Inositol Hexaniacinate: a Safer Alternative to Niacin

Inositol Hexaniacinate: A Safer Alternative to Niacin

Kathleen A. Head, N.D.

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. (Alt Med Rev 1996;1(3):176-184.)

Importance of Niacin to Human Health: Niacin (B3, nicotinic acid) is vital to cellular metabolism, principally through its role in the coenzymes, nicotine-adenine dinucleotide (NAD) and nicotine-adenine dinucleotide phosphatate (NADP), in oxidation-reduction reactions. Niacin is primarily metabolized in the liver to niacinamide (nicotinamide) and other derivatives. Niacinamide is, in turn, a precursor to NAD and NADP.1 Due to its vasodilatory effects, niacin (but not niacinamide) has, for decades, been prescribed by orthodox and alternative practitioners alike for the treatment of cardiovascular disease, particularly the hyperlipidemias.1-2 In addition, the use of niacin for the treatment of peripheral vascular disorders including Raynaud’s disease and intermittent claudication has been widely studied.3-6 Besides the use of niacin in therapeutic doses, there are certain fractions of the general population that may be deficient in niacin, requiring supplementation to prevent pellagra (the disease of niacin deficiency). These groups include alcoholics7 and the elderly.8

Adverse Effects of Niacin: Although niacin has numerous therapeutic benefits, it may also result in a considerable number of side effects both acute and chronic, subjective and objective. The acute, subjective symptoms include flushing, particularly of the face and neck with pruritis and burning skin, GI complaints and weakness.9 These effects are due to histamine release from the mast cells, starting approximately 20 minutes after ingestion and lasting from one to one and a half hours.

FIGURE 1.

Side effects are often N rare.1 Coppola and minimized by the ad- Brady12 reported on N dition of aspirin N four cases of niacin- which may create CO induced hepatotoxic- further problems. O ity. All four were tak- Although there may OCO OCO ing sustained-release also be a reduction of niacin. Fulminant symptoms after sev- Esterase liver failure may oc- HO OCO eral days by increas- O cur with the use of ing the dose gradu- COOH high doses of sus- ally and by taking CO tained-release niacin the niacin with N as evidenced by the N meals, many people N case of a 44-year- discontinue its use NIACIN old male who devel- before ever reaching oped liver failure af- optimal therapeutic ter three days on 6 doses. Sustained-release niacin preparations grams daily of timed-release niacin, reported may minimize flushing but result in more gas- by Mullin et al.13 He had previously consumed trointestinal complaints, according to at least up to 6 grams daily of regular crystalline nia- one study.1 Chronic conditions may also re- cin. After 16 months on this regime his liver sult from the use of niacin. These may in- enzymes had remained normal. Gibbons et clude hepatoxicity, hyperuricemia, glucose al14 reported on the prevalence of side-effects intolerance, ocular effects, exacerbation of of both sustained-release and regular niacin peptic ulcer, postural hypotension, particularly in a clinical setting. 110 patients in 133 sepa- in patients taking antihypertensive agents, and rate trials were given nicotinic acid during a skin disorders including acanthosis nigricans.1-2 five year period. The results were that 43% of The ocular effects may include decreased vi- individuals given regular nicotinic acid and sion, cystoid macular edema, periorbital 42% of those receiving the sustained-release edema, loss of eyebrows or eyelashes and su- form were forced to discontinue treatment perficial punctate keratitis. These may occur because of side-effects.14 with the use of niacin in high doses and are 10 reversible if it is discontinued. Niacin com- Inositol Hexaniacinate: petes with uric acid for renal excretion with subsequent elevation of serum uric acid levels. Biochemistry and Metabolism On rare occasions, this may lead to the de- Because of the therapeutic importance velopment of gout or uric acid kidney stones.11 of this vitamin it is imperative that we explore The hepatotoxic effects are perhaps of safer and perhaps more effective forms of ad- the most concern to those administering this ministration. One such form, and probably therapy on a long-term basis. Abnormalities the most studied, is the hexanicotinic acid es- noted on liver function tests may include dose ter of meso-inositol, inositol hexaniacinate related increases in aspartate aminotransferase (IHN), also called inositol hexanicotinate or and alkaline phosphatase. Liver pathology inositol nicotinate. The compound consists of may include cholestasis, hepatocellular disar- six molecules of nicotinic acid and one mol- ray and nodular formation by fibrous tissue. ecule of inositol (See Figure 1).15 It is me- Severe liver toxicity with regular niacin is quite tabolized in the body into its component parts,

