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June 2001

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Melatonin references

1. Shamir E, et al., Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000; May;61(5):373-7.

2. Citera G, et al., The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol 2000;19(1):9-13.

3. Nagtegaal JE, et al., Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome. J Psychosom Res 2000; Jan;48(1):45-50.

4. Skene DJ, et al., Use of melatonin in the treatment of phase shift and sleep disorders. Adv Exp Med Biol 1999;467:79-84.

5. Shilo L, et al., Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000; Jan;17(1):71-6.

6. Ishizaki A, et al., Usefulness of melatonin for developmental sleep and emotional/behavior disorders—studies of a melatonin trial on 50 patients with developmental disorders. No To Hattatsu 1999; Sep;31(5):428-37.

7. Brusco LI, et al., Effect of melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999; Jan-Apr;8(1-2):126-31.

8. Skene DJ, et al., Melatonin in circadian sleep disorders in the blind. Biol Signals Recept 1999; Jan-Apr;8(1-2):90-5.

9. Mainetti C, et al., L-tryptophan-induced eosinophilia-myalgia syndrome. II. Partial correction of abnormal tryptophan metabolism by pyridoxine. Dermatologica 1991; 183(1):62-5.

10. Dakshinamurti K, et al., Influence of B vitamins on binding properties of serotonin receptors in the CNS of rats. Klin Wochenschr 1990; Jan 19;68(2):142-5.

11. Bernstein AL, Vitamin B6 in clinical neurology. Ann N Y Acad Sci 1990; 585:250-60.

12. Lee NS, et al., Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism. Pharmacol Biochem Behav 1988; Mar;29(3):559-64.

13. McCarty MF, High-dose pyridoxine as an ‘anti-stress' strategy. Med Hypotheses 2000; May;54(5):803-7.

14. Hartvig P, et al., Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography. J Neural Transm Gen Sect 1995; 102(2):91-7.

15. Anderson RA., Chromium as an essential nutrient for humans. Regul Toxicol Pharmacol 1997; Aug;26 (1 Pt 2):S35-41.

16. Linday LA, Trivalent chromium and the diabetes prevention program. Med Hypotheses 1997; Jul;49(1):47-9.

17. Morris BW, et al., The trace element chromium—a role in glucose homeostasis. Am J Clin Nutr 1992; May;55(5):989-91.

18. Jeejeebhoy KN, The role of chromium in nutrition and therapeutics and as a potential toxin. Nutr Rev 1999; Nov;57(11):329-35.

19. Mertz W . Chromium research from a distance: from 1959 to 1980. J Am Coll Nutr 1998; Dec;17(6):544-7.

20. Hornyak M, et al., Magnesium therapy for periodic leg movements, related insomnia and restless legs syndrome: an open pilot study. Sleep 1998; Aug 1;21(5):501-5

21. Popoviciu L, et al., Clinical, EEG, electromyographic and polysomnographic studies in restless legs syndrome caused by magnesium deficiency. Rom J Neurol Psychiatry 1993; Jan-Mar;31(1):55-61.

22. Okawa M, et al., Vitamin B12 treatment for sleep-wake rhythm disorders. Sleep 1990; Feb;13(1):15-23.

23. Brunner DP, et al., Chronobiological sleep disorders and their treatment possibilities. Ther Umsch 1993; Oct;50(10):704-8.

24. Honma K, et al., Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock? Experientia 1992; Aug 15;48(8):716-20.

25. Takahashi K, et al. Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders. Psychiatry Clin Neurosci 1999; Apr;53(2):211-3.

26. Ohta T, et al., Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12). Sleep 1991; Oct;14(5):414-8.


Protective effect of policosanol on atherosclerotic lesions in rabbits with exogenous hypercholesterolemia.

