enhancement of some water-insoluble drugs in the presence of nicotinamide and related compounds. J Pharm Sci 1991 Apr;80(4):387-393.
Abstract: The solubilities of five poorly water-soluble drugs, diazepam, griseofulvin, progesterone, 17 beta-estradiol, and testosterone, were studied in the presence of nicotinamide. All solubilities were found to increase in a nonlinear fashion as a function of nicotinamide concentration. The K1:1 and K1:2 stability constants were as follows: for diazepam, K1:1 = 5.23 M-1 and K1:2 = 8.6 M-2; for griseofulvin, K1:1 = 5.54 M-1 and K1:2 = 8.82 M-2; for progesterone, K1:1 = 5.48 M-1 and K1:2 = 42.47 M-2; for 17 beta-estradiol, K1:1 = 5.38 M-1 and K1:2 = 36.9 M-2; and for testosterone, K1:1 = 5.07 M-1 and K1:2 = 27.47 M-2. Two aliphatic analogues of nicotinamide (nipecotamide and N,N-dimethylacetamide) were studied as ligands with diazepam and griseofulvin and were found to increase the solubilities of both drugs in a linear fashion. The aromatic analogue, N,N-diethylnicotinamide, showed a nonlinear solubilization relationship similar to that seen with nicotinamide. In addition, three other aromatic analogues (isonicotinamide, 1-methylnicotinamide iodide, and N-methylnicotinamide) were studied. These ligands were not soluble enough in water to be studied over the wide range of concentrations used for nicotinamide and N,N-diethylnicotinamide; however, in the concentration range studied, these ligands solubilized diazepam and griseofulvin to a degree similar to that observed with comparable concentrations of nicotinamide. These results suggest that the aromaticity (Pi-system) of the pyridine ring is an important factor in complexation because the aromatic amide ligands were found to enhance the aqueous solubilities of the test drugs to a greater extent than the aliphatic amide ligands.

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