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 177 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission niacin and inositol (hexahydroxycyclohexane). Raynaud’s disease and intermittent claudica- In the United States it was first described by tion. Promising applications which bear fur- Badgett et al. in 1945.15 It appears that the ther investigation include its use for stasis ulcers, compound is slowly metabolized, not reach- dysmenorrhea, dermatitis herpetiformis, alcohol- ing maximum serum levels for approximately ism, diabetes, cancer prevention and hyperten- 10 hours after ingestion.15 When IHN is ad- sion. These will each be addressed below. ministered orally to humans, the result is a sustained increase in the level of free nicotinic Hyperlipidemia: acid in blood and plasma.16 Pharmacokinetic Numerous epidemiological studies, studies have indicated that these esters are, at both prospective and retrospective, have least in part, absorbed intact and hydrolyzed demonstrated that hyperlipidemia is a major in the body with release of free niacin and risk factor for the development of athero- inositol. The rise in niacin levels was more sclerosis. High levels of very low density than could be explained by observation of the lipoproteins (VLDL), low density lipopro- rate of hydrolysis of these esters in buffered teins (LDL), total cholesterol and triglycer- solutions of various pHs, designed to simu- ides correlate positively with an increased late the gastric and intestinal juices. There- risk for cardiovascular disease (CVD) while fore, it was assumed that another mechanism elevated levels of high density lipoproteins was involved. This was demonstrated by (HDL) convey cardioprotection.2,20 Harthon and Brattsand16 to be an active, en- Niacin, in doses up to 6 grams daily, zymatic hydrolysis in the bloodstream. has long been known to effectively reduce triglycerides, total cholesterol, and LDL choles- Safety of Inositol Hexaniacinate terol while at the same time elevating HDL IHN appears to be safe and free of side levels1,2,21,22 Supplemental niacin will also effects at doses up to 4 grams. Welsh and Ede reduce the risk of MI in patients with a previ- studied a group of 153 patients with a variety ous history.23 Niacin appears to effect blood of conditions ranging from Raynaud’s disease lipids by a number of different mechanisms. to psoriasis and reported not a single side ef- It lowers LDL and triglyceride levels by de- fect, with doses ranging from 600 to 1800 mg creasing VLDL synthesis in the liver. This daily. They compared this to patients with the decrease occurs as a chain reaction, beginning same conditions receiving nicotinic acid. Ap- with the activation of the enzyme, phosphodi- proximately 1/3 of them reported one or more esterase and inhibition of adenylate cyclase of the following symptoms: flushing, nausea, activity by nicotinic acid. This in turn inhib- vomiting, giddiness and weakness. Further- its cAMP production in adipocytes.. There is more, the IHN patients tolerated without side a subsequent decrease in release of free fatty effects dosages 3 or 4 times larger than the acids (FFA) from peripheral adipose tissue nicotinic acid group.15 Numerous other in- resulting in a decrease in FFA transport to the vestigators, studying the use of dosages of IHN liver followed by a reduction of VLDL forma- in the range of 4 grams daily, reported not a tion which results in a decrease in the LDL single adverse reaction.3,17-19 cholesterol fraction. The decrease in VLDL and LDL then leads to a decrease in serum trig- Therapeutic Applications of IHN lycerides, phospholipids and cholesterol which IHN has a fairly broad range of thera- generally combine with these lipoproteins.24 peutic applications. The most well researched Niacin also inhibits cholesterol synthe- conditions include the hyperlipidemias, sis from acetate in the liver and appears to