Policosanol is a mixture of higher aliphatic alcohols purified from sugar cane wax, with cholesterol-lowering effects demonstrable in experimental models and in patients with type II hypercholesterolemia. The protective effects of policosanol on atherosclerotic lesions experimentally induced by lipofundin in rabbits and rats and spontaneously developed in stumptail monkeys have been described. The present study was conducted to determine whether policosanol administered orally to rabbits with exogenous hypercholesterolemia also protects against the development of atherosclerotic lesions. Male New Zealand rabbits weighing 1.5 to 2 kg were randomly divided into three experimental groups which received 25 or 200 mg/kg policosanol (N = 7) orally for 60 days with acacia gum as vehicle or acacia gum alone (control group, N = 9). All animals received a cholesterol-rich diet (0.5%) during the entire period. Control animals developed marked hypercholesterolemia, macroscopic lesions and arterial intimal thickening. Intima thickness was significantly less (32.5 +/- 7 and 25.4 +/- 4 microm) in hypercholesterolemic rabbits treated with policosanol than in controls (57.6 +/- 9 microm). In most policosanol-treated animals, atherosclerotic lesions were not present, and in others, thickness of fatty streaks had less foam cell layers than in controls. We conclude that policosanol has a protective effect on the atherosclerotic lesions occurring in this experimental model.

Braz J Med Biol Res 2000 Jul;33(7):835-40

A double-blind, placebo-controlled study of the effects of policosanol in patients with intermittent claudication.

This study was undertaken to evaluate the efficacy and tolerability of policosanol, a new cholesterol-lowering drug with concomitant antiplatelet effects, in patients with intermittent claudication. After a baseline period of 6 weeks, 62 patients were randomized to receive, under double-blind conditions, either placebo (31 patients) or policosanol (31), 10 mg twice daily. Walking distances in a treadmill (constant speed 3.2 km/hr, slope 10 degrees) were assessed before and after 6 months of treatment. Both groups were similar at randomization. Policosanol increased significantly (p < 0.01) the initial claudication distance from 132.5+/-13.5 m (baseline) to 205.7+/-36.3 m (after therapy) and the absolute claudication distance (p<0.0001) from 229.5+/-22.0 m to 365.4+/-46.9 m; meanwhile both variables remained unchanged in the placebo group (p<0.05). The reduction of lower limb symptoms showed a greater benefit in the policosanol group. There was no significant change in either group in the ankle/arm pressure ratio. The treatment was well tolerated. There were 10 discontinuations (seven placebo, three policosanol) from the study. Six withdrawals occurred because of adverse events (AE); all were in placebo patients. There were five serious vascular AEs in the placebo group but none in the policosanol group (p<0.05). Overall, 12/31 (38.7%) placebo patients and 3/31 (9.7%) policosanol patients experienced AEs after randomization, which showed a lesser incidence of AEs in the policosanol group (p<0.01). The present study demonstrates a beneficial effect of policosanol in patients with intermittent claudication.

Angiology 1999 Feb;50(2):123-30

Effects of policosanol in patients with type II hypercholesterolemia and additional coronary risk factors.

INTRODUCTION: This study was undertaken to evaluate the efficacy, safety, and tolerability of policosanol, a new cholesterol-lowering drug, in patients with type II hypercholesterolemia and additional coronary risk factors. PATIENTS AND METHODS: After 5 weeks of a standard step-1 lipid-lowering diet, 437 patients were randomized to receive, under double-blind conditions, 5 mg policosanol or placebo once a day with the evening meal for 12 weeks and 10 mg policosanol or placebo for the next 12 weeks. RESULTS: Both groups were similar at randomization. Policosanol (5 and 10 mg/day) significantly reduced (P < .001) serum low-density lipoprotein cholesterol (18.2% and 25.6%, respectively) and cholesterol (13.0% and 17.4%), and it significantly raised (P < .01) high-density lipoprotein cholesterol (15.5% and 28.4%). Triglycerides remained unchanged after the first 12 weeks and lowered significantly (5.2%; P < .01) at study completion. Policosanol was safe and well tolerated, and no drug-related disturbances were observed. Two male patients who received placebo died during the study--one because of a myocardial infarction and the other because of a cardiac arrest that occurred during a surgical intervention. There were 11 serious adverse events (5.1%) in 10 patients who received placebo (4.6%), 7 of which were vascular, compared with no serious adverse events reported in patients receiving policosanol (P < .01). CONCLUSIONS: Subjects in the group treated with policosanol did not have serious adverse events during the 24-week study. This study shows that policosanol is effective, safe, and well tolerated in patients with hypercholesterolemia and concomitant coronary risk factors.

Clin Pharmacol Ther 1999 Apr;65(4):439-47

Oral administration of policosanol inhibits in vitro copper ion-induced rat lipoprotein peroxidation.

