Acipimox

An orally active xenobiotic nicotinic acid analogue that suppresses lipolysis and the release of free fatty acids (FFAs) into the bloodstream, thereby increasing autophagic protein recycling in addition to lowering triglyceride and VLDL.

This page contains a summary of the major research results concerning acipimox (also called Olbetam) taken from published studies in the peer-reviewed literature.

For complete details concerning the pharmacology, contraindicators, precautions, drug interactions, adverse reactions, dosage and administration see the Manufacturer Information for acipimox/Olbetam.

Safety and Interactions

1. "Acipimox in high doses up to 2250 mg/d was well tolerated except for initial gastric complaints and of flushing"^R

Potential Benefits on Protein Turnover from Increased Autophagy

1. "The process of ageing denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and not completed housekeeping, with an accumulation of altered ROS-hypergenerating organelles in older cells. It has been shown that autophagy is the only tier of defence against the accumulation of effete mitochondria and peroxisomes; that functioning of autophagy declines with increasing age and determinates cell and individual lifespan; that autophagy can be intensified by drugs; and that the pharmacological intensification of autophagy may be a big step towards retardation of ageing and prevention and therapy of age-associated diseases including neurodegeneration."
   "Conclusions: There may be support to the hypothesis that during evolution, in order to promote rapid growth and successful reproduction, Nature tuned down autophagic degradation too much and function of cell maintenance suffered and determinated lifespan. A dramatically increasing number of scientific contributions is being published showing that autophagy is primarily a pro-survival mechanism (Levine and Yuan, 2005). Currently available data show that the pharmacological intensification of the process of autophagic degradation may be a big step towards retardation of ageing and prevention and therapy of neurodegenerative diseases."^R
2. "The administration of an anti-lipolytic agent to fasting rats causes a sudden decline of free fatty acids and glucose and an increase in the glucagon/insulin ratio leading to an intensification of autophagic proteolysis, as shown by an increase in liver autophagic compartment and a release of valine in plasma (Pollera et al., 1990; Bergamini and Kovacs, 1990; Bergamini et al., 1993). ... Very recent results show that treatment can rescue older liver cells from the age-related accumulation of oxidative damage in the mtDNA in less than 6 h (Donati et al., in press). These latter results invite to conclude that the age-related changes in mtDNA and function are a likely consequence of an age-dependent failure in the regulation of macroautophagy, impairing recognition and/or disposal of a small number of severely injured mitochondria.
   A life-long pharmacological stimulation of macroautophagy can intensify the anti-aging effect of caloric restriction. For instance, a life-long weekly treatment with anti-lipolytic agents may enhance the beneficial effects of a mild (10%, fasting 1-day-a-week) calorie restriction on two parameters that are known to correlate with lifeexpectancy: the age-related changes in liver macroautophagy and the accumulation of dolichol in the liver tissue (Donati et al., 2004). In conclusion, a way was found to pharmacologically intensify the beneficial effects of a mild dietary restriction in humans (Bergamini et al., 2004a).
   Conclusion: Data support the hypothesis that macroautophagy has a major role in the retardation of the aging process by anti-aging interventions. According to this hypothesis, ad libitum feeding may inhibit, and caloric restriction and disruption of insulin-like signaling may intensify, macroautophagy throughout the life. Data with the PISA model show that safe pharmacological procedure are available to intensify the process"^R