increase its degradation as well.24 In addi- small, dense LDL particles seem to be more tion, elevated blood levels of lipoprotein A easily oxidized than their larger, more buoy- have been studied as an independent risk fac- ant counterparts. Niacin has been found to tor for CVD.25 Niacin appears to play a role convert the smaller easily oxidized particles by altering the function of lipoprotein A-I and to the larger, oxidation-resistant LDL par- reducing synthesis of lipoprotein A-II.2 This ticles.26 is believed to result in an elevation of HDL The wonders of niacin aside, the prob- levels.2 lem of side-effects in the doses often neces- Another interesting effect of niacin is sary to effect a change is significant. The pre- discussed by O’Keefe, Lavis and McCallister. scription medications available for treatment The susceptibility of LDL to oxidative stress of hyperlipidemia are also not without side ef- appears to be as or more important than actual fects. For a brief summary of these medica- levels of LDL cholesterol. It appears that LDL tions, mechanisms of action and potential side particles must be oxidized by free radicals effects, see Table 1. before they become atherogenic. Relatively

Table 1. Hypolipidemic Drugs: Mechanism of Action and Adverse Reactions Category Mechanism of Action Adverse Reactions Bile Acid sequestrants: decreases LDL by binding GI disturbances; may bind (cholestyramine; colestipol) bile acids and increasing certain medications and fat activity of LDL receptors soluble vitamins; decreased prothrombin Nicotinic Acid decreases FFA flushing; pruritus; GI mobilization; decreases complaints; hepatotoxicity; LDL and triglycerides by hyperuricemia; impaired decreasing VLDL synthesis; glucose tolerance increases HDL by decreased catabolism Inositol Hexaniacinate assumed to be same No side effects reported mechanism as nicotinic acid with the addition of the lipotropic effects of inositol HMG-CoA reductase decreases LDL by inhibition carcinogenicity; inhibitors: (fluvastatin; of HMC-CoA reductase; hepatotoxicity; elevation of lovastatin; mevastatin; increases activity of LDL creatine kinase; pravastatin; simvastatin) receptors rhabdomyolysis; myositis; stomach ulcers Fibric Acid derivatives: decreases triglycerides by carcinogenicity; (bezafibrate; ciprofibrate; increasing lipoprotein lipase abdominal discomfort; clofibrate; fenofibrate; activity; increases HDL gallstones; impaired glucose gemfibrozil) tolerance; hepatotoxicity; creatine kinase elevation Probucol decreases LDL by increase in QT interval; increasing non-receptor nonspecific GI complaints; mediated LDL clearance reduced HDL; anemia

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 179 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission IHN appears to be a safer, effective studies on the use of IHN (often prescribed in alternative to many of the lipid lowering Europe as a patented drug called Hexopal) in drugs currently in vogue. Dorner and Raynaud’s disease. As early as 1961, Welsh Fischer17 reported statistically significant and Ede reported on the progress of one pa- reductions of cholesterol without side effects tient on a dose of 1800 mg. daily. “Large ne- in 16 hyperlipidemic patients treated with crotic areas involving the finger tips healed 400 mg IHN 3 times daily for one month normally, flexibility of fingers and hands in- followed by 400 mg 4 times daily for a total creased, and it was assumed that the periph- of 40 weeks. A study comparing IHN and eral circulation had improved, inasmuch as the nicotinic acid on blood lipid levels in hy- patient no longer complained of coldness and perlipidemic Buscat rabbits demonstrated a discomfort.”15 marked reduction in total serum lipid levels Ring and Bacon,27 in a preliminary at a daily dose of 30mg/kg body weight. The 1977 pilot study, using quantitative thermo- IHN treated group had a 62.2% reduction in graphic assessment, a non-invasive procedure, total blood lipids while the niacin group to measure basal hand temperatures found IHN demonstrated a 58.3% reduction. Total cho- to be most effective at raising temperatures if lesterol decreased in the IHN treated group used for several months. This precipitated by 79.5%, in the niacin treated group by speculation that the mechanism of action must 74.9%. The greatest difference between the be something other than transient vasodilation two groups occured when triglyceride lev- and prompted further study in which 15 pa- els were compared, the IHN group exhibit- tients were given IHN at a dosage of 4 grams ing a 63.2 % decrease, the niacin group a daily for 36 weeks. The same means of as- 30.9% decrease.24 These findings agree with sessment was used as in the preliminary trial. Welsh and Ede who found IHN more effec- Objective improvement in the thermal gradi- tive than niacin in its antihypertensive, ent of the hand after cold challenge was ob- hypocholesterolemic and lipotropic ef- served. In addition, subjective improvement fects.15 in patient reported symptoms of coldness, pain, numbness and burning was statistically signifi- Peripheral Vascular Disorders: cant.18 IHN demonstrates particular effective- Holt further confirmed the necessity ness in the treatment of peripheral vascular dis- for a long build-up period with IHN.3 An as- orders. Among the most thoroughly re- sessment of a group of 30 patients, by evalu- searched conditions are Raynaud’s disease ating total and nutrient digital blood flow as (syndrome; phenomenon) and intermittent well as by recording the time required to in- claudication. Raynaud’s disease is character- duce Raynaud’s phenomenon, yielded signifi- ized by coldness and intermittent pallor or cant beneficial effects from IHN at dosages cyanosis of the distal portions of the digits, of 1 gram 4 times daily for 12 weeks. A study generally precipitated by exposure to cold or by Sunderland et al19 of 23 patients receiving emotional stress. It is caused by vasospasm 4 grams daily during cold weather yielded of the digital arteries and arterioles and may positive results, with patients reporting shorter last from minutes to hours. It may occur as a and fewer attacks of vasospasm during the trial primary disease or secondary to some other period. Mansel reported on a group of 20 fe- underlying pathology, usually a collagen vas- males with primary Raynaud’s disease who cular disease. A review of the literature over were prescribed 3 or 4 grams daily for 9 the last 35 years reveals numerous positive months. Statistically significant increases in