Policosanol, a new cholesterol-lowering agent, is a mixture of higher aliphatic primary alcohols isolated from sugar cane (Saccharum officinarum L.) wax, which prevents the onset of espontaneously and experimentally induced atherosclerotic lesions in experimental models. Because the oxidation of low-density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis, we investigate the effect of policosanol on copper oxidative susceptibility of rat lipoprotein fractions (VLDL + LDL). Rats fed normal diet were treated with policosanol (250-500 mg/kg/day) for up to 4 weeks. EDTA-free lipoprotein particles were oxidized in a cell-free system by the addition of copper ions, and conjugated dienes generation was monitored by changes of optical density at 234 nm. Thiobarbituric acid-reactive substances (TBARS) content and lysine-amino group reactivity were investigated. After administration, there was no change in cholesterol, triglycerides, and phospholipid content of lipoprotein fractions; however, policosanol significantly prolongs the lag time and reduces the propagation rate of diene generation. Also, policosanol reduces TBARS content and increases lysine reactivity in lipoprotein fractions treated with Cu2+. In conclusion, policosanol, in addition to its cholesterol-lowering effect, has other properties that enables it to reduce the potential of lipoprotein to undergo lipid peroxidation. Such effect can be considered of promissory value in the management of atherosclerosis.

Physiol Behav 1999 Aug 1;67(1):1-7

Comparative effects of policosanol and two HMG-CoA reductase inhibitors on type II hypercholesterolemia.

BACKGROUND: Policosanol is a new cholesterol lowering agent derived from sugar cane. AIM: To compare the cholesterol lowering efficacy of policosanol with HMG CoA inhibitors. PATIENTS AND METHODS: Patients with a LDL cholesterol over 160 mg/dl were studied. If, after 6 weeks of diet, cholesterol persisted elevated, they were doubly blind randomized to receive policosanol 10 mg/day (55 patients), lovastatin 20 mg/day (26 patients) or simvastatin 10 mg/day (25 patients). Serum cholesterol was measured again after eight weeks of therapy. RESULTS: Initial demographic and laboratory data were similar among treatment groups. A 24% LDL cholesterol reduction was obtained with policosanol, compared with a 22% reduction with lovastatin and a 15% reduction with simvastatin. HDL cholesterol significantly increased in patients on policosanol and did not change in the other treatment groups. Adverse effects of policosanol were mild and unspecific. No changes in hepatic enzymes were observed. CONCLUSIONS: Policosanol is a safe and effective cholesterol reducing agent.

Rev Med Chil 1999 Mar;127(3):286-94

Long-term therapy with policosanol improves treadmill exercise-ECG testing performance of coronary heart disease patients.

This study examined the effects of long-term lipid-lowering therapy with policosanol on the clinical evolution, and exercise-ECG testing responses of 45 coronary heart disease (CHD) patients with myocardial ischemia, documented by exercise 201T1-myocardial perfusion scintigraphy, in an overall randomized, double-blind, placebo-controlled trial, made for different test endpoints. Fifteen patients were treated with 5 mg of policosanol twice daily; another 15 patients were administered the same drug dose plus 125 mg aspirin; and the other 15 patients received placebo plus equal aspirin dose. They were followed for 20 months, previous baseline observations, with treadmill exercise-ECG, besides serum lipid test. Beneficial changes on proportions among the 2 policosanol groups and the placebo group, showed an increment on functional capacity class, a decrement on rest and exercise angina, and a significant decrease in cardiac events, and in ischemic ST segment response, especially in the policosanol plus aspirin group (p = 0.05, X2(2df) = 5.8; p = 0.04, p = 0.02; Fisher). After treatment, sets of mean changes revealed an increase on maximum oxygen uptake, and a decline on double product simultaneously in both policosanol groups (p < or = 0.02, p < or = 0.002; Pillais, Hotellings' T2), while the placebo group was impaired. Aerobic functional capacity percent showed an increment in policosanol groups (p < or = 0.05, paired T). Lipid levels improved as other endpoints already reported. A supposed ergogenic effect of octacosanol, policosanol's main active compound, was not detected with this design. These results show that policosanol-treated CHD patients improved clinical evolution, and exercise-ECG responses, owing to the amelioration of myocardial ischemia, even more when administered with aspirin.