3. "The finding that daily stimulation of autophagic proteolysis by fasting may prevent the age-associated deregulation of the process in life-long calorie restricted rats, invited studies on the chronic pharmacological stimulation of macroautophagy on the age-dependent decline in autophagic proteolysis. Stimulation of macroautophagy was performed by the administration to fasted rats of antilipolytic drugs like 3,5-dimethylpyrazole or ACIPIMOX, which is available on the market for human use. Treatment causes a sudden decrease in the availability of lipid fuel and induces a compensatory increase in protein degradation. The chronic weekly administration of the drug, starting from age six months, restored autophagic proteolysis and its hormonal control in 24-month old rats and prevented the accumulation of the biomarker of aging, dolichol in liver tissue."^R
4. "The age-related accumulation of mitochondria rich in oxidatively altered DNA may be a biomarker of malfunctioning and increased oxidative stress. Macroautophagy is the cell repair mechanism responsible for the disposal of excess or altered mitochondria under the inhibitory control of nutrition and insulin, and may mediate the antiaging effects of caloric restriction. The authors investigated the effects of stimulation of macroautophagy by the injection of an antilipolytic agent on the age-related accumulation of oxidatively altered mitochondrial DNA (mtDNA) in rat liver cells. Results showed that treatment rescued older cells from the accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the mtDNA in less than 6 hours. It is concluded that the age-related changes in mtDNA and function are likely to be the consequence of a failure of macroautophagy in the recognition and disposal of a small number of severely injured mitochondria, and that easy and safe ways are available to counteract this change."^R
5. "The intensification of autophagic proteolysis in fasting animals by the administration of an antilipolytic agent provides a convenient (i.e. a safe, highly reproducible and timable) physiologic model to study the effects of hormone(low insulin-high glucagon)-induced macroautophagy in liver cells ... Preliminary results show that life-long weekly treatment with antilipolytic agents may enhance the beneficial effects of a mild (fasting 1-day-a-week) 10% calorie restriction on two parameters that are known to correlate with life-expectancy: the ageing-related changes in liver macroautophagy ... and dolichol accumulation in the liver tissue ... In conclusion, a way was found to pharmacologically intensify dietary suppression of ageing."
   "Conclusion: It is well known that ad libitum feeding (i.e. overfeeding) may cause an increase in plasma glucose, in insulin secretion and in amino acid, insulin and IGF-1 plasma levels. The afore mentioned metabolic and endocrine changes may suppress macroautophagy and slow down the turnover rate of long lived protein, membrane and organelles. Longer biological life of cell macromolecules and structures may magnify the accumulation of peroxidized macromolecules and defective organelles in cells, and accelerate ageing. Accumulation of altered membranes (De Cabo et al., 2004) mitochondria (Brunk & Terman, 2002; Huang & Manton, 2004) and peroxisomes (Legakis et al., 2002; Badr & Birnbaum, 2004) might enhance free radical production and cell injury. It was proposed that increased free radical generation and alteration in membrane free-radical metabolism and cell signaling may start a vicious circle, which eventually leads to irreversibility of the cell changes (see Fig. 5 and references Bergamini & Gori, 1995). Calorie restriction, physical exercise and genetic disruptions of the insulin and GH/IGF-1 axis may lower insulin and IGF-1 levels and break the cycle: macroautophagy may be enhanced; accumulation of altered macromolecules and subcellular components may be prevented and life-span might be extended. Antilipolytic drugs and severe atrophy of the fat tissue (e.g. by genetic disruption of the fat insulin receptor Blueher et al., 2003) may cause a shortage of FFA and enhance the rate of autophagic proteolysis and glucogenesis during fasting to compensate for the missing fuel and improve cell maintenance and extend longevity as a secondary effect."^R