transcutaneous blood velocity were reported. improvement in oxygen transport is induced In each study, the most significant results were by IHN.28 Kiff studied 80 patients with inter- achieved by long-term administration of the mittent claudication over a 3 month period in IHN.4 a double-blind, placebo-controlled trial with The earlier speculations that the IHN at a dosage of 2 grams twice daily. Symp- mechanism of action must, in addition to tran- toms, maximum treadmill distance and walk- sitory vasodilation, include something else ing time were assessed. The most significant have been borne out. Holti suggested that en- finding in this study was that reduction of ciga- hanced fibrinolysis and lowering of serum lip- rette smoking had a major influence on tread- ids may play a significant role.3 Mansel con- mill measurements. When smoking was fac- firmed statistically significant reductions in tored out of the equation, the IHN group had cholesterol, triglycerides and plasma fibrino- significant improvement in treadmill distance.5 gen in his group during the first 3 months of Tyson found improvement in walking time and the study, levels which were sustained number of paces, as measured by stop watch throughout the remaining 6 months of the and pedometer, in a group of 86 patients, with trial.4 statistical significance of IHN over placebo in Intermittent claudication, a deficiency the most severely effected group.29 Intermit- of blood supply to an exercising muscle, re- tent claudication poses some difficulties in sults in pain, ache, cramping or fatigue, usu- assessment as the exercise, in itself, will ben- ally in the calf, after a short period of walking efit both the placebo and the test group. The but not at rest. It may also involve hip, thigh, IHN, in all studies cited above, seemed to have buttocks and foot. It is caused by arterial in- been tolerated as well or better than placebo. sufficiency, generally secondary to atheroscle- Seckfort has reported that in chronic cases of rosis. The use of niacin esters, IHN in par- vascular insufficiency, doses up to 1800 mg. ticular, for this condition has been examined daily were administered without noticeable extensively. O’Hara,6,28 in a double-blind, side effect.30 placebo-controlled study, reported on a group IHN appears to have application in the of 100 patients who were given either 2 grams treatment of other conditions resulting from of IHN or placebo twice daily for 3 months. peripheral vascular insufficiency. A review of They were tested monthly on a special exer- the literature uncovered a report of 8 patients cise machine that simulated box-stepping. The with atherosclerosis for whom amputation was elapsed time and the number of steps taken to avoided, and 18 cases of manifested or threat- achieve claudication pain were recorded. ened gangrene who responded remarkably There was a gradual increase in time to clau- well to IHN.15 This same report noted posi- dication pain in both groups over the 3-month tive results in cases of restless leg syndrome, period, but the changes were statistically sig- presumably if it is related to poor circulation.15 nificant only in the IHN group. Furthermore, Welsh and Ede15 reported on 40 patients with after 3 months, the patients receiving IHN re- stasis dermatitis with or without ulceration, ported significantly greater subjective im- secondary to peripheral circulatory failure. provement than did the placebo group. Patients with pruritis stasis experienced As with Raynaud’s, discussion of the marked relief from itching while receiving mechanisms involved has led to controversy. inositol hexaniacinate. One of these patients While arterial dilation may be involved, it has also suffered from migraine headaches asso- been postulated that reduction in fibrinogen, ciated with atherosclerosis and had tried all improvement in blood viscosity and resultant