Int J Clin Pharmacol Ther 1998 Sep;36(9):469-73

Effect of policosanol on arterial blood pressure in rats. Study of the pharmacological interaction with nifedipine and propranolol.

BACKGROUND: Policosanol is a natural mixture of higher aliphatic primary alcohols isolated from sugar cane wax (Saccharum officinarum, L) with cholesterol-lowering effects demonstrated in experimental models and in patients with type II hyperlipoproteinemia. The purpose of this study is to determine the effect of policosanol on arterial blood pressure and its interaction with propranolol and nifedipine. METHODS: Single doses of policosanol (25, 50 and 200 mg/kg) orally administered to spontaneously hypertensive rats (SHR) did not significantly change arterial pressure. RESULTS: The study on pharmacological interactions between policosanol (200 mg/kg) and both antihypertensive agents revealed that pretreatment with high doses of policosanol significantly increased propranolol-induced hypotensive effects, while the effects of nifedipine remained unchanged. CONCLUSIONS: Our results show that policosanol does not antagonize the hypotensive effect of beta-blockers but it can increase the hypotensive effect of beta-blockers without modifying cardiac frequency.

Arch Med Res 1998 Spring;29(1):21-4

A 12-month study of policosanol oral toxicity in Sprague Dawley rats.

Policosanol is a natural mixture of higher aliphatic primary alcohols. Oral toxicity of policosanol was evaluated in a 12-month study in which doses from 0.5 to 500 mg/kg were given orally to Sprague Dawley (SD) rats (20/sex/group) daily. There was no treatment-related toxicity. Thus, effects on body weight gain, food consumption, clinical observations, blood biochemistry, hematology, organ weight ratios and histopathological findings were similar in control and treated groups. This study supports the wide safety margin of policosanol when administered chronically.

Toxicol Lett 1994 Jan;70(1):77-87

Effect of policosanol on lipofundin-induced atherosclerotic lesions in rats.

Policosanol is a mixture of higher aliphatic alcohols isolated from sugar cane wax, showing cholesterol-lowering effects and preventing the development of lipofundin-induced lesions in New Zealand rabbits. This study was conducted to determine whether policosanol orally administered to rats also protects against the development of lipofundin-induced atherosclerotic lesions. Fifty four male Wistar rats were randomly distributed amongst a negative control group, a positive control group intravenously injected with lipofundin for eight days, and four experimental groups also injected with lipofundin, but orally receiving policosanol at 0.5, 2.5, 5 and 25 mg kg-1, respectively. Policosanol treatment was orally administered once-a-day for eight days, while control groups similarly received equivalent amounts of vehicle. A significant reduction of the atherosclerotic lesions in the treated animals was observed. It is concluded that policosanol has a protective effect on lipofundin-induced aortic lesions in Wistar rats.

J Pharm Pharmacol 1995 Apr;47(4):289-91

Effects of policosanol chronically administered in male monkeys (Macaca arctoides).

Policosanol, administered orally, has shown a cholesterol-lowering effect in different experimental models. Because lipid-lowering therapy is administered chronically, it is necessary to know the effects of these drugs after long-term administration. 18 adult male Macaca arctoides monkeys were used to study the cholesterol-lowering effects and possible toxicity produced by oral administration of policosanol (0.25, 2.5 and 25 mg/kg) for 54 wk. After 8 wk, a significant reduction of serum total cholesterol and low-density lipoprotein cholesterol was observed in policosanol-treated animals when compared with the controls; this effect persisted throughout the study. The animals' behavioural repertoire, physical condition, haematology and blood biochemistry, as well as spermiogram analysis and electrocardiography, were monitored during the study; ophthalmological and pathological anatomy examinations were performed at the end of the administration period. No drug-related toxicity was detected by any examination. The results gave further evidence of the marked and persistent cholesterol-lowering effects of policosanol that had been observed in different experimental models. There was a significant reduction of spontaneous aortic atherosclerotic lesions in treated animals compared with controls. Policosanol (0.25-25 mg/kg) administered orally for 54 wk brought about a persistent reduction in blood cholesterol levels and was very safe and well tolerated during long-term administration.

Food Chem Toxicol 1994 Jun;32(6):565-75


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