6. "Groups of 3-month-old male Sprague-Dawley rats were (a) given standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted 1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by the gastric tube. ... It is concluded that life-long weekly-repeated transient inhibition of insulin secretion by antilipolytic drugs may have an anti-aging effect, additive to the anti-aging effect of a milder caloric restriction. Speculation is that transiently lower plasma insulin levels might stimulate the anti-aging cell-repair mechanism autophagy, which has longer lasting effects on cell housekeeping." Also from the full paper: "Rats on a caloric restricted regimen spend most of the day in a state of fasting and higher autophagic proteolysis. The administration of antilipolytic drugs suppresses the release of FFA by the adipose tissue and stimulates autophagy. We have observed that Acipimox does not affect autophagy and biomarkers of aging if given to rats fed ad libitum (unpublished). Present observation shows that treatment with the antilipolytic drug intensifies the anti-aging effects of submaximal calorie restrictions and makes them maximal."^R
7. "Function of autophagic proteolysis can easily be intensified in vivo by a pharmacological intervention on the physiological regulatory mechanism. The administration of anti-lipolytic agents to fasted rats may provide a convenient (i.e. an inexpensive, highly reproducible and timable) physiologic model to study hormone (low insulin-high glucagon and corticosterone)-induced autophagy in liver cells [53,54]. Treatment caused a significant degradation of selected liver cell organelles including peroxisomes and, to a minor extent, mitochondria [55]. Preliminary results showed that life-long weekly stimulation of autophagy by the intragastric administration of an anti-lipolytic agent licensed for human use maximized the beneficial effects of a mild (one-day-a week, 10%) calorie restriction on two parameters that are known to correlate with life expectancy: the ageing-related changes in liver autophagy and dolichol accumulation in the liver[56]. ... enhanced autophagy can prevent the age-related accumulation of deteriorated subcellular components (including altered mitochondria) and extend lifespan. Anti-lipolytic drugs and severe atrophy of the fat tissue (e.g. by genetic disruption of the fat insulin receptor) may cause a shortage of FFA and a compensatory intensification of autophagic proteolysis and glucogenesis during fasting, which may account for beneficial effects on longevity."^R
8. "The mechanisms involved in the inhibitory effects of antilipolytic agents on rat liver peroxisomal fatty acid oxidative activity have been explored. Treatment of fasting rats with antilipolytic drugs (either 3,5-dimethylpyrazole (12 mg/kg body weight) or Acipimox (25 mg/kg body weight] resulted in a decrease in free fatty acid and glucose plasma levels within 5-10 and in a significant increase in the plasma glucagon to insulin ratio within 15. Changes in the fatty acid oxidative activity appeared with a 2.5-3 h delay and were then very rapid (a 30-40% decrease in the activity occurred in additional 2 h). Many peroxisomal enzyme activities (including non-beta-oxidative activities such as uricase and D-amino acid oxidase) exhibited similar changes with the same delay. Simultaneously with the enzyme changes, at the electron microscope level many autophagic vacuoles were detected in the liver cells, often containing peroxisomal structures. Glutamine, an inhibitor of proteolysis in vivo, prevented the decrease in enzyme activities. It was concluded that the decrease in peroxisomal enzyme activities may be the consequence of enhanced peroxisome degradation due to the stimulation of autophagic processes in liver cells."^R