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 181 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission the usually prescribed medications for the pre- sible deficiency of NAD.31 A five year study vious 10 years. After 10 months of IHN at a of 507 alcoholics receiving 3 or more grams dosage of 1200 mg daily, this patient experi- daily of niacin reported that 30-60% of alco- enced complete relief from the headaches.15 holics benefit from supplementation by re- One patient in this group who had lesions of duced recidivism and symptom reduction.32 scleroderma improved markedly on 1200 mg Most studies examined recommended a mini- daily.15 Also studied were patients with a va- mum of 500 mg daily for therapeutic efficacy. riety of other dermatological problems, either The obvious concern lies with the supplemen- those that had previously reported benefit from tation of high doses of niacin to a population oral niacin or problems the researchers asso- with already compromised liver status. The ciated with defects in lipid metabolism. In the use of IHN with its apparent lack of side ef- former group, patients with acne, dermatitis fects coupled with the well-known lipotropic herpetiformis and exfoliative glossitis were effects of inositol would seem a better choice. evaluated. None reported side effects as they The use of niacin in diabetics is some- had with niacin and 4 out of 5 of the patients what controversial. Niacin is part of glucose with dermatitis herpetiformis were helped con- tolerance factor (GTF). Therefore, a defi- siderably by the IHN. The bulk of the patients ciency of niacin will interfere with GTF syn- in the latter group had psoriasis. In a number thesis.33 Furthermore, animal studies indicate of patients pruritis was relieved and skin le- that niacin may retard the development of dia- sions improved but a number of patients betic nephropathy.34 However, as previously showed little or no response.15 It appears that mentioned, niacin, at least in large doses, may the dermatological problems most dramati- impair glucose tolerance. It is not known cally effected by IHN are those related to vas- whether nicotinic acid increases blood glucose cular insufficiency. Welsh and Edes15 further by decreasing insulin secretion or by promot- reported on a study by Donatelli et al with a ing insulin resistance.1 If it is the latter, then group of 64 hypertensive patients who had a it would not be an issue for Type I diabetics 93% favorable response to IHN. A single dose since they have virtually no endogenous insu- of 200 mg IHN reduced blood pressure 10-45 lin secretion anyway. A 1977 study combin- mmHg (an average of 30 mmHg) for an aver- ing IHN at a dose of 250 mg 3 times daily age of 12 hours. with Mg-chlorophenoxyisobutyrate for the treatment of hyperlipidemia found no influ- Other Conditions Which Respond ence on glucose tolerance with this regime.35 Favorably to Niacin Therapy: The inositol fraction of the IHN may be ben- There are a number of other conditions eficial to diabetics as sorbitol accumulation, which respond favorably to niacin therapy. It implicated in many of the long term effects of is this author’s contention that they might re- diabetes may be a result of inositol loss.36 spond as well or better to treatment with IHN. Positive studies of inositol for the treatment A brief review of some of these conditions of diabetic neuropathy have been reported.37-38 follows. Elevated levels of acetaldehyde are It should be noted that the typical therapeutic postulated to contribute to addiction in alco- dose for inositol for the treatment of diabetic holics while a possible deficiency of NAD is neuropathy is in the range of 1 gram or more believed to cause restlessness and irritability daily. A 600 mg dosage of IHN contains 90 in this population. Niacin oxidizes alcohol to mg inositol. Thus, addition inositol might be reduce acetaldehyde levels and also saturates required to achieve optimal results. NAD receptors in the brain to abolish a pos-

There is evidence that niacin may be References beneficial for the treatment of dysmennorhea. 1. Figge HL, Figge J, Souney P, et al. Nicotinic Hudgins reported on a group of 80 women acid: A review of its clinical use in the suffering from painful menstrual cramps who treatment of lipid disorders. Pharmacother were supplemented with 100 mg niacin twice 1988;8:287-294. daily, beginning 7-10 days before the onset of 2. Alderman JD, Pasternak RC, Sacks FM, et al. menses and then every 2-3 hours during heavy Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high cramps. Ninety percent of participants expe- density lipoprotein cholesterol and the 39 rienced significant relief. The dosage re- cholesterol to high density lipoprotein ratio. quired during heavy cramping is high enough Am J Cardiol 1989;64:725-729. to cause unpleasant side effects. It would seem 3. Holti G. An experimentally controlled that the use of IHN might be indicated. In evaluation of the effect of inositol nicotinate addition, the inositol would provide lipotro- upon the digital blood flow in patients with pic effects. Lipotropic agents help in the me- Raynaud’s phenomenon. J Int Med Res tabolism of hormones by the liver, important 1979;7:473-483. 4. Aylward M. Hexopal in Raynaud’s disease. J for the prevention of PMS. Int Med Res 1979;7:484-491. Jacobson et al have initiated studies to 5. Kiff RS, Quick CRG. Does inositol nicotinate evaluate the potential of niacin in the preven- (Hexopal) influence intermittent claudication? tion of human carcinogenesis.40 The known — a controlled trial. Br J Clin Practice role of ADP-ribose polymer metabolism in 1988;42:141-145. limiting carcinogenesis and the dependence of 6. O’Hara J. A double-blind placebo-controlled this metabolic function on intracellular NAD study of Hexopal in the treatment of intermit- levels leads to the prediction that niacin defi- tent claudication. J Int Med Res 1985;13:322- 40 327. ciency may enhance carcinogenesis. With 7. Jolliffe N. (list other authors here). Nicotinic this in mind, it would seem imperative to con- acid deficiency encephalopathy. JAMA sider broad scale supplementation of niacin in 1940;114:307-312. a safe, well-tolerated form. 8. Baker H, Frank O, Thind IS, et al. Vitamin profiles in elderly persons living at home or in Conclusion: nursing homes, versus profiles in healthy subjects. J Am Geriatr Soc 1979;27:44. Inositol hexaniacinate as been shown 9. Farmer JA, Gotto AM Jr. Currently available to be a safer alternative than conventional nia- hypolipidaemic drugs and future therapeutic cin supplementation, free from the acute reac- developments. Baillieres Clin Endocrinol tions and more harmful long term effects most Metab 1995;9:825-847. often associated with moderate to high dose 10. Fraunfelder FW, Fraunfelder FT, Illingworth niacin therapy. The effectiveness of IHN for DR. Adverse ocular effects associated with the treatment of hyperlipidemias and periph- niacin therapy. Br J Ophthalmol 1995;79:54- eral vascular disorders, including Raynaud’s 56. 11. Pfeiffer CC. Mental and Elemental Nutrients. disease and intermittent claudication, has been New Canaan, CT: Keats Publishing; 1975:121. demonstrated, in numerous studies, to be equal 12. Coppola A, Brady PG, Nord HJ. Niacin- to or better than niacin. The use of IHN in induced hepatoxicity: unusual presentations. other conditions which respond positively to South Med J 1994;87:30-32. niacin therapy such as hypertension, alcohol- 13. Mullin GE, Greenson JK, Mitchell MC. ism, diabetes and dysmennorhea merits fur- Fulminant hepatic failure after ingestion of ther investigation. sustained-release nicotinic acid. Ann Intern Med 1989;111:253-255.