Proven Benefits on Cholesterol and Glucose Control

1. "Sixty NIDDM patients (43 males and 17 females) took part in a randomized controlled trial of acipimox or placebo for 12 weeks. ... Fasting blood glucose was unchanged (mean difference v placebo, -0.5 mmol x L(-1); 95% confidence interval [CI], -1.4 to 0.3 mmol x L[-1]), but serum fructosamine decreased (mean difference v placebo, -26 micromol x L(-1); 95% CI, -51 to 0 mmol x L[-1]), as did the standardized hemoglobin A1 ([HbA1] mean difference v placebo, -1.4%; 95% CI, -3.0% to -0.1%). ... acipimox caused a modest beneficial improvement in overall glycemic control and plasma lipids in NIDDM patients and could be a useful agent in the treatment of dyslipidemic NIDDM patients."^R
2. "A total of 16 patients enrolled in a double-blind, randomized, placebo-controlled and two-period crossover study. After an 8 week run-in period, patients were randomly assigned into two groups receiving either acipimox (250 mg, twice daily) or placebo treatment. A total of 12 weeks later, these two groups switched their treatment for an additional 12 weeks. ... our data suggest that acipimox significantly lowered TG without perturbation of insulin sensitivity in hypertriglyceridemic NIDDM patients."^R
3. "The effect of Olbetam on serum lipid and lipoproteins was studied in 30 diabetic patients with hyperlipidemia in four weeks trial. The dose of Olbetram was 500 mg/d. The results showed serum concentrations of TC, TG, and VLDL-C were decreased while HDL-C especially HDL2-C increased significantly after treatment. There were no significant changes in FBG, blood creatinine and urine acid. This result suggests Olbetam can improve dyslipidemia in NIDDM and was well tolerated by all patients."^R
4. "The authors give summary on the pathogenesis of hyperlipoproteinaemia in patients with diabetes mellitus. They investigated the effects of acid nicotinic derivate acipimox on lipid metabolism in these patients. They treated with acipimox 15 patients who suffered from non-insulin-dependent diabetes mellitus, as well as II/B, IV type hyperlipoproteinaemia by Fredrickson. They investigated the effect of acipimox on the lipoprotein content and quality in the sera and uric acid and carbohydrate metabolism. The authors found decreased cholesterol, triglyceride, apolipoprotein-B, glycosilated haemoglobin, glucose and uric acid levels in the sera and they found that the atherogenic index decreased too. During the treatment they could not recognise a change in the low-density lipoprotein level of the sera while the high density lipoprotein and apo-A1 level increased."^R
5. "acipimox, 250 mg four times daily for 4 weeks in eight obese Type 2 diabetic patients ... Three days of acipimox treatment reduced 24-h serum NEFA [non-esterfied fatty acid] levels by 10%, but the difference disappeared after 4 weeks of treatment mainly due to a two-fold rise in morning NEFA concentrations (p < 0.01). After 3 days of acipimox treatment, fasting and 24-h plasma glucose and serum triglyceride concentrations were significantly reduced (p < 0.05), but no longer after 4 weeks of treatment. Despite the rebound rise in NEFA, acute administration of acipimox still inhibited both oxidative and non-oxidative NEFA metabolism in the basal state (p < 0.01-0.001) and during insulin infusion (p < 0.05-0.001). Inhibition of NEFA metabolism was associated with increased insulin-stimulated glucose uptake (from 3.56 +/- 0.28 to 5.14 +/- 0.67 mumol kg-1 min-1, p < 0.05), mainly due to stimulation of non-oxidative glucose disposal (from 1.74 +/- 0.23 to 3.03 +/- 0.53 mumol kg-1 min-1, p < 0.05). In conclusion, acipimox administered acutely inhibits NEFA appearance (lipolysis), which is associated with improved glucose uptake."^R
6. "The aim of the presented work was to compare the hypolipidaemic effect of fish oils rich in omega-3 fatty acids ... with a nicotinic acid derivative, acipimox (Olbetam) ... The preparations were administered for a three-week period to two groups of patients with hypertriglyceridaemia and low HDL cholesterol levels. The groups had comparable body weights and baseline parameters of lipid metabolism. In the group treated with Olbetam (750 mg/day) ... after treatment significant changes of the following parameters were recorded: triglycerides (-18%; P < 0.001), HDL cholesterol (+19%; P < 0.01), HDL2 and HDL3 cholesterol (+33%; +14%; P < 0.001, P < 0.01), apo B (+25%; P < 0.01), apo A-I (+7%; P < 0.01), ratio of apoB/A-I (+17%; P < 0.01). Furthermore, there was s drop of the atherogenic index (total cholesterol/HDL cholesterol) by 22% (P < 0.001). In the group of subjects ... whose diet was enriched with omega-3 fatty acids (3.5 g/day), the following parameters changed significantly: triglycerides (-44%; P < 0.001), the atherogenic index (-23%; P < 0.001), HDL cholesterol (+11%, P < 0.01), HDL2 and HDL3 cholesterol (+13%, +17%; P < 0.01, P < 0.05). Changes of apo B, apo A-I concentrations and their ratios were not significant. Comparison of the effect of the two preparations on the investigated parameters revealed a more marked rise of the HDL cholesterol (P < 0.05), apo B (P < 0.01) concentrations and the apo B/-A-I ratio (P < 0.05) during Olbetam treatment."^R
7. "Acipimox is effective in reducing fasting total cholesterol and total triglycerides in patients with Type 2 diabetes with acceptable blood glucose control but persistent hyperlipidaemia. Acipimox does not adversely affect glucose tolerance."^R

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Initially posted 4/26/2007

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