Alternative Medicine Review ◆ Volume 1, Number 3 ◆ 1996 Page 183 Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission 14. Gibbons LW, Gonzales V, Gordon N, Grundy 27. Ring EF, Bacon PA. Quantitative thermo- S. The prevalence of side effects with regular graphic assessment of inositol nicotinate and sustained-release nicotinic acid. Am J therapy in Raynaud’s phenomena. J Int Med Med 1995;99:378-385. Res 1977;5:217-222. 15. Welsh AL, Ede M. Inositol hexanicotinate for 28. O’Hara J, Jolly PN, Nicol CG. The therapeutic improved nicotinic acid therapy. Int Record efficacy of inositol nicotinate (Hexopal) in Med 1961;174:9-15. intermittent claudication: a controlled trial. Br 16. Harthon L, Brattsand R. Enzymatic hydrolysis J Clin Practice 1988;42:377-383. of pentaerythritoltetranicotinate and meso- 29. Tyson VCH. Treatment of intermittent inositolhexanicotinate in blood and tissues. claudication. Practitioner 1979;223:121-126. Arzneim-Forsch 1979;29:1859-1862. 30. Seckfort H. Treating circulatory problems 17. Dorner V, Fischer FW. The influence of m- with inositol nicotinic acid ester. Med Klin inositol hexanicotinate ester on the serum 1959;10:416-418. lipids and lipoproteins. Arzneim-Frosch 31. Cleary JP. The NAD deficiency diseases. J 1961;11:110-113. Orthomol Med 1986;1:149-157. 18. Ring EFJ, Porto LO, Bacon PA. Quantitative 32. Smith RF. A five-year trial of massive nico- thermal imaging to assess inositol nicotinate tinic acid therapy of alcoholics in Michigan. J treatment for Raynaud’s syndrome. J Int Med Orthomol Psychiat 1974; 3:327-331. Res 1981;9:393-400. 33. Mertz W. Effects and metabolism of glucose 19. Sunderland GT, JJF Belch, RD Sturrock, et al. tolerance factor. Nutr Rev 1975;33:129-135. A double blind randomized placebo controlled 34. Wahlberg G, Carlson LA, Wasserman J, trial of Hexopal in primary Raynaud’s disease. Ljungquist A. Protective effect of nicotina- Clin Rheum 1988;7:46-49. mide against nephropathy in diabetic rats. 20. Wechsler JG, Hutt V, Klor HU, Ditschuneit H. Diabetes Res 1985;2:307. Lipids and lipoproteins in hyperlipidemia type 35. Pistautz H. Clinical study with a new IIa during treatment with different lipid antihyperlipidemic combination. Arzneim- lowering drugs. Artery 1980;8:519-529. Forsch 1977;27:152-156. 21. Carlson LA, Oro L. Effect of treatment of 36. Werbach M. Nutritional Influences on Illness. nicotinic acid for one month on serum lipids Tarzana, CA: Third Line Press, Inc.; in patients with different types of 1993:251. hyperlipidemias. Atherosclerosis 1973;18:1-9. 37. Clements RS, Vourganti B, Kuba T, et al. 22. Grundy SM, Mok HY, Zech L, Berman M. Dietary myo-inositol intake and peripheral Influence of nicotinic acid on metabolism of nerve function in diabetic neuropathy. cholesterol and triglycerides in man. J Lipid Metabolism 1979;28:477. Res 1981;22:24-36. 38. Salway JG et al. Effect of myo-inositol on 23. The coronary drug project research group. peripheral-nerve function in diabetes. Lancet JAMA 1975;213:360. 1978;2:1282. 24. El-Enein AMA, Hafez YS, Salem H, Abdel M. 39. Hudgins AP. Vitamins P, C and niacin for The role of nicotinic acid and inositol dysmennorhea therapy. West J Surg & Gyn hexaniacinate as anticholesterolemic and 1954;62:610-611. antilipemic agents. Nutr Reports Int 40. Jacobson EL, Dame AJ, Pyrek JS, Jacobson 1983;28:899-911. MK. Evaluating the role of niacin in human 25. Bays H, Dujovne CA, Mays JB. Elevated carcinogenesis. Biochimie 1995;77:394-398. lipoprotein (a) levels as the single treatable atherosclerotic risk factor in patients with coronary artery disease. J Ky Med Assoc 1993;91:498-500. 26. O’Keefe JH Jr, Lavie CJ Jr, McCallister BD. Insights into the pathogenesis and prevention of coronary artery disease. Mayo Clin Proc 1995;70:69